Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.
- MeSH
- antitumorózní látky farmakologie MeSH
- buněčná smrt MeSH
- epigeneze genetická MeSH
- kyselina mevalonová metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní farmakoterapie genetika metabolismus patologie MeSH
- pohyb buněk MeSH
- proliferace buněk MeSH
- statiny farmakologie MeSH
- transkriptom účinky léků MeSH
- výpočetní biologie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Determining the side effects of pesticides on pollinators is an important topic due to the increasing loss of pollinators. We aimed to determine the effects of chronic sublethal exposure of the neonicotinoid pesticide imidacloprid on the bumblebee Bombus terrestris under laboratory conditions. The analytical standard of imidacloprid in sugar solution was used for the treatment. Verification of pesticides using UHPLC-QqQ-MS/MS in the experimental bumblebees showed the presence of only two compounds, imidacloprid and imidacloprid-olefin, which were found in quantities of 0.57 ± 0.22 and 1.95 ± 0.43 ng/g, respectively. Thus, the level of the dangerous metabolite imidacloprid-olefin was 3.4-fold higher than that of imidacloprid. Label-free nanoLC-MS/MS quantitative proteomics of bumblebee heads enabled quantitative comparison of 2883 proteins, and 206 proteins were significantly influenced by the imidacloprid treatment. The next analysis revealed that the highly downregulated markers are members of the terpenoid backbone biosynthesis pathway (KEGG: bter00900) and that imidacloprid treatment suppressed the entire mevalonate pathway, fatty acid synthesis and associated markers. The proteomics results indicate that the consequences of imidacloprid treatment are complex, and the marker changes are associated with metabolic and neurological diseases and olfaction disruption. This study provides important markers and can help to explain the widely held assumptions from biological observations. SIGNIFICANCE: The major finding is that all markers of the mevalonate pathway were substantially downregulated due to the chronic imidacloprid exposure. The disbalance of mevalonate pathway has many important consequences. We suggest the mechanism associated with the novel toxicogenic effect of imidacloprid. The results are helpful to explain that imidacloprid impairs the cognitive functions and possesses the delayed and time cumulative effect.
- MeSH
- dusíkaté sloučeniny farmakologie MeSH
- insekticidy farmakologie MeSH
- kyselina mevalonová metabolismus MeSH
- mastné kyseliny biosyntéza MeSH
- neonikotinoidy farmakologie MeSH
- včely metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Statins belong to the major class of hypolipidemic drugs. They act as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the cholesterol biosynthetic pathway. This inhibition not only leads to the depletion of cholesterol and its fatty acid esters, but also to the depletion of the intermediates of this metabolic pathway (mainly pyrophosphates), which can play an important role in tumor proliferation. The aim of the current study was to establish a versatile multi-analyte method capable of quantitative determination of various currently-used statins, together with free cholesterol (FC), cholesterol esters (CEs), and some key intermediates of the mevalonate pathway occurring in human serum. Various methods of sample preparation were examined in order to minimize the content of potentially interfering serum proteins, and simultaneously to assure acceptable recovery of the target analytes. Following protein precipitation with 2-propanol, separation of the sample components using ultra-high performance liquid chromatography coupled with tandem high resolution mass spectrometry (U-HPLC-HRMS/MS) was performed, employing a hyphenated quadrupole Orbitrap mass analyzer. The potential of the developed method was validated on human serum samples from patients treated with statins. This versatile method possesses wide applicability, in both clinical and experimental medicine.
- MeSH
- cholesterol biosyntéza krev MeSH
- estery cholesterolu krev MeSH
- kyselina mevalonová metabolismus MeSH
- lidé MeSH
- polyisoprenylfosfáty krev MeSH
- seskviterpeny krev MeSH
- statiny krev MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- validační studie MeSH
Comparison of the genomes of free-living Bodo saltans and those of parasitic trypanosomatids reveals that the transition from a free-living to a parasitic life style has resulted in the loss of approximately 50% of protein-coding genes. Despite this dramatic reduction in genome size, B. saltans and trypanosomatids still share a significant number of common metabolic traits: glycosomes; a unique set of the pyrimidine biosynthetic pathway genes; an ATP-PFK which is homologous to the bacterial PPi -PFKs rather than to the canonical eukaryotic ATP-PFKs; an alternative oxidase; three phosphoglycerate kinases and two GAPDH isoenzymes; a pyruvate kinase regulated by fructose-2,6-bisphosphate; trypanothione as a substitute for glutathione; synthesis of fatty acids via a unique set of elongase enzymes; and a mitochondrial acetate:succinate coenzyme A transferase. B. saltans has lost the capacity to synthesize ubiquinone. Among genes that are present in B. saltans and lost in all trypanosomatids are those involved in the degradation of mureine, tryptophan and lysine. Novel acquisitions of trypanosomatids are components of pentose sugar metabolism, pteridine reductase and bromodomain-factor proteins. In addition, only the subfamily Leishmaniinae has acquired a gene for catalase and the capacity to convert diaminopimelic acid to lysine.
