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.
Highlights
Oxidative stress mediated by reactive oxygen species (ROS) has been implicated as a major cause of cellular damage and contributes to inflammation, aging, cancer, arteriosclerosis, hypertension and diabetes [1,2,3]
We have indicated that butin protected against H2O2-induced apoptosis [15]
H2O2 treatment induced a dramatical increase in Bcl-2-associated x protein (Bax) expression and decrease in B-cell lymphoma 2 (Bcl-2) expression, suggesting that changes in the pro-apoptotic and anti-apoptotic Bcl-2 family proteins may contribute to apoptosis
Summary
Oxidative stress mediated by reactive oxygen species (ROS) has been implicated as a major cause of cellular damage and contributes to inflammation, aging, cancer, arteriosclerosis, hypertension and diabetes [1,2,3]. Mitochondrial dysfunction results in increased ROS production that enhances oxidative stress if the cellular defense systems are overwhelmed [5]. Previous studies have indicated that ROS might alter intracellular redox states, change the inner mitochondrial membrane potential ( m) and release soluble inter-membrane proteins, including cytochrome c, from mitochondria into the cytosol [6,7]. It is well known that ROS plays a crucial role in triggering the mitochondria-mediated apoptotic pathway, which is associated with activation of the caspase cascade and the family of Bcl-2 proteins [8,9,10]
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