异甘草酸镁改善顺铂诱导的大鼠心肌损伤

doi:10.11958/20231833

天津医药 ›› 2024, Vol. 52 ›› Issue (8): 809-814.doi: 10.11958/20231833

异甘草酸镁改善顺铂诱导的大鼠心肌损伤

王欣爽¹^,²(), 安亚娟¹^,², 管秀菊¹^,², 李娇², 刘玥², 魏丽萍², 齐新²^,^△()

1 天津中医药大学研究生院（邮编301617）
2 天津市人民医院心脏科

收稿日期:2023-11-29 修回日期:2024-02-05 出版日期:2024-08-15 发布日期:2024-08-16
通讯作者: △E-mail：qixinx2011@126.com
作者简介:王欣爽（1998），女，硕士在读，主要从事中医药防治心血管疾病研究。E-mail：846884412@qq.com
基金资助:
天津市中医药管理局项目(2021028);天津市中医药管理局项目(2021155);天津市卫生健康科技项目(TJWJ2022QN037)

Study of magnesium isoglycyrrhizinate in ameliorating cisplatin induced myocardial injury in rats

WANG Xinshuang¹^,²(), AN Yajuan¹^,², GUAN Xiuju¹^,², LI Jiao², LIU Yue², WEI Liping², QI Xin²^,^△()

1 Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
2 Department of Cardiology, Tianjin Union Medical Center

Received:2023-11-29 Revised:2024-02-05 Published:2024-08-15 Online:2024-08-16
Contact: △E-mail：qixinx2011@126.com

王欣爽, 安亚娟, 管秀菊, 李娇, 刘玥, 魏丽萍, 齐新. 异甘草酸镁改善顺铂诱导的大鼠心肌损伤[J]. 天津医药, 2024, 52(8): 809-814.

WANG Xinshuang, AN Yajuan, GUAN Xiuju, LI Jiao, LIU Yue, WEI Liping, QI Xin. Study of magnesium isoglycyrrhizinate in ameliorating cisplatin induced myocardial injury in rats[J]. Tianjin Medical Journal, 2024, 52(8): 809-814.

摘要/Abstract

摘要：

目的探究异甘草酸镁（MgIG）对顺铂（CDDP）诱导大鼠心肌损伤的保护作用及机制。方法将24只Wistar大鼠随机分为正常对照组（Control组）、顺铂模型组（CDDP组）、顺铂+异甘草酸镁低剂量组（MgIG-L组）、顺铂+异甘草酸镁高剂量组（MgIG-H组），每组6只。每日监测大鼠体质量变化。给药结束后经超声心动图检测心功能指标[左室射血分数（LVEF）、左室短轴缩窄率（LVFS）、左室收缩末期内径（LVESD）、左室舒张末期内径（LVEDD）]；HE染色观察心肌组织形态；酶联免疫吸附试验（ELISA）检测血清中肌酸激酶同工酶MB（CK-MB）、肌钙蛋白I（cTnI）水平；检测心肌组织匀浆中超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽（GSH）、活性氧（ROS）及亚铁离子（Fe²⁺）水平；Western blot法检测心肌组织中核因子E2相关因子2（Nrf2）、长链脂酰辅酶A合成酶4（ACSL4）、谷胱甘肽过氧化物酶4（GPX4）、铁蛋白重链1（FTH1）蛋白表达。结果 Control组大鼠在饲养期间体质量呈增长趋势，CDDP组体质量呈降低趋势；与CDDP组相比，MgGL-L组和MgGL-H组大鼠给药5 d、9 d、13 d时体质量均增加（P<0.05）。与Control组相比，CDDP组的LVEF、LVFS降低，LVESD、LVEDD升高，心肌纤维排列紊乱、心肌纤维变形和断裂，血清CK-MB、cTnI水平升高，心肌组织中MDA、Fe²⁺、ROS水平升高，SOD、GSH水平降低，心肌组织中Nrf2、GPX4和FTH1蛋白表达水平降低，ACSL4蛋白表达水平升高（P<0.05）。与CDDP组相比，MgIG-L组和MgIG-H组上述指标及心肌组织病理改变均明显改善。结论异甘草酸镁通过调节心肌氧化应激水平、抑制心肌细胞铁死亡，从而改善顺铂引起的大鼠心肌损伤。

