Hence, Building discipline for success phytotherapy adjuvant is Querrcetin main healer for fungal infections Qurcetin for pharmaceutical companies. From our results, the expressions of both genes were upregulated by more than two folds after exposure to QCT and FCZ Fig. Sagdic, O.

Video

QUERCETIN 🍎🧅🧅🥦----Antioxidant, Anti-Inflammatory, Anti-Histamine, Anti-Microbial, Immune Modulation.

Quercetin and anti-fungal properties -

The antimycotic activity of QCT seemed to stronger than that of FCZ as the former could be more efficient to inhibit yeast-to-hypha transition in C. albicans 04 isolate Fig. In CLSM results, the fluorescent intensity FI was between and the FIs were even more than in several biofilm areas in the control.

The dispersion was monitored in h pre-formed biofilm in C. albicans 04 isolate after drug treatments. A pre-formed biofilm dispersion by OD value at nm and B fungal quantitation on surface by colony counting in C.

It could be observed that the down-regulations of ALS1 , ALS3 , HWP1 , SUN41 , UME6 and ECE1 were of 2. qRT-PCR analyses of the mRNA expressions of ALS1 , ALS3 , HWP1 , SUN41 , UME6 , ECE1 , PDE2 , NRG1 and HSP90 normalized to housekeeping gene ACT1 in C.

albicans 04 isolate. From the images of lavage, we observed abundantly criss-cross filamentous cells in the control Fig. QCT has been demonstrated to possess a series of functions as well as antifungal potentials [ 19,32,33,34 ].

However, QCT appeared to have strong synergism with FCZ in FCZ-resistant C. albicans isolates Table 2 and Fig. As a matter of fact, most of the flavonoids were good at inhibiting the growth of FCZ-susceptible free-living cells and bad at dealing with FCZ-resistant clinical isolates and biofilms in C.

albicans , but they usually performed satisfactorily in combination with FCZ in biofilm removal [ 18,28,35,36 ]. Combinatorial therapy has become a universal approach in the prevention and management of C. albicans biofilms [ 37 ]. albicans biofilms represent a new type of mode of fungal survival and confer to fungal pathogen greater resistance that was even up to hundreds of folds greater than their planktonic counterparts, resulting in single use of currently available antifungal agents futile.

albicans biofilms under static state demonstrated in a previous and our studies Table 2 , and can be even higher under flow condition [ 38,39 ]. Fungal adherence was one of the most important determinants of pathogenesis.

Concerning VVC infection, the clinical C. albicans isolates from VVC patients have been shown in vitro the ability to adhere to the surfaces of both microtiter plates and intrauterine contraceptive devices [ 40,41 ].

Herein, the combination of QCT and FCZ could significantly inhibit the adherence of VVC isolate Fig. ALS1 , ALS3 and HWP1 , Fig. ALS1 and ALS3 were members of the Agglutinin-Like Sequence ALS gene family and had great impacts on biofilm formation in the early stage i.

adherence stage [ 42,43,44 ]. HWP1 was a well-characterized genes encoding an important cell surface protein in C. The cell surface hydrophobicity CSH of C.

albicans was reported to be implicated in the adhesion, biofilm formation and FCZ resistance, as greater CSH mostly resulted in higher ability of adherence to surface, biofilm formation, resistance to FCZ [ 47,48 ]. Apart from cell-surface adherence, the adhesins e.

Als1, Als3 and Hwp1 also conferred a property of cell-cell adhesion in C. albicans , i. flocculation [ 49 ]. It could be observed that combined use of QCT and FCZ reduced the flocculation and CSH in VVC-originated C. albicans isolate Fig. The yeast-to-hypha transition was a well-known virulence factor to cause tissue damage and a mark of biofilm development in C.

albicans [ 50 ]. In this experiment, concomitant used of QCT and FCZ evidently inhibited the yeast-to-hypha transition Fig. Notably, it was reported that ALS1 and HWP1 were also hypha-specific genes as the expression of former mRNA was correlated well with hyphal growth and the protein product encoded by the latter was only expressed on hyphae [ 51,52,53 ].

Sun41, a putative cell wall glycosidase, is required in biofilm formation, cell wall integrity, and virulence [ 54 ], while UME6 -mediated regulation of hyphal growth and biofilm development of C. albicans was dependent on the expression of SUN41 [ 55 ].

The expressions of ECE1 and PDE2 were closely related with hyphal growth of C. albicans dependent on cAMP-PKA signaling pathway [ 56 ]. Our results indicated that QCT in combination with FCZ could dramatically influence the expressions of hypha-, biofilm-related genes i. ALS1 , HWP1 , SUN41 , UME6 , PBS2 and PDE2 , Fig.

Dispersion was also believed to be an important stage in C. albicans biofilm development, and the dispersion process occurred throughout the whole biofilm development. Fungal dispersion resulted in an initiation of fungal recolonization and a new round of Candida biofilm formation accompanying with disseminated candidiasis [ 12 ].

Although the dispersed fungal cells had different susceptibility and metabolic pattern, a hypothesis was accepted that the cells free from the protection of biofilm matrix would be more easily to be eradicated by host immune system and antifungal agents.

