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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 -
Expert Review of Anti-infective Therapy Jan 2011Oropharyngeal candidiasis is a commonly encountered problem in daily clinical practice. Topical therapies for oropharyngeal candidiasis are considered preferable to...
Oropharyngeal candidiasis is a commonly encountered problem in daily clinical practice. Topical therapies for oropharyngeal candidiasis are considered preferable to systemic therapies in most patient populations. However, traditional topical therapies have limitations including short contact time with the oral mucosa and the need for multiple doses each day. Miconazole mucoadhesive tablet has recently been approved in Europe (Loramyc®) and the USA (Oravig™) for the treatment of oropharyngeal candidiasis. This tablet adheres to the oral mucosa and provides sustained local release of miconazole over a period of several hours with just one daily application. This article reviews the pharmacology, safety and efficacy of this novel agent.
Topics: Administration, Topical; Antifungal Agents; Candidiasis, Oral; Europe; Humans; Miconazole; Mouth Mucosa; Oropharynx; Randomized Controlled Trials as Topic; Tablets; United States
PubMed: 21171872
DOI: 10.1586/eri.10.152 -
Antimicrobial Agents and Chemotherapy May 1980A total of 440 fresh clinical isolates of yeasts from cancer patients were tested by an agar dilution technique against miconazole, miconazole nitrate, and ketoconazole... (Comparative Study)
Comparative Study
In vitro activities of miconazole, miconazole nitrate, and ketoconazole alone and combined with rifampin against Candida spp. and Torulopsis glabrata recovered from cancer patients.
A total of 440 fresh clinical isolates of yeasts from cancer patients were tested by an agar dilution technique against miconazole, miconazole nitrate, and ketoconazole individually and combined with 5 micrograms of rifampin per ml. Most strains of Candida albicans were susceptible to 0.5 microgram or less of the imidazoles per ml. Candida tropicalis required 2 to 4 micrograms of miconazole and its nitrate base per ml for inhibition and was resistant to ketoconazole. The 100% minimal inhibitory concentration of the imidazoles for Candida krusei was 1 microgram/ml. Susceptibility to 4 micrograms of miconazole and miconazole nitrate per ml occurred in 73 and 87% of Torulopsis glabrata strains, respectively, and none was susceptible to ketoconazole. Miconazole was most effective against the Candida spp., whereas its nitrate base was most active against T. glabrata. Synergy was observed when rifampin was combined with miconazole and miconazole nitrate but was not observed when rifampin was combined with ketoconazole. Synergy occurred most frequently when rifampin was combined with miconazole nitrate.
Topics: Antifungal Agents; Candida; Drug Synergism; Humans; Imidazoles; Ketoconazole; Miconazole; Microbial Sensitivity Tests; Neoplasms; Piperazines; Rifampin
PubMed: 6249197
DOI: 10.1128/AAC.17.5.871 -
Pharmaceutics Feb 2023Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded...
Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded bilosomes (BSs) for the improvement of therapeutic efficacy. MZBSs were prepared by using the thin-film hydration method and further optimized by using the Box-Behnken statistical design (BBD). The optimized miconazole bilosome (MZBSo) showed nano-sized vesicles, a low polydispersity index, a high entrapment efficiency, and zeta potential. Further, MZBSo was incorporated into the gel using carbopol 934P and chitosan polymers. The selected miconazole bilosome gel (MZBSoG2) demonstrated an acceptable pH (6.4 ± 0.1), viscosity (1856 ± 21 cP), and spreadability (6.6 ± 0.2 cm). Compared to MZBSo (86.76 ± 3.7%), MZBSoG2 showed a significantly ( < 0.05) slower drug release (58.54 ± 4.1%). MZBSoG2 was found to be a non-irritant because it achieved a score of zero (standard score) in the HET-CAM test. It also exhibited significant antifungal activity compared to pure MZ against and . The stability study results showed no significant changes after stability testing under accelerated conditions. MZ-loaded gels could serve as effective alternative carriers for improving therapeutic efficacy.
PubMed: 36839903
DOI: 10.3390/pharmaceutics15020581 -
PloS One 2014The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due...
The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L-1, respectively) followed by promethazine (1.6 and 0.18 mg L-1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L-1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.
Topics: Animals; Aquatic Organisms; Daphnia; Drug Design; Levonorgestrel; Miconazole; Promethazine; Risk Assessment; Water Pollutants, Chemical
PubMed: 25140792
DOI: 10.1371/journal.pone.0105028 -
Journal of Medicinal Chemistry Dec 2023Developing drugs for brain infection by is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to...
Developing drugs for brain infection by is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected were tested against . Nine primary hits with EC ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound . The -enantiomer of produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the -configuration over the -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, - and -, had an improved EC and compared to . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of - was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.
