Research Article

*Author for correspondence:

Department of Environmental Engineering & Sciences Applied in Oral Health Graduate Program, São Paulo State University (Unesp), Institute of Science & Technology, São José dos Campos, São Paulo, 12245-000, Brazil

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Aline da Graça Sampaio

https://orcid.org/0000-0001-9453-3905

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Cristiane Yumi Koga-Ito‡

https://orcid.org/0000-0002-2416-2173

‡Authors contributed equally

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Angela Bruzzaniti‡

https://orcid.org/0000-0003-0389-4604

Department of Biomedical & Applied Sciences, Indiana University School of Dentistry, Indianapolis, IN 46202, USA

‡Authors contributed equally

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Published Online:17 Apr 2024https://doi.org/10.2217/fmb-2023-0188

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Abstract

Aim: To evaluate the behavior of oral keratinocytes in the presence of Vitamin C (Vit C) and its anti-inflammatory potential. Materials & methods: Oral keratinocytes were initially exposed to 0.1–2.5 mM of Vit C and the metabolic activity and cell migration were evaluated using MTS assay and Ibidi culture inserts, respectively. After, the cells were challenged with Candida albicans and inflammatory markers were analyzed by qPCR. Results: The treatment was not cytotoxic, and the highest concentrations increased the metabolic activity at 24 h. Vit C delayed the cell migration at 48 and 72 h. Interestingly, it downregulated the genes IL-8 and IL-1β. Conclusion: Vit C could be an interesting adjuvant to anti-fungal treatment due to its anti-inflammatory potential.

