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Apocynum venetum leaf extract alleviated doxorubicin-induced cardiotoxicity through the AKT/Bcl-2 signaling pathway
Abstract
Background Doxorubicin (DOX) is a broad-spectrum anti-tumor drug that has been associated with cardiotoxicity. Plant extracts have been shown to confer protection against DOX-induced cardiotoxicity. Apocynum venetum L. belongs to the Apocynaceae family. Flavonoid extracted from Apocynum venetum L. possess various biological effects, such as lowering blood pressure levels, sedation, diuresis, anti-aging, and improving immunity.Purpose This study investigated the mechanism by which dry leaf extract of Apocynum venetum L. (AVLE) alleviates DOX-induced cardiomyocyte apoptosis.Methods HPLC-MS/MS and HPLC methods were used to analyze the components of AVLE. The effects of DOX and AVLE on apoptosis of H9c2 and HMC cells were assessed using the MTT assay. Calcein AM/PI, TUNEL, and flow cytometry were carried out to determine the effects of AVLE on DOX-induced apoptosis. The effect of AVLE on DOX-induced oxidative stress in cardiomyocytes was investigated using ELISA test. Mito-Tracker Red CMXRos, JC-1, and RT-qPCR assays were performed to evaluate the impact of AVLE on DOX-induced cardiomyocyte mitochondrial activity and membrane permeability. Western blot assay was carried out to determine the activation of multiple signaling molecules, including phosphorylated-protein kinase B (p-AKT), Cytochrome c, Bcl-2 family, and caspase family in the apoptosis pathway. The AKT inhibitor was used to block AKT/Bcl-2 signaling pathway to investigate the role of AKT in the protection conferred by AVLE against DOX-induced cardiotoxicity.Results A total of 8 compounds, including rutin, hyperoside, isoquercetin, unidentified compounds, myricetin, quercetin, quercetin-3-O-glucuronide and kaempferol, were detected in AVLE. Of note, DOX suppressed lactate dehydrogenase (LDH) levels, aggravated oxidative stress, and promoted cardiomyocyte apoptosis. It also upregulated the mRNA expression levels of voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD), while suppressing mitochondrial activity and mitochondrial membrane permeability. Treatment with DOX altered the expression levels of apoptosis-associated proteins, Bcl-2 and Bax. However, AVLE treatment alleviated DOX-induced effects on cardiomyocytes. In addition, application of AKT inhibitors promoted DOX-induced apoptosis and reversed the inhibitory effects of AVLE on DOX-induced apoptosis.Conclusions AVLE confer cardio protection by suppressing oxidative stress and apoptosis of cardiomyocytes via AKT/Bcl-2 signaling pathway.
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Doxorubicin-induced senescence in H9c2 myocardial cells results in increased expression of 4-HNE and GPX4, decreased SIRT1 expression, and heightened levels of pro-inflammatory cytokines (IL-6, IL-17, and TNF-α), while the anti-inflammatory cytokine IL-4 is reduced.
“In addition, doxorubicin-induced senescence in H9c2 myocardial cells results in increased expression of 4-HNE and GPX4, decreased SIRT1 expression, and heightened levels of pro-inflammatory cytokines (IL-6, IL-17, and TNF-α), while the anti-inflammatory cytokine IL-4 is reduced.291–293”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [292]
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Metadata
- Authors
- Zhang, Y., Liu, S., Ma, J.-L., Chen, C., Huang, P., Ji, J.-H., Wu, D., & Ren, L.-Q.
- Affiliations
- Jilin University (CN)
- Venue
- Phytomedicine
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 94
- Pages
- 153815
- ISSN
- 0944-7113 (ISSN-L)
- OpenAlex
- W3210259248
- Cited by
- 65
- References
- 47
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 14 · 2023: 14 · 2022: 7
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Phytomedicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81773934)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Physical Sciences › Materials Science › Biomaterials › Phytochemistry and Bioactive Compounds
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- Apocynum venetum, doxorubicin cardiotoxicity, cardioprotection, cardiomyocyte apoptosis, oxidative stress, mitochondrial membrane permeability, flavonoids, quercetin, rutin, hyperoside, isoquercitrin, myricetin, kaempferol, cyclophilin D
- MeSH terms
- Doxorubicin, Humans, Plant Extracts, Signal Transduction, Apoptosis, Oxidative Stress, Apocynum, Myocytes, Cardiac, Proto-Oncogene Proteins c-akt, Tandem Mass Spectrometry, Cardiotoxicity
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