Topics: Miconazole; 14-alpha Demethylase Inhibitors; Naegleria fowleri; Drug Discovery
PubMed: 38085955
DOI: 10.1021/acs.jmedchem.3c01898 -
Antimicrobial Agents and Chemotherapy Feb 1978Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum... (Comparative Study)
Comparative Study
Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum levels higher than the minimum inhibitory concentration for the challenge strain. However, maximal tolerable doses of miconazole gave no increase in survival. When combined with amphotericin B, miconazole demonstrated neither additive nor antagonistic effects on survival. Spleen and brain counts of cryptococci were not lowered by miconazole; also, miconazole did not alter the effect of amphotericin B on reducing tissue counts. In vitro studies confirmed that the strain of Cryptococcus neoformans was quite susceptible to both miconazole and amphotericin B. However, miconazole had a delayed onset of antifungal activity. This was apparent even at miconazole levels 20 times greater than the minimum inhibitory concentration. Also, the antifungal activity of miconazole was markedly inhibited by serum. Delayed antifungal activity and serum inhibition may limit the in vivo effectiveness of miconazole in murine cryptococcosis.
Topics: Amphotericin B; Animals; Cryptococcosis; Cryptococcus neoformans; Drug Therapy, Combination; Imidazoles; Male; Mice; Mice, Inbred BALB C; Miconazole; Microbial Sensitivity Tests
PubMed: 348099
DOI: 10.1128/AAC.13.2.277 -
Turkish Journal of Medical Sciences Jun 2018Background/aim: Dermatophytes are the causative agents of dermatophytosis, which is a common disease worldwide that affects the hair, skin, and nails. Dermatophytes...
Background/aim: Dermatophytes are the causative agents of dermatophytosis, which is a common disease worldwide that affects the hair, skin, and nails. Dermatophytes comprise more than 40 species in 3 genera: Microsporum, Trichophyton, and Epidermaphyton. In this study, we aimed to determine the effectiveness of seven antifungal agents: amphotericin B, terbinafine, itraconazole, voriconazole, ketoconazole, miconazole, and fluconazole. Materials and methods: A sensitivity study was performed using a microdilution method in accordance with the CLSI M38-A2 standards using isolates of Trichophyton rubrum (n = 55), Microsporum canis (n = 9), and Trichophyton interdigitale (n = 2), which were identified by sequencing the internal transcribed spacer region of the rDNA. Results: According to the results of antifungal sensitivity tests, the geometric mean (GM) minimum inhibitory concentration (MIC) against T. rubrum was 0.10 μg/mL for ketoconazole, 0.20 μg/mL for itraconazole, 0.07 μg/mL for miconazole, 0.48 μg/mL for fluconazole, 2.27 μg/mL for amphotericin B, 0.06 μg/mL for voriconazole, and 0.06 μg/mL for terbinafine. Conclusion: The most effective antifungal drugs were voriconazole and terbinafine, both of which had a GM MIC of 0.06 μg/mL.
PubMed: 29916221
DOI: 10.3906/sag-1709-157 -
Medical Mycology Journal 2013Malassezia pachydermatis is the major species in Malassezia isolated from dogs, and there is a presumably Malassezia-associated skin disease,"Malassezia dermatitis" in... (Review)
Review
Malassezia pachydermatis is the major species in Malassezia isolated from dogs, and there is a presumably Malassezia-associated skin disease,"Malassezia dermatitis" in the dog. The skin lesion is characterized by relatively demarcated erythema with some scaling at the sebum-rich areas, in which lichenification and hyperpigmentation could be involved in the chronic stage. The clinical features suggest that it corresponds to seborrheic dermatitis in humans. Hence, it might be possible to identify essential pathogenesis of the disease by clarifying its differences in humans and animals as a shared disease.
Topics: Animals; Antifungal Agents; Dermatomycoses; Detergents; Dog Diseases; Dogs; Humans; Ketoconazole; Malassezia; Miconazole; Skin; Zoonoses
PubMed: 23470954
DOI: 10.3314/mmj.54.45 -
Pharmaceutics Jun 2020Opportunistic fungal infections are responsible for over 1.5 million deaths per year. This has created a need for highly effective antifungal medication to be as potent...
Opportunistic fungal infections are responsible for over 1.5 million deaths per year. This has created a need for highly effective antifungal medication to be as potent as possible. In this study, we improved the efficacy of a common over the counter (OTC) antifungal skin medication, miconazole, by encapsulating nano-molecules of the drug in cholesterol/sodium oleate nano-vesicles. These nano-vesicles were characterized to optimize their size, zeta potential, polydispersity index and encapsulation efficiency. Furthermore, these nano-vesicles were compared to a conventional miconazole-based commercially available cream to determine potential improvements via permeation through the stratum corneum, cytotoxicity, and antifungal capabilities. Our results found that the vesicle size was within the nano range (~300 nm), with moderate polydispersity and stability. When compared with the commercially available cream, Actavis, as well as free miconazole, the miconazole nano-vesicle formulation displayed enhanced fungal inhibition by a factor of three or more when compared to free miconazole. Furthermore, with smaller nanoparticle (NP) sizes, higher percentages of miconazole may be delivered, further enhancing the efficacy of miconazole's antifungal capability. Cytotoxicity studies conducted with human dermal fibroblast cells confirm its biosafety and biocompatibility, as cell survival rate was observed to be twofold higher in nano-vesicle formulation than free miconazole. This formulation has the potential to treat fungal infections through increasing the retention time in the skin, improving the treatment approach, and by enhancing the efficacy via the use of nano-vesicles.
PubMed: 32517047
DOI: 10.3390/pharmaceutics12060516