关键词: 甘草酸, 顺铂, 心肌, 氧化性应激, 铁死亡

Abstract:

Objective To investigate the protective effect and mechanism of magnesium isoglycyrrhizinate (MgIG) on cisplatin (CDDP)-induced myocardial injury in rats. Methods Twenty-four Wistar rats were randomly divided into the normal control group, the cisplatin model group (CDDP group), the cisplatin + magnesium isoglycyrrhizinate low-dose group (MgIG-L group) and the cisplatin + magnesium isoglycyrrhizinate high-dose group (MgIG-H group), with 6 rats in each group. Changes of body mass of rats were monitored daily. At the end of drug administration, cardiac function indexes including left ventricular ejection fraction (LVEF), left ventricular short-axis narrowing rate (LVFS), left ventricular end-systolic internal diameter (LVESD) and left ventricular end-diastolic internal diameter (LVEDD) were detected by echocardiography. The morphology of myocardial tissue was observed by HE staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of creatine kinase isoenzyme MB (CK-MB) and troponin I (cTnI). Levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione synthase (GSH), reactive oxygen species (ROS) and ferrous ion (Fe²⁺) in homogenates of myocardial tissue were measured biochemically. The protein expressions of nuclear factor E2-associated factor 2 (Nrf2), long-chain fatty acyl coenzyme A synthase 4 (ACSL4), glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein were detected by Western blot assay. Results The body mass of rats in the control group showed an increasing trend during feeding, and the body mass of rats in the CDDP group showed a decreasing trend. Compared with the CDDP group, the body mass of rats in the MgIG-L group and the MgIG-H group increased after 5 d, 9 d and 13 d of treatment (P<0.05). Compared with the control group, the CDDP group showed decreased LVEF and LVFS, increased LVESD and LVEDD, disturbed myocardial fiber alignment, myocardial fiber degeneration and fracture, increased serum CK-MB and cTnI levels, increased levels of MDA, Fe²⁺ and ROS in myocardial tissue, decreased levels of SOD and GSH, and decreased levels of Nrf2, GPX4, and decreased FTH1 protein expression levels and increased ACSL4 protein expression levels in myocardial tissue (P<0.05). Compared with the CDDP group, the above indicators and myocardial histopathological changes were significantly improved in the MgIG-L group and the MgIG-H group. Conclusion Magnesium isoglycyrrhizinate can ameliorate cisplatin-induced myocardial injury by regulating myocardial oxidative stress and inhibiting cardiomyocyte iron death in rats.

Key words: glycyrrhizic acid, cisplatin, myocardium, oxidative stress, ferroptosis

中图分类号:

