葡萄籽原花青素提取物对多柔比星致慢性心脏毒性的防治作用

doi:10.11958/20252608

天津医药 ›› 2026, Vol. 54 ›› Issue (4): 358-363.doi: 10.11958/20252608

葡萄籽原花青素提取物对多柔比星致慢性心脏毒性的防治作用

翟志红¹(), 李润琦², 杜晴晴³, 秦文娟⁴

¹ 石河子大学第一附属医院心血管内科（邮编832000）
² 石河子大学第一附属医院肾病内科（邮编832000）
³ 石河子大学第一附属医院内分泌代谢病科（邮编832000）
⁴ 石河子大学第一附属医院超声医学科（邮编832000）

收稿日期:2025-07-29 修回日期:2025-10-08 出版日期:2026-04-15 发布日期:2026-04-14
作者简介:翟志红（1979），男，主任医师，主要从事心血管疾病的基础与临床方面研究。E-mail：jznkzzh@126.com
基金资助:
第三师图木舒克市科技计划项目(KY2021GG01)

Study on the preventive and therapeutic effects of grape seed proanthocyanidin extract on doxorubicin-induced chronic cardiotoxicity

ZHAI Zhihong¹(), LI Runqi², DU Qingqing³, QIN Wenjuan⁴

¹ Department of Cardiovascular Medicine, the First Affiliated Hospital of Shihezi University, Shihezi 832000, China
² Department of Nephrology, the First Affiliated Hospital of Shihezi University, Shihezi 832000, China
³ Department of Endocrinology and Metabolism, the First Affiliated Hospital of Shihezi University, Shihezi 832000, China
⁴ Department of Ultrasound Medicine, the First Affiliated Hospital of Shihezi University, Shihezi 832000, China

Received:2025-07-29 Revised:2025-10-08 Published:2026-04-15 Online:2026-04-14

翟志红, 李润琦, 杜晴晴, 秦文娟. 葡萄籽原花青素提取物对多柔比星致慢性心脏毒性的防治作用[J]. 天津医药, 2026, 54(4): 358-363.

ZHAI Zhihong, LI Runqi, DU Qingqing, QIN Wenjuan. Study on the preventive and therapeutic effects of grape seed proanthocyanidin extract on doxorubicin-induced chronic cardiotoxicity[J]. Tianjin Medical Journal, 2026, 54(4): 358-363.

摘要/Abstract

摘要：

目的探讨葡萄籽原花青素提取物（GSPE）通过调控核因子E2相关因子（Nrf2）/血红素氧合酶1（HO-1）信号通路对多柔比星（DOX）诱导的慢性心脏毒性的影响。方法 36只6周龄雄性SD大鼠按随机数字表法均分为正常对照（Control）组、DOX组、DOX+低剂量GSPE（L-GSPE）组、DOX+中剂量GSPE（M-GSPE）组、DOX+高剂量GSPE（H-GSPE）组及DOX+TBHQ阳性对照（TBHQ）组。除Control组外，其余各组大鼠每周1次腹腔注射2.5 mg/kg的DOX，连续6周；Control组给予等体积的生理盐水腹腔注射。第1天注射DOX后L-GSPE组、M-GSPE组、H-GSPE组分别予以100、200及400 mg/kg的GSPE溶液灌胃，TBHQ组予以25 mg/kg的TBHQ溶液灌胃，Control组、DOX组予以等体积的双蒸水灌胃。心脏超声观察各组大鼠的心脏结构和功能变化；HE、Masson染色观察心肌组织形态及纤维化；试剂盒测定血清超氧化物歧化酶（SOD），丙二醛（MDA）水平；ELISA法检测血清白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）、肌钙蛋白T（cTnT）、B型钠尿肽（BNP）水平；Western blot和实时荧光定量PCR检测心肌组织Nrf2、HO-1、醌氧化还原酶（NQO1）蛋白和mRNA的表达。结果与DOX组比较，不同剂量的GSPE干预组心脏结构及功能、心肌损伤和心肌纤维化程度均有改善，且L-GSPE组、M-GSPE组、H-GSPE组及TBHQ组TNF-α、IL-6、MDA、cTnT及BNP水平均降低，血清SOD和心肌组织Nrf2、HO-1、NQO1蛋白及mRNA表达水平均升高，且与L-GSPE组比较，H-GSPE组改善更明显（P<0.05）。结论 GSPE可通过激活Nrf2/HO-1信号通路发挥对DOX致慢性心脏毒性的防治作用。

