Abstract | CONTEXT: OBJECTIVE: To investigate the effects of ADI on DOX-induced cardiotoxicity and its mechanism. MATERIALS AND METHODS: ICR mice were randomly divided into six groups: control, ADI-L, ADI-H, DOX, DOX + ADI-L and DOX + ADI-H. DOX (i.p., 0.03 mg/10 g) was administered in the presence or absence of ADI (i.p., 0.1 or 0.2 mL/10 g) for two weeks. Heart pathology and levels of AST, LDH, CK, CK-MB and BNP were assessed. H9c2 cells were treated with DOX in the presence or absence of ADI (1, 4, 10%). Cell viability, caspase-3 activity, nuclear morphology, and CBR1 expression were then evaluated. DOX and doxorubicinol (DOXol) concentrations in heart, liver, kidneys, serum, and cells were analysed by UPLC-MS/MS. RESULTS: High-dose ADI significantly reduced DOX-induced pathological changes and the levels of AST, LDH, CK, CK-MB and BNP to normal. Combined treatment with ADI (1, 4, 10%) improved the cell viability, and IC50 increased from 68.51 μM (DOX alone) to 83.47, 176.9, and 310.8 μM, reduced caspase-3 activity by 39.17, 43.96, and 61.82%, respectively. High-dose ADI inhibited the expression of CBR1 protein by 32.3%, reduced DOXol levels in heart, serum and H9c2 cells by 59.8, 72.5 and 48.99%, respectively. DISCUSSION AND CONCLUSIONS: ADI reduces DOX-induced cardiotoxicity by inhibiting CBR1 expression, which provides a scientific basis for the rational use of ADI.
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Authors | Yuan Lu, Wen Liu, Ting Lv, Yanli Wang, Ting Liu, Yi Chen, Yang Jin, Jin Huang, Lin Zheng, Yong Huang, Yan He, Yongjun Li |
Journal | Pharmaceutical biology
(Pharm Biol)
Vol. 60
Issue 1
Pg. 1616-1624
(Dec 2022)
ISSN: 1744-5116 [Electronic] England |
PMID | 35980105
(Publication Type: Journal Article, Randomized Controlled Trial, Veterinary)
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Chemical References |
- Antibiotics, Antineoplastic
- Doxorubicin
- Carbonyl Reductase (NADPH)
- Creatine Kinase, MB Form
- Caspase 3
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Topics |
- Animals
- Antibiotics, Antineoplastic
(toxicity)
- Carbonyl Reductase (NADPH)
- Cardiotoxicity
(metabolism)
- Caspase 3
- Chromatography, Liquid
- Creatine Kinase, MB Form
- Doxorubicin
(toxicity)
- Mice
- Mice, Inbred ICR
- Tandem Mass Spectrometry
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