R285.5

图/表 7

参考文献 23

[1]	CUI Y, LI C, ZENG C, et al. Tongmai Yangxin pills anti-oxidative stress alleviates cisplatin-induced cardiotoxicity:Network pharmacology analysis and experimental evidence[J]. Biomed Pharmacother, 2018, 108:1081-1089. doi:10.1016/j.biopha.2018.09.095.
[2]	马治, 王欣爽, 刘玥, 等. 甘草次酸的差向异构体对顺铂诱导H9c2心肌细胞损伤的保护机制[J]. 天津医药, 2022, 50(12):1264-1269.
	MA Z, WANG X S, LIU Y, et al. The protective mechanism of differential isomers of glycyrrhetinic acid on cisplatin-induced H9c2 cardiomyocyte injury[J]. Tianjin Med J, 2022, 50(12):1264-1269. doi:10.11958/20220987.
[3]	XU J, ZHANG B, CHU Z, et al. Wogonin alleviates cisplatin-induced cardiotoxicity in mice via inhibiting gasdermin D-mediated pyroptosis[J]. J Cardiovasc Pharmacol, 2021, 78(4):597-603. doi:10.1097/FJC.0000000000001085.
[4]	XIA J, HU J N, ZHANG R B, et al. Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro[J]. Phytomedicine, 2022, 104:154331. doi:10.1016/j.phymed.2022.154331.
[5]	ZHAO L, TAO X, QI Y, et al. Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress[J]. Redox Biol, 2018, 16:189-198. doi:10.1016/j.redox.2018.02.026.
[6]	王栋, 黄凯, 郭淑贞. 致心脏毒性中药的减毒及防治心脏毒性中药的研究进展[J]. 中国中药杂志, 2022, 47(1):18-23.
	WANG D, HUANG K, GUO S Z. Detoxification of cardiotoxic traditional Chinese medicine and traditional Chinese medicine for prevention of cardiotoxicity:a review[J]. China Journal of Chinese Materia Medica, 2022, 47(1):18-23. doi:10.19540/j.cnki.cjcmm.20210917.703.
[7]	邓桃妹, 彭灿, 彭代银, 等. 甘草化学成分和药理作用研究进展及质量标志物的探讨[J]. 中国中药杂志, 2021, 46(11):2660-2676.
	DENG T M, PENG C, PENG D Y, et al. Research progress on chemical constituents and pharmacological effects of Glycyrrhizae Radix et Rhizoma and discussion of Q-markers[J]. China Journal of Chinese Materia Medica, 2021, 46(11):2660-2676. doi:10.19540/j.cnki.cjcmm.20210304.201.
[8]	YANG Y Z, LIU Z H, WANG S C, et al. Magnesium isoglycyrrhizinate alleviates fructose-induced liver oxidative stress and inflammatory injury through suppressing NOXs[J]. Eur J Pharmacol, 2020, 883:173314. doi:10.1016/j.ejphar.2020.173314.
[9]	韩竹俊, 许美娟, 刘玲, 等. 异甘草酸镁的药理作用及临床应用研究进展[J]. 药学与临床研究, 2023, 31(3):238-242.
	HAN Z J, XU M J, LIU L, et al. Pharmacological effects and clinical application progress of magnesium isoglycyrrhizinate[J]. Pharmaceutical and Clinical Research, 2023, 31(3):238-242. doi:10.13664/j.cnki.pcr.2023.03.011.
[10]	李艳阳, 王云姣, 吕仕超. 中药注射液防治抗肿瘤药物心脏毒性的效应和机制[J]. 中国临床药理学与治疗学, 2023, 28(5):572-577.
	LI Y Y, WANG Y J, LYU S C. Effects and mechanism of traditional Chinese medicine injection in prevention and treatment of cardiotoxicity induced by antineoplastic drugs[J]. Chin J Clin Pharm Therap, 2023, 28(5):572-577. doi:10.12092/j.issn.1009-2501.2023.05.012.
[11]	邱月清, 王振涛, 郭宗耀. 炙甘草汤防治心血管疾病的实验与机制概述[J]. 中华中医药学刊, 2023(8):1-12.
	QIU Y Q, WNAG Z T, GUO Z Y. Experiment and Mechanism of Zhigancao Decoction in the Prevention and Treatment of Cardiovascular Diseases[J]. Chinese Archives of Traditional Chinese Medicine, 2023(8):1-12.