关键词: 多柔比星, 心脏毒性, 血红素加氧酶-1, 葡萄籽原花青素提取物, Nrf2信号通路

Abstract:

Objective To investigate the effect of grape seed proanthocyanidin extract (GSPE) on doxorubicin-induced chronic cardiotoxicity by regulating the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Methods Thirty-six 6-week-old SD rats were randomly divided into six groups (n=6 for each group): the control group (control), the doxorubicin group (DOX), the doxorubicin+low-dose GSPE group (L-GSPE), the doxorubicin+medium-dose GSPE group (M-GSPE), the doxorubicin+ high-dose GSPE group (H-GSPE) and the doxorubicin+tert-butylhydroquinone group (TBHQ). Except for the control group, rats in the other groups were injected intraperitoneally with doxorubicin (2.5 mg/kg) once weekly for 6 consecutive weeks to establish the chronic cardiotoxicity model. The control group received equal volume of intraperitoneal injection of 0.9% NaCl solution (1 mL/kg). Starting from the first day of doxorubicin injection, the L-GSPE, M-GSPE and H-GSPE groups were administered GSPE solutions at doses of 100 mg/kg, 200 mg/kg and 400 mg/kg, respectively, via oral gavage. The TBHQ group was given 25 mg/kg TBHQ solution, while the control group and the DOX group were given an equal volume of ddH₂O. Cardiac structure and function were evaluated using echocardiography. Cardiac tissue morphology and fibrosis were observed via HE and Masson staining. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cardiac troponin T (cTnT) and brain natriuretic peptide (BNP) were measured using commercial kits and ELISA. Western blot assay and qRT-PCR were employed to assess protein and mRNA expression levels of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1) and HO-1 in cardiac tissue. Results Compared with the DOX group, the cardiac structure and function, myocardial injury and fibrosis were all improved in the GSPE-treated groups, serum levels of TNF-α, IL-6, MDA, cTnT and BNP decreased, and serum SOD activity, protein and mRNA expression levels of Nrf2, HO-1 and NQO1 increased. Notably, the H-GSPE group demonstrated more significant improvement compared to the L-GSPE group (P<0.05). Conclusion GSPE may exert preventive and therapeutic effects against doxorubicin-induced chronic cardiotoxicity by activating the Nrf2/HO-1 signaling pathway.

Key words: doxorubicin, cardiotoxicity, heme oxygenase-1, grape seed proanthocyanidin extract, Nrf2 signaling pathway

中图分类号:

R541

图/表 9

参考文献 23

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基因名称	引物序列（5′→3′）	产物大小/bp
Nrf2	上游：TCCATTTACGGAGACCCAC	106
	下游：GTGTTGGCTGTGCTTTAGGT	106
HO-1	上游：AGCGAAACAAGCAGAACC	191
	下游：CAGCAGCTCAGGATGAGTAC	191
NQO1	上游：GAAGGGTGGAAGAAGCGT	292
	下游：TGGAACAAAGGCGAAAACT	292
GAPDH	上游：CAAGTTCAACGGCACAG	138
	下游：CCAGTAGACTCCACGACAT	138

基因名称	引物序列（5′→3′）	产物大小/bp
Nrf2	上游：TCCATTTACGGAGACCCAC	106
	下游：GTGTTGGCTGTGCTTTAGGT	106
HO-1	上游：AGCGAAACAAGCAGAACC	191
	下游：CAGCAGCTCAGGATGAGTAC	191
NQO1	上游：GAAGGGTGGAAGAAGCGT	292
	下游：TGGAACAAAGGCGAAAACT	292
GAPDH	上游：CAAGTTCAACGGCACAG	138
	下游：CCAGTAGACTCCACGACAT	138

组别	LVEDD/mm	LVESD/mm	LVEDV/mL
Control组	4.22±0.87	2.43±0.14	0.32±0.08
DOX组	6.40±0.24^a	3.38±0.14^a	0.55±0.05^a
L-GSPE组	5.76±0.43^a	3.21±0.15^a	0.42±0.34^b
M-GSPE组	4.98±0.60^b	2.91±0.16^ab	0.37±0.08^b
H-GSPE组	4.67±0.18^bc	2.69±0.48^bc	0.36±0.03^b
TBHQ组	5.46±0.22	3.10±0.16^a	0.41±0.29^b
F	7.736^＊＊	6.548^＊＊	5.996^＊＊
组别	LVESV/mL	LVEF	LVFS
Control组	0.06±0.03	0.82±0.01	0.45±0.02
DOX组	0.13±0.01^a	0.56±0.05^a	0.33±0.02^a
L-GSPE组	0.10±0.02	0.65±0.03^ab	0.35±0.04^a
M-GSPE组	0.10±0.03	0.75±0.03^abc	0.40±0.01^abc
H-GSPE组	0.08±0.02^b	0.80±0.02^bc	0.42±0.02^bc
TBHQ组	0.10±0.02	0.71±0.01^abc	0.34±0.03^a
F	2.145	36.999^＊＊	21.478^＊＊

