复方苦参注射液减轻肝癌大鼠5-氟尿嘧啶化疗不良反应的机制研究

doi:10.11958/20241277

天津医药 ›› 2025, Vol. 53 ›› Issue (1): 24-28.doi: 10.11958/20241277

复方苦参注射液减轻肝癌大鼠5-氟尿嘧啶化疗不良反应的机制研究

王若宇(), 张宇, 王佳慧, 张占霞()

上海中医药大学附属龙华医院肿瘤研究所（邮编200032）

收稿日期:2024-09-04 修回日期:2024-10-14 出版日期:2025-01-15 发布日期:2025-02-06
通讯作者: ^△E-mail：13564353259@163.com
作者简介:王若宇（1999），女，硕士在读，主要从事抗癌药物方面研究。E-mail：fsew0731@163.com
基金资助:
上海市自然科学基金资助项目(20ZR1459100)

Study on the mechanism of Fu Fang Ku Shen Zhu She Ye alleviating adverse reactions of 5-fluorouracil chemotherapy in rats with liver cancer

WANG Ruoyu(), ZHANG Yu, WANG Jiahui, ZHANG Zhanxia()

Tumor Research Institute, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China

Received:2024-09-04 Revised:2024-10-14 Published:2025-01-15 Online:2025-02-06
Contact: ^△E-mail：13564353259@163.com

王若宇, 张宇, 王佳慧, 张占霞. 复方苦参注射液减轻肝癌大鼠5-氟尿嘧啶化疗不良反应的机制研究[J]. 天津医药, 2025, 53(1): 24-28.

WANG Ruoyu, ZHANG Yu, WANG Jiahui, ZHANG Zhanxia. Study on the mechanism of Fu Fang Ku Shen Zhu She Ye alleviating adverse reactions of 5-fluorouracil chemotherapy in rats with liver cancer[J]. Tianjin Medical Journal, 2025, 53(1): 24-28.

摘要/Abstract

摘要：

目的探讨复方苦参注射液对肝癌大鼠5-氟尿嘧啶（5-FU）化疗不良反应的影响及其作用机制。方法通过二乙基亚硝胺（DEN）构建肝癌大鼠模型，将其分为肝癌组，化疗组和化疗+复方低（L）、中(M)、高剂量（H）组。化疗组、化疗+复方组大鼠成模后24 h腹腔注射5-FU 100 mg/kg，1次/周，化疗+复方L、M、H组分别腹腔注射复发苦参注射液0.7、1.4、2.8 mL/kg，1次/d，连续8周。比较各组心功能、心肌损伤标志物水平和心肌组织病理改变，酶联免疫吸附试验检测血清脑钠肽（BNP）、肌钙蛋白I（cTnI）、肌酸激酶同工酶（CK-MB）水平，Western blot检测心肌组织葡萄糖调节蛋白78（GRP78）、激活转录因子6（ATF6）、内质网应激相关蛋白（CHOP）蛋白表达，比较各组免疫功能指标变化。结果相比肝癌组，化疗组的左室射血分数（LVEF）、左室收缩末期前壁厚度（LVAWs）降低（P<0.05），左室收缩末期内径（LVEDs）和BNP、cTnI、CK-MB水平升高（P<0.05），心肌组织肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1β、IL-6水平和GRP78、ATF6、CHOP蛋白表达升高（P<0.05），CD3⁺、CD4⁺、CD4⁺/CD8⁺和IgG、IgM、IgA水平降低（P<0.05），心肌组织排列杂乱、空泡和炎性细胞浸润。相比化疗组，化疗+复方L、M、H组的上述指标水平和心肌病理变化有明显改善，且高剂量组改善作用更明显。结论复方苦参注射液减轻5-FU所致肝癌大鼠心脏毒性损伤可能与缓解内质网应激有关，还能缓解免疫抑制情况。

关键词: 复方苦参注射液, 肝肿瘤, 氟尿嘧啶, 心脏毒性, 内质网应激, 免疫功能

Abstract:

