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Biocontrol Science 2022Calcineurin (CN) is a conserved Ca-calmodulin activated protein phosphatase, which plays important roles in immune regulation, cardiac hypertrophy, and apoptosis in...
Calcineurin (CN) is a conserved Ca-calmodulin activated protein phosphatase, which plays important roles in immune regulation, cardiac hypertrophy, and apoptosis in humans. In pathogenic fungi, CN is essential for stress survival, sexual development, and virulence. The immunosuppressant tacrolimus (FK506) is a specific inhibitor of CN in humans and fungi including nonpathogenic fission yeast. Although calcineurin inhibition by FK506 or CN deletion in fission yeast does not induce growth defects, treatment with some anti-fungal drugs such as micafungin and valproic acid, induced synthetic lethality with calcineurin inhibition. Here, we searched for the compounds that induce synthetic growth defects with CN inhibition in fission yeast. We found that ellagic acid (EA) preferentially induced growth inhibition in CN deletion cells. Consistently, co-treatment with EA and FK506 induced severe growth inhibition in the wild-type cells, whereas neither of the single treatment with each compound did so. Moreover, deletion of the calcineurin-regulated transcription factor Prz1 also induced a marked EA sensitivity. Intriguingly, EA also enhanced the growth inhibitory effect of other anti-fungal drugs, including micafungin and miconazole. Thus, our data suggesting the synergistic growth inhibitory effect of the calcineurin inhibitor FK506 and EA may be useful to understand the mechanism to overcome the antifungal resistance.
Topics: Calcineurin; Calcineurin Inhibitors; Ellagic Acid; Humans; Schizosaccharomyces; Tacrolimus
PubMed: 35314558
DOI: 10.4265/bio.27.31 -
Drug Delivery Dec 2021Recurrent aphthous ulcer (RAU) is a well-known painful, inflammatory disease with uncertain etiology for which local symptomatic therapy is only available. The aim of...
Recurrent aphthous ulcer (RAU) is a well-known painful, inflammatory disease with uncertain etiology for which local symptomatic therapy is only available. The aim of this study was to formulate and characterize muco-adhesive sponges containing a mixture of tenoxicam and miconazole nitrate to manage pain, inflammation and avoid candida infection that may accompany RAU due to poor oral hygiene. Two polymers at different concentrations were used to prepare sponges applying simple freeze-drying. Medicated chitosan (2%) sponges (mC2) showed acceptable physical appearance, surface pH (6.3 ± 0.042), porosity (25.7% ± 1.8), swelling index (5.7 ± 0.11), and muco-adhesion time (115 min.±0.813 and 155 min.±1.537, respectively), muco-adhesion force (0.09 N ± 0.002) and scanning electron microscope (SEM) images. For concurrent clear-cut determination of tenoxicam and miconazole nitrate from mC2, a new UPLC method was developed and validated. mC2 sponges exhibited superior drug release profiles where ∼100% of tenoxicam released within 5 min for fast pain relief with a more prolonged miconazole nitrate release. Furthermore, animal study revealed that mC2 caused a significant decrease in the acetic acid-induced ulcer size in rats after 6 days of treatment ( < .0001) compared to negative and positive controls. Additionally, histopathological examination showed faster healing with complete restoration of the normal oral histology in rats. The present study concludes that chitosan sponge loaded with a combination of tenoxicam and miconazole nitrate could improve healing of RAU cases.
Topics: Adhesives; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antifungal Agents; Carboxymethylcellulose Sodium; Chitosan; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Freeze Drying; Hydrogen-Ion Concentration; Miconazole; Microscopy, Electron, Scanning; Piroxicam; Rats; Stomatitis, Aphthous; Wound Healing
PubMed: 33342321
DOI: 10.1080/10717544.2020.1858999 -
Pharmaceuticals (Basel, Switzerland) Feb 2021Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although...
Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although some antifungal drugs to treat candidiasis are available, resistant strains to current therapies are emerging. Therefore, the search for new candicidal compounds is certainly a priority. In this regard, a series of indazole and pyrazole derivatives were designed in this work, employing bioisosteric replacement, homologation, and molecular simplification as new anticandidal agents. Compounds were synthesized and evaluated against , , and strains. The series of 3-phenyl-1-indazole moiety () demonstrated to have the best broad anticandidal activity. Particularly, compound , with ,-diethylcarboxamide substituent, was the most active against and both miconazole susceptible and resistant species. Therefore, the 3-phenyl-1-indazole scaffold represents an opportunity for the development of new anticandidal agents with a new chemotype.
PubMed: 33668364
DOI: 10.3390/ph14030176 -
BMC Genomics Apr 2021Trichophyton mentagrophyte (TM), a zoonotic pathogen, has been endangering public health due to emerging drug resistance. Although increased attention is paid to this...
BACKGROUND
Trichophyton mentagrophyte (TM), a zoonotic pathogen, has been endangering public health due to emerging drug resistance. Although increased attention is paid to this issue, there is very limited research available on drug resistance in TM. In this study, we studied the gene and proteomic changes, morphological changes, cellular fat localization, fat content changes, and biofilm of TM treated with different substances.
RESULTS
The TM growth curve showed a positive correlation with the concentration of Fenarimol (FE), genistein (GE), clotrimazole (KM), and Miconazole nitrate salt (MK). The morphology of TM cells changed in different degrees after treatment with different substances as observed by TEM and SEM. The results showed that under KM and berberine hydrochloride (BB) treatment, a total of 3305 differentially expressed genes were detected, with the highest number in the KM-treated group (578 up-regulated and 615 down-regulated). A total of 847 proteins and 1850 peptides were identified in TM proteomics. Nile red staining showed that the fat content of TM was significantly higher in the BB-, ethidium bromide- (EB), FE-, KM-, Adriamycin hydrochloride- (YA), and MK-treated group compared to the control group. Results of the biofilm thickness showed that it gradually increased under treatment with specific concentrations of KM or BB, which may be related to the up-regulation of ERG25 and CYP related gene proteins.
CONCLUSIONS
It is suggested that in order to effectively deal with dermatomycosis caused by TM, it is necessary to inhibit the expression of ERG25 and CYP related genes and fat metabolism, which can result in the inhibition of the production of biofilm by the fungus and solve the problem of fungal drug resistance in clinical settings.
Topics: Arthrodermataceae; Drug Resistance, Fungal; Miconazole; Proteomics; Trichophyton
PubMed: 33827426
DOI: 10.1186/s12864-021-07520-6 -
Metabolites Apr 2023Human AKR 7A2 broadly participates in the metabolism of a number of exogenous and endogenous compounds. Azoles are a class of clinically widely used antifungal drugs,...
Human AKR 7A2 broadly participates in the metabolism of a number of exogenous and endogenous compounds. Azoles are a class of clinically widely used antifungal drugs, which are usually metabolized by CYP 3A4, CYP2C19, and CYP1A1, etc. in vivo. The azole-protein interactions that human AKR7A2 participates in remain unreported. In this study, we investigated the effect of the representative azoles (miconazole, econazole, ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole) on the catalysis of human AKR7A2. The steady-state kinetics study showed that the catalytic efficiency of AKR7A2 enhanced in a dose-dependent manner in the presence of posaconazole, miconazole, fluconazole, and itraconazole, while it had no change in the presence of econazole, ketoconazole, and voriconazole. Biacore assays demonstrated that all seven azoles were able to specifically bind to AKR7A2, among which itraconazole, posaconazole, and voriconazole showed the strongest binding. Blind docking predicted that all azoles were apt to preferentially bind at the entrance of the substrate cavity of AKR7A2. Flexible docking showed that posaconazole, located at the region, can efficiently lower the binding energy of the substrate 2-CBA in the cavity compared to the case of no posaconazole. This study demonstrates that human AKR7A2 can interact with some azole drugs, and it also reveals that the enzyme activity can be regulated by some small molecules. These findings will enable a better understanding of azole-protein interactions.