组别	LVEDD/mm	LVESD/mm	LVEDV/mL
Control组	4.22±0.87	2.43±0.14	0.32±0.08
DOX组	6.40±0.24^a	3.38±0.14^a	0.55±0.05^a
L-GSPE组	5.76±0.43^a	3.21±0.15^a	0.42±0.34^b
M-GSPE组	4.98±0.60^b	2.91±0.16^ab	0.37±0.08^b
H-GSPE组	4.67±0.18^bc	2.69±0.48^bc	0.36±0.03^b
TBHQ组	5.46±0.22	3.10±0.16^a	0.41±0.29^b
F	7.736^＊＊	6.548^＊＊	5.996^＊＊
组别	LVESV/mL	LVEF	LVFS
Control组	0.06±0.03	0.82±0.01	0.45±0.02
DOX组	0.13±0.01^a	0.56±0.05^a	0.33±0.02^a
L-GSPE组	0.10±0.02	0.65±0.03^ab	0.35±0.04^a
M-GSPE组	0.10±0.03	0.75±0.03^abc	0.40±0.01^abc
H-GSPE组	0.08±0.02^b	0.80±0.02^bc	0.42±0.02^bc
TBHQ组	0.10±0.02	0.71±0.01^abc	0.34±0.03^a
F	2.145	36.999^＊＊	21.478^＊＊

组别	MDA/ （μmol/L）	SOD/ （U/mL）	cTnT/ （ng/L）	BNP/ （ng/L）
Control组	5.49±0.68	52.66±3.85	53.37±4.79	678.21±122.68
DOX组	11.65±0.35^a	24.70±1.00^a	131.58±16.76^a	1 629.78±43.77^a
L-GSPE组	8.90±0.57^ab	28.21±2.03^ab	98.61±4.11^ab	1 369.97±137.91^ab
M-GSPE组	8.33±0.75^abc	33.48±1.19^abc	82.88±8.57^abc	1 243.06±119.51^abc
H-GSPE组	6.41±0.85^abc	42.23±2.09^abc	74.56±5.06^abc	1 048.78±94.94^abc
TBHQ组	7.71±1.20^abc	37.51±1.25^bc	81.46±6.09^abc	1 107.62±97.37^abc
F	136.564^＊＊	404.964^＊＊	163.411^＊＊	162.285^＊＊

葡萄籽原花青素提取物对多柔比星致慢性心脏毒性的防治作用

Study on the preventive and therapeutic effects of grape seed proanthocyanidin extract on doxorubicin-induced chronic cardiotoxicity

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参考文献 23

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组别	Nrf2	HO-1	NQO1
Control组	1.00±0.18	0.96±0.13	1.00±0.08
DOX组	0.45±0.06^a	0.74±0.04^a	0.46±0.04^a
L-GSPE组	1.01±0.22^b	1.17±0.06^b	1.01±0.06^b
M-GSPE组	1.20±0.18^b	1.27±0.03^ab	1.16±0.07^ab
H-GSPE组	1.53±0.13^abc	1.46±0.07^abc	1.16±0.06^abc
TBHQ组	1.23±0.03^b	1.12±0.09^b	0.95±0.08^b
F	17.098^＊＊	30.919^＊＊	63.830^＊＊

组别	Nrf2 mRNA	HO-1 mRNA	NQO1 mRNA
Control组	0.96±0.07	1.05±0.14	1.01±0.08
DOX组	0.65±0.08^a	0.62±0.08^a	0.67±0.09^a
L-GSPE组	0.95±0.17^b	1.20±0.23^b	1.12±0.12^b
M-GSPE组	1.17±0.07^abc	1.90±0.17^abc	1.43±0.24^abc
H-GSPE组	1.40±0.19^abc	2.13±0.43^abc	1.72±0.21^abc
TBHQ组	1.11±0.12^b	1.36±0.58^b	1.20±0.92^b
F	25.050^＊＊	53.708^＊＊	36.521^＊＊

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