We found that QCT could assist FCZ to facilitate the dispersion of biofilm cells Fig. It has been reported that NRG1 and HSP90 were negatively in charges of fungal biofilm dispersion [ 57,58 ]. From our results, the expressions of both genes were upregulated by more than two folds after exposure to QCT and FCZ Fig.

A previous study demonstrated that C. albicans could adhere the vaginal mucosa and form a complex three-dimensional architecture of a typical biofilm with abundant extracellular matrix after h of infection [ 59 ], and several key transcriptional regulators e.

NRG1 and UME6 were implicated in the immunopathogenesis of Candida vaginitis via the yeast-to-hypha switch and the associated morphogenetic response [ 60 ]. After the treatments of QCT and FCZ, the fungal loading decreased Fig.

Together with these results, it could be demonstrated that QCT could be a favorable antifungal agent and a promising synergist with FCZ in the clinical management of VVC caused by C.

albicans biofilms. This study is supported by the project of medical research and experimental development of Henan province No. Sign In or Create an Account.

Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Cellular Physiology and Biochemistry. Advanced Search. Toggle Menu Menu. Skip Nav Destination Close navigation menu Article navigation. Volume 40, Issue Materials and Methods.

Disclosure Statement. Article Navigation. Research Articles November 30 Quercetin Assists Fluconazole to Inhibit Biofilm Formations of Fluconazole-Resistant Candida Albicans in In Vitro and In Vivo Antifungal Managements of Vulvovaginal Candidiasis Subject Area: Further Areas.

Mei Gao ; Mei Gao. a Department of Gynecology, the First People's Hospital of Shangqiu, Shangqiu City, Henan Province, China. This Site. Google Scholar. Hui Wang ; Hui Wang. LiJuan Zhu LiJuan Zhu. Cellular Physiology and Biochemistry 40 : — Article history Accepted:.

Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Table 1 Primers for PCR. View large. View Large. View large Download slide. Foxman B, Marsh JV, Gillespie B, Sobel JD: Frequency and response to vaginal symptoms among white and african american women: Results of a random digit dialing survey.

J Womens Health ; Sobel JD: Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol ; Fidel PL, Jr. Infect Immun ; Am J Reprod Immunol ; Fan S, Liao Q, Liu X, Liu Z, Zhang D: Vaginal allergic response in women with vulvovaginal candidiasis.

Int J Gynecol Obstet ; Achkar JM, Fries BC: Candida infections of the genitourinary tract. Clin Microbiol Rev ; Richter SS, Galask RP, Messer SA, Hollis RJ, Diekema DJ, Pfaller MA: Antifungal susceptibilities of candida species causing vulvovaginitis and epidemiology of recurrent cases.

J Clin Microbiol ; Choukri F, Benderdouche M, Sednaoui P: In vitro susceptibility profile of recent clinical isolates of candida spp. To topical antifungal treatments of vulvovaginal candidiasis, the imidazoles and nystatin agents.

J Mycol Med ; Sobel JD: Vulvovaginal candidosis. Lancet ; Al-Fattani MA, Douglas LJ: Biofilm matrix of candida albicans and candida tropicalis: Chemical composition and role in drug resistance. J Med Microbiol ; Tobudic S, Kratzer C, Lassnigg A, Presterl E: Antifungal susceptibility of candida albicans in biofilms.

Mycoses ; Uppuluri P, Chaturvedi AK, Srinivasan A, Banerjee M, Ramasubramaniam AK, Kohler JR, Kadosh D, Lopez-Ribot JL: Dispersion as an important step in the candida albicans biofilm developmental cycle.

PLoS Pathog ;6:e Taff HT, Mitchell KF, Edward JA, Andes DR: Mechanisms of candida biofilm drug resistance. The MIC of quercetin reduced the number of regenerated protoplasts by Half the MIC 0. In contrast, the MIC and 0. The FAS1 gene was repressed in the presence of MICs of quercetin, trans-chalcone, fluconazole and cerulenin.

The ERG6 gene was induced in the presence of MICs of fluconazole and cerulenin and was repressed in the presence of MICs of trans-chalcone and quercetin. Trans-chalcone and quercetin inhibited the enzymatic activity of FAS, with IC 50 values of Trans-chalcone and quercetin showed antifungal activity against T.

rubrum , reducing ergosterol levels and modulating the expression of FAS1 and ERG6. Peer Review reports. Dermatophytosis is a cutaneous mycosis caused by fungi of the family Arthrodermataceae Dermatophytes , which are able to digest keratin.

This mycosis is a common infection worldwide [ 1 ]. The main etiological agent of dermatophytosis is the anthropophilic and cosmopolitan fungus Trichophyton rubrum , which accounts for Infections caused by this species are difficult to treat and there is only a limited number of antifungal drugs available for clinical use, especially when compared to the arsenal of antibacterial drugs [ 4 , 5 ].

Therefore, novel drugs with more specific and effective mechanisms of action against dermatophytes are urgently needed. In this respect, natural products provide a rich source of chemical diversity for the development of new drugs [ 6 ]. However, the lack of suitable targets and the similarities between fungal and mammalian cells often result in compounds that are highly toxic to humans [ 7 , 8 ].

An interesting target is fatty acid synthase FAS , an enzyme that participates in endogenous fatty acid synthesis [ 9 ]. The fact that this enzyme shows marked structural differences between fungal and mammalian cells makes it a promising target for the development of new antifungal drugs [ 10 ].

