Abstract
Herba Cynomorii (Cynomorium songaricum Rupr., Cynomoriaceae) is one of the most commonly used ‘Yang-invigorating’ tonic herbs in Traditional Chinese Medicine (TCM). An earlier study in our laboratory has demonstrated that HCY2, an ursolic acid-enriched fraction derived from Herba Cynomorii, increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, thereby protecting against oxidant injury in H9c2 cells. In this study, we demonstrated that pre-incubation of H9c2 cells with HCY2 increased mitochondrial reactive oxygen species (ROS) generation in these cells, which is likely an event secondary to the stimulation of the mitochondrial electron transport chain. The suppression of mitochondrial ROS by the antioxidant dimethylthiourea abrogated the HCY2-induced enhancement of mitochondrial uncoupling and glutathione reductase (GR)-mediated glutathione redox cycling, and also protected against menadione-induced cytotoxicity. Studies using specific inhibitors of uncoupling protein and GR suggested that the HCY2-induced mitochondrial uncoupling and glutathione redox cycling play a determining role in the cytoprotection against menadione-induced oxidant injury in H9c2 cells. Experimental evidence obtained thus far supports the causal role of HCY2-induced mitochondrial ROS production in eliciting mitochondrial uncoupling and glutathione antioxidant responses, which offer cytoprotection against oxidant injury in H9c2 cells.
Highlights
The mitochondrion serves as a platform for cellular energy metabolism as well as signal transduction pathways relevant to the regulation of cell survival and death [1]
A previous study in our laboratory has demonstrated that HCY2, an ursolic acid (UA) -enriched fraction derived from Herba Cynomorii increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, resulting in protection against oxidant injury in H9c2 cells [9]
We examined the effect of HCY2 on mitochondrial reactive oxygen species (ROS) production and provided evidence for the supporting the role of mitochondrial
Summary
The mitochondrion serves as a platform for cellular energy metabolism as well as signal transduction pathways relevant to the regulation of cell survival and death [1]. A previous study in our laboratory has demonstrated that HCY2, an ursolic acid (UA) -enriched fraction derived from Herba Cynomorii increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, resulting in protection against oxidant injury in H9c2 cells [9]. The increased formation of ROS within mitochondria would further trigger cellular responses, including mitochondrial uncoupling and glutathione redox cycling [13], with resultant protection against oxidant injury. To test this hypothesis, we examined the effect of HCY2 on mitochondrial ROS production and provided evidence for the supporting the role of mitochondrial. The effects of an antioxidant and specific inhibitors of uncoupling protein (UCP) and glutathione reductase (GR), an enzyme for catalyzing the regeneration of reduced glutathione (GSH) from oxidized glutathione (GSSG), on HCY2-induced protection against menadione-induced cytotoxicity were investigated
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