Plain language summary

Vitamin C, also known as ascorbic acid, is a vitamin commonly found in fruits and vegetables. It is popular for supporting our immune system, so is commonly taken as a supplement. We looked at the action of vitamin C on cells from the mouth and its potential to reduce inflammation in a fungal disease of the mouth – oral candidiasis. We showed that vitamin C is not toxic to cells of the mouth and may reduce inflammation in cells infected by the fungus. This suggests that vitamin C could be used as a complementary therapy for oral candidiasis.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Vila T, Sultan AS, Montelongo-Jauregui D, Jabra-Rizk MA. Oral candidiasis: a disease of opportunity. J. Fungi. 6(1), 1–28 (2020). • Interesting review about oral candidiasis.
Google Scholar
2. Singh A, Verma R, Murari A, Agrawal A. Oral candidiasis: an overview. J. Oral Maxillofac. Pathol. 18(Suppl. 1), S81–S85 (2014).
MedlineGoogle Scholar
3. Lewis MAO, Williams DW. Diagnosis and management of oral candidosis. Br. Dent. J. 223(9), 675–681 (2017).
Medline CASGoogle Scholar
4. Costa-de-oliveira S, Rodrigues AG. Candida albicans antifungal resistance and tolerance in bloodstream infections: the triad yeast-host-antifungal. Microorganisms 8(2), 154 (2020).
Medline CASGoogle Scholar
5. Fuentefria AM, Pippi B, Dalla Lana DF, Donato KK, de Andrade SF. Antifungals discovery: an insight into new strategies to combat antifungal resistance. Lett. Appl. Microbiol. 66(1), 2–13 (2018).
Medline CASGoogle Scholar
6. Al-Niaimi F, Chiang NYZ. Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications. J. Clin. Aesthet. Dermatol. 10(7), 14–17 (2017).
MedlineGoogle Scholar
7. Van Hauwenhuyse F, Fiori A, Van Dijck P. Ascorbic acid inhibition of candida albicans Hsp90-mediated morphogenesis occurs via the transcriptional regulator Upc2. Eukaryot Cell 13(10), 1278–1289 (2014). •• This study investigated Vitamin C mechanisms of action on Candida albicans strains.
MedlineGoogle Scholar
8. Ojha R, Manzoor N, Khan LA. Ascorbic acid modulates pathogenecity markers of Candida albicans. Int. J. Microbiol. Res. 1(1), 19–24 (2009). •• Interesting manuscript about Vitamin C modulatory effects on Candida albicans strains.
Google Scholar
9. Avci P, Freire F, Banvolgyi A, Mylonakis E, Wikonkal NM, Hamblin MR. Sodium ascorbate kills Candida albicans in vitro via iron-catalyzed Fenton reaction: importance of oxygenation and metabolism. Future Microbiol. 11(12), 1535–1547 (2016). •• Indicated that ascorbate may present antimicrobial effects against Candida albicans strains.
CASGoogle Scholar
10. Lee AJ, Lim JW, Kim H. Ascorbic acid suppresses house dust mite-induced expression of interleukin-8 in human respiratory epithelial cells. J. Cancer Prev. 26(1), 64–70 (2021). •• Demonstrated in a different model of infection that vitamin C may present an anti-inflammatory effect.
MedlineGoogle Scholar
11. Mohammed Ahmed Yussif N, Abdul-Waniss Mohammed Abdul-Aziz M, Reda Abdel Rahman A. Evaluation of the anti-inflammatory effect of locally delivered vitamin C in the treatment of persistent gingival inflammation: clinical and histopathological study. J. Nutr. Metab. 2016, 2978741 (2016).
MedlineGoogle Scholar
12. Jablonská E, Kubásek J, Vojtěch D, Ruml T, Lipov J. Test conditions can significantly affect the results of in vitro cytotoxicity testing of degradable metallic biomaterials. Sci. Rep. 11, 6628 (2021).
Medline CASGoogle Scholar
13. da Sampaio AG, Chiappim W, Milhan NVM, Botan Neto B, Pessoa R, Koga-Ito CY. Effect of the pH on the antibacterial potential and cytotoxicity of different plasma-activated liquids. Int. J. Mol. Sci. 23(22), 13893 (2022).
MedlineGoogle Scholar
14. Suarez-Arnedo A, Torres Figueroa F, Clavijo C, Arbeláez P, Cruz JC, Muñoz-Camargo C. An image J plugin for the high throughput image analysis of in vitro scratch wound healing assays. PLOS ONE 15(7), e0232565 (2020).
Medline CASGoogle Scholar
15. Vitale RG. Role of antifungal combinations in difficult to treat candida infections. J. Fungi. 7(9), 731 (2021).
CASGoogle Scholar
16. Böttger F, Vallés-Martí A, Cahn L, Jimenez CR. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer. J. Exp. Clin. Cancer Res. 40(1), 343 (2021).
Medline CASGoogle Scholar
17. Zylinska L, Lisek M, Guo F, Boczek T. Vitamin C modes of action in calcium-involved signaling in the brain. Antioxidants 12(2), 231 (2023).
Medline CASGoogle Scholar
18. Aytekin Z, Arabacı T, Toraman A, Bayır Y, Albayrak M, Üstün K. Immune modulatory and antioxidant effects of locally administrated vitamin C in experimental periodontitis in rats. Acta Odontol. Scand. 78(6), 425–432 (2020).
MedlineGoogle Scholar
19. Lu SY. Oral candidosis: pathophysiology and best practice for diagnosis, classification, and successful management. J. Fungi 7(7), 555 (2021).
CASGoogle Scholar
