Carvacrol Induces Candida albicans Apoptosis Associated With Ca2+/Calcineurin Pathway.

Chao Niu,Jianhua Cheng,Ke Xu,Jian Zhang,Maoping Chu,Yijia Yang,Ruiyao Chen,Yingzhi Zhuge,Jingqi Li,Chang Jia,Haiyan Chen,Chunxiang Zhang,Chenglu Wang,Chunhua Ren

doi:10.3389/fcimb.2020.00192

Abstract

As the prevalence of systemic fungal infections caused by Candida albicans gradually increases, it is necessary to explore potential and effective antifungals. Carvacrol is reported to be lethally toxic to C. albicans, involving several potential mechanisms. However, the form and specific mechanism of cell death caused by this compound has not been delineated. In this study, we found that carvacrol could significantly decrease C. albicans survival rates, consistent with previous researches. Further examination proved that carvacrol treatment caused cell membrane permeability and depolarization. To elucidate the association between cell death and apoptosis, DNA fragmentation and metacaspase activation were determined; as expected, these two apoptosis-related markers were clearly observed. Moreover, total and mitochondrial reactive oxygen species (ROS) levels were elevated, and both mitochondrial transmembrane potential and morphology were disrupted. Additionally, cytosolic and mitochondrial calcium levels were also increased by carvacrol. Calcineurin inhibition experiments revealed cyclosporine A (CsA) addition notably rescued cell growth and inhibited metacaspase activation, indicating that carvacrol triggered C. albicans apoptosis through inducing calcineurin activation. Carvacrol was demonstrated to both have low toxicity and be effective in alleviating systemic infections with C. albicans, which might be via its antifungal and immunomodulation activities. This study suggests that carvacrol has excellent potential as a natural protective compound against C. albicans infections.

Highlights

Candida albicans can lead to both topical epithelial and fatal invasive infections in immunocompromised patients, contributing to its status as the fourth most common cause of nosocomial blood-stream infections in US hospitals (Klepser, 2006)
The mechanism of its action has been delineated to some extent, some aspects have remained unclear, such as the form and specific mechanism of cell death in C. albicans caused by carvacrol
We found that carvacrol could trigger C. albicans apoptosis as well as cause membrane disruption

Summary

INTRODUCTION

Candida albicans can lead to both topical epithelial and fatal invasive infections in immunocompromised patients, contributing to its status as the fourth most common cause of nosocomial blood-stream infections in US hospitals (Klepser, 2006). A monoterpene phenol, is major component of essential oil extracts from plants in the family Lamiaceae including oregano (Origanum vulgare L.) and marjoram (Origanum marjoram L.) (Nunes Wolffenbuttel et al, 2015) This phytomolecule in low concentration is considered safe for humans and it is commonly applied as a flavoring agent (Suntres et al, 2015). This compound has extensively demonstrated pharmacological properties, including antifungal and antibacterial activities, and immunoregulatory potential (Wieten et al, 2010). The antifungal effect and immunoregulation activity of carvacrol were determined in a murine model of C. albicans infection.

MATERIALS AND METHODS

Evaluation of Immunomodulatory Effect of Carvacrol

RESULTS

DISCUSSION

ETHICS STATEMENT