Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway

Huang, Po-Chiun; Kuo, Wei Wen; Shen, Chia Yao; Chen, Yu Feng; Lin, Yueh Min; Ho, Tsung Jung; Padma, V. Vijaya; Lo, Jeng‐Fan; Huang, Chih Yang

doi:10.3390/ijms17091588

Cited by 30 publications

(18 citation statements)

References 71 publications

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“…To further ascertain the role of IGF-IIRα in DOX-induced cardiac damage, we determined the protein expression of survival markers upon IGF-IIRα overexpression and/or DOX treatment in both in vitro and in vivo systems. In line with our previous studies, 18,19 we observed a significant decline in p-Akt and ERβ/α in groups subjected to DOX treatment. Interestingly, transgenic rats overexpressing IGF-IIRα specifically in heart resulted in more adverse suppression of survival markers compared with WT animals.…”

Section: Discussionsupporting

confidence: 93%

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

Pandey

Kuo

et al. 2019

J of Cellular Biochemistry

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Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin‐like growth factor receptor type II α (IGF‐IIRα) which is a novel stress‐inducible protein was explored in doxorubicin‐induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD‐TG [IGF‐IIRα]) overexpressing IGF‐IIRα specifically in heart, we found that IGF‐IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin‐induced cardiac stress. Overexpression of IGF‐IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p‐Akt and estrogen receptor β/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin‐I, and apoptosis‐inducing agents such as p53, Bax, and cytochrome C, respectively. IGF‐IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF‐IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF‐IIRα is a novel stress‐induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin‐induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy.

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Section: Discussionsupporting

confidence: 93%

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

Pandey

Kuo

et al. 2019

J of Cellular Biochemistry

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“…Their harmful effect, as exemplified by doxorubicin, is based on, e.g., ROS overproduction, initiation of cell apoptosis, and arrest of the cell cycle [30]. Polyphenols may increase their cytotoxic activity in relation to tumor cells (synergistic effect) or decrease it with respect to normal cells [31,32]. Therefore, we determined the ability of the compounds to inhibit the cytotoxicity of doxorubicin, one of the most popular chemotherapy drugs administered intravenously.…”

Section: Resultsmentioning

confidence: 99%

The Impact of O-Glycosylation on Cyanidin Interaction with RBCs and HMEC-1 Cells—Structure–Activity Relationships

Cyboran-Mikołajczyk

Solarska-Ściuk

Mieszała

et al. 2019

IJMS

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With the aim of contributing to the knowledge about their potential therapeutic activity, we determined the biological activities of cyanidin and its selected O-glycosides in relation to erythrocytes (RBCs) and human dermal vascular endothelial cells (HMEC-1). Furthermore, on the basis of changes in the physical/functional properties of the cells, the structure–activity relationships of the compounds were determined. Concerning erythrocytes, we analyzed the antioxidant activity of the compounds and their impact on the RBCs’ shape and transmembrane potential. The compounds’ cytotoxic activity, ability to modulate apoptosis, cell cycle, and intracellular ROS generation, as well as inhibitory activity against AAPH-inducted oxidative stress, were determined in relation to HMEC-1 cells. We demonstrated that biological activity of cyanidin and its O-glycosides strongly depends on the number and type of sugar substituents, and varies depending on the extracellular environment and type of cells. The compounds are practically non-cytotoxic, and do not induce apoptosis or disturb the progression of the cell cycle. Additionally, the compounds alter the shape of RBCs, but they do not affect their transmembrane potential. They effectively protect erythrocytes against free radicals and affect intracellular reactive oxygen spices (ROS) generation under physiological and AAPH-induced oxidative stress conditions. Our results suggest a potential beneficial effect of cyanidin on the cardiovascular system.

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“…ERα and ERβ proteins transmit the action of estrogens into target cells [54,55]. Although generated by individual genes, ERα and ERβ have almost 100% amino acid homology in their DNA-binding domain and about 60% amino acid homology in their protein-interacting domains [56]. Interestingly, in vivo and in vitro experiments demonstrated differential or opposite effects of ERα and ERβ on biological features of breast cancer cells [57].…”

Section: Impacts Of Alternative Splicing Events On Apoptosismentioning

confidence: 99%

Differential Impacts of Alternative Splicing Networks on Apoptosis

Lin

Tsao

Lin

2016

IJMS

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Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases.

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Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway

Cited by 30 publications

References 71 publications

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

Upregulation of IGF‐IIRα intensifies doxorubicin‐induced cardiac damage

The Impact of O-Glycosylation on Cyanidin Interaction with RBCs and HMEC-1 Cells—Structure–Activity Relationships

Differential Impacts of Alternative Splicing Networks on Apoptosis

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