The best known natural inhibitor of FAS is cerulenin, an epoxide produced by the fungus Cephalosporium caeruleus. This compound covalently binds to the catalytic site of FAS and disrupts the condensation reaction of acetyl-COA and malonyl-COA, inhibiting the biosynthesis of fatty acids and sterols in yeast [ 11 ].

In this study, we explored the antifungal activity of quercetin and five other flavonoids described as inhibitors of FAS against T. rubrum [ 12 ]. DNA microarray studies using T.

rubrum and synthetic inhibitors of FAS PHS11A and PHS11B have shown marked transcriptional modulation of several genes such as FAS1 and FAS2 , ERG6 a gene involved in ergosterol metabolism , and multidrug resistance genes [ 13 , 14 ].

We evaluated the antifungal activity of flavonoids against T. rubrum and their effects on fatty acid and ergosterol synthesis using a wild-type strain and a mutant strain Δ TruMDR2 that carries a disrupted version of an ABC transporter involved in multidrug resistance [ 15 ].

The T. rubrum strain H6 ATCC MYA and the mutant strain Δ TruMDR2 obtained by disruption of the TruMDR2 gene of strain MYA were submitted to standard techniques for fungal manipulation and growth as described previously by Fachin et al.

Cerulenin and the natural products were purchased from Sigma-Aldrich St. Louis, MO, USA. The final concentration of all solvents DMSO, ethanol, and methanol used in the antifungal assay was fixed at a maximum of 0. Fluconazole and cerulenin were used as positive controls.

The solvent controls consisted of the solvent DMSO, ethanol, or methanol without the tested flavonoids at a final concentration of 0. Susceptibility of the MYA and Δ TruMDR2 T. rubrum strains 1. Microtiter trays were incubated at 28°C and MICs were recorded after 7 days of incubation.

The MIC was defined as the lowest concentration of flavonoids that completely inhibited the growth of MYA and Δ TruMDR2. The assays were carried out in three independent experiments performed in triplicate.

Mycelia of strain MYA or Δ TruMDR2 were incubated in 50 mL liquid Sabouraud glucose medium for 24 h at 28°C under gentle shaking at rpm. The mycelia were harvested aseptically and transferred to 20 mL fresh Sabouraud medium containing MICs of quercetin and of the controls cerulenin and fluconazole.

The MIC and 0. Next, the material was incubated for 48 h under the same conditions as described above and harvested by filtration.

Ergosterol was extracted as described by Arthington-Skaggs et al. Protoplasts were obtained from each T. Regenerated protoplasts were selected on solid minimal medium [ 17 ] supplemented with 1 M sucrose, 0.

Quantitative RT-PCR was used to evaluate the transcription level of the FAS1 and ERG6 genes involved in fatty acid and ergosterol biosynthesis, respectively, during exposure of T.

rubrum to the flavonoids. Total RNA was extracted from approximately 30 mg mycelia grown for 16 h in the presence of MICs of quercetin, trans-chalcone, cerulenin, and fluconazole as described by Fachin et al.

Mycelia grown in the presence of 1. Complementary DNA was synthesized from 2 μg total RNA in a μL reaction volume using the RevertAID H Minus First Strand cDNA Synthesis kit Fermentas ®.

The quantitative RT-PCR experiments were performed in triplicate using the SYBR Taq Ready Mix kit Sigma on an Mx QPCR system Stratagene. The gene-specific primers are shown in Table 1. Expression levels were calculated by the comparative Ct method using 18S rRNA as normalizer gene and untreated mycelia as reference.

The results are reported as the mean ± standard deviation of three experiments. The method described by Li et al. The extracted proteins were resuspended in the same buffer and dialyzed for 24 h in phosphate buffer.

Total proteins were quantified and then stored at °C for one week. The enzymatic assay was performed according to Li et al.

The assay of FAS inhibition by flavonoids was carried out in well plates in a final volume of μL. First, the previously diluted proteins were incubated with quercetin and trans-chalcone for 30 min at room temperature. Next, 50 μL of this mixture was added to mM reaction phosphate buffer containing 1 mM malonyl CoA, 1 mM NADPH, and 40 μM acetyl CoA.

The microplate was read immediately for 10 min at nm. The readings were obtained at intervals of 2 min until the end of analysis. FAS activity was calculated by subtracting the OD value obtained after 1 min from the OD value obtained after 10 min.

The IC 50 was determined by linear regression. The negative control consisted of protein plus reaction buffer. Another control consisted of buffer reaction without protein. Quercetin and trans-chalcone were the most effective compounds against both the wild-type MYA and mutant strain ΔTruMDR2 of T.

In contrast, no antifungal activity was observed for ellagic acid, galangin or genistein. Luteolin exhibited antifungal activity against both strains, but to a lesser extent than trans-chalcone and quercetin against the wild-type T.

rubrum strain. Similar MICs were obtained for cerulenin, which was used as a positive control. However, the highest inhibitory activity against the T. rubrum strains was observed for trans-chalcone, which exhibited markedly lower MICs MYA 7. No antifungal activity was observed for any of the solvent controls at the final concentration tested 0.

A reduction in ergosterol content of rubrum strains cultured in the presence of the MIC of quercetin when compared to untreated cells.