- MeSH
- aminokyseliny metabolismus MeSH
- Bacteria genetika metabolismus MeSH
- dolichol metabolismus MeSH
- ergosterol biosyntéza MeSH
- Eukaryota genetika metabolismus MeSH
- fosfolipidy metabolismus MeSH
- glukoneogeneze MeSH
- glykolýza MeSH
- Kinetoplastida enzymologie genetika metabolismus MeSH
- koenzymy metabolismus MeSH
- kyselina listová metabolismus MeSH
- kyselina mevalonová metabolismus MeSH
- metabolismus lipidů MeSH
- metabolismus sacharidů MeSH
- mikrotělíska metabolismus MeSH
- mitochondrie enzymologie metabolismus MeSH
- močovina metabolismus MeSH
- oxidoreduktasy metabolismus MeSH
- pentózofosfátový cyklus MeSH
- peroxizomy metabolismus MeSH
- polyaminy metabolismus MeSH
- prenylace proteinů MeSH
- protozoální geny genetika MeSH
- protozoální proteiny genetika MeSH
- puriny biosyntéza metabolismus MeSH
- pyrimidiny biosyntéza metabolismus MeSH
- reaktivní formy kyslíku MeSH
- Trypanosomatina enzymologie genetika metabolismus MeSH
- ubichinon metabolismus MeSH
- vitaminy metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Several pre-clinical and clinical studies have demonstrated zoledronic acid (Zol), which regulates the mevalonate pathway, has efficient anti-cancer effects. Zol can also induce autophagy. The aim of this study is to add new understanding to the mechanism of autophagy induction by Zol. LC3B-II, the marker for autophagy was increased by Zol treatment in breast cancer cells. Autophagosomes induced by Zol were visualized and quantified in both transient (pDendra2-hLC3) and stable MCF-7-GFP-LC3 cell lines. Acidic vesicular organelles were quantified using acridine orange. Zol induced a dose and time dependent autophagy. Treatment of Zol increased oxidative stress in MCF-7 cells, which was reversed by GGOH or anti-oxidants. On the other hand, treatment with GGOH or anti-oxidants resulted in decreased levels of LC3B-II. Further, the induced autophagy was irreversible, as the washout of Zol after 2 h or 24 h resulted in similar levels of autophagy, as induced by continuous treatment after 72 h. Thus, it can be summarized that Zol can induce a dose dependent but irreversible autophagy, by its effect on the mevalonate pathway and oxidative stress. This study adds to the understanding of the mechanism of action of Zol, and that it can induce autophagy at clinically relevant shorter exposure times in cancer cells.
- MeSH
- autofagie účinky léků MeSH
- bisfosfonáty farmakologie terapeutické užití MeSH
- imidazoly farmakologie terapeutické užití MeSH
- inhibitory kostní resorpce farmakologie terapeutické užití MeSH
- kyselina mevalonová metabolismus MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádory prsu farmakoterapie metabolismus MeSH
- oxidační stres účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Inhibitory HMG-CoA reduktázy (statiny) patří mezi klíčové léky v léčbě hypercholesterolémie. Kromě této významné funkce se v poslední době stále více do popředí dostává i úloha statinů jako látek blokujících tvorbu aterogenního plátu, zlepšujících funkci endotelu či fibrinolytickou aktivitu, snižujících agregaci destiček či jejich přímé protektivní účinky na mortalitu při akutním infarktumyokardu. Trochu stranou hlavního zájmu lékařské veřejnosti i farmaceutických společností zůstávají nepochybné a, jak vyplývá z výzkumných studií, velmi významné protinádorové vlastnosti této skupiny léků. Inhibicí HMG-CoA reduktázy, klíčového enzymu v syntéze cholesterolu, totiž dochází také k depleci jednotlivých meziproduktů v syntéze cholesterolu, z nichž nejvýznamnější je farnesyl pyrofosfát hrající důležitou roli v buněčné signalizaci ovlivňující apoptózu. Předmětem článku je sumarizovat dosavadní znalosti této problematiky a poukázat na ohromný léčebný potenciál této skupiny léků.
HMG-CoA reductase inhibitors (statins) belong to the key hypocholesterolemic drugs. Besides this very important function, several others have been recently demonstrated such as the inhibition of atherogenous plaque formation, platelet aggregation, or improvement of endothelial function and fibrinolytic activity, or even the direct protective effects of statins on the mortality of acute myocardial infarction. Aside from the major interest of both the medical community and pharmaceutical companies remain the very important anti-tumor effects of this group of drugs. As based on recent medical research, inhibition of HMG-CoA reductase, the key enzyme in the cholesterol biosynthesis, brings about depletion of several intermediates. The most important one seems to be farnesyl pyrophosphate, which has a very important role in the cell signaling affecting apoptosis. The aim of the survey is to summarize present knowledge in this medical field and to demonstrate the enormous curative potential of this group of drugs.
- MeSH
- buněčné dělení fyziologie účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- kyselina mevalonová antagonisté a inhibitory metabolismus MeSH
- lovastatin farmakologie MeSH
- nádory farmakoterapie MeSH
- protoonkogenní proteiny p21(ras) MeSH
- statiny farmakologie terapeutické užití MeSH
- Publikační typ
- klinické zkoušky MeSH
- přehledy MeSH
- MeSH
- autoimunitní nemoci etiologie genetika MeSH
- dítě MeSH
- familiární středomořská horečka diagnóza genetika terapie MeSH
- horečka diagnóza etiologie terapie MeSH
- kyselina mevalonová analogy a deriváty genetika metabolismus MeSH
- lidé MeSH
- periodicita MeSH
- receptory interferonů genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- kongresy MeSH
Kazuistické sdělení dvou případů syndromu hyperimunoglobulinémie D (HIDS) u dvou sourozenců. Diskutováno je o diagnostice a léčebné možnosti HIDS.
Two case reports of hyperimmunoglobulinemia D syndrome (HIDS) in siblings are described. Clinical features of the cases and therapeutic possibilities are discussed.
- MeSH
- dítě MeSH
- horečka imunologie komplikace MeSH
- kojenec MeSH
- kyselina mevalonová analogy a deriváty metabolismus MeSH
- lidé MeSH
- nemoci imunitního systému diagnóza etiologie komplikace MeSH
- syndrom MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- dítě MeSH
- fosfotransferasy genetika nedostatek MeSH
- hypergamaglobulinemie enzymologie genetika MeSH
- kyselina mevalonová metabolismus MeSH
- lidé MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
