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Inhibitory effect of berberine hydrochloride against Candida albicans and the role of the HOG-MAPK pathway

The Journal of Antibiotics volume 74, pages 807–816 (2021)Cite this article

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Abstract

Berberine hydrochloride (BH), an active component of Coptis chinensis and other plant taxa, has broad antimicrobial activity and may be useful for the treatment of Candida infections. In this study, the mechanisms underlying the inhibitory effect of BH against Candida albicans were evaluated, with a focus on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway, which regulates multiple physiological functions. BH (256 and 64 μg ml−1) significantly increased intracellular glycerol and ROS levels in C. albicans, inhibited germ tube and hyphal formation, and increased chitin and β−1,3-glucan exposure on the cell wall. The inhibitory effect of BH was positively correlated with its concentration, and the inhibitory effect of 256 μg ml−1 BH was greater than that of 4 μg ml−1 fluconazole (FLC). Furthermore, RT-PCR analysis showed that 256 and 64 μg ml−1 BH altered the HOG-MAPK pathway in C. albicans. In particular, the upregulation of the core genes, SLN1, SSK2, HOG1, and PBS2 may affect the expression of key downstream factors related to glycerol synthesis and osmotic pressure (GPD1), ROS accumulation (ATP11 and SOD2), germ tube and hyphal formation (HWP1), and cell wall integrity (CHS3 and GSC1). BH affects multiple biological processes in C. albicans; thus, it can be an effective alternative to conventional azole antifungal agents.

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References

  1. Rauseo AM, Coler-Reilly A, Larson L, Spec A. Hope on the horizon: novel fungal treatments in development. Open Forum Infect Dis. 2020;7:ofaa016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu DQ, Chen SP, Sun J, Wang XM, Chen N, Zhou YQ, et al. Berberine protects against ischemia-reperfusion injury: a review of evidence from animal models and clinical studies. Pharm Res. 2019;148:104385.

    Article  CAS  Google Scholar 

  3. Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis vulgaris): a clinical review. Phytother Res. 2019;33:504–23.

    Article  PubMed  Google Scholar 

  4. Tillhon M, Ortiz LMG, Lombardi P, Scovassi AI. Berberine: new perspectives for old remedies. Biochem Pharmacol. 2012;84:1260–7.

    Article  CAS  PubMed  Google Scholar 

  5. Horie T, Tatebayashi K, Yamada R, Saito H. Phosphorylated Ssk1 prevents unphosphorylated Ssk1 from activating the Ssk2 mitogen-activated protein kinase in the yeast high-osmolarity glycerol osmoregulatory pathway. Mol Cell Biol. 2008;28:5172–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cheetham J, Smith DA, da Silva DA, Doris KS, Patterson MJ, Bruce CR, et al. A single MAPKKK regulates the Hog1 MAPK pathway in the pathogenic fungus Candida albicans. Mol Biol Cell. 2007;18:4603–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S, Brown AJP, et al. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol Biol Cell. 2006;17:1018–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Román E, Correia I, Prieto D, Alonso R, Pla J. The HOG MAPK pathway in Candida albicans: more than an osmosensing pathway. Int Microbiol. 2020;23:23–9.

    Article  PubMed  CAS  Google Scholar 

  9. Liu S, Chen C. Advances in MAPK signaling pathway  in pathogenic fungi. Hunan Agric Sci. 2017;11:119–22.

    Google Scholar 

  10. Dunayevich P, Baltanás R, Clemente JA, Couto A, Sapochnik D, Vasen G, et al. Heat-stress triggers MAPK crosstalk to turn on the hyperosmotic response pathway. Sci Rep. 2018;8:15168.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Correia I, Alonso-Monge R, Pla J. The Hog1 MAP kinase promotes the recovery from cell cycle arrest induced by hydrogen peroxide in Candida albicans. Front Microbiol. 2017;6:2133.

    Google Scholar 

  12. Lee YM, Kim E, An J, Lee Y, Choi E, Choi W, et al. Dissection of the HOG pathway activated by hydrogen peroxide in Saccharomyces cerevisiae. Environ Microbiol. 2017;19:584–97.

    Article  CAS  PubMed  Google Scholar 

  13. Su C, Lu Y, Liu H. Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity. Mol Biol Cell. 2013;24:385–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alonso-Monge R, Carvaihlo S, Nombela C, Rial E, Pla J. The Hog1 MAP kinase controls respiratory metabolism in the fungal pathogen Candida albicans. Microbiol. 2009;155:413–23.

    Article  CAS  Google Scholar 

  15. Morales-Menchén A, Navarro-García F, Guirao-Abad JP, Román E, Prieto D. Coman IV, et al. Non-canonical activities of Hog1 control sensitivity of Candida albicans to killer toxins from debaryomyces hansenii. Front Cell Infect Microbiol. 2018;8:135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hu TL, Yun Y, Xu ZQ, Duan QJ, Shao J, Wang TM, et al. Butyl alcohol extract of Baitouweng decoction inhibits Candida albicans cell membrane. J Chin Mater Med. 2017;42:3185–90.