This result is comparable to the reduction caused by MICs of fluconazole and cerulenin, which ranged from 40 to In contrast, the 0. As can be seen in Table 4 , trans-chalcone was the best compound to inhibit protoplast regeneration in the two T.

rubrum strains when tested at the MIC and 0. Similar results were obtained for cerulenin, a finding suggesting that trans-chalcone also acts by disrupting cell membrane homeostasis. Interestingly, protoplast regeneration was higher in the mutant strain than in the wild-type strain in the presence of 0.

Half the MIC of quercetin did not reduce the number of regenerated wild-type fungal colonies, but caused a Quantitative RT-PCR was used to evaluate the modulation of FAS1 and ERG6 gene expression in the presence of flavonoids.

The FAS1 gene of T. rubrum was repressed in the presence of MICs of quercetin, trans-chalcone, fluconazole, and cerulenin. The ERG6 gene was induced in the presence of MICs of fluconazole and cerulenin and was repressed in the presence of MICs of trans-chalcone and quercetin after 16 h of growth of T.

rubrum Figure 2. Relative fold change in the FAS1 and ERG6 genes determined by quantitative RT-PCR. The IC 50 value was Chalcones 1,3-diarylpropenone are open-chain flavonoids that are mainly synthesized by plants. These compounds have been shown to exert significant antifungal activity, especially against dermatophytes [ 18 ].

Most chalcones inhibit the biosynthesis of the yeast cell wall [ 19 ], but there is evidence that chalcones also block FAS in yeast 12 and fatty acid synthase II in mycobacteria [ 20 ]. In the present study, the MICs of quercetin, trans-chalcone, cerulenin and fluconazole were always lower for the mutant strain than for the wild-type strain MYA This higher susceptibility of the mutant strain might be explained by disruption of the TruMDR2 gene.

This gene encodes an ABC transporter that is involved in the resistance to various antifungal agents, such as terbinafine, 4NQO, and ethidium bromide [ 15 ]. To our knowledge, this is the first study reporting the involvement of the TruMDR2 transporter in flavonoid-mediated FAS inhibition.

This team has further reported the antifungal potential of flavonoids that have been recognized as FAS inhibitors which modulate the fatty acid synthesis gene expressions in T.

The crude and butanolic leaf extract of Terminalia catappa contain the active components of hydrolyzable tannins punicalin, punicalagin , gallic acid, and flavonoid C-glycosides that exhibits antifungal activity against Candida sp. Similarly, crude and ethanol leaf extracts of Carya illinoensis contain gallic acid, ellagic acid, rutin, catechins and epicatechins that exhibits antifungal activity against different Candida strains with MIC range of 6.

Gallic acid is established to have potent antifungal property against Candida spp. Gallic acid is isolated from acetone fraction of Buchenavia tomentosa that inhibits the proliferation rate and disrupts 48 h-biofilm abruptly in C.

albicans [ 77 ]. Ethyl acetate and butanolic extracts of Punica granatum contain ellagic acid, gallagic acid, punicalins, and punicalagins which show antifungal activities against C.

albicans , C. neoformans , and A. fumigatus [ 78 ]. Curcumin is a renowned flavonoid present in turmeric, which has potential anti-candidal activity against various clinical isolates of C. albicans [ 79 ] and C. gattii [ 80 ]. Curcumin can decrease the colony width, sprouting, and sporulation of A.

flavus and C. albicans [ 81 ]. Similarly, C urcumin-silver nanoparticles have also exhibited potential anti-candidal activity against Candida species acquired from clinical samples of infected HIV individuals with MIC range of All these findings strongly recommend that flavonoids exhibit a broad spectrum of antifungal activity against Candida spp.

Flavonoids have been extensively used for many centuries in the treatment of the range of human diseases. Flavonoids often inhibit fungal growth with various underlying mechanisms, including plasma membrane disruption, the induction of mitochondrial dysfunction, and inhibiting the following: cell wall formation, cell division, RNA and protein synthesis, and the efflux mediated pumping system Figure 1.

Figure 1. Mechanism of antifungal activity of flavonoids. The ergosterols are a vital component for the manufacturing of cell membranes. This inadequate formation or disruption of the plasma membrane leads to a lesion or membrane permeability changes [ 85 ].

Furthermore, excess production of reactive oxygen species ROS also causes severe oxidative stress to the cell, which results in the progressive membrane permeabilization, or injury to nucleic acids and oxidation of fatty acids and amino acids [ 86 ] [ 87 ] [ 88 ].

ROS often encounter the membrane lipids in C. albicans and generate lipid hydroperoxides; this is known as lipid peroxidation [ 89 ]. Lipid peroxidation has been demonstrated to disturb the lipid bilayer and alter membrane potentials, resulting in reduced fluidity, increased permeability, and disruption of phospholipids [ 90 ].

The relationship between ROS generation and the lipid bilayer leads to the synthesis of malondialdehyde, which is a chief marker of lipid peroxidation [ 24 ] [ 91 ] [ 92 ] [ 93 ] [ 94 ] [ 95 ] [ 96 ].

Apigenin has exerted antioxidant and antifungal activity against C. albicans, C. parapsilosis, Malassezia furfur, T. rubrum, and T. Antioxidant potential of the flavonoid inhibits biofilm formation and stimulates membrane disturbances, resulting in the reduction of cell size and leakage of intracellular components [ 97 ].

