journal article Open Access Jan 18, 2022

Therapeutic Potential of Perillaldehyde in Ameliorating Vulvovaginal Candidiasis by Reducing Vaginal Oxidative Stress and Apoptosis

Antioxidants Vol. 11 No. 2 pp. 178 · MDPI AG
View at Publisher Save 10.3390/antiox11020178
Abstract
Vulvovaginal candidiasis (VVC) is one of the most frequent diseases induced by Candida albicans (C. albicans) during pregnancy, which results in enormous pain to women and their partners in daily life. Perillaldehyde (PAE), a natural monoterpenoid, has significant anti-microbial, anti-inflammatory and anti-oxidation effects. Reactive oxygen species (ROS) are key factors for the host to resist the invasion of fungi. However, excess ROS can cause additional damage independent of the pathogen itself, and the mechanism of ROS in VVC has not been investigated. In this murine study, we revealed that C. albicans infection increased the expression of NADPH oxidase 2 (NOX2) and the content of malonaldehyde (MDA). C. albicans inhibited the activity of antioxidant enzymes in the vagina, including superoxide dismutase (SOD), Catalase (CAT), glutathione peroxidase (GSH-PX) and heme oxygenase (HO-1), which were returned to normal levels after treatment with PAE. Furthermore, PAE inhibited the activities of Keap1 and promoted Nrf2 transfer from cytoplasm to nucleus, which were mediated by excessive accumulation of ROS in the VVC mice. In this study, we also indicated that PAE inhibited the apoptosis of vagina cells via Caspase 9- Caspase 7-PARP pathway and prevented the release of IL-1ꞵ in VVC mice. In summary, this study revealed that the treatment of VVC in mice with PAE might be mediated by inhibition of ROS, and established the therapeutic potential of PAE as an antifungal agent for the treatment of VVC.
Topics