    Google Scholar 

  17. Saibabu V, Fatima Z, Ahmad K, Khan LA, Hameed S. Octyl gallate triggers dysfunctional mitochondria leading to ROS driven membrane damage and metabolic inflexibility along with attenuated virulence in Candida albicans. Med Mycol. 2020;58:380–92.

    Article  CAS  PubMed  Google Scholar 

  18. Zhong H, Hu DD, Hu GH, Su J, Bi S, Zhang ZE, et al. Activity of Sanguinarine against Candida albicans biofilms. Antimicrob Agents Chemother. 2017;61:e02259–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee HS, Kim Y. Paeonia lactiflora inhibits cell wall synthesis and triggers membrane depolarization in Candida albicans. J Microbiol Biotechnol. 2017;27:395–404.

    Article  CAS  PubMed  Google Scholar 

  20. CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. 4th ed. Wayne (PA): Clinical and Laboratory Standards Institute; 2017.

  21. Ding T, Wang SF, Zhang XY, Zai WJ, Fan JJ, Chen W, et al. Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome. Phytomedicine. 2018;41:45–53.

    Article  CAS  PubMed  Google Scholar 

  22. Afri M, Frimer AA, Cohen Y. Active oxygen chemistry within the liposomal bilayer. Part IV: locating 2ʼ,7ʼ-dichlorofluorescein (DCF), 2ʼ,7ʼ-dichlorodihydrofluorescein (DCFH) and 2ʼ,7ʼ-dichlorodihydrofluorescein diacetate (DCFH-DA) in the lipid bilayer. Chem Phys Lipids. 2004;131:123–33.

    Article  CAS  PubMed  Google Scholar 

  23. Özdemir A, Altıntop MD, Sever B, Gençer HK, Kapkaç HA, Atlı O, et al. A new series of pyrrole-based chalcones: synthesis and evaluation of antimicrobial activity, cytotoxicity, and genotoxicity. Molecules. 2017;22:E2112.

    Article  PubMed  CAS  Google Scholar 

  24. Nakamura A, Takigawa K, Kurishita Y, Kuwata K, Ishida M, Shimoda Y, et al. Hoechst tagging: a modular strategy to design synthetic fluorescent probes for live-cell nucleus imaging. Chem Commun. 2014;50:6149–52.

    Article  CAS  Google Scholar 

  25. Zhao XY, Guo G, Su PP, Yang LJ, Zhu LJ, Tian ZQ, et al. Inhibitory effect of housefly antimicrobial peptide AMP-17 on hyphae of Candida albicans. Microbiol China. 2017;12:1–15.

    Google Scholar 

  26. Li Y, Sun H, Zhu X, Bian C, Wang YC, Si S. Identification of new antifungal agents targeting chitin synthesis by a chemical-genetic method. Molecules. 2019;24:E3155.

    Article  PubMed  CAS  Google Scholar 

  27. Liu YF, Tang QJ, Zhang JS, Zhou S, Wang CG, Yang Y, et al. Determination of β-1,3-glucan content and analysis of polysaccharide composition from Ganoderma lingzhi extract. Mycosystema. 2018;37:1525–31.

    Google Scholar 

  28. Haque F, Alfatah M, Ganesan K, Bhattacharyya MS. Inhibitory effect of sophorolipid on Candida albicans biofilm formation and hyphal Growth. Sci Rep. 2016;6:23575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mancuso R, Chinnici J, Tsou C, Busarajan S, Munnangi R, Maddi A. Functions of Candida albicans cell wall glycosidases Dfg5p and Dcw1p in biofilm formation and HOG MAPK pathway. PeerJ. 2018;6:e5685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Guerra-Moreno A, Ang J, Welsch H, Jochem M, Hanna J. Regulation of the unfolded protein response in yeast by oxidative stress. FEBS Lett. 2019;593:1080–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu NN, Uppulur P, Broggi A, Besold A, Ryman K, Kambara H, et al. Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog. 2018;14:e1007076.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hohmann S. An integrated view on a eukaryotic osmoregulation system. Curr Genet. 2015;61:373–82.

    Article  CAS  PubMed  Google Scholar 

  33. Vogt S, Rhiel A, Weber P, Ramzan R. Revisiting Kadenbach: electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS. Bioessays. 2016;38:556–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang ZG, Ackerman SH. Identification of functional domains in Atp11p.Protein required for assembly of the mitochondrial F1-ATPase in yeast. J Biol Chem. 1996;271:4887–94.

    Article  CAS  PubMed  Google Scholar 

  35. Lefebvre-Legendre L, Salin B, Schaëffer J, Brèthes D, Dautant A, Ackerman SH, et al. Failure to assemble the alpha 3 beta 3 subcomplex of the ATP synthase leads to accumulation of the alpha and beta subunits within inclusion bodies and the loss of mitochondrial cristae in Saccharomyces cerevisiae. J Biol Chem. 2005;280:18386–92.

