The sesquiterpenes alantolactone (ATL) and germacrone (GER) are potential anticancer agents of natural origin. Their toxicity and biological activity have been evaluated using the differentiated HepaRG (dHepaRG) cells, a hepatocyte-like model. The half-maximal inhibitory concentrations of cell viability after 24-h treatment of dHepaRG cells are approximately 60 µM for ATL and 250 µM for GER. However, both sesquiterpenes induce reactive oxygen species (ROS) formation in non-toxic concentrations and significantly dysregulate the mRNA expression of several functional markers of mature hepatocytes. They similarly decrease the protein level of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and their transcription target, intercellular adhesion molecule 1 (ICAM-1). Based on the results of a BATMAN-TCM analysis, the effects of sesquiterpenes on cholesterol and lipid metabolism were studied. Sesquiterpene-mediated dysregulation of both cholesterol and lipid metabolism was observed, during which these compounds influenced the protein expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP-2), as well as the mRNA expression of HMGCR, CYP19A1, PLIN2, FASN, SCD, ACACB, and GPAM genes. In conclusion, the two sesquiterpenes caused ROS induction at non-toxic concentrations and alterations in cholesterol and lipid metabolism at slightly toxic and toxic concentrations, suggesting a risk of liver damage if administered to humans.
- MeSH
- buňky Hep G2 MeSH
- cholesterol metabolismus MeSH
- exprese genu účinky léků MeSH
- fytogenní protinádorové látky toxicita MeSH
- hydroxymethylglutaryl-CoA-reduktasy genetika metabolismus MeSH
- játra metabolismus MeSH
- laktony toxicita MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- mezibuněčná adhezivní molekula-1 metabolismus MeSH
- NF-kappa B metabolismus MeSH
- protein SREBP2 genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- seskviterpeny eudesmanové toxicita MeSH
- seskviterpeny germakranové toxicita MeSH
- transkripční faktor STAT3 metabolismus MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.
- MeSH
- antifungální látky chemie farmakologie toxicita MeSH
- Arthrodermataceae účinky léků MeSH
- buněčná stěna účinky léků MeSH
- Candida účinky léků MeSH
- laktony chemie farmakologie toxicita MeSH
- leukocyty účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- vyvíjení léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antagonisté receptorů pro angiotenzin škodlivé účinky terapeutické užití toxicita MeSH
- bisfosfonáty škodlivé účinky terapeutické užití MeSH
- fraktury femuru etiologie komplikace MeSH
- informační služby o lécích normy organizace a řízení využití MeSH
- játra účinky léků MeSH
- karcinogeny MeSH
- laktony škodlivé účinky terapeutické užití toxicita MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- nežádoucí účinky léčiv komplikace MeSH
- statistika jako téma MeSH
- vládní organizace využití zákonodárství a právo MeSH
- Check Tag
- lidé MeSH
- MeSH
- Cynara scolymus * chemie toxicita MeSH
- ekdysteroidy farmakokinetika farmakologie toxicita MeSH
- experimenty na zvířatech MeSH
- flavonoidy farmakokinetika farmakologie toxicita MeSH
- koně MeSH
- krysa rodu rattus MeSH
- laktony farmakokinetika farmakologie toxicita MeSH
- Leuzea * chemie MeSH
- lidé MeSH
- potravní doplňky MeSH
- protinádorové látky terapeutické užití MeSH
- rostlinné extrakty * MeSH
- stonky rostlin MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- MeSH
- alanintransaminasa krev MeSH
- alkalická fosfatasa krev MeSH
- aspartátaminotransferasy krev MeSH
- buněčné dělení účinky léků MeSH
- Ehrlichův tumor farmakoterapie MeSH
- experimentální nádory mléčných žláz farmakoterapie MeSH
- experimentální nádory farmakoterapie MeSH
- experimentální sarkom farmakoterapie MeSH
- hepatocelulární karcinom farmakoterapie MeSH
- ketokyseliny krev MeSH
- krysa rodu rattus MeSH
- laktony farmakologie toxicita MeSH
- myši MeSH
- nádory jater farmakoterapie MeSH
- nehodgkinský lymfom farmakoterapie MeSH
- prognóza MeSH
- protinádorové látky farmakologie toxicita MeSH
- sarkom 180 farmakoterapie MeSH
- sarkom Yoshidův farmakoterapie MeSH
- sodík farmakologie MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
