Matoušková, Lenka*
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Glutathione peroxidases (GPxs) belong to the eight-member family of phylogenetically related enzymes with different cellular localization, but distinct antioxidant function. Several GPxs are important selenoproteins. Dysregulated GPx expression is connected with severe pathologies, including obesity and diabetes. We performed a comprehensive bioinformatic analysis using the programs miRDB, miRanda, TargetScan, and Diana in the search for hypothetical microRNAs targeting 3'untranslated regions (3´UTR) of GPxs. We cross-referenced the literature for possible intersections between our results and available reports on identified microRNAs, with a special focus on the microRNAs related to oxidative stress, obesity, and related pathologies. We identified many microRNAs with an association with oxidative stress and obesity as putative regulators of GPxs. In particular, miR-185-5p was predicted by a larger number of programs to target six GPxs and thus could play the role as their master regulator. This microRNA was altered by selenium deficiency and can play a role as a feedback control of selenoproteins' expression. Through the bioinformatics analysis we revealed the potential connection of microRNAs, GPxs, obesity, and other redox imbalance related diseases.
- MeSH
- 3' nepřekládaná oblast MeSH
- glutathionperoxidasa genetika metabolismus MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- obezita genetika metabolismus patologie MeSH
- oxidační stres MeSH
- regulace genové exprese * MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Colon cancer is the most common type of gastrointestinal cancer. Despite advances during the last two decades, the efficacy of colorectal cancer treatment is still insufficient and new anticancer agents are necessary. METHODS: In our study, colon cancer cells derived from a primary tumor (SW480) and lymph node metastasis (SW620) from the same patient were used and compared. The effect of flubendazole (FLU) on cell adhesion and migration was monitored using the x-CELLigence Real-Time Cell Analysis system. Expressions of molecules involved in adhesion and migration were analyzed using RT-PCR and western blot. Furthermore, RNA silencing of nuclear factor-κB in SW620 cells was used to determine the involvement of the NF-κB p65 regulation pathway in FLU action. RESULTS: FLU significantly suppressed the adhesion of SW480 cells and reduced the expression of adhesion markers (ICAM-1, αE-catenin; β-catenin; integrin α5 and β1). Moreover, a significant anti-migratory potential of FLU was manifested in the SW620 cells. In addition, FLU suppressed the phosphorylation of NF-κB p65 and potentiated the suppression of several metastatic markers (ICAM-1, EpCAM, integrin α5, β1, α-tubulin) caused by NF-κB p65 silencing. CONCLUSION: FLU has a significant anti-migratory effect in intestinal cancer cell SW480 and its lymph node metastatic cells SW620. FLU decreases the expression of some proteins involved in metastatic processes and inhibits activation of NF-κB p65.
- MeSH
- buněčná adheze účinky léků MeSH
- lidé MeSH
- mebendazol analogy a deriváty chemie farmakologie MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- nádory tračníku farmakoterapie patologie MeSH
- pohyb buněk účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
Xenobiotic-metabolizing enzymes (XMEs) modulate the biological activity and behavior of many drugs, including anthelmintics. The effects of anthelmintics can often be abolished by XMEs when the drugs are metabolized to an inefficient compound. XMEs therefore play a significant role in anthelmintic efficacy. Moreover, differences in XMEs between helminths are reflected by differences in anthelmintic metabolism between target species. Taking advantage of the newly sequenced genomes of many helminth species, progress in this field has been remarkable. The present review collects up to date information regarding the most important XMEs (phase I and phase II biotransformation enzymes; efflux transporters) in helminths. The participation of these XMEs in anthelmintic metabolism and their possible roles in drug resistance are evaluated.
- MeSH
- anthelmintika metabolismus farmakologie MeSH
- cizopasní červi účinky léků enzymologie MeSH
- genom u helmintů genetika MeSH
- interakce hostitele a parazita genetika MeSH
- léková rezistence genetika MeSH
- proteiny červů genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.
- MeSH
- alkoholoxidoreduktasy antagonisté a inhibitory biosyntéza genetika metabolismus MeSH
- bupropion metabolismus MeSH
- butanony metabolismus MeSH
- butyrofenony metabolismus MeSH
- chinoliziny metabolismus MeSH
- daunomycin metabolismus MeSH
- doxorubicin metabolismus MeSH
- fenylpropionáty metabolismus MeSH
- haloperidol metabolismus MeSH
- indoly metabolismus MeSH
- lidé MeSH
- nádory enzymologie MeSH
- polyfenoly farmakologie MeSH
- regulace genové exprese enzymů MeSH
- substrátová specifita MeSH
- xenobiotika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
