Abstract
ObjectiveTo investigate the effects of honokiol on induction of reactive oxygen species (ROS), antioxidant defense systems, mitochondrial dysfunction, and apoptosis in Candida albicans.MethodsTo measure ROS accumulation, 2′,7′-dichlorofluorescein diacetate fluorescence was used. Lipid peroxidation was assessed using both fluorescence staining and a thiobarbituric acid reactive substances (TBARS) assay. Protein oxidation was determined using dinitrophenylhydrazine derivatization. Antioxidant enzymatic activities were measured using commercially available detection kits. Superoxide dismutase (SOD) genes expression was measured using real time RT-PCR. To assess its antifungal abilities and effectiveness on ROS accumulation, honokiol and the SOD inhibitor N,N′-diethyldithiocarbamate (DDC) were used simultaneously. Mitochondrial dysfunction was assessed by measuring the mitochondrial membrane potential (mtΔψ). Honokiol-induced apoptosis was assessed using an Annexin V-FITC apoptosis detection kit.ResultsROS, lipid peroxidation, and protein oxidation occurred in a dose-dependent manner in C. albicans after honokiol treatment. Honokiol caused an increase in antioxidant enzymatic activity. In addition, honokiol treatment induced SOD genes expression in C. albicans cells. Moreover, addition of DDC resulted in increased endogenous ROS levels and potentiated the antifungal activity of honokiol. Mitochondrial dysfunction was confirmed by measured changes to mtΔψ. The level of apoptosis increased in a dose-dependent manner after honokiol treatment.ConclusionsCollectively, these results indicate that honokiol acts as a pro-oxidant in C. albicans. Furthermore, the SOD inhibitor DDC can be used to potentiate the activity of honokiol against C. albicans.
Highlights
Most fungal infections in immunocompromised individuals are induced by Candida albicans, an opportunistic fungal pathogens [1,2]
reactive oxygen species (ROS), lipid peroxidation, and protein oxidation occurred in a dose-dependent manner in C. albicans after honokiol treatment
Honokiol induces reactive oxygen species generation. These results indicate that honokiol acts as a pro-oxidant in C. albicans
Summary
Most fungal infections in immunocompromised individuals are induced by Candida albicans, an opportunistic fungal pathogens [1,2]. Treating C. albicans infections can be difficult, as there are only a few available classes of antifungals, including echinocandins, polyenes, and azoles [3]. This coupled with increased incidence of candidiasis as well as the rise in drug resistance in C. albicans, makes the development of novel and effective antifungal agents critically important [3,4]. A common fungicidal mechanism employed by most antifungal drugs involves the production of reactive oxygen species (ROS), such as superoxide anion radicals and hydrogen peroxide [5] To this end, mitochondria play important roles in energy production, the synthesis of key metabolites, apoptosis regulation, calcium buffering, and in the generation of endogenous reactive oxygen species [6]. SOD1, SOD4, SOD5, and SOD6 are Cu, Zn-containing SOD which can be inhibited by the Cu, Zn-SOD inhibitor N,N0-diethyldithiocarbamate (DDC) [9]
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