reactivation process
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Proces stárnutí je předmětem zájmu mnoha vědních oborů. Život mnohobuněčného organizmu je udržován rovnováhou mezi produkcí nových buněk a zánikem starých. Celý tento proces je řízen řadou faktorů, regulačních mechanizmů. Ve stáři dochází k určitým změnám v oblasti antioxidační kapacity, metabolizmu mastných kyselín a biosyntězy cholesterolu. Studiem těchto změn bychom mohli přispět k podačení nepříznivého účinku aktivních forem kyslíku a zpomalení procesu stárnutí.
The process of ageing has been the focus of many research disciplines. A multicellular organism is kept alive through a balance of new cell production and old cell decay. There are a number of factors - regulating mechanisms controlling the whole process. Old age is characterized by certain changes as to antioxidant capacity, fatty acid netabolism and cholesterol biosynthesis. Research into these changes may help to suppress the undesirable effect of free oxygen radicals and slow down the process of ageing.
- MeSH
- apoptóza genetika imunologie účinky léků MeSH
- cholesterol biosyntéza MeSH
- homeostáza fyziologie genetika imunologie MeSH
- lidé MeSH
- lipidy MeSH
- metabolismus lipidů MeSH
- reaktivní formy kyslíku škodlivé účinky MeSH
- stárnutí fyziologie imunologie metabolismus MeSH
- vitaminy terapeutické užití MeSH
- Check Tag
- lidé MeSH
Organophosphorus compounds such as nerve agents inhibit, practically irreversibly, cholinesterases by their phosphorylation in the active site of these enzymes. Current antidotal treatment used in the case of acute nerve agent intoxications consists of combined administration of anticholinergic drug (usually atropine) and acetylcholinesterase (AChE, EC 3.1.1.7) reactivator (HI-6, obidoxime, pralidoxime), which from a chemical view is a derivative from the group of pyridinium or bispyridinium aldoximes (commonly called "oxime"). Oximes counteract acetylcholine increase, resulting from AChE inhibition. In the human body environment these compounds are powerful nucleophiles and are able to break down the bond between AChE and nerve agent molecule. This process leads to renewal of enzyme functionality -- to its reactivation. The usefulness of oxime in the reactivation process depends on its chemical structure and on the nerve agent whereby AChE is inhibited. Due to this fact, selection of suitable reactivator in the treatment of intoxications is very important. In our work, we have compared differences in the in vitro inhibition potency of VX and Russian VX on rat, pig and human brain, and subsequently we have tested reactivation of rat brain cholinesterase inhibited by these agents using oxime HI-6, obidoxime, pralidoxime, trimedoxime and methoxime. The results showed that no major differences in the reactivation process of both VX and Russian VX-inhibited cholinesterase. The similarity in reactivation was caused by analogous chemical structure of either nerve agent; and that oxime HI-6 seems to be the most effective reactivator tested, which confirms that HI-6 is currently the most potent reactivator of AChE inhibited by nerve agents. The results obtained in our study should be considered in the future development of new AChE reactivators.
- MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory toxicita MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mozek enzymologie účinky léků MeSH
- organothiofosforové sloučeniny toxicita MeSH
- oximy farmakologie MeSH
- prasata MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- MeSH
- chování MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- fyziologický stres MeSH
- lidé MeSH
- manželé MeSH
- manželství MeSH
- socioekonomické faktory MeSH
- teoretické modely MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- aktivace enzymů MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- fosfor chemie MeSH
- katalytická doména MeSH
- konformace proteinů MeSH
- kvantová teorie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- myši MeSH
- organofosfáty chemie MeSH
- oximy chemie MeSH
- proteosyntéza MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- sarin chemie MeSH
- shluková analýza MeSH
- simulace molekulového dockingu * MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Roztroušená skleróza (RS) je multifaktoriální onemocnění s genetickými, imunologickými, hormonálními a environmentálními vlivy. Velká pozornost je věnována rovněž vlivu virových agens na vznik a rozvoj RS. I když nejsou jasné důkazy o kauzální roli virů u RS, zcela jistě se viry účastní procesů v modulaci neuroimunitního systému u geneticky vnímavých jedinců. Existuje více hypotéz o možném zásahu virů do imunologických dějů u RS (molekulární mimikry, „bystander“ aktivace, epitopový „spreading“, teorie „úrodného pole“ či „déjà vu“). Do patogeneze RS může být zapojena celá řada virových agens (herpesviry, adenoviry, papilomaviry, polyomaviry, hepadnaviry, virus lymfocytární choriomeningitidy, některé flaviviry a bunyaviry) a jejich přímý a nepřímý vliv je často diskutován. Na druhou stranu použití moderních přípravků s imunomodulačním účinkem s sebou může nést zvýšené riziko reaktivace latentně se vyskytujících virů. Při výběru preparátů pro konkrétního pacienta by se proto mělo postupovat individuálně se zvážením všech rizik.
Multiple sclerosis (MS) is multifactorial disease influenced by genetic, immunological, hormonal and environmental factors. Involvement of viral infections in MS triggering and development is considered. There is no clear evidence of causal role of viruses in MS pathophysiology nevertheless their involvement in neuroimmune system modulation in susceptible individuals is well known. Several hypothesis of viral involvement in MS immunological processes is investigated (molecular mimicry, bystander activation, epitop spreading, „fertile field“ theory or theory of „déjà vu“). A number of viruses can be directly or indirectly connected with the pathogenesis of MS (herpesviruses, adenoviruses, papilomaviruses, polyomaviruses, hepadnaviruses, lymphocytic choriomeningitis virus, some of flaviviruses and bunyaviruses). On the other hand, using of modern immunomodulating drugs can be a risk for latent virus reactivation. Therefore appropriate drug therapy for each patient should be considered individually with careful assessment of all known risks.
- MeSH
- demyelinizační nemoci epidemiologie virologie MeSH
- imunokompromitovaný pacient MeSH
- imunosupresivní léčba metody škodlivé účinky MeSH
- imunoterapie metody škodlivé účinky MeSH
- lidé MeSH
- lidský herpesvirus 6 metabolismus patogenita MeSH
- oportunní infekce prevence a kontrola virologie MeSH
- progresivní multifokální leukoencefalopatie epidemiologie virologie MeSH
- retrovirové infekce MeSