Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade

This study investigates the endothelial protective activity of flavokawain A (FKA) against oxidative stress induced by ochratoxin A (OTA), which acts as a mycotoxin, and its primary mechanisms in in vitro models. Reactive oxygen species, in general, regulate oxidative stress that significantly contr...

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Autores principales:	Peramaiyan Rajendran, Abdullah M. Alzahrani, Vishnu Priya Veeraraghavan, Emad A. Ahmed
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	flavokawain A ochratoxin A oxidative stress apoptosis Nrf2 Medicine R
Acceso en línea:	https://doaj.org/article/176880142ab242aab8eeed9abb67e6b3
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spelling	oai:doaj.org-article:176880142ab242aab8eeed9abb67e6b32021-11-25T19:08:30ZAnti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade10.3390/toxins131107452072-6651https://doaj.org/article/176880142ab242aab8eeed9abb67e6b32021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6651/13/11/745https://doaj.org/toc/2072-6651This study investigates the endothelial protective activity of flavokawain A (FKA) against oxidative stress induced by ochratoxin A (OTA), which acts as a mycotoxin, and its primary mechanisms in in vitro models. Reactive oxygen species, in general, regulate oxidative stress that significantly contributes to the pathophysiology of endothelial dysfunctions. OTA exerts toxicity through inflammation and the accumulation of ROS. This research is aimed at exploring the defensive function of FKA against the endothelial injury triggered by OTA through the Nrf2 pathway regulated by PI3K/AKT. OTA exposure significantly increased the nuclear translocation of NFκB, whereas we found a reduction in inflammation via NFκB inhibition with FKA treatment. FKA increased the PI3K and AKT phosphorylation, which may lead to the stimulation of antioxidative and antiapoptotic signaling in HUVECs. It also upregulated the phosphorylation of Nrf2 and a concomitant expression of antioxidant genes, such as HO-1, NQO-1, and γGCLC, depending on the dose under the oxidative stress triggered by OTA. Knockdown of Nrf2 through small interfering RNA (siRNA) impedes the protective role of FKA against the endothelial toxicity induced by OTA. In addition, FKA enhanced Bcl2 activation while suppressing apoptosis marker proteins. Therefore, FKA is regarded as a potential agent against endothelial oxidative stress caused by the deterioration of the endothelium. The research findings showed that FKA plays a key role in activating the p-PI3K/p-AKT and Nrf2 signaling pathways, while suppressing caspase-dependent apoptosis.Peramaiyan RajendranAbdullah M. AlzahraniVishnu Priya VeeraraghavanEmad A. AhmedMDPI AGarticleflavokawain Aochratoxin Aoxidative stressapoptosisNrf2MedicineRENToxins, Vol 13, Iss 745, p 745 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	flavokawain A ochratoxin A oxidative stress apoptosis Nrf2 Medicine R
spellingShingle	flavokawain A ochratoxin A oxidative stress apoptosis Nrf2 Medicine R Peramaiyan Rajendran Abdullah M. Alzahrani Vishnu Priya Veeraraghavan Emad A. Ahmed Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
description	This study investigates the endothelial protective activity of flavokawain A (FKA) against oxidative stress induced by ochratoxin A (OTA), which acts as a mycotoxin, and its primary mechanisms in in vitro models. Reactive oxygen species, in general, regulate oxidative stress that significantly contributes to the pathophysiology of endothelial dysfunctions. OTA exerts toxicity through inflammation and the accumulation of ROS. This research is aimed at exploring the defensive function of FKA against the endothelial injury triggered by OTA through the Nrf2 pathway regulated by PI3K/AKT. OTA exposure significantly increased the nuclear translocation of NFκB, whereas we found a reduction in inflammation via NFκB inhibition with FKA treatment. FKA increased the PI3K and AKT phosphorylation, which may lead to the stimulation of antioxidative and antiapoptotic signaling in HUVECs. It also upregulated the phosphorylation of Nrf2 and a concomitant expression of antioxidant genes, such as HO-1, NQO-1, and γGCLC, depending on the dose under the oxidative stress triggered by OTA. Knockdown of Nrf2 through small interfering RNA (siRNA) impedes the protective role of FKA against the endothelial toxicity induced by OTA. In addition, FKA enhanced Bcl2 activation while suppressing apoptosis marker proteins. Therefore, FKA is regarded as a potential agent against endothelial oxidative stress caused by the deterioration of the endothelium. The research findings showed that FKA plays a key role in activating the p-PI3K/p-AKT and Nrf2 signaling pathways, while suppressing caspase-dependent apoptosis.
format	article
author	Peramaiyan Rajendran Abdullah M. Alzahrani Vishnu Priya Veeraraghavan Emad A. Ahmed
author_facet	Peramaiyan Rajendran Abdullah M. Alzahrani Vishnu Priya Veeraraghavan Emad A. Ahmed
author_sort	Peramaiyan Rajendran
title	Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
title_short	Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
title_full	Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
title_fullStr	Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
title_full_unstemmed	Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade
title_sort	anti-apoptotic effect of flavokawain a on ochratoxin-a-induced endothelial cell injury by attenuation of oxidative stress via pi3k/akt-mediated nrf2 signaling cascade
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/176880142ab242aab8eeed9abb67e6b3
work_keys_str_mv	AT peramaiyanrajendran antiapoptoticeffectofflavokawainaonochratoxinainducedendothelialcellinjurybyattenuationofoxidativestressviapi3kaktmediatednrf2signalingcascade AT abdullahmalzahrani antiapoptoticeffectofflavokawainaonochratoxinainducedendothelialcellinjurybyattenuationofoxidativestressviapi3kaktmediatednrf2signalingcascade AT vishnupriyaveeraraghavan antiapoptoticeffectofflavokawainaonochratoxinainducedendothelialcellinjurybyattenuationofoxidativestressviapi3kaktmediatednrf2signalingcascade AT emadaahmed antiapoptoticeffectofflavokawainaonochratoxinainducedendothelialcellinjurybyattenuationofoxidativestressviapi3kaktmediatednrf2signalingcascade
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Anti-Apoptotic Effect of Flavokawain A on Ochratoxin-A-Induced Endothelial Cell Injury by Attenuation of Oxidative Stress via PI3K/AKT-Mediated Nrf2 Signaling Cascade

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