Sodium New Houttuyfonate Inhibits Candida albicans Biofilm Formation by Inhibiting the Ras1-cAMP-Efg1 Pathway Revealed by RNA-seq

Wu, Jiadi; Wu, Donghui; Zhao, Yeye; Si, Yuanqing; Mei, Longfei; Shao, Jing; Wang, Tianming; Ge, Yan; Wang, Changzhong

doi:10.3389/fmicb.2020.02075

Cited by 28 publications

(24 citation statements)

References 84 publications

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“…Candida albicans , a yeast-hypha dimorphic fungus, is widely found in the vagina, gastrointestinal tract, oral cavity, and on skin surface ( Richardson et al, 2019 ), which easily results in opportunistic infection under certain circumstances and causes diseases such as Vulvovaginal Candidiasis (VVC). Adhesion of C. albicans to host cells is a key link for the opportunistic infection caused by this fungus ( Mayer et al, 2013 ; Wu et al, 2020 ), which makes it prone to survive in the vagina, oral cavity, or other body parts ( Krachler and Orth 2013 ). Multiple mechanisms are involved in the regulation of this adhesion.…”

Section: Introductionmentioning

confidence: 99%

Berberine Inhibits the Adhesion of Candida albicans to Vaginal Epithelial Cells

et al. 2022

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Vulvovaginal candidiasis (VVC) is an inflammatory disease of the vagina mainly caused by Candida albicans (C. albicans), which affects around three-quarters of all women during their reproductive age. Although some antifungal drugs such as azoles have been applied clinically for many years, their therapeutic value is very limited due to the emergence of drug-resistant strains. Previous studies have shown that the adhesion of C. albicans to vaginal epithelial cells is essential for the pathogenesis of VVC. Therefore, preventing the adhesion of C. albicans to vaginal epithelial cells may be one of the most effective strategies for the treatment of VVC. Berberine (BBR) is a biologically active herbal alkaloid that was used to treat VVC. However, so far, its mechanism has remained unclear. This study shows BBR significantly inhibits the adhesion of C. albicans to vaginal epithelial cells by reducing the expressions of ICAM-1, mucin1, and mucin4 in vaginal epithelial cells, which play the most important role in modulating the adhesion of C. albicans to host cells, and balancing IL-2 and IL-4 expressions, which play a key effect on regulating the inflammatory response caused by C. albicans infection. Hence, our findings demonstrate that BBR may be a potential therapeutic agent for VVC by interfering with the adhesion of C. albicans to vaginal epithelial cells and represents a new pathway for developing antifungal therapies agents from natural herbs.

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Section: Introductionmentioning

confidence: 99%

Berberine Inhibits the Adhesion of Candida albicans to Vaginal Epithelial Cells

et al. 2022

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“…Drug repurposing is a promising technique to develop antifungal treatments, which has identified several non-antifungal agents with antifungal activity, such as antibacterial drugs, immunosuppressants, and statins ( Kim et al, 2020 ; Zhang et al, 2021 ). SNH, initially used the treatment of respiratory infections, was also found to have anti-fungal activity against C. albicans ( Shao et al, 2017 ; Wu et al, 2020 ). The current study demonstrated that SNH had fungistatic activity against A. fumigatus by inhibiting the synthesis of ergosterol.…”

Section: Discussionmentioning

confidence: 99%

“…Cell membrane permeability is subsequently elevated, thus contributing to the inhibition of cell growth or inducing death. The underlying anti- C. albicans mechanism of SH and SNH have been reported to be closely involved with the synthesis and transport of β-1,3-glucan and the Ras1-cAMP-Efg1 pathway, respectively ( Shao et al, 2017 ; Wu et al, 2020 ). However, in our transcriptomic data, the expression of these related genes showed no significant change (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…However, SNH has better clinical value and higher chemical stability than SH ( Zhao et al, 2020 ). Investigations have also confirmed that SNH exhibits antibacterial effects against Staphylococcus aureus and methicillin-resistant S. aureus ( Lu et al, 2013 ; Li et al, 2020 ), Streptococcus pneumoniae ( Yang et al, 2016 ), and C. albicans ( Wu et al, 2020 ). Although SNH acts as an anti-inflammatory medicine and has various anti-bacterial and anti- C. albicans activities, the anti-fungal effect against A. fumigatus , particularly various triazole-resistant strains, has not been reported.…”