PubMed: 37233642
DOI: 10.3390/metabo13050601 -
Scientific Reports Jun 2024Zoonotic yeast species have been implicated in disease development in both humans and cats. This study analyzed the yeast mycobiota present in feline facial hair and... (Comparative Study)
Comparative Study
Zoonotic yeast species have been implicated in disease development in both humans and cats. This study analyzed the yeast mycobiota present in feline facial hair and human nails and explored potential interspecies associations. A total of 118 biological specimens were examined, including 59 feline facial hair and 59 human nail samples. DNA extraction and DNA sequencing were performed to identify the specific yeast species. The most predominant yeast species in humans and cats were selected for antifungal susceptibility testing (itraconazole, ketoconazole, miconazole, and terbinafine). The findings unveiled diverse yeast species in cats and humans. Malassezia pachydermatis (45.8%) and Malassezia furfur (30.5%) were the most common yeast species in cats and humans, respectively. However, no significant correlation was detected between the yeast species identified in cats and their owners residing in the same household (p > 0.05). Miconazole exhibited the highest minimum inhibitory concentrations (MICs) against Malassezia pachydermatis and Malassezia furfur in both cat and human isolates, whereas terbinafine showed the lowest MICs against most Malassezia pachydermatis and Malassezia furfur in both cat and human isolates. Diverse yeast species in cat facial hair and human nails suggest possible cross-contamination among humans, pets, and environments.
Topics: Cats; Humans; Antifungal Agents; Animals; Nails; Microbial Sensitivity Tests; Malassezia; Hair; Yeasts; Terbinafine; Miconazole; Male; Animal Fur; Female
PubMed: 38926524
DOI: 10.1038/s41598-024-65730-w -
Miconazole Contributes to NRF2 Activation by Noncanonical P62-KEAP1 Pathway in Bladder Cancer Cells.Drug Design, Development and Therapy 2020Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated...
PURPOSE
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.
MATERIALS AND METHODS
After miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining.
RESULTS
We demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production.
CONCLUSION
Our study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.
Topics: Dose-Response Relationship, Drug; Humans; Kelch-Like ECH-Associated Protein 1; Miconazole; NF-E2-Related Factor 2; Reactive Oxygen Species; Sequestosome-1 Protein; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms
PubMed: 32273683
DOI: 10.2147/DDDT.S227892 -
TheScientificWorldJournal 2021and are the leading causes of human fungal infections worldwide. There is an increase in resistance of pathogens to existing antifungal drugs leading to a need to... (Comparative Study)
Comparative Study
and are the leading causes of human fungal infections worldwide. There is an increase in resistance of pathogens to existing antifungal drugs leading to a need to find new sources of antifungal agents. Tormentic acid has been isolated from different plants including and has been found to possess antimicrobial properties, including antifungal activity. The study aimed to determine the effects of tormentic and extracts from on and . and a possible mode of action. The extracts and tormentic acid were screened for antifungal activity using the broth microdilution method. The growth of both species was inhibited by the extracts, and was more susceptible to the extract compared to . . The growth of . was inhibited by 80% at 100 g/ml of both the DCM: methanol extract and the ethanol: water extract. Tormentic acid reduced the growth of by 72% at 100 g/ml. The effects of the extracts and tormentic acid on ergosterol content in were determined using a UV/Vis scanning spectrophotometer. At concentrations of tormentic acid of 25 g/ml, 50 g/ml, 100 g/ml, and 200 g/ml, the content of ergosterol was decreased by 22%, 36%, 48%, and 78%, respectively. Similarly, the DCM: methanol extract at 100 g/ml and 200 g/ml decreased the content by 78% and 88%, respectively. A dose-dependent decrease in ergosterol content was observed in cells exposed to miconazole with a 25 g/ml concentration causing a 100% decrease in ergosterol content. Therefore, tormentic acid inhibits the synthesis of ergosterol in . Modifications of the structure of tormentic acid to increase its antifungal potency may be explored in further studies.
