Podnětem pro toto sdělení byla inspirativní přednáška nositele Nobelovy ceny za fyziologii a lékařství Petera J. Ratcliffeho, všeobecně se zamýšlející nad poznáváním fyziologických mechanismů. Sdělení odkazuje na úsilí, které jsme před 50 lety vynaložili na poznání molekulárních mechanismů, kterými nedostatek kyslíku aktivuje tvorbu erytropoetinu. Dokázali jsme výlučnou úlohu kyslíku v aktivaci tvorby erytropoetinu. Porovnáním s reakcí periferních chemoreceptorů v glomus caroticum na nedostatek kyslíku, která je spojena s tvorbou ATP, jsme hledali metabolickou podstatu závislosti tvorby erytropoetinu na nedostatku kyslíku. Vyloučili jsme závislost tvorby erytropoetinu na spotřebě kyslíku mitochondriemi a na tvorbě ATP. Pro rozšíření a přijetí těchto našich výsledků bylo významné uspořádání mezinárodního setkání vědců v roce 1970 v Praze, Symposium Erythropoieticum. Tento náš výzkum je příkladem významu publikování negativních výsledků v případě, kdy je správně vymezen výzkumný problém. Sdělení ukazuje na různé okolnosti, které znesnadňují nebo znemožňují dosažení výzkumných cílů a ovlivňují jejich přijetí. Ukazuje, že i po poznání molekulární a buněčné podstaty fyziologických dějů je jejich uplatnění v celém organismu významně ovlivněno komplexností fyziologických regulací.
This work was inspired by the seminal lecture of Nobel prize winner Sir Peter J. Ratcliffe in which he discussed various approaches to generating new knowledge in physiology. This report reflects and summarizes our efforts 50 years ago to reveal the molecular mechanisms involved in hypoxia-induced erythropoietin production. In this work, we demonstrated the unique role of oxygen in the activation of erythropoietin production and demonstrated that erythropoietin production is independent of oxygen consumption linked with ATP generation. The Symposium Erythropoieticum held in Prague in 1970 played a significant role in the acceptance of these results. This research is also an example of the significance of publishing negative results in cases where the research question is correctly defined. Circumstances influencing the acceptance and elaboration of research results by the broader scientific community are considered, as are the timing and external conditions that restrict the achievement of research goals and their acceptance. This report also demonstrates that even a deep understanding of the molecular and cellular mechanisms that underlie physiological functions is not necessarily sufficient to explain their role in vivo where they are modified by complex control mechanisms.
- MeSH
- biomedicínský výzkum * dějiny MeSH
- buňky metabolismus MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- erythropoetin * dějiny MeSH
- hypoxie * dějiny MeSH
- kyslík MeSH
- lidé MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- Publikační typ
- historické články MeSH
- Geografické názvy
- Česká republika MeSH
The potential of nanomaterials use is huge, especially in fields such as medicine or industry. Due to widespread use of nanomaterials, their cytotoxicity and involvement in cellular pathways ought to be evaluated in detail. Nanomaterials can induce the production of a number of substances in cells, including reactive oxygen species (ROS), participating in physiological and pathological cellular processes. These highly reactive substances include: superoxide, singlet oxygen, hydroxyl radical, and hydrogen peroxide. For overall assessment, there are a number of fluorescent probes in particular that are very specific and selective for given ROS. In addition, due to the involvement of ROS in a number of cellular signaling pathways, understanding the principle of ROS production induced by nanomaterials is very important. For defense, the cells have a number of reparative and especially antioxidant mechanisms. One of the most potent antioxidants is a tripeptide glutathione. Thus, the glutathione depletion can be a characteristic manifestation of harmful effects caused by the prooxidative-acting of nanomaterials in cells. For these reasons, here we would like to provide a review on the current knowledge of ROS-mediated cellular nanotoxicity manifesting as glutathione depletion, including an overview of approaches for the detection of ROS levels in cells.
