Abstract
Coumarin (1,2-benzopyrone), an aromatic oxygen-containing heterocyclic compound, has various biological functions. Previous studies have demonstrated that coumarin and its derivatives exhibit antifungal activity against Candida albicans. In this study, we investigated the exact mechanism by which coumarin works against this fungus using Annexin V-FITC/PI double staining, TUNEL assay, and DAPI staining, and found that it induced a series of apoptotic features, including phosphatidylserine (PS) externalization, DNA fragmentation, and nuclear condensation. Moreover, it also induced cytochrome c release from the mitochondria to the cytoplasm and metacaspase activation. Further study revealed that intracellular reactive oxygen species (ROS) levels were increased and mitochondrial functions, such as mitochondrial membrane potential and mitochondrial morphology, were altered after treatment with coumarin. Cytosolic and mitochondrial Ca2+ levels were also found to be elevated. However, pretreatment with ruthenium red (RR), a known mitochondrial Ca2+ channel inhibitor, attenuated coumarin-mediated DNA fragmentation and metacaspase activity, indicating that the coumarin-induced C. albicans apoptosis is associated with mitochondrial Ca2+ influx. Finally, coumarin was found to be low-toxic and effective in prolonging the survival of C. albicans-infected mice. This study highlights the antifungal activity and mechanism of coumarin against C. albicans and provides a potential treatment strategy for C. albicans infection.
Highlights
Candida albicans is a commensal fungus that normally inhabits the human gastrointestinal tract and skin
To evaluate whether the decreased growth was related to cell death, the survival of the strains was examined after pretreatment with coumarin for 4 h
Inhibition of the mitochondrial Ca2+ influx remarkably decreased DNA fragmentation and metacaspase activity (Figures 6A,B and Figures S3, S4). These results demonstrated that coumarin-induced C. albicans apoptosis was relevant to elevated mitochondrial Ca2+ levels
Summary
Candida albicans is a commensal fungus that normally inhabits the human gastrointestinal tract and skin. In individuals who are immunocompromised due to AIDS or cancer chemotherapy, C. albicans can cause severe mucosal infections as well as fatal invasive infections (Ganguly and Mitchell, 2011). In the USA, fungal bloodstream infections caused by Candida spp. rank fourth among the nosocomial infections with considerable mortality rates (Edmond et al, 1999; Wisplinghoff et al, 2004). The presently used antifungal drugs mainly include azoles, polyenes, allylamines, echinocandins, and 5-fluorocytosine. With the large-scale application of broad-spectrum antifungal agents, the prevalence of opportunistic pathogen infections has Coumarin Triggers Apoptosis gradually increased. Exploring novel and more effective antifungals is required to cope with lethal candidiasis
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