[12]	杨梦霞, 芦殿荣, 朱世杰, 等. 炙甘草汤治疗抗肿瘤药物致心脏毒性作用机制的网络药理学研究[J]. 中国中医急症, 2022, 31(5):753-757.
	YANG M X, LU D R, ZHU S J, et al. Study on the mechanism of zhigancao decoction in the treatment of antineoplastic drug-induced cardiotoxicity[J]. Journal of Emergency in Traditional Chinese Medicine, 2022, 31(5):753-757. doi:10.3969/j.issn.1004-745X.2022.05.001.
[13]	蔡晓月, 邓林华, 李甜, 等. 基于cAMP/PKA信号通路探讨通脉养心丸对缓慢性心律失常大鼠心率的影响[J]. 现代中西医结合杂志, 2022, 31(17):2337-2341,2373.
	CAI X Y, DENG L H, LI T, et al. Effect of Tongmai Yangxin pill on heart rate of rats with bradyarrhythmia based on cAMP/PKA signaling pathway[J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2022, 31(17):2337-2341,2373. doi:10.3969/j.issn.1008-8849.2022.17.001.
[14]	CHENG M, ZHANG J, YANG L, et al. Recent advances in chemical analysis of licorice (Gan-Cao)[J]. Fitoterapia, 2021, 149:104803. doi:10.1016/j.fitote.2020.104803.
[15]	WANG L, ZHANG Y, WAN H, et al. Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury through the PI3K/AKt signaling pathway[J]. J Nat Med, 2017, 71(1):27-35. doi:10.1007/s11418-016-1023-z.
[16]	YU Y, YAN Y, NIU F, et al. Ferroptosis:a cell death connecting oxidative stress,inflammation and cardiovascular diseases[J]. Cell Death Discov, 2021, 7(1):193. doi:10.1038/s41420-021-00579-w.
[17]	ROSIC G, SREJOVIC I, ZIVKOVIC V, et al. The effects of N-acetylcysteine on cisplatin-induced cardiotoxicity on isolated rat hearts after short-term global ischemia[J]. Toxicol Rep, 2015, 2:996-1006. doi:10.1016/j.toxrep.2015.07.009.
[18]	LI J, ZHOU Y, WANG H, et al. Oxidative stress-induced ferroptosis in cardiovascular diseases and epigenetic mechanisms[J]. Front Cell Dev Biol, 2021, 9:685775. doi:10.3389/fcell.2021.685775.
[19]	MANCARDI D, MEZZANOTTE M, ARRIGO E, et al. Iron overload,oxidative stress,and ferroptosis in the failing heart and liver[J]. Antioxidants(Basel), 2021, 10(12):1864. doi:10.3390/antiox10121864.
[20]	DODSON M, CASTRO-PORTUGUEZ R, ZHANG D D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23:101107. doi:10.1016/j.redox.2019.101107.
[21]	LI J, CAO F, YIN H L, et al. Ferroptosis:past, present and future[J]. Cell Death Dis, 2020, 11(2):88. doi:10.1038/s41419-020-2298-2.
[22]	王青青, 张莉芬, 马金苗, 等. 附萸汤通过调控Nrf2/GPX4介导的铁死亡对心力衰竭大鼠心肌纤维化的影响[J]. 中国中药杂志, 2023(8):1-10.
	WANG Q Q, ZHANG L F, MA J M, et al. Fuyu Decoction ameliorates myocardial fibrosis in rat model of heart failure by regulating Nrf2/GPX4-mediated ferroptosis[J]. China Journal of Chinese Materia Medica, 2023(8):1-10. doi:10.19540/j.cnki.cjcmm.20230815.703.
[23]	蒋志明, 张辽, 刘磊, 等. 电针心经激活核因子E2相关因子2/血红素氧合酶信号通路抑制铁死亡改善急性心肌缺血[J]. 针刺研究, 2023, 48(5):461-468.
	JIANG Z M, ZHANG L, LIU L, et al. Elextroacupuncture improves ischemic myocardial injury by activating Nrf2/HO-1 signaling pathway to inhibit ferroptosis in rat[J]. Acupuncture Research, 2023, 48(5):461-468. doi:10.13702/j.1000-0607.20211358.