In the previous study, LicoA demonstrated antifungal activities against T. rubrum with MIC of In an earlier study, prenylflavanone 8PP obtained from Dalea elegans , had potential antifungal activity against C.

glabrata, C. neoformans, and T. mentagrophytes [ 99 ]. In this study, prenylflavanone 8PP potentially inhibited the biofilms of sensitive and azole-resistant C. albicans at μM through the gathering and elevation of endogenous ROS and reactive nitrogen intermediates [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ].

Similarly, Baicalein has been isolated from Scutellaria baicalensis , which shows inhibitory effects towards Candida spp. Baicalein has induced the apoptosis through alteration in the membrane potentials of mitochondria and elevates intracellular ROS and upstream regulation of redox-related genes [ ].

In another study, baicalein presented antifungal activities toward T. rubrum , C. albicans , T. mentagrophytes , and A. fumigatus with MICs of , 30, 60, and μM respectively [ ]. Baicalein has induced concentration-dependent ROS generation, deformation of membrane structure, and efflux of a cotton-like constituents that are alleged to degenerate cytosol in fungal bodies of T.

rubrum, T. mentagrophytes, A. fumigatus , and C. albicans [ ]. However, Kang et al. krusei isolates showed higher alteration in the mitochondrial homeostasis without elevating the intracellular ROS, thereby causing apoptosis [ ].

Antifungal activities of fisetin inhibit the growth of C. neoformans, C. gattii, M. gypseum, T. mentagrophytes, T. In this study, reductions of ergosterol levels and structural alterations were detected in C.

gattii [ ] [ ]. Fatty acid synthase is a significant enzyme essential for endogenous fatty acid synthesis in the membrane of fungi, indicating it as a potential target for novel antifungal drugs [ ]. Quercetin has been reported to have individual or synergic antifungal properties with flucanazole, which is recognized as an inhibitor of fatty acid synthase.

rubrum [ ]. These active flavonoids induce the activation of phosphatidylserine, which inhibits fatty acid synthase. In addition, they stimulate the intracellular accumulation of ROS, structural modifications, apoptosis, mitochondrial depolarization, and fragmentation of DNA in C.

tropicalis [ 70 ]. Isoquercitrin has also shown antifungal activities against C. albicans, M. furfur, C. parapsilosis, T. beigelii with MIC values of 2. The cell walls of fungi are primarily composed of β-glucans and chitin.

The antifungal mechanism has been based on cell wall deformation which is caused by the inhibition of the synthesis of those compounds [ 84 ] [ ]. Glabridin is a chief active isoflavane isolated from Glycyrrhiza glabra , and has significant antifungal activities against C.

tropicalis C. neoformans, and C. The antifungal process is achieved based on the cell wall deformation which includes the remarkable decreasing of cell size and increasing membrane permeability [].

Similarly, glabridin treatment enhances the expression of various genes in C. glabrata which participate in the fragmentation of DNA chromatin condensation resulting in apoptosis [ ].

These deformations of the cell wall normally occur due to the presence of the prenylation of glabridin [ ]. albicans and Cryptococcus spp. Infected animals administered with mixed doses of epigallocatechin-o-gallate and amphotericin B exhibited an augmented survival rate compared to animals administered with amphotericin B.

The results show that epigallocatechin-o-gallate exclusively inhibits the hyphal formation and ergosterol synthesis in C.

albicans [ 68 ]. The investigations of propidium iodide assay and artificial membrane permeability study specified that pedalitin stimulates the elevation of permeability and physical alarm of the plasma membrane, permitting the diffusion of molecules smaller than about 3.

Inhibition of the mitochondrial electron transport chain ETC leads to diminishing membrane potential. This inhibition generally takes place in the ETC by inhibition of proton pumps, which reduces ATP synthesis, and thus, cell death [ ]. Wogonin 5,7-dihydroxymethoxy flavone showed antifungal activity against A.

fumigates, T. rubrum , and T. mentagrophytes with MICs of , 60, and 60 µM respectively. The treatment with wogonin induces accumulation of ROS in mitochondria and causes a decreased membrane potential and reducing ATP synthesis and eventually contraction or cracking of fungal filaments [ ].

The results of confocal scanning laser microscopy, flow cytometry, and transmission-electron-microscopy analysis have shown baicalein treatment reduces cell surface hydrophobicity and mRNA expression, and elevates apoptosis that is connected to the failure of mitochondrial membrane potential [ ].

All these compounds exhibit pro-apoptotic functions, mediated by the ability to discharge of cytochrome c from mitochondria, or indirectly by upregulating pro-apoptotic proteins of Bcl-2 expressions and downregulating anti-apoptotic proteins [ ] [ ]. Honey extract also contains a flavonoid that improves mitochondrial functions and decreases the vacuolization, adjusting the branching process connected with virulence.

Honey extract induces alterations in the cell cycle, membrane integrity, functions of mitochondria, and biogenesis [ ].