Topics: Antifungal Agents; Candida albicans; Candida tropicalis; Ergosterol; Melaleuca; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Extracts; Plant Leaves; Species Specificity; Spectrophotometry, Ultraviolet; Triterpenes
PubMed: 34594161
DOI: 10.1155/2021/8856147 -
Drug Delivery Dec 2022Nanocapsules can be equated to other nanovesicular systems in which a drug is entrapped in a void containing liquid core surrounded by a coat. The objective of the...
Nanocapsules can be equated to other nanovesicular systems in which a drug is entrapped in a void containing liquid core surrounded by a coat. The objective of the present study was to investigate the potential of polymeric and lipid nanocapsules (LNCs) as innovative carrier systems for miconazole nitrate (MN) topical delivery. Polymeric nanocapsules and LNCs were prepared using emulsification/nanoprecipitation technique where the effect of poly(ε-caprolactone (PCL) and lipid matrix concentrations with respect to MN were assessed. The resulted nanocapsules were examined for their average particle size, zeta potential, %EE, and drug release. Optimum formulation in both polymeric and lipidic nanocapsules was further subjected to anti-fungal activity and permeation tests. Based on the previous results, nanoencapsulation strategy into polymeric and LNCs created formulations of MN with slow biphasic release, high %EE, and improved stability, representing a good approach for the delivery of MN. PNCs were best fitted to Higuchi's diffusion while LNCs followed Baker and Lonsdale model in release kinetics. The encapsulated MN either in PNCs or LNCs showed higher cell viability in WISH amniotic cells in comparison with free MN. PNCs showed less permeation. PNCs were accompanied by high stability and more amount drug deposition (32.2 ± 3.52 µg/cm) than LNCs (12.7 ± 1.52 µg/cm). The antifungal activity of the PNCs was high 19.07 mm compared to 11.4 mm for LNCs. In conclusion, PNCs may have an advantage over LNCs by offering dual action for both superficial and deep fungal infections.
Topics: Administration, Cutaneous; Animals; Antifungal Agents; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Drug Carriers; Drug Liberation; Drug Stability; Humans; Lipids; Male; Miconazole; Nanocapsules; Nanoparticle Drug Delivery System; Particle Size; Polyesters; Rats; Rats, Sprague-Dawley; Surface Properties
PubMed: 35037528
DOI: 10.1080/10717544.2022.2026535 -
Veterinary Medicine and Science Nov 2023Fungal and yeast infections, including those caused by Malassezia spp., are becoming increasingly difficult to treat, likely due to the occurrence of drug resistance.
BACKGROUND
Fungal and yeast infections, including those caused by Malassezia spp., are becoming increasingly difficult to treat, likely due to the occurrence of drug resistance.
OBJECTIVES
This study aimed to evaluate the antifungal effects of omeprazole (OME), a proton pump inhibitor, against antifungal-resistant Malassezia pachydermatis and to investigate the potential synergistic effects between OME and other antifungal compounds.
METHODS
In total, 15 samples of M. pachydermatis isolated from the skin of dogs were tested. The susceptibility of M. pachydermatis to itraconazole, ketoconazole, miconazole, terbinafine and OME was assessed using a modified broth microdilution (BM) method. The in vitro efficacy of OME alone and in combination with other antifungal compounds was evaluated for all isolates using the BM chequerboard method. The data obtained were analysed using the fractional inhibitory concentration index (FICI).
RESULTS
The minimum inhibitory concentration (MIC) values of antifungal compounds and OME against quality control strain (M. pachydermatis CBS1879) were lower than the MIC values of same drugs against clinically collected strains. There was no significant difference in MIC values between drugs alone and combination. According to the analysis by the FICI method, no interaction was observed with OME and antifungal compounds.
CONCLUSIONS
Most M. pachydermatis strains were resistant to azole antifungal compounds. OME exerted antifungal effects against Malassezia spp. and even showed good effects on antifungal-resistant strains. No synergistic effects were observed between the antifungal compounds and OME.
Topics: Animals; Dogs; Antifungal Agents; Malassezia; Omeprazole; Drug Resistance, Fungal
PubMed: 37872836
DOI: 10.1002/vms3.1305