Inhibition of fungal lanosterol-14 alpha-demethylase (CYP51) is the working principle of the antifungal activity of azoles used in agriculture and medicine. Inhibition of human CYP51 may result in endocrine disruption since follicular fluid-meiosis activating steroid (FF-MAS), the direct product of lanosterol demethylation, is involved in the control of meiosis. To investigate the specificity of antifungal agents for the fungal enzyme, assays to determine inhibitory potencies of 13 agricultural fungicides and 6 antimycotic drugs were established. FF-MAS product formation was measured by LC-MS/MS analysis in the incubations using lanosterol as substrate. Recombinant human enzyme (hCYP51) was available from BD Gentest. CYP51 of Candida albicans (cCYP51) was co-expressed with Candida tropicalis oxidoreductase in the baculovirus system. IC(50) values of 13 fungicides for cCYP51 ranged about six-fold (0.059-0.35 microM); for hCYP51 the range was about 30-fold (1.3-37.2 microM). The most favourable IC(50) ratio human to Candida was observed for imazalil (440-fold), while the specificity of epoxiconazole and tebuconazole for cCYP51 was only by a factor of 10. For the antimycotic drugs, the range of IC(50) values for cCYP51 was similar to those of fungicides (0.039-0.30 microM). For the inhibition of hCYP51, IC(50) values split into two classes: the newer drugs fluconazole and itraconazole showed little inhibition (> or = 30 microM) while the older drugs were even more potent than the agricultural fungicides, with miconazole being the most potent (0.057 microM). No correlation was seen between the IC(50) values determined for the two enzymes, indicating that a housekeeping gene can show significant diversity if inhibition is concerned. Our data indicate that fungicide residues in food are unlikely to exert a relevant inhibition of CYP51 in humans whereas systemic use of some antimycotic drugs, e.g. ketoconazole or miconazole, should be carefully considered regarding disturbance of human steroid biosynthesis.
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http://dx.doi.org/10.1016/j.tox.2006.08.007 | DOI Listing |
J Nat Prod
January 2025
Department of Chemical and Biological engineering, School of Engineering and Technology, National University of Mongolia, Ulaanbaatar 14201, Mongolia.
A chemical examination of a root extract of led to the isolation and identification of 23 compounds, including oxazole-type alkaloids and isoflavonoid derivatives. Notably, three oxazole-type alkaloids (, , and ) and two isoflavonoid derivatives ( and ) were obtained from a natural source for the first time. In addition, derived 2,5-diphenyloxazoles and their derivatives were synthesized.
View Article and Find Full Text PDFNat Prod Res
January 2025
Department of Applied Science, Faculty of Engineering & Technology, Gurukula Kangri (Deemed to be University), Haridwar, India.
The present study aimed to evaluate the nutrition value, phytochemical content, and diverse pharmacological activities of different solvent extracts of L. fruit. Among all, the hydro-alcoholic extract showed high DPPH and ABTS radical scavenging activities with IC values of 82.
View Article and Find Full Text PDFJ Transl Med
January 2025
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Background: KRAS-G12C inhibitors mark a notable advancement in targeted cancer therapies, yet identifying predictive biomarkers for treatment efficacy and resistance remains essential for optimizing clinical outcomes.
Methods: This systematic meta-analysis synthesized studies available through September 2024 across PubMed, Cochrane Library, SpringerLink, and Embase. Using CRISPR/Cas9 technology, this study generated cells with KEAP1 and STK11 knockouts, and utilized lentiviral vectors to overexpress PD-L1.
Fitoterapia
January 2025
State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, Guizhou, China. Electronic address:
Four new alkaloids, meloformisine A (1), meloformine B (2), meloformine F (3), meloformine G (4), along with five known alkaloids (5-9) were isolated from the leaves and twigs of Melodinus fusiformis. Their structures were elucidated on the basis of detailed spectroscopic evidence, including 1D and 2D NMR, MS, and single-crystal X-ray diffraction analysis. The structure of 1 was a novel indole alkaloid with an unprecedented 6/5/5/5/5 pentacyclic skeleton.
View Article and Find Full Text PDFBiochem Pharmacol
January 2025
Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; Institute of Biosciences, University Research Center Ioannina, University of Ioannina, Ioannina, Greece. Electronic address:
PTEN, a tumor suppressor phosphatase, regulates cellular functions by antagonizing the growth promoting PI3K/Akt/mTOR pathway through the dephosphorylation of the second messenger PIP. Many preclinical cellular and animal studies have used PTEN inhibitors to highlight specific disease contexts where acute activation of PI3K/Akt/mTOR pathway might offer therapeutic advantages. In the present study we have re-evaluated first-generation PTEN inhibitors, including established bisperoxo-vanadium complexes (bpVs).
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