组别	1 d	5 d	9 d	13 d	F
Control组	251.83±7.41	282.50±9.13^A	302.67±11.78^AB	323.17±10.26^ABC	58.006^＊＊
CDDP组	251.00±10.41	239.33±20.05^aA	216.33±28.31^aAB	194.33±31.08^aABC	6.661^＊＊
MgGL-L组	250.16±7.57	243.33±11.52^b	243.67±15.53^b	246.33±13.35^b	0.393
MgGL-H组	250.00±17.58	259.50±27.70^b	269.50±32.00^b	282.67±21.00^bc	1.847
F	0.032	6.655^＊	14.762^＊＊	42.542^＊＊

组别	1 d	5 d	9 d	13 d	F
Control组	251.83±7.41	282.50±9.13^A	302.67±11.78^AB	323.17±10.26^ABC	58.006^＊＊
CDDP组	251.00±10.41	239.33±20.05^aA	216.33±28.31^aAB	194.33±31.08^aABC	6.661^＊＊
MgGL-L组	250.16±7.57	243.33±11.52^b	243.67±15.53^b	246.33±13.35^b	0.393
MgGL-H组	250.00±17.58	259.50±27.70^b	269.50±32.00^b	282.67±21.00^bc	1.847
F	0.032	6.655^＊	14.762^＊＊	42.542^＊＊

组别	LVEF/%	LVFS/%	LVEDD/mm	LVESD/mm
Control组	81.63±1.06	51.49±1.13	6.64±0.33	3.22±0.18
CDDP组	63.59±3.30^a	35.68±2.49^a	7.22±0.14^a	4.64±0.17^a
MgIG-L组	71.18±4.65^b	41.76±4.20^b	6.91±0.17^b	4.02±0.31^b
MgIG-H组	77.42±5.38^bc	47.54±5.49^bc	6.81±0.22^b	3.57±0.37^b
F	23.660^＊＊	20.666^＊＊	6.960^＊＊	30.931^＊＊

组别	LVEF/%	LVFS/%	LVEDD/mm	LVESD/mm
Control组	81.63±1.06	51.49±1.13	6.64±0.33	3.22±0.18
CDDP组	63.59±3.30^a	35.68±2.49^a	7.22±0.14^a	4.64±0.17^a
MgIG-L组	71.18±4.65^b	41.76±4.20^b	6.91±0.17^b	4.02±0.31^b
MgIG-H组	77.42±5.38^bc	47.54±5.49^bc	6.81±0.22^b	3.57±0.37^b
F	23.660^＊＊	20.666^＊＊	6.960^＊＊	30.931^＊＊

组别	CK-MB/（μg/L）	cTnI/（ng/L）
Control组	6.58±2.19	209.48±38.26
CDDP组	14.27±2.08^a	482.88±57.12^a
MgIG-L组	11.47±0.63^b	363.18±33.56^b
MgIG-H组	9.74±0.87^b	306.94±25.14^bc
F	24.247^＊＊	48.211^＊＊

异甘草酸镁改善顺铂诱导的大鼠心肌损伤

Study of magnesium isoglycyrrhizinate in ameliorating cisplatin induced myocardial injury in rats

引用本文

RichHTML

PDF (PC)

可视化

摘要/Abstract

使用本文

图/表 7

参考文献 23

相关文章 15

编辑推荐

Metrics

本文评价

组别	GSH/（mg/g prot）		SOD/（U/mg）		MDA/（nmol/mg）
Control组	228.81±32.38		213.35±8.63		3.03±0.85
CDDP组	68.21±17.80^a		148.78±3.01^a		11.48±0.89^a
MgIG-L组	102.17±33.74^b		162.45±3.75^b		8.22±1.19^b
MgIG-H组	169.03±13.15^bc		196.98±3.55^bc		5.49±0.68^bc
F	45.726^＊＊		194.776^＊＊		93.706^＊＊
组别		ROS		Fe²⁺/（μmol/kg）
Control组		7 682.83±987.21		77.63±21.19
CDDP组		32 552.33±2 891.39^a		176.78±13.52^a
MgIG-L组		25 078.50±7 051.95^b		156.09±9.54^b
MgIG-H组		10 400.33±3 759.23^bc		77.89±22.55^bc
F		46.191^＊＊		53.480^＊＊