- MeSH
- buňky účinky léků metabolismus MeSH
- glutathion metabolismus MeSH
- lidé MeSH
- nanostruktury toxicita MeSH
- oxidační stres účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Higher plants represent a large group of eukaryotes where centrosomes are absent. The functions of γ-tubulin small complexes (γ-TuSCs) and γ-tubulin ring complexes (γ-TuRCs) in metazoans and fungi in microtubule nucleation are well established and the majority of components found in the complexes are present in plants. However, plant microtubules are also nucleated in a γ-tubulin-dependent but γ-TuRC-independent manner. There is growing evidence that γ-tubulin is a microtubule nucleator without being complexed in γ-TuRC. Fibrillar arrays of γ-tubulin were demonstrated in plant and animal cells and the ability of γ-tubulin to assemble into linear oligomers/polymers was confirmed in vitro for both native and recombinant γ-tubulin. The functions of γ-tubulin as a template for microtubule nucleation or in promoting spontaneous nucleation is outlined. Higher plants represent an excellent model for studies on the role of γ-tubulin in nucleation due to their acentrosomal nature and high abundancy and conservation of γ-tubulin including its intrinsic ability to assemble filaments. The defining scaffolding or sequestration functions of plant γ-tubulin in microtubule organization or in nuclear processes will help our understanding of its cellular roles in eukaryotes.
- MeSH
- buňky metabolismus MeSH
- centrozom metabolismus MeSH
- lidé MeSH
- rostliny metabolismus MeSH
- sekvence aminokyselin MeSH
- tubulin chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Klíčová slova
- mitochondriální pór přechodné propustnosti,
- MeSH
- akutní nekrotizující pankreatitida patologie MeSH
- Alzheimerova nemoc etiologie MeSH
- amyotrofická laterální skleróza etiologie MeSH
- buňky metabolismus MeSH
- Huntingtonova nemoc etiologie MeSH
- ionty chemie MeSH
- kardiovaskulární nemoci MeSH
- mitochondriální membrány patologie MeSH
- mitochondrie fyziologie patologie MeSH
- nealkoholová steatóza jater etiologie MeSH
- oxidační stres MeSH
- Parkinsonova nemoc etiologie MeSH
- reperfuzní poškození myokardu farmakoterapie MeSH
- Reyeův syndrom etiologie MeSH
- salicylany toxicita MeSH
- syndromy suchého oka etiologie MeSH
- vápník chemie metabolismus MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- aminokyseliny imunologie metabolismus MeSH
- buňky * imunologie metabolismus MeSH
- glukosa metabolismus MeSH
- glykolýza imunologie MeSH
- imunitní systém * fyziologie metabolismus MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- mastné kyseliny imunologie metabolismus MeSH
- T-lymfocyty imunologie MeSH
- Warburgův efekt MeSH
- Check Tag
- lidé MeSH
The nanotechnological concept is based on size-dependent properties of particles in the 1-100 nm range. Nevertheless, the connection between their size and effect is still not clear. Thus, we focused on reductive colloidal synthesis, characterization and biological testing of Pt nanoparticles (PtNPs) capped with biocompatible polymer polyvinylpyrrolidone (PVP). Synthesized PtNPs were of 3 different primary sizes (approx. ∼10; ∼14 and > 20 nm) and demonstrated exceptional haemocompatibility. In vitro treatment of three different types of malignant cells (prostate - LNCaP, breast - MDA-MB-231 and neuroblastoma - GI-ME-N) revealed that even marginal differences in PtNPs diameter resulted in changes in their cytotoxicity. The highest cytotoxicity was observed using the smallest PtNPs-10, where 24IC50 was lower (3.1-6.2 μg/mL) than for cisplatin (8.1-19.8 μg/mL). In contrast to MDA-MB-231 and LNCaP cells, in GI-ME-N cells PtNPs caused noticeable changes in their cellular structure without influencing their viability. Post-exposure analyses revealed that PtNPs-29 and PtNPs-40 were capable of forming considerably higher amount of reactive oxygen species with consequent stimulation of expression of metallothionein (MT1/2 and MT3), at both mRNA and protein level. Overall, our pilot study demonstrates that in the nanoscaled world even the smallest differences can have crucial biological effect.
- MeSH
- buněčné linie MeSH
- buňky účinky léků metabolismus MeSH
- kovové nanočástice chemie MeSH
- lidé MeSH
- nanotechnologie MeSH
- platina chemie farmakologie MeSH
- polymery chemická syntéza chemie MeSH
- povidon chemická syntéza chemie farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- velikost částic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin), chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea), direct inhibition of the activity of replicative DNA polymerases (aphidicolin) and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide). As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses.
- MeSH
- antitumorózní látky chemie farmakologie MeSH
- buňky účinky léků metabolismus MeSH
- fyziologický stres * účinky léků MeSH
- lidé MeSH
- replikace DNA * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