20. Tsukaguchi H, Tokui T, Mackenzie B et al. A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature 399(6731), 70–75 (1999).
Medline CASGoogle Scholar
21. Ghahremani-Nasab M, Del Bakhshayesh AR, Akbari-Gharalari N, Mehdipour A. Biomolecular and cellular effects in skin wound healing: the association between ascorbic acid and hypoxia-induced factor. J. Biol. Eng. 17(1), 62 (2023).
Medline CASGoogle Scholar
22. Cho S, Chae JS, Shin H et al. Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer cell lines according to SVCT-2 expression. Sci. Rep. 8(1), 11372 (2018).
MedlineGoogle Scholar
23. Castellano-Pellicena I, Thornton MJ. Isolation of epidermal keratinocytes from human skin: the scratch-wound assay for assessment of epidermal keratinocyte migration. Methods Mol. Biol. 2154, 1–12 (2020).
Medline CASGoogle Scholar
24. Chong WT, Tan CP, Cheah YK, Lai OM. In-vitro and in-vivo evaluations of tocotrienol-rich nanoemulsified system on skin wound healing. PLOS ONE 17(5), e0267381 (2022).
Medline CASGoogle Scholar
25. Chaitrakoonthong T, Ampornaramveth R, Kamolratanakul P. Rinsing with L-ascorbic acid exhibits concentration-dependent effects on human gingival fibroblast in vitro wound healing behavior. Int. J. Dent. 2020, 4706418 (2020).
MedlineGoogle Scholar
26. Yi Y, Wu M, Zhou X et al. Ascorbic acid 2-glucoside preconditioning enhances the ability of bone marrow mesenchymal stem cells in promoting wound healing. Stem Cell Res. Ther. 13(1), 119 (2022).
Medline CASGoogle Scholar
27. Savini I, Rossi A, Duranti G, Avigliano L, Catani MV, Melino G. Characterization of keratinocyte differentiation induced by ascorbic acid: protein kinase C involvement and vitamin C. J. Invest. Dermatol. 118(2), 372–379 (2002).
Medline CASGoogle Scholar
28. Egusa H, Nikawa H, Makihira S, Yatani H, Hamada T. In vitro mechanisms of interleukin-8-mediated responses of human gingival epithelial cells to Candida albicans infection. Int. J. Med. Microbiol. 296(4–5), 301–311 (2006).
Medline CASGoogle Scholar
29. Dongari-Bagtzoglou A, Kashleva H. Granulocyte-macrophage colony-stimulating factor responses of oral epithelial cells to Candida albicans. Oral Microbiol. Immunol. 18(3), 165–170 (2003).
Medline CASGoogle Scholar
30. Griffiths JS, Camilli G, Kotowicz NK, Ho J, Richardson JP, Naglik JR. Role for IL-1 family cytokines in fungal infections. Front Microbiol. 12, 633047 (2021).
MedlineGoogle Scholar
31. Gao Y, Liang G, Wang Q et al. Different host immunological response to C. albicans by human oral and vaginal epithelial cells. Mycopathologia 184(1), 1–12 (2019).
Medline CASGoogle Scholar
32. Kang JS, Kim HN, Jung DJ et al. Regulation of UVB-induced IL-8 and MCP-1 production in skin keratinocytes by increasing vitamin C uptake via the redistribution of SVCT-1 from the cytosol to the membrane. J. Invest. Dermatol. 127(3), 698–706 (2007).
Medline CASGoogle Scholar
33. Bowie AG, O'Neill LAJ. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol. 165(12), 7180–7188 (2000).
Medline CASGoogle Scholar
34. Gęgotek A, Skrzydlewska E. Antioxidative and anti-inflammatory activity of ascorbic acid. Antioxidants 11(10), 1993 (2022).
Medline CASGoogle Scholar
35. Ghalibaf MHE, Kianian F, Beigoli S et al. The effects of vitamin C on respiratory, allergic and immunological diseases: an experimental and clinical-based review. Inflammopharmacology 31(2), 653–672 (2023).
MedlineGoogle Scholar
36. Cárcamo JM, Bórquez-Ojeda O, Golde DW. Vitamin C inhibits granulocyte macrophage-colony-stimulating factor-induced signaling pathways. Blood 99(9), 3205–3212 (2002).
Medline CASGoogle Scholar
37. Chen Y, Luo G, Yuan J et al. Vitamin C Mitigates Oxidative Stress and Tumor Necrosis Factor-Alpha in Severe Community-Acquired Pneumonia and LPS-Induced Macrophages. Mediators Inflamm. 2014, 426740 (2014). •• In this study, a different model of infection was performed, in which vitamin C showed anti-inflammatory effect.
MedlineGoogle Scholar
38. Ness T, Abdallah M, Adams J et al. Candida albicans-derived mannoproteins activate NF-κB in reporter cells expressing TLR4, MD2 and CD14. PLOS ONE 12(12), e0189939 (2017).
MedlineGoogle Scholar
39. Lopes JP, Lionakis MS. Pathogenesis and virulence of Candida albicans. Virulence 13(1), 89–121 (2022).
Medline CASGoogle Scholar

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History

Received 22 August 2023

Accepted 8 December 2023

Published online 17 April 2024

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Financial disclosure

This work was supported by the São Paulo State Research Foundation (FAPESP) [2022/04598-7; 2022/04723-6; 2019/05856-7] and by funds from the Indiana University School of Dentistry. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

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Ascorbic acid as a modulator of inflammatory response against Candida albicans

Abstract

Plain language summary

Graphical abstract

References