组别	Nrf2	ACSL4	GPX4	FTH1
Control组	1.01±0.23	0.96±0.07	1.06±0.03	1.10±0.09
CDDP组	0.46±0.07^a	1.46±0.29^a	0.78±0.07^a	0.44±0.17^a
MgIG-L组	0.66±0.02^b	0.97±0.17^b	1.14±0.10^b	0.62±0.10^b
MgIG-H组	0.91±0.11^bc	0.91±0.15^b	1.13±0.16^b	0.91±0.09^bc
F	10.947^＊＊	10.355^＊＊	8.356^＊＊	18.848^＊＊

[1]	张春虹, 黄洪超, 刘越, 杜立龙, 许海委, 黎宁, 李勇进. 基于RNA测序和生物信息学分析鉴定椎旁肌退变中关键的铁死亡基因[J]. 天津医药, 2024, 52(9): 991-995.
[2]	刘斌, 杨龙, 李文莉, 邵宁宁, 董津睿. 小胶质细胞铁死亡在烟雾吸入性脑损伤中的作用机制探讨[J]. 天津医药, 2024, 52(8): 791-797.
[3]	秦汉林, 胡长路, 赵亚梅, 牛维纳. 四联方案预防含顺铂方案多日化疗致恶心呕吐的效果和安全性研究[J]. 天津医药, 2024, 52(8): 835-839.
[4]	杨睿, 魏琼, 孙逸坤, 赵梦竹, 程序, 刘梦华, 张冬梅. 缺氧H9c2来源外泌体对HUVEC增殖、迁移和成管能力的影响[J]. 天津医药, 2024, 52(7): 714-719.
[5]	吴波, 朱卓农, 郑丽娟, 陈俊如. 苦参碱对特应性皮炎炎症、氧化应激和伤口愈合的影响[J]. 天津医药, 2024, 52(6): 566-571.
[6]	肖锦亮, 汪威廉, 但家朋. 瑞马唑仑调节EPAC1/RAP1信号通路对急性心肌梗死大鼠心肌损伤的影响[J]. 天津医药, 2024, 52(5): 475-479.
[7]	吴纪昆, 徐榕笛, 许景涵, 王乐, 丛洪良. 6种常见模型评分对NSTEMI患者远期预后预测价值的验证和比较[J]. 天津医药, 2024, 52(5): 541-547.
[8]	黎敏, 龚坚, 吴伟伟, 刘巧. Nrf2/HO-1通路在银屑病中作用的研究进展[J]. 天津医药, 2024, 52(5): 552-556.
[9]	解有成, 王菲, 徐进, 于晓辉. SIRT1在糖尿病心肌病发病中的研究进展[J]. 天津医药, 2024, 52(4): 443-448.
[10]	何颖, 张广华, 田立东, 于泳浩. 富氢液通过增加自噬治疗大鼠神经病理性疼痛[J]. 天津医药, 2024, 52(3): 261-265.
[11]	陈静, 魏运姣, 罗超, 黄利华, 陈橙, 段莎莎. 基于Nrf2/ARE抗氧化应激途径探究乌梅丸对溃疡性结肠炎小鼠的作用机制[J]. 天津医药, 2024, 52(3): 278-254.
[12]	李晓卫, 高静, 刘寅, 高明东, 肖健勇. 早期与晚期支架内血栓致4b型急性心肌梗死患者临床结局比较[J]. 天津医药, 2024, 52(3): 290-296.
[13]	张晓旭, 杨文奇. 沙库巴曲缬沙坦治疗AMI后射血分数中间值心力衰竭的疗效研究[J]. 天津医药, 2024, 52(2): 177-181.
[14]	高光仁, 冯连荣, 付金国, 郭润, 牛和平, 李凤鹏, 张倩玉, 张军. 急性心肌梗死合并胸腔积液患者的心肌损伤特点及对远期预后的影响[J]. 天津医药, 2024, 52(2): 197-200.
[15]	缪春波, 许迎春, 常以芳. 根皮苷通过下调miR-125a-5p减轻缺氧/复氧诱导的H9C2细胞氧化应激和凋亡[J]. 天津医药, 2024, 52(12): 1233-1238.