A synergistic study has also investigated the synergy between epigallocatechin gallate and conventional antimycotics agents, such as miconazole, fluconazole, and amphotericin B, against biofilms of C.

parapsilosis, C. kefyr, C. tropicalis , and C. Similarly, epigallocatechin gallate has described as an anti-candidal agent, which has been demonstrated through the mechanism of mitochondrial membrane dysfunction [ ]. Likewise, Spondias tuberosa rich flavonoids elevate the levels of the superoxide anion via the lysosome, causing hyperpolarization in the mitochondrial membrane, so granting anti- Candida activity [ ].

The inhibition of cell division generally causes inhibition of microtubule polymerization, which inhibits the mitotic spindle formation [ ]. Honey flavonoid extract inhibits the proliferation of C. albicans phenotypes, diminishes the infection, and reduce the distressing membrane integrity.

This inhibition is measured by using flow cytometry and scanning electron microscopy analyses. Studies show that alizarin and chrysazin suppress biofilm formation in C. albicans , and effectively inhibit hyphal formation and inhibit the cell cycle [ ].

Another study shows that magnolol and honokiol inhibit the growth of C. albicans through the Ras1-cAMP-Efg1 pathway. These compounds have potential inhibitory effects on the cell cycle and biofilm-formation-ability of C. Rubus chingii is a well-known traditional Chinese medicinal plant that possesses flavonoid-rich compounds, known to have significant antimicrobial and antifungal activities.

The crude extract of this plant synergistically interacts with fluconazole to inhibit C. The probable mechanism behind this synergistic interaction could be the cell cycle arrest at S phase in C.

The crude extract containing flavonoids reduce the efflux of Cdr1 ABC transporter, which may be the reason for fluconazole resistance [ ]. Similarly, daphnegiravone D, a prenylated flavonoid, has cytotoxic effects and significantly inhibits cell division.

Efflux pumps are transporters present in most living cells, including fungi; they have the noteworthy function of removing toxic substances from the fungal body [ ] [ ] [ ]. This transporter can detoxify a fungal cell through the removal of a drug being accumulated.

Hence, inhibiting the efflux pumps is a crucial aim for reducing drug resistance [ ] [ ]. albicans when synergistically combined with miconazole.

This combination reduces ergosterol biosynthesis and inhibits drug efflux pumps with IC 50 of This compound is well recognized as a lipooxygenase inhibitor or efflux pump inhibitor when in combination with fluconazole; it decreases the capacity of the cells to efflux out drugs [ ] [ ].

Similarly, diorcinol D is another natural compound obtained from a lichen endophytic fungus, Aspergillus versicolor , that inhibits the efflux pump activity by decreasing the Cdr1 expression in C. Curcumin from rhizomes of Curcuma longa is also another natural polyphenolic compound that modulates the efflux pump activity in Saccharomyces cerevisiae, and overexpresses the C.

albicans ATP binding cassette ABC multidrug transporters, Candida drug resistance protein 1, and Candida drug resistance protein 2 [ ] [ ].

Similarly, the quorum-sensing molecule farnesol is drug efflux a modulator that mediates through ABC multidrug transporters and synergizes with fluconazole, ketoconazole, miconazole, and amphotericin B in C.

This synergistic interaction of quorum-sensing molecule farnesol with those antifungal drugs leads to ROS generation, which causes early apoptosis [ ] [ ]. Naturally occurring flavones, such as apigenin, chrysin, baicalein, luteolin, tangeritin, scutellarein, 6-hydroxyflavone, and wogonin inhibit efflux mediated pumps that induce cell death in the fungi [ 45 ] [ ] [ ].

An isoflavone, sedonan A extracted from Dalea formosa , also inhibits efflux pumps in C. glabrata, and disturbs various intracellular transcription genes with MIC of 15 and 7. Another isoflavone has been identified as dorsmanin isolated from dorstenia mannii that inhibits efflux pumps in C.

The antifungal agent generally enters into the cell through active transport that reaches into the nucleus, and thus inhibits DNA, RNA, and protein synthesis. The inhibition of protein synthesis is well-recognized as an antifungal target [ ] [ ].

For instance, 5-flurocytosine inhibits nucleic acid synthesis by the formation of fluorinated pyrimidine metabolites, which can cause a deficit of cytosine deaminase, resulting in the deregulation of the pyrimidine biosynthesis [ ] [ ]. Similarly, Catechin inhibits C. albicans nucleic acid synthesis; analysis by flow cytometry shows that it exhibits the inhibition of FCS-induced hyphal formation; western blotting results also reveal that the treatment with catechin in the C.

albicans reduces the hypha-specific gene expression in mitogen-activated protein kinase cascade and the cyclic adenosine 3,5-monophosphate pathway.

Based on the findings, the team in question highlighted catechin as a potential antifungal candidate in clinical therapy for the management and prevention of candidosis [ ] [ ].

Similarly, flavonols myricetin, kaempferol, fisetin, quercetin, 3-hydroxy flavone, and 3,7-dihydroxyflavone , a flavone luteolin , a flavanone naringenin , and isoflavones genistein, biochanin A inhibit filamentous fungus Cochliobolus lunatus through the inhibition of nucleic acid synthesis [ ].

Apigenin is a well-known flavone found in a wide variety of plants and herbs that interferes with the translational activity of fungal foot-and-mouth disease driven by the internal ribosome entry site, and was thus identified as a potential drug for foot-and-mouth disease infection [ ].