Objective To explore effects and action mechanism of Fu Fang Ku Shen Zhu She Ye on adverse reactions of 5-fluorouracil (5-FU) chemotherapy in rats with liver cancer.Methods The rat model of liver cancer was constructed by diethylnitrosamine (DEN). Model rats were divided into the liver cancer group, the chemotherapy group and the chemotherapy +Fu Fang-L/M/H groups. At 24 h after modeling, the chemotherapy group and the chemotherapy + Fu Fang groups were given intraperitoneally injection of 5-FU (100 mg/kg, once/week), and the chemotherapy + Fu Fang-L/M/H groups were given intraperitoneally injection of Fu Fang Ku Shen Zhu She Ye [0.7, 1.4 and 2.8 mL/kg, once/d] for 8 weeks. The cardiac function, myocardial injury markers and pathological changes of myocardial tissue were compared between different groups. Serum levels of brain natriuretic peptide (BNP), cardiac troponin I (cTnI) and creatine kinase MB (CK-MB) were detected by enzyme-linked immunosorbent assay. The expression levels of glucose-regulating protein 78 (GRP78), activating transcription factor 6 (ATF6) and endoplasmic reticulum stress-related protein (CHOP) in myocardial tissue were detected by Western blot assay. Changes of immune function indexes were compared between different groups.Results Compared with the liver cancer group, left ventricular ejection fraction (LVEF) and left ventricular anterior wall thickness in systole (LVAWs) were decreased in the chemotherapy group (P<0.05), left ventricular end diameter in systole (LVEDs), levels of BNP, cTnI and CK-MB were increased (P<0.05), levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in myocardial tissue, expression levels of GRP78, ATF6 and CHOP were increased (P<0.05). Levels of CD3⁺, CD4⁺, CD4⁺/CD8⁺, IgG, IgM and IgA were decreased in the chemotherapy group (P<0.05). The myocardial tissue was disordered, vacuolated and infiltrated by inflammatory cells. Compared with the chemotherapy group, the above indexes and pathological changes of myocardial tissue were significantly improved in the chemotherapy + Fu Fang-L/M/H groups, and the improvement was more significant in the chemotherapy + Fu Fang-H group.Conclusion Fu Fang Ku Shen Zhu She Ye injection can alleviate cardiotoxic injury induced by 5-FU in rats with liver cancer, which may be related to alleviating endoplasmic reticulum stress. It can also alleviate immunosuppression.

Key words: Fu Fang Ku Shen Zhu She Ye, liver cancer, fluorouracil, cardiotoxicity, endoplasmic reticulum stress, immune function

中图分类号:

R285.5

图/表 7

参考文献 26

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组别	LVEDd/mm		LVAWs/mm		LVAWd/mm
肝癌组	6.15±0.32		1.60±0.19		0.98±0.17
化疗组	6.23±0.40		0.90±0.20^a		1.02±0.20
化疗+复方L组	6.20±0.47		1.00±0.18		1.02±0.23
化疗+复方M组	6.10±0.52		1.45±0.10^bc		1.05±0.27
化疗+复方H组	6.12±0.46		1.48±0.15^bc		1.03±0.23
F	0.098		21.072^＊＊		0.073
组别		LVEF		LVEDs/mm
肝癌组		0.707±0.040		3.20±0.21
化疗组		0.468±0.038^a		4.87±0.31^a
化疗+复方L组		0.535±0.049^b		4.22±0.35^b
化疗+复方M组		0.588±0.036^bc		3.72±0.31^bc
化疗+复方H组		0.652±0.045^bcd		3.28±0.37^bcd
F		30.641^＊＊		29.191^＊＊

组别	LVEDd/mm		LVAWs/mm		LVAWd/mm
肝癌组	6.15±0.32		1.60±0.19		0.98±0.17
化疗组	6.23±0.40		0.90±0.20^a		1.02±0.20
化疗+复方L组	6.20±0.47		1.00±0.18		1.02±0.23
化疗+复方M组	6.10±0.52		1.45±0.10^bc		1.05±0.27
化疗+复方H组	6.12±0.46		1.48±0.15^bc		1.03±0.23
F	0.098		21.072^＊＊		0.073
组别		LVEF		LVEDs/mm
肝癌组		0.707±0.040		3.20±0.21
化疗组		0.468±0.038^a		4.87±0.31^a
化疗+复方L组		0.535±0.049^b		4.22±0.35^b
化疗+复方M组		0.588±0.036^bc		3.72±0.31^bc
化疗+复方H组		0.652±0.045^bcd		3.28±0.37^bcd
F		30.641^＊＊		29.191^＊＊

