Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway
Introduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the inf...
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1315001/full |
| _version_ | 1797258620920922112 |
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| author | Lei Wang Jiulong Ma Chen Chen Bin Lin Sicong Xie Weiwei Yang Jiajia Qian Yang Zhang Yang Zhang Yang Zhang |
| author_facet | Lei Wang Jiulong Ma Chen Chen Bin Lin Sicong Xie Weiwei Yang Jiajia Qian Yang Zhang Yang Zhang Yang Zhang |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Introduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the influence of IQC on preventing the THP-induced cardiotoxicity in vivo and in vitro.Methods: The optimal concentration and time required for IQC to prevent THP-induced cardiomyocyte damage were determined by an MTT assay. The protective effect was further verified in H9c2 and HCM cells using dichlorodihydrofluorescein diacetate fluorescent probes, MitoTracker Red probe, enzyme-linked immunosorbent assay, JC-1 probe, and real time-quantitative polymerase chain reaction (RT-qPCR). Rats were administered THP to establish cardiotoxicity. An electrocardiogram (ECG) was performed, and cardiac hemodynamics, myocardial enzymes, oxidative stress indicators, and hematoxylin-eosin staining were studied. Voltage-dependent anion channel 1 (VDAC1), adenine nucleotide translocase 1 (ANT1), and cyclophilin D (CYPD) were detected by qRT-PCR, and the Phlpp1/AKT/Bcl-2 axis proteins were detected by western blot, confirming that IQC markedly increased cell viability and superoxide dismutase (SOD) levels, diminished the levels of ROS and MDA, and elevated mitochondrial function and apoptosis in vivo and in vitro.Results: Results showed that IQC reduced THP-induced myocardial histopathological injury, electrocardiogram (ECG) abnormalities, and cardiac dysfunction in vivo. IQC also decreased serum levels of MDA, BNP, CK-MB, c-TnT, and LDH, while increasing levels of SOD and GSH. We also found that IQC significantly reduced VDAC1, ANT1, and CYPD mRNA expression. In addition, IQC controlled apoptosis by modulating Phlpp1/AKT/Bcl-2 signaling pathways. IQC markedly increased H9c2 and HCM cell viability and SOD levels, diminished the levels of ROS and MDA, and elevated mitochondrial function in H9c2 and HCM cells to defend against THP-induced cardiomyocyte apoptosis in vitro. The AKT inhibitor IMQ demonstrated that IQC lacked antioxidant and anti-apoptotic properties. Moreover, our data showed that IQC regulates Phlpp1 expression, thereby influencing the expression levels of p-AKT, cytochrome c, caspase-3, caspase-9, Bcl-2, and Bax.Discussion: In conclusion, our results indicate that IQC protects the changes in mitochondrial membrane permeability in cardiomyocytes by regulating the Phlpp1/AKT/Bcl-2 signaling pathway, inhibits the release of cytc from the mitochondrial inner membrane to the cytoplasm, forms apoptotic bodies, induces cell apoptosis, and reduces THP induced cardiotoxicity. |
| first_indexed | 2024-04-24T22:56:26Z |
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| spelling | doaj.art-ce9fc03685b44b788a038746a33e96c62024-03-18T04:48:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13150011315001Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathwayLei Wang0Jiulong Ma1Chen Chen2Bin Lin3Sicong Xie4Weiwei Yang5Jiajia Qian6Yang Zhang7Yang Zhang8Yang Zhang9Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Jilin, ChinaDepartment of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Jilin, ChinaKey Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Huzhou, ChinaDepartment of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Jilin, ChinaKey Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Huzhou, ChinaIntroduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the influence of IQC on preventing the THP-induced cardiotoxicity in vivo and in vitro.Methods: The optimal concentration and time required for IQC to prevent THP-induced cardiomyocyte damage were determined by an MTT assay. The protective effect was further verified in H9c2 and HCM cells using dichlorodihydrofluorescein diacetate fluorescent probes, MitoTracker Red probe, enzyme-linked immunosorbent assay, JC-1 probe, and real time-quantitative polymerase chain reaction (RT-qPCR). Rats were administered THP to establish cardiotoxicity. An electrocardiogram (ECG) was performed, and cardiac hemodynamics, myocardial enzymes, oxidative stress indicators, and hematoxylin-eosin staining were studied. Voltage-dependent anion channel 1 (VDAC1), adenine nucleotide translocase 1 (ANT1), and cyclophilin D (CYPD) were detected by qRT-PCR, and the Phlpp1/AKT/Bcl-2 axis proteins were detected by western blot, confirming that IQC markedly increased cell viability and superoxide dismutase (SOD) levels, diminished the levels of ROS and MDA, and elevated mitochondrial function and apoptosis in vivo and in vitro.Results: Results showed that IQC reduced THP-induced myocardial histopathological injury, electrocardiogram (ECG) abnormalities, and cardiac dysfunction in vivo. IQC also decreased serum levels of MDA, BNP, CK-MB, c-TnT, and LDH, while increasing levels of SOD and GSH. We also found that IQC significantly reduced VDAC1, ANT1, and CYPD mRNA expression. In addition, IQC controlled apoptosis by modulating Phlpp1/AKT/Bcl-2 signaling pathways. IQC markedly increased H9c2 and HCM cell viability and SOD levels, diminished the levels of ROS and MDA, and elevated mitochondrial function in H9c2 and HCM cells to defend against THP-induced cardiomyocyte apoptosis in vitro. The AKT inhibitor IMQ demonstrated that IQC lacked antioxidant and anti-apoptotic properties. Moreover, our data showed that IQC regulates Phlpp1 expression, thereby influencing the expression levels of p-AKT, cytochrome c, caspase-3, caspase-9, Bcl-2, and Bax.Discussion: In conclusion, our results indicate that IQC protects the changes in mitochondrial membrane permeability in cardiomyocytes by regulating the Phlpp1/AKT/Bcl-2 signaling pathway, inhibits the release of cytc from the mitochondrial inner membrane to the cytoplasm, forms apoptotic bodies, induces cell apoptosis, and reduces THP induced cardiotoxicity.https://www.frontiersin.org/articles/10.3389/fphar.2024.1315001/fullisoquercitrinPhlpp1/AKT/Bcl-2 signaling pathwaypirarubicinapoptosisoxidative damage |
| spellingShingle | Lei Wang Jiulong Ma Chen Chen Bin Lin Sicong Xie Weiwei Yang Jiajia Qian Yang Zhang Yang Zhang Yang Zhang Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway Frontiers in Pharmacology isoquercitrin Phlpp1/AKT/Bcl-2 signaling pathway pirarubicin apoptosis oxidative damage |
| title | Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway |
| title_full | Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway |
| title_fullStr | Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway |
| title_full_unstemmed | Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway |
| title_short | Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway |
| title_sort | isoquercitrin alleviates pirarubicin induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through phlpp1 akt bcl 2 signaling pathway |
| topic | isoquercitrin Phlpp1/AKT/Bcl-2 signaling pathway pirarubicin apoptosis oxidative damage |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1315001/full |
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