    Article  CAS  PubMed  Google Scholar 

  36. Netto LE, Antunes F. The roles of peroxiredoxin and thioredoxin in hydrogen peroxide sensing and in signal transduction. Mol Cells. 2016;39:65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yan L, Li M, Cao Y, Gao P, Cao Y, Wang Y, et al. The alternative oxidase of Candida albicans causes reduced fluconazole susceptibility. J Antimicrob Chemother. 2009;64:764–73.

    Article  CAS  PubMed  Google Scholar 

  38. Lu Y, Su C, Liu H. Candida albicans hyphal initiation and elongation. Trends Microbiol. 2014;22:707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim S, Nguyen QB, Wolyniak MJ, Frechette G, Lehman CR, Fox BK, et al. Release of transcriptional repression through the HCR promoter region confers uniform expression of HWP1 on surfaces of Candida albicans germ tubes. PLoS ONE. 2018;13:e0192260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Lee JH, Kim YG, Khadke SK, Yamano A, Watanabe A, Lee J. Inhibition of biofilm formation by Candida albicans and polymicrobial microorganisms by nepodin via hyphal-growth suppression. ACS Infect Dis. 2019;5:1177–87.

    Article  CAS  PubMed  Google Scholar 

  41. Lee JH, Kim YG, Choi P, Ham J, Park JG, Lee J. Antibiofilm and antivirulence activities of 6-gingerol and 6-shogaol against Candida albicans due to hyphal inhibition. Front Cell Infect Microbiol. 2018;8:299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Cullen PJ, Edgerton M. Unmasking fungal pathogens by studying MAPK-dependent cell wall regulation in Candida albicans. Virulence. 2016;7:502–5.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Eggimann P, Garbino J, Pittet D. Management of Candida species infections in critically ill patients. Lancet Infect Dis. 2003;3:772–85.

    Article  CAS  PubMed  Google Scholar 

  44. Knafler HC, Smaczynska-de RII, Walker LA, Lee KK, Gow NAR, Ayscough KR. AP-2-dependent endocytic recycling of the chitin synthase Chs3 regulates polarized growth in Candida albicans. mBio. 2019;10:e02421–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ugbogu EA, Wang K, Schweizer LM, Schweizer M. Metabolic gene products have evolved to interact with the cell wall integrity pathway in Saccharomyces cerevisiae. FEMS Yeast Res. 2016;16:fow092.

    Article  PubMed  CAS  Google Scholar 

  46. Wang O, Gellynck X, Verbeke W. Chinese consumers and European beer: associations between attribute importance, socio-demographics, and consumption. Appetite. 2017;108:416–24.

    Article  PubMed  Google Scholar 

  47. Orlean P. Architecture and biosynthesis of the Saccharomyces cerevisiae cell wall. Genetics. 2012;192:775–818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Benedetti VP, Savi DC, Aluizio R, Adamoski D, Kava V, Galli-Terasawa LV, et al. ERG11 gene polymorphisms and susceptibility to fluconazole in Candida isolates from diabetic and kidney transplant patients. Rev Soc Bras Med Trop. 2019;52:e20180473.

    Article  PubMed  Google Scholar 

  49. Zorić N, Kosalec I, Tomić S, Bobnjarić I, Jug M, Vlainić T, et al. Membrane of Candida albicans as a target of berberine. BMC Complement Alter Med. 2017;17:268.

    Article  CAS  Google Scholar 

  50. Guirao-Abad JP, Sánchez-Fresneda R, Román E, Pla J, Argüelles JC, Alonso-Monge R. The MAPK Hog1 mediates the response to amphotericin B in Candida albicans. Fungal Genet Biol. 2020;136:103302.

    Article  CAS  PubMed  Google Scholar 

  51. Wang YT, Liu JY, Shi C, Zhao JT, Xiang MJ. Knocking out ERG3 gene of Candida albicans and Iits effect on drug resistance. J Shanghai Jiaotong Univ (Med Sci). 2020;40:163–70.

    Google Scholar 

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Acknowledgements

This work was supported by the Health Commission of Sichuan Province, People’s Republic of China (20PJ163), and the “Xinglin Scholar” Scientific Research Project of Chengdu University of TCM (JSZX2018006). We would like to thank Editage [www.editage.cn] for English language editing.

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Authors and Affiliations

  1. College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    Xiaoxue Huang, Zhen Song, Dongmei Li & Yan Li

  2. West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China

    Xiaoxue Huang

  3. The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, China

    Yuling Yi

  4. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    Jiangyan Yong

  5. Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    Jiayi Sun

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X.H. and Y.L. conceived and designed the research. X.H. and Y.Y. performed most of the experiments. J.Y. and J.S. contributed to reagents, data analysis, and results in interpretation with the assistance of Z.S. and D.L. X.H. wrote the initial paper and Y.L. revised the paper. All authors approved the manuscript for publication.

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Correspondence to Yan Li.

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Huang, X., Yi, Y., Yong, J. et al. Inhibitory effect of berberine hydrochloride against Candida albicans and the role of the HOG-MAPK pathway. J Antibiot 74, 807–816 (2021). https://doi.org/10.1038/s41429-021-00463-w

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