Dataset Information

Hyperoside alleviates doxorubicin-induced myocardial cells apoptosis by inhibiting the apoptosis signal-regulating kinase 1/p38 pathway.

ABSTRACT:

Background

Cardiotoxicity is a side effect of the anthracycline broad-spectrum anti-tumor agent, doxorubicin (DOX). Hyperoside, a flavonoid glycoside extracted from many herbs, has anti-apoptotic and anticancer properties. However, its impact on the alleviation of DOX-induced apoptosis in cardiomyocytes remains elusive.

Methods

The HL-1 cell line was treated with 100 µ M hyperoside for 1 h prior to treatment with 100 µ M hyperoside and 1 µ M DOX for 24 h. The cell counting kit-8 (CCK-8) assay was used to detect cell viability; DCFH-DA fluorescent probe was used to detect (reactive oxygen species) ROS; biochemical methods were used to detect the activity of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA); the degree of apoptosis following DOX insult was assessed using immunofluorescence staining and terminal deoxynucleotidyl transferase mediated deoxy uridine triphosphate nick end labeling (TUNEL) assay; the change in protein expression of apoptosis signal-regulating kinase 1 (ASK1), p38, and apoptosis markers was determined using western blot.

Results

Hyperoside ameliorated DOX-induced oxidative stress in HL-1 cells, up-regulated GSH, SOD and CAT activity, reduced ROS production and inhibited MDA overproduction. Moreover, in addition to promoting HL-1 cell apoptosis, DOX administration also increased B-cell lymphoma (Bcl)-2-associated X-protein and cleaved caspase-3 protein levels and decreased Bcl-2 protein level. Hyperoside therapy, however, significantly reversed the impact of DOX on the cardiomyocytes. Mechanically, DOX treatment increased the phosphorylation of the ASK1/p38 axis whereas hyperoside treatment attenuated those changes. In a further step, hyperoside synergizes with DOX to kill MDA-MB-231 cells.

Conclusions

Hyperoside protects HL-1 cells from DOX-induced cardiotoxicity by inhibiting the ASK1/p38 signaling pathway. Meanwhile, hyperoside maintained the cytotoxicity of DOX in MDA-MB-231 cells.

SUBMITTER: Chen L

PROVIDER: S-EPMC10200097 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Hyperoside alleviates doxorubicin-induced myocardial cells apoptosis by inhibiting the apoptosis signal-regulating kinase 1/p38 pathway.

Chen Lingxia L Qin Zhi Z Ruan Zhong-Bao ZB

PeerJ 20230518

<h4>Background</h4>Cardiotoxicity is a side effect of the anthracycline broad-spectrum anti-tumor agent, doxorubicin (DOX). Hyperoside, a flavonoid glycoside extracted from many herbs, has anti-apoptotic and anticancer properties. However, its impact on the alleviation of DOX-induced apoptosis in cardiomyocytes remains elusive.<h4>Methods</h4>The HL-1 cell line was treated with 100 µ M hyperoside for 1 h prior to treatment with 100 µ M hyperoside and 1 µ M DOX for 24 h. The cell counting kit-8 ( ...[more]

PMID: 37220525

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Project description:Systemic hypertension increases cardiac workload causing cardiomyocyte hypertrophy and increased cardiac fibrosis. An underlying feature is increased production of reactive oxygen species. Redox-sensitive ASK1 (apoptosis signal-regulating kinase 1) activates stress-regulated protein kinases (p38-MAPK [mitogen-activated protein kinases] and JNKs [c-Jun N-terminal kinases]) and promotes fibrosis in various tissues. Here, we determined the specificity of ASK1 signaling in the heart, with the hypothesis that ASK1 inhibitors may be used to manage fibrosis in hypertensive heart disease. Using immunoblotting, we established that moderate levels of H2O2 activate ASK1 in neonatal rat cardiomyocytes and perfused rat hearts. ASK1 was activated during ischemia in adult rat hearts, but not on reperfusion, consistent with activation by moderate (not high) reactive oxygen species levels. In contrast, IL (interleukin)-1β activated an alternative kinase, TAK1 (transforming growth factor-activated kinase 1). ASK1 was not activated by IL1β in cardiomyocytes and activation in perfused hearts was due to increased reactive oxygen species. Selonsertib (ASK1 inhibitor) prevented activation of p38-MAPKs (but not JNKs) by oxidative stresses in cultured cardiomyocytes and perfused hearts. In vivo (C57Bl/6J mice with osmotic minipumps for drug delivery), selonsertib (4 mg/[kg·d]) alone did not affect cardiac function/dimensions (assessed by echocardiography). However, it suppressed hypertension-induced cardiac hypertrophy resulting from angiotensin II (0.8 mg/[kg·d], 7d), with inhibition of Nppa/Nppb mRNA upregulation, reduced cardiomyocyte hypertrophy and, notably, significant reductions in interstitial and perivascular fibrosis. Our data identify a specific reactive oxygen species→ASK1→p38-MAPK pathway in the heart and establish that ASK1 inhibitors protect the heart from hypertension-induced cardiac remodeling. Thus, targeting the ASK1→p38-MAPK nexus has potential therapeutic viability as a treatment for hypertensive heart disease.

Project description:BackgroundCapsaicin (CAP), a frequently occurring alkaloid component found in spicy peppers, has demonstrated therapeutic potential against tumors, metabolic disease, and cardiovascular disorders. Doxorubicin (DOX), a widely used anthracycline drug in chemotherapy, is notorious for its cardiotoxicity. This study aimed to investigate the potential of CAP in mitigating DOX toxicity in mouse hearts and H9C2 cells, as well as to explore the underlying mechanisms.MethodsIn our study, we conducted experiments on both mice and H9C2 cells. The mice were divided into four groups and treated with different substances: normal saline, CAP, DOX and CAP+DOX. We evaluated the induction of ferroptosis by DOX and the remission of ferroptosis by CAP using various methods, including echocardiography, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining, and determination of ferroptosis metabolites, genes and proteins. Additionally, we employed RNA-seq to identify the inhibitory effect of CAP on DOX-induced myocardial apoptosis, which was further confirmed through western blotting. Similar approaches were applied to H9C2 cells, yielding reliable results.ResultsOur study demonstrated that treatment with CAP improved the survival rate of DOX-treated mice and reduced myocardial injury. Mechanistically, CAP downregulated transferrin (Trf) and upregulated solute carrier family 40 member 1 (SLC40A1), which helped maintain iron levels in the cells and prevent ferroptosis. Furthermore, CAP inhibited DOX-induced apoptosis by modulating the phosphoinositide 3-kinase (PI3K)- protein kinase B (Akt) signaling pathway. Specifically, CAP activated the PI3K-Akt pathway and regulated downstream BCL2 and BAX to mitigate DOX-induced apoptosis. Therefore, our results suggest that CAP effectively alleviates acute myocardial injury induced by DOX.ConclusionOur findings demonstrate that CAP has the potential to alleviate DOX-induced ferroptosis by regulating iron homeostasis. Additionally, it can inhibit DOX-induced apoptosis by activating PI3K-Akt signaling pathway.

Dataset Information

Hyperoside alleviates doxorubicin-induced myocardial cells apoptosis by inhibiting the apoptosis signal-regulating kinase 1/p38 pathway.

Background

Methods

Results

Conclusions

Publications

Hyperoside alleviates doxorubicin-induced myocardial cells apoptosis by inhibiting the apoptosis signal-regulating kinase 1/p38 pathway.

Similar Datasets

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