Section: Introductionmentioning

confidence: 89%

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Antifungal Activity of Sodium New Houttuyfonate Against Aspergillus fumigatus in vitro and in vivo

et al. 2022

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Aspergillus fumigatus is an important pathogen causing invasive aspergillosis, which is associated with high morbidity and mortality in immunocompromised people. However, the treatment of A. fumigatus infection is a growing challenge, owing to the limited availability antifungal agents and the continual emergence of drug-resistant strains. Drug repurposing is a potential strategy to solve this current problem. Sodium new houttuyfonate (SNH), derived from houttuynin, extracted from Houttuynia cordata, has anti-bacterial and anti-Candida albicans effects. However, whether it has anti-A. fumigatus activity had not been reported. In this study, the antifungal properties of SNH against A. fumigatus, including the standard strain AF293, itraconazole resistant clinical strains, and voriconazole resistant clinical strains, were evaluated in vitro and in vivo. Moreover, the potential mechanism of SNH was characterized. SNH exhibited significant fungicidal activity toward various A. fumigatus strains. SNH also inhibited fungal growth, sporulation, conidial germination and pigment formation, and biofilm formation. Further investigations revealed that SNH interfered with the A. fumigatus cell steroid synthesis pathway, as indicated by transcriptomic and quantitative real-time polymerase chain reaction analyses, and inhibited ergosterol synthesis, as indicated by cell membrane stress assays and ergosterol quantification. Moreover, daily gastric gavage of SNH significantly decreased the fungal burden in mice with disseminated infection (kidney, liver, and lung) and local tissue damage. In addition, the application of SNH downregulated the production of IL-6 and IL-17A. Together, these findings provided the first confirmation that SNH may be a promising antifungal agent for the treatment of A. fumigatus infection.

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“…We evaluated the effect of TA on the formation and preformation of the biofilm of drug-resistant C. albicans CA23 through microscopic observation and cell staining (Soll and Daniels, 2016;Wu et al, 2020). First, we cultured C. albicans CA23 in SDB medium overnight, then washed the fungal cells three times with PBS, resuspended them in RPMI-1640 (+10% FBS) medium, and adjusted it to 1 × 10 5 CFU/mL (final concentration).…”

Section: Antifungal Kinetics Assaymentioning

confidence: 99%

Antifungal Activity and Potential Mechanism of 6,7, 4′-O-Triacetylscutellarein Combined With Fluconazole Against Drug-Resistant C. albicans

Liao

et al. 2021

Front. Microbiol.

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The increased resistance of Candida albicans to conventional antifungal drugs poses a huge challenge to the clinical treatment of this infection. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. This study assessed the effect of 6,7,4′-O-triacetylscutellarein (TA) combined with fluconazole (FLC) on C. albicans in vitro and in vivo. TA combined with FLC showed good synergistic antifungal activity against drug-resistant C. albicans in vitro, with a partial inhibitory concentration index (FICI) of 0.0188–0.1800. In addition, the time-kill curve confirmed the synergistic effect of TA and FLC. TA combined with FLC showed a strong synergistic inhibitory effect on the biofilm formation of resistant C. albicans. The combined antifungal efficacy of TA and FLC was evaluated in vivo in a mouse systemic fungal infection model. TA combined with FLC prolonged the survival rate of mice infected with drug-resistant C. albicans and reduced tissue invasion. TA combined with FLC also significantly inhibited the yeast-hypha conversion of C. albicans and significantly reduced the expression of RAS-cAMP-PKA signaling pathway-related genes (RAS1 and EFG1) and hyphal-related genes (HWP1 and ECE1). Furthermore, the mycelium growth on TA combined with the FLC group recovered after adding exogenous db-cAMP. Collectively, these results show that TA combined with FLC inhibits the formation of hyphae and biofilms through the RAS-cAMP-PKA signaling pathway, resulting in reduced infectivity and resistance of C. albicans. Therefore, this study provides a basis for the treatment of drug-resistant C. albicans infections.

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Sodium New Houttuyfonate Inhibits Candida albicans Biofilm Formation by Inhibiting the Ras1-cAMP-Efg1 Pathway Revealed by RNA-seq

Cited by 28 publications

References 84 publications

Berberine Inhibits the Adhesion of Candida albicans to Vaginal Epithelial Cells

Berberine Inhibits the Adhesion of Candida albicans to Vaginal Epithelial Cells

Antifungal Activity of Sodium New Houttuyfonate Against Aspergillus fumigatus in vitro and in vivo

Antifungal Activity and Potential Mechanism of 6,7, 4′-O-Triacetylscutellarein Combined With Fluconazole Against Drug-Resistant C. albicans

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