Carvacrol, a chalcone extracted from Lavandula multifida L. that inhibits the nucleic acid synthesis and disrupts the cellular cytoplasmic membrane, eventually causes apoptosis in various candida species [ ].

Gallic acid extracted from Paeonia rockii inhibits the protein synthesis of C. Similarly, gallotannin obtained from Syzygium cordatum inhibits RNA synthesis and possess antifungal activity against C.

albicans with an MIC value of 0. The combination of natural products with antifungal drugs is recognized as an effective strategy to fight invasive fungal infections and microbial resistance [ ]. This combination is often beneficial and effective for both the rate and degree of microbial killing [ ].

Generally, each drug has a diverse mechanism of action, and two drugs may play on diverse targets, resulting in multi-targeting. Based on the multi-targeting strategy, the progress of drug resistance can be reduced [ ] [ ].

Toxicity and intolerance of the drug can also be evaded with the aid of two or more collective drug treatments. Several in vitro studies have shown a reduced inhibitory concentration of natural products with antifungal drugs [ ] [ ] [ ]. For instance, bioactive compounds help elevate the intracellular concentration of related antifungals by potentiating their action, inhibiting the efflux pumps, and inhibiting the morphogenesis of drug-resistant C.

albicans [ ] [ ]. Studies have exhibited that Brazilian Red Propolis and Acca sellowiana produce in vitro synergistic activity with fluconazole against resistant fungal isolates of C.

parapsilosis and C. glabrata [ ] [ ]. Propolis offered action on the cell membrane, permitting fluconazole penetration into the cells [ ] [ ]. The synergistic effect accelerates between the extracts of Uncaria tomentosa and fluconazole against C andida non-albicans, and quite likely this effect is connected to teamwork events happening outside the cell membrane [ ].

This combination may trigger the healing of lesions and control most of the symptoms connected to fungal infections [ ] [ ].

Hence, the phytotherapy adjuvant is the main healer for fungal infections exclusively for pharmaceutical companies. Curcumin, when combined with fluconazole, miconazole, ketoconazole, nystatin, and amphotericin B in vitro, results in synergistic interaction against C.

Curcumin elevates the level of ROS and regulation of expression of numerous genes related to fungal oxidative stress, including superoxide dismutase, catalase, and oxydoreductase [ ]. Chalcones are naturally occurring flavonoids that have been synthesized by aldol condensation, which possess significant antifungal properties when combined with fluconazole and resistant strains of C.

Chalcones are the main inhibitors of the efflux pump, which in combination with fluconazole decrease the ability of cells to efflux out the drugs [ ] [ ]. Osthole is a natural methylated derivative of coumarin isolated from Candida fructus, which has been extensively used for the treatment of supportive dermatitis and vaginitis in China.

It is synergistically combined with fluconazole and possesses significant antifungal effects through the generation of ROS [ ]. Similarly, eugenol-tosylate, a semi-synthetic analog of eugenol, has a synergistic interaction with fluconazole that exhibits antifungal activity against fluconazole-resistant C.

albicans which occurs through the inhibiting of ergosterol biosynthesis [ ] [ ]. Glabridin exhibits a synergistic combination with fluconazole against resistant strains of C.

albicans, causing cell wall alteration [ ]. albicans biofilm, which is isolated from vulvovaginal candidiasis patients. These drugs combined, have the ability to avert the adhesion of cell-cell communication and disturb the expression of genes accountable for biofilm formation [ ].

The elevation of fungal infections is alarming. They lead to high levels of morbidity and mortality globally. Emerging new fungal species and the incidence of elevated drug resistance for fungal diseases continues to rise.

The scenario of the existing antifungal agents and their complications is quite critical. There are limitations manifest by antifungal agents: the lower fungistatic ability, high toxicity, and kidney failure. Hence, it is vital to search novel agents as alternative therapies that are potentially active against most fungal diseases.

Medicinal plants containing flavonoids are recognized as safe and endowed with numerous biological functions. Various flavonoids have been extracted and investigated in association with their anti-fungal activities and can be promising, efficient, and cost-effective agents for the inhibition of fungal infections.

They often inhibit fungal growth in various underlying mechanisms by enhancing the disruption of the plasma membrane and mitochondrial dysfunction; and inhibiting cell wall formation, cell division, protein synthesis, and the efflux-mediated pumping system.

These flavonoids are capable and efficient in synergetic combination therapy with conventional drugs, which can be more appropriate and supportive for finding novel drug therapies against fungal pathogens. Encyclopedia Scholarly Community. Entry Journal Book Video Image About Entry Entry Video Image.

Submitted Successfully! Thank you for your contribution! You can also upload a video entry or images related to this topic.

Version Summary Created by Modification Content Size Created at Operation 1 Suresh Mickymaray. Vivi Li. Video Upload Options Do you have a full video? Send video materials Upload full video. Confirm Are you sure to Delete? Yes No. If you have any further questions, please contact Encyclopedia Editorial Office.

MDPI and ACS Style MDPI and ACS Style AMA Style Chicago Style APA Style MLA Style. Mickymaray, S. Anti-Fungal Efficacy of Flavonoids. Mickymaray S, Al Aboody MS. Accessed February 15, Mickymaray, Suresh, Mohammed Saleh Al Aboody. In Encyclopedia.