No keywords indexed for this article. Browse by subject →

References
61
[1]
Peters, B.M., Yano, J., Noverr, M.C., and Fidel, P.L. (2014). Candida vaginitis: When opportunism knocks, the host responds. PLoS Pathog., 10. 10.1371/journal.ppat.1003965
[2]
Sobel "Vaginitis" N. Engl. J. Med. (1997) 10.1056/nejm199712253372607
[3]
Hong "Vulvovaginal candidiasis as a chronic disease: Diagnostic criteria and definition" J. Low. Genit. Tract. Dis. (2014) 10.1097/lgt.0b013e318287aced
[4]
Sobel "Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis" N. Engl. J. Med. (2004) 10.1056/nejmoa033114
[5]
Denning "Global burden of recurrent vulvovaginal candidiasis: A systematic review" Lancet Infect. Dis. (2018) 10.1016/s1473-3099(18)30103-8
[6]
Fidel "History and update on host defense against vaginal candidiasis" Am. J. Reprod. Immunol. (2007) 10.1111/j.1600-0897.2006.00450.x
[7]
Yano "Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins" Cytokine (2012) 10.1016/j.cyto.2011.11.021
[8]
Warnatsch "Reactive oxygen species localization programs inflammation to clear microbes of different size" Immunity (2017) 10.1016/j.immuni.2017.02.013
[9]
Chen "Cinnamaldehyde inhibits Candida albicans growth by causing apoptosis and its treatment on vulvovaginal candidiasis and oropharyngeal candidiasis" Appl. Microbiol. Biotechnol. (2019) 10.1007/s00253-019-10119-3
[10]
Qu "Cinnamaldehyde, a promising natural preservative against Aspergillus flavus" Front. Microbiol. (2019) 10.3389/fmicb.2019.02895
[11]
Tian "Regional variation in components and antioxidant and antifungal activities of Perilla frutescens essential oils in China" Ind. Crop Prod. (2014) 10.1016/j.indcrop.2014.04.048
[12]
Tian "Calcium and oxidative stress mediate perillaldehyde-induced apoptosis in Candida albicans" Appl. Microbiol. Biotechnol. (2017) 10.1007/s00253-017-8146-3
[13]
Qu "Effect of perillaldehyde on prophylaxis and treatment of vaginal candidiasis in a murine model" Front. Microbiol. (2019) 10.3389/fmicb.2019.01466
[14]
Chen "Perillaldehyde: A promising antifungal agent to treat oropharyngeal candidiasis" Biochem. Pharmacol. (2020) 10.1016/j.bcp.2020.114201
[15]
Erhunmwunsee, F., Pan, C., Yang, K., Li, Y., Liu, M., and Tian, J. (2021). Recent development in biological activities and safety concerns of perillaldehyde from perilla plants: A review. Crit. Rev. Food Sci. Nutr., 1–13. 10.1080/10408398.2021.1900060
[16]
Krist "Antimicrobial effect of vapours of terpineol, (R)-(-)-linalool, carvacrol, (S)-(-)-perillaldehyde and 1,8-cineole on airborne microbes using a room diffuser" Flavour Frag. J. (2008) 10.1002/ffj.1893
[17]
Tian "Perillaldehyde, a promising antifungal agent used in food preservation, triggers apoptosis through a metacaspase-dependent pathway in Aspergillus flavus" J. Agric. Food Chem. (2016) 10.1021/acs.jafc.6b03546
[18]
Tian "Efficacy and possible mechanisms of perillaldehyde in control of Aspergillus niger causing grape decay" Int. J. Food Microbiol. (2015) 10.1016/j.ijfoodmicro.2015.02.022
[19]
Tian "Induced cell death in Ceratocystis fimbriata by pro-apoptotic activity of a natural organic compound, perillaldehyde, through Ca2+ overload and accumulation of reactive oxygen species" Plant Pathol. (2019) 10.1111/ppa.12937
[20]
Keesen "Anti-Leishmania and cytotoxic activities of perillaldehyde epoxide synthetic positional isomers" Nat. Prod. Res. (2019) 10.1080/14786419.2018.1448813
[21]
Hobbs "Genotoxicity assessment of the flavouring agent, perillaldehyde" Food Chem. Toxicol. (2016) 10.1016/j.fct.2016.08.029
[22]
Song "Perilla aldehyde attenuates CUMS-induced depressive-like behaviors via regulating TXNIP/TRX/NLRP3 pathway in rats" Life Sci. (2018) 10.1016/j.lfs.2018.05.038
[23]
Uemura "Intestinal anti-inflammatory activity of perillaldehyde" J. Agric. Food Chem. (2018) 10.1021/acs.jafc.8b00353
[24]
Fuyuno "Perillaldehyde inhibits AHR signaling and activates NRF2 antioxidant pathway in human keratinocytes" Oxid. Med. Cell Longev. (2018) 10.1155/2018/9524657
[25]
Jha "Multiple drug targeting potential of novel ligands against virulent proteins of Candida albicans" Int. J. Pept. Res. Ther. (2020) 10.1007/s10989-019-09897-1
[26]
Broz "Inflammasomes: Mechanism of assembly, regulation and signalling" Nat. Rev. Immunol. (2016) 10.1038/nri.2016.58
[27]
Munoz "Antifungal activity of the biphosphinic cyclopalladate C7a against Candida albicans yeast forms in vitro and in vivo" Front. Microbiol. (2017) 10.3389/fmicb.2017.00771
[28]
Kaur "Developments of polysorbate (tween) based microemulsions: Preclinical drug delivery, toxicity and antimicrobial applications" Int. J. Pharm. (2017) 10.1016/j.ijpharm.2017.06.059
[29]
Kogan "Microemulsions as transdermal drug delivery vehicles" Adv. Colloid. Interface Sci. (2006) 10.1016/j.cis.2006.05.014
[30]
Iguchi "Growth of normal mouse vaginal epithelial cells in and on collagen gels" Proc. Natl. Acad. Sci. USA (1983) 10.1073/pnas.80.12.3743
[31]
Indran "Recent advances in apoptosis, mitochondria and drug resistance in cancer cells" Biochim. Biophys. Acta (2011) 10.1016/j.bbabio.2011.03.010
[32]
Fang "Free radicals, antioxidants, and nutrition" Nutrition (2002) 10.1016/s0899-9007(02)00916-4
[33]
Kurata "Antioxidant systems and erythrocyte life-span in mammals" Comp. Biochem. Physiol. B (1993) 10.1016/0305-0491(93)90121-k
[34]
Ando "Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress" J. Immunol. (2008) 10.4049/jimmunol.181.12.8382
[35]
Kirkman "Mammalian catalase: A venerable enzyme with new mysteries" Trends Biochem. Sci. (2007) 10.1016/j.tibs.2006.11.003
[36]
Somwar "Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines" Proc. Natl. Acad. Sci. USA (2011) 10.1073/pnas.1113554108
[37]
Abraham "Pharmacological and clinical aspects of heme oxygenase" Pharmacol. Rev. (2008) 10.1124/pr.107.07104
[38]
Forte "The pathophysiological role of NOX2 in hypertension and organ damage" High Blood Press Cardiovasc. Prev. (2016) 10.1007/s40292-016-0175-y
[39]
Stewart "A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress" Nutr. Metab. Cardiovasc. Dis. (2005) 10.1016/j.numecd.2005.05.003
[40]
Amoutzias, G.D., Bornberg-Bauer, E., Oliver, S.G., and Robertson, D.L. (2006). Reduction/oxidation-phosphorylation control of DNA binding in the bZIP dimerization network. BMC Genom., 7. 10.1186/1471-2164-7-107
[41]
Cullinan "The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: Oxidative stress sensing by a Cul3-Keap1 ligase" Mol. Cell Biol. (2004) 10.1128/mcb.24.19.8477-8486.2004
[42]
Bhola "Mitochondria-judges and executioners of cell death sentences" Mol. Cell (2016) 10.1016/j.molcel.2016.02.019
[43]
Burke "Mitochondria, bioenergetics and apoptosis in cancer" Trends Cancer (2017) 10.1016/j.trecan.2017.10.006
[44]
Wei "Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death" Science (2001) 10.1126/science.1059108
[45]
Murphy "Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells" Cell Death Differ. (2000) 10.1038/sj.cdd.4400597
[46]
Tewari "Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase" Cell (1995) 10.1016/0092-8674(95)90541-3
[47]
Nicholson "Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis" Nature (1995) 10.1038/376037a0
[48]
Li "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade" Cell (1997) 10.1016/s0092-8674(00)80434-1
[49]
Inflammasomes: mechanism of action, role in disease, and therapeutics

Haitao Guo, Justin B Callaway, Jenny P-Y Ting

Nature Medicine 2015 10.1038/nm.3893
[50]
Shadel "Mitochondrial ROS signaling in organismal homeostasis" Cell (2015) 10.1016/j.cell.2015.10.001

Showing 50 of 61 references

Cited By
17