Butin (7,3′,4′-Trihydroxydihydroflavone) Reduces Oxidative Stress-Induced Cell Death via Inhibition of the Mitochondria-Dependent Apoptotic Pathway

Abstract

Recently, we demonstrated that butin (7,3′,4′-trihydroxydihydroflavone) protected cells against hydrogen peroxide (H2O2)-induced apoptosis by: (1) scavenging reactive oxygen species (ROS), activating antioxidant enzymes such superoxide dismutase and catalase; (2) decreasing oxidative stress-induced 8-hydroxy-2′-deoxyguanosine levels via activation of oxoguanine glycosylase 1, and (3), reducing oxidative stress-induced mitochondrial dysfunction. The objective of this study was to determine the cytoprotective effects of butin on oxidative stress-induced mitochondria-dependent apoptosis, and possible mechanisms involved. Butin significantly reduced H2O2-induced loss of mitochondrial membrane potential as determined by confocal image analysis and flow cytometry, alterations in Bcl-2 family proteins such as decrease in Bcl-2 expression and increase in Bax and phospho Bcl-2 expression, release of cytochrome c from mitochondria into the cytosol and activation of caspases 9 and 3. Furthermore, the anti-apoptotic effect of butin was exerted via inhibition of mitogen-activated protein kinase kinase-4, c-Jun NH2-terminal kinase (JNK) and activator protein-1 cascades induced by H2O2 treatment. Finally, butin exhibited protective effects against H2O2-induced apoptosis, as demonstrated by decreased apoptotic bodies, sub-G1 hypodiploid cells and DNA fragmentation. Taken together, the protective effects of butin against H2O2-induced apoptosis were exerted via blockade of membrane potential depolarization, inhibition of the JNK pathway and mitochondria-involved caspase-dependent apoptotic pathway.

The cytoprotective effect of butin against oxidative stress is mediated by the up‐regulation of manganese superoxide dismutase expression through a PI3K/Akt/Nrf2‐dependent pathway

“…These compounds usually contain aromatic hydroxyl groups that are responsible for the antioxidant activities of flavonoids [van Acker et al, 2000]. Recently, we demonstrated that butin protected cells against H 2 O 2 -induced apoptosis by scavenging ROS and activating antioxidant enzymes, by activating the PI3K/Akt/ oxoguanine glycosylase 1 pathway and by inhibiting mitochondrial dysfunction [Zhang et al, 2008[Zhang et al, , 2010[Zhang et al, , 2011Kang et al, 2009a]. In the present study, we demonstrated that butin modulated Mn SOD induction via the PI3K/Akt/Nrf2 pathway.…”

“…Recently, much attention has been focused on the potential uses of flavonoid-based drugs for the prevention and therapy of free radical-mediated human diseases, such as atherosclerosis, ischemia, inflammation, neuronal degeneration, and cardiovascular diseases [van Acker et al, 2000]. Recently, we demonstrated that butin protected cells against H 2 O 2 -induced damage [Zhang et al, 2008], protected DNA against oxidative damage [Kang et al, 2009a], and reduced oxidative stress-induced mitochondrial dysfunction and mitochondria-dependent apoptosis [Zhang et al, 2010[Zhang et al, , 2011. Butin (7,3 0 ,4 0 -trihydroxydihydroflavone) has been isolated from several medicinal herbs, such as Dalbergia odorifera, Adenanthera pavanina, and Vernonia anthelmintica Willd [Tian et al, 2004;Liu et al, 2005;Su et al, 2007], and is reported to possess biological properties such as skin-whitening and contraception [Bhargava, 1986;Lee et al, 2006].…”

“…Butin (7,3 0 ,4 0 -trihydroxydihydroflavone) has been isolated from several medicinal herbs, such as Dalbergia odorifera, Adenanthera pavanina, and Vernonia anthelmintica Willd [Tian et al, 2004;Liu et al, 2005;Su et al, 2007], and is reported to possess biological properties such as skin-whitening and contraception [Bhargava, 1986;Lee et al, 2006]. Recently, we demonstrated that butin protected cells against H 2 O 2 -induced damage [Zhang et al, 2008], protected DNA against oxidative damage [Kang et al, 2009a], and reduced oxidative stress-induced mitochondrial dysfunction and mitochondria-dependent apoptosis [Zhang et al, 2010[Zhang et al, , 2011. To the best of our knowledge, few studies have investigated the mechanism underlying the protective properties of butin in mitochondria.…”

Vitamin K4 inhibits the proliferation and induces apoptosis of U2OS osteosarcoma cells via mitochondrial dysfunction

“…It is well established that the mitochondria serve key roles in the regulation of cell death and proliferation through the production of ROS (14,25). Mitochondrial apoptosis is associated with ROS production and MMP dissipation (26). In the present study, VK4 increased ROS generation and decreased the MMP in U2OS cells in a dose-dependent manner.…”

Phytochemical profile, antioxidant and cytotoxic potential of Parkinsonia aculeata L. growing in Saudi Arabia

“…Estimation was based on IC 50 values as follows: IC 50 ≤ 20 μg/mL, highly active; IC 50 = 21–200 μg/mL, moderately active; IC5 0 = 201–500 μg/mL, weakly active; and IC 50 > 501 μg/mL, inactive, which is in a good accordance with the American National Cancer Institute protocol ( Al-Yousef et al, 2020 )The results showed that PAE possesses a moderate cytotoxic activity with IC 50 = 56.9 ± 3.1 and 95.8 ± 3.8 µg/mL for HepG-2 and MCF-7cell lines compared to cisplatin with IC 50 = 3.67 ± 0.22 and 5.71 ± 0.57 μg/ml, respectively. PAE activity may be attributed to the presence of vitexin ( He et al, 2016 ), homoplantaginin ( Genc et al, 2020 ), orientin ( Lam et al, 2016 ) and butin (3′,4′,7-trihydroxyflavanone) ( Zhang et al, 2011 ). During this work, vitexin, orientin, homoplantaginin, and butin were detected in LC-MS analysis of ethyl acetate fraction as major compounds.…”