Mickymaray, Suresh and Mohammed Saleh Al Aboody. Copy Citation. Home Entry Topic Review Current: Anti-Fungal Efficacy of Flavonoids. This entry is adapted from the peer-reviewed paper flavonoids fungal diseases mode of action antifungal activity.

Introduction Fungal illness often can be fatal, killing more than 1. Antifungal Activities of Flavonoids The screening of antifungal flavonoids from plants has been assayed by using broth dilution, spore germination, and agar well or the disk diffusion.

Actions of Antifungal Flavonoids Flavonoids have been extensively used for many centuries in the treatment of the range of human diseases. Induced Plasma Membrane Disruption The ergosterols are a vital component for the manufacturing of cell membranes.

Inhibition of Cell Wall Formation The cell walls of fungi are primarily composed of β-glucans and chitin. Induced Mitochondrial Dysfunction Inhibition of the mitochondrial electron transport chain ETC leads to diminishing membrane potential. Inhibition of Cell Division The inhibition of cell division generally causes inhibition of microtubule polymerization, which inhibits the mitotic spindle formation [ ].

Inhibition of Efflux Pumps Efflux pumps are transporters present in most living cells, including fungi; they have the noteworthy function of removing toxic substances from the fungal body [ ] [ ] [ ]. Synergistic Action between Flavonoids and Antifungals The combination of natural products with antifungal drugs is recognized as an effective strategy to fight invasive fungal infections and microbial resistance [ ].

Conclusions The elevation of fungal infections is alarming. References Bongomin, F. Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision. Journal of Fungi , 3, 57, doi Efficacy and Mechanisms of Flavonoids against the Emerging Opportunistic Nontuberculous Mycobacteria.

Antibiotics Basel, Switzerland , 9, , doi Lu, M. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole. International Journal of Antimicrobial Agents , 49, , doi Vijayakumar, R.

Distribution of biocide resistant genes and biocides susceptibility in multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii — A first report from the Kingdom of Saudi Arabia. Journal of Infection and Public Health , 11, , doi Ganesan, K.

Causal Relationship between Diet-Induced Gut Microbiota Changes and Diabetes: A Novel Strategy to Transplant Faecalibacterium prausnitzii in Preventing Diabetes. International Journal of Molecular Sciences , 19, , doi Targeting Programmed Fusobacterium nucleatum Fap2 for Colorectal Cancer Therapy.

Cancers , 11, , doi Sanglard, D. Emerging Threats in Antifungal-Resistant Fungal Pathogens. Frontiers in Medicine , 3, doi Lu, S. Limonin: A triterpenoid exerts protective effect during lipopolysaccharide stimulated inflammation in BV2 microglial cells.

Pharmacognosy Magazine , 16, , doi de Almeida, R. New diphenylphosphane derivatives of ketoconazole are promising antifungal agents. Scientific Reports , 9, doi Vinodhini R, M. Prevalence And Antifungal Susceptibility Pattern of Candida Dubliniensis Isolated From Urine Samples.

Int J Recent Sci Res , 7, Devi AC, D. Diagnostic value of real time PCR and associated bacterial and fungal infections in female genital tuberculosis. Biomed Pharmacol J , 3, Screening and antibacterial efficacy of selected Indian medicinal plants.

Asian Pac J Trop Biomed , 6, Suresh, M. Investigations of Bioactivity of Acalypha indica L. and Croton bonplandianus Baill against Multidrug Resistant Bacteria and Cancer Cells.

Ng, K. Candidaspecies epidemiology a laboratory-based report. Wang, Y. Looking intoCandida albicansinfection, host response, and antifungal strategies. Virulence , 6, , doi Polke, M. Candida Survival Strategies. Advances in Applied Microbiology , , doi Alsagaby, S.

Transcriptomics-Based Characterization of the Toxicity of ZnO Nanoparticles Against Chronic Myeloid Leukemia Cells. Int J Nanomedicine , 15, , doi Hurtado, J. Mortality due to Cryptococcus neoformans and Cryptococcus gattii in low-income settings: an autopsy study.

Molina-Leyva, A. Cutaneous Cryptococcus laurentii infection in an immunocompetent child. International Journal of Infectious Diseases , 17, ee, doi Smith, N. Perspectives on non-neoformanscryptococcal opportunistic infections.

Journal of Community Hospital Internal Medicine Perspectives , 7, , doi Calista, F. Cryptococcus laurentii Diarrhea in a Neoplastic Patient. Case Rep Oncol Med , , , doi

Mei GaoHui Support your bodys natural metabolismLiJuan Zhu; Quercetin Assists Fluconazole to Inhibit Propertiea Formations Quercetin and anti-fungal properties Fluconazole-Resistant Aanti-fungal Albicans in Wnti-fungal Support your bodys natural metabolism Querdetin In Propertis Building discipline for success Managements of Thermogenesis and cold exposure Candidiasis. Cellular Physiology and Biochemistry 9 December ; 40 : — Background: Vulvovaginal candidiasis VVC is a common gynecological disease. Candida albicans is believed to be mainly implicated in VVC occurrence, the biofilm of which is one of the virulence factors responsible for resistance to traditional antifungal agents especially to fluconazole FCZ. Quercetin QCT is a dietary flavonoid and has been demonstrated to be antifungal against C. albicans biofilm.