组别	BNP	cTnI	CK-MB
肝癌组	263.94±10.81	738.36±12.49	982.48±21.11
化疗组	443.68±11.62^a	973.14±15.62^a	1 287.66±34.48^a
化疗+复方L组	410.62±12.41^b	914.08±14.71^b	1 201.39±23.56^b
化疗+复方M组	383.50±13.82^bc	866.32±13.99^bc	1 135.72±28.31^bc
化疗+复方H组	343.83±12.81^bcd	799.87±15.63^bcd	1 058.56±27.44^bcd
F	189.170^＊＊	242.606^＊＊	115.913^＊＊

组别	BNP	cTnI	CK-MB
肝癌组	263.94±10.81	738.36±12.49	982.48±21.11
化疗组	443.68±11.62^a	973.14±15.62^a	1 287.66±34.48^a
化疗+复方L组	410.62±12.41^b	914.08±14.71^b	1 201.39±23.56^b
化疗+复方M组	383.50±13.82^bc	866.32±13.99^bc	1 135.72±28.31^bc
化疗+复方H组	343.83±12.81^bcd	799.87±15.63^bcd	1 058.56±27.44^bcd
F	189.170^＊＊	242.606^＊＊	115.913^＊＊

组别	TNF-α	IL-1β	IL-6
肝癌组	31.84±2.18	2.23±0.18	13.81±1.12
化疗组	58.43±2.29^a	9.12±0.25^a	28.63±2.63^a
化疗+复方L组	52.68±2.41^b	7.51±0.39^b	24.59±1.87^b
化疗+复方M组	46.51±2.33^bc	5.46±0.48^bc	21.36±1.93^bc
化疗+复方H组	39.44±2.27^bcd	3.88±0.20^bcd	17.61±1.58^bcd
F	125.597^＊＊	444.470^＊＊	56.385^＊＊

复方苦参注射液减轻肝癌大鼠5-氟尿嘧啶化疗不良反应的机制研究

Study on the mechanism of Fu Fang Ku Shen Zhu She Ye alleviating adverse reactions of 5-fluorouracil chemotherapy in rats with liver cancer

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组别	GRP78	ATF6	CHOP
肝癌组	0.21±0.05	0.30±0.04	0.38±0.05
化疗组	0.81±0.05^a	0.94±0.05^a	1.05±0.05^a
化疗+复方L组	0.67±0.04^b	0.78±0.05^b	0.89±0.04^b
化疗+复方M组	0.52±0.05^bc	0.59±0.06^bc	0.71±0.06^bc
化疗+复方H组	0.36±0.05^bcd	0.45±0.04^bcd	0.53±0.04^bcd
F	159.315^＊＊	146.288^＊＊	179.106^＊＊

组别	CD3⁺/%	CD4⁺/%	CD4⁺/CD8⁺
肝癌组	72.42±2.46	45.85±1.89	1.48±0.12
化疗组	58.18±3.21^a	31.54±1.96^a	0.94±0.10^a
化疗+复方L组	62.44±2.48^b	34.58±1.73^b	1.15±0.11^b
化疗+复方M组	66.81±2.70^bc	38.43±1.54^bc	1.30±0.12^bc
化疗+复方H组	69.95±2.08^bcd	41.96±1.28^bcd	1.49±0.09^bcd
F	28.796^＊＊	67.498^＊＊	27.887^＊＊

组别	IgG	IgM	IgA
肝癌组	15.84±1.58	1.87±0.10	2.68±0.13
化疗组	9.04±1.22^a	1.32±0.12^a	1.89±0.14^a
化疗+复方L组	10.84±1.31^b	1.46±0.12^b	2.11±0.11^b
化疗+复方M组	12.93±1.08^bc	1.61±0.11^bc	2.34±0.12^bc
化疗+复方H组	14.57±1.16^bcd	1.79±0.13^bcd	2.57±0.15^bcd
F	27.623^＊＊	23.597^＊＊	37.224^＊＊

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