The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

Lagoa, Ricardo; Gañan, Carlos M.; López‐Sánchez, Carmen; García‐Martínez, Virginio; Gutiérrez‐Merino, Carlos

doi:10.3109/1354750x.2014.885084

Cited by 26 publications

(15 citation statements)

References 77 publications

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“…In particular, depletion of ROS reverses the EndMT process in HAECs [44]. LIPUS has been documented to reduce ROS accumulation via protein kinase A-mediated inhibition of NAD(P)H oxidases [45]. In agreement with these findings, we demonstrated here that LIPUS suppressed EndMT primarily via its anti-oxidant action, which represents the first to identify the cytoprotective effects of LIPUS against oxidative stress-induced arterial endothelium injuries.…”

Section: Discussionsupporting

confidence: 79%

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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Background/Aims: Endothelial-mesenchymal transition (EndMT) has been shown to take part in the generation and progression of diverse diseases, involving a series of changes leading to a loss of their endothelial characteristics and an acquirement of properties typical of mesenchymal cells. Low-intensity pulsed ultrasound (LIPUS) is a new therapeutic option that has been successfully used in fracture healing. However, whether LIPUS can inhibit oxidative stress-induced endothelial cell damages through inhibiting EndMT remained unknown. This study aimed to investigate the protective effects of LIPUS against oxidative stress-induced endothelial cell damages and the underlying mechanisms. Methods: EndMT was induced by H₂O₂ (100 µm for seven days). Human aortic endothelial cells (HAECs) were exposed to H₂O₂ with or without LIPUS treatment for seven days. The expression of EndMT markers (CD31, VE-cadherin, FSP1 and α-SMA) were analyzed. The levels of total and phosphorylated PI3K and AKT proteins were detected by Western Blot analysis. Cell chemotaxis was determined by wound healing and transwell assay. Results: LIPUS relieved EndMT by decreasing ROS accumulation and increasing activation of the PI3K signaling cascade. LIPUS alleviated the migration of EndMT-derived mesenchymal-like cells through reducing extracellular matrix (ECM) deposition that is associated with matrix metallopeptidase (MMP) proteolytic activity and collagen production. Conclusion: LIPUS produces cytoprotective effects against oxidative injuries to endothelial cells through suppressing the oxidative stress-induced EndMT, activating the PI3K/AKT pathway under oxidative stress, and limiting cell migration and excessive ECM deposition.

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Section: Discussionsupporting

confidence: 79%

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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“…Peroxidase activity was measured by the Amplex Red assay as used in previous works by our laboratory . In a previous work, we found that epicatechin, quercetin, kaempferol, apigenin, and naringenin do not interfere with the Amplex Red assay and have no significant effect on the response to H 2 O 2 as assessed with calibration curves in the absence and in the presence of the flavonoids .…”

Section: Resultsmentioning

confidence: 99%

“…Cardiolipin‐induced peroxidase activity of Cyt c was measured by the Amplex Red assay adapting the procedures followed by other authors and in previous works from our laboratory . Cyt c (1 μM) was mixed with lipid vesicles (PC or PC/CL SUV) at a concentration of 100 μM, for 5 min at 37°C, and oxidation of Amplex Red (5 μM) to the fluorescent product resorufin was initiated with 25 μM H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

Correlation between the potency of flavonoids for cytochrome c reduction and inhibition of cardiolipin‐induced peroxidase activity

2017

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There are large differences between flavonoids to protect against apoptosis, a process in which cytochrome c (Cyt c) plays a key role. In this work, we show that 7 of 13 flavonoids studied have a capacity to reduce Cyt c similar or higher than ascorbate, the flavonols quercetin, kaempferol and myricetin, flavanol epigallocatechin-gallate, anthocyanidins cyanidin and malvidin, and the flavone luteolin. In contrast, the kaempferol 3(O)- and 3,4'(O)-methylated forms, the flavanone naringenin, and also apigenin and chrysin, had a negligible reducing capacity. Equilibrium dialysis and quenching of 1,6-diphenyl-1,3,5-hexatriene fluorescence experiments showed that flavonoids did not interfere with Cyt c binding to cardiolipin (CL)/phosphatidylcholine (PC) vesicles. However, the CL-induced loss of Cyt c Soret band intensity was largely attenuated by flavonoids, pointing out a stabilizing action against Cyt c unfolding in the complex. Moreover, flavonoids that behave as Cyt c reductants also inhibited the pro-apoptotic CL-induced peroxidase activity of Cyt c, indicating that modulation of Cyt c signaling are probable mechanisms behind the protective biological activities of flavonoids. © 2016 BioFactors, 43(3):451-468, 2017.

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“…It has been recognized that DOX-induced cardiotoxicity is also characterized by excessive intracellular ROS production [ 25 ]. ROS mediates cell apoptosis via multiple mechanisms such as impairing membrane integrity and causing mitochondrial damage.…”

Section: Discussionmentioning

confidence: 99%

Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity

et al. 2017

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BackgroundAnthracyclines-induced cardiotoxicity has become one of the major restrictions of their clinical applications. Klotho showed cardioprotective effects. This study aimed to investigate the effects and possible mechanisms of klotho on doxorubicin (DOX)-induced cardiotoxicity.Material/MethodsRats and isolated myocytes were exposed to DOX and treated with exogenous klotho. Specific inhibitors and siRNAs silencing MAPKs were also used to treat the animals and/or myocytes. An invasive hemodynamic method was used to determine cardiac functions. Intracellular ROS generation was evaluated by DHE staining. Western blotting was used to determine the phosphorylation levels of JNK, ERK, and p38 MAPKs in plasma extracts and Nrf2 in nuclear extracts. Nuclear translocation of Nrf2 in myocytes was evaluated by immunohistochemistry. Cell apoptosis was evaluated by TUNEL assay and flow cytometry.ResultsKlotho treatment improved DOX-induced cardiac dysfunction in rats. The DOX-induced ROS accumulation and cardiac apoptosis were attenuated by klotho. Impaired phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also attenuated by klotho treatment. However, the anti-oxidant and anti-apoptotic effects of klotho on DOX-exposed myocardium and myocytes were impaired by both specific inhibitors and siRNAs against MAPKs. Moreover, the recovery effects of klotho on phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also impaired by specific inhibitors and siRNAs against MAPKs.ConclusionsBy recovering the activation of MAPKs signaling, klotho improved cardiac function loss which was triggered by DOX-induced ROS mediated cardiac apoptosis.

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The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

Cited by 26 publications

References 77 publications

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

Correlation between the potency of flavonoids for cytochrome c reduction and inhibition of cardiolipin‐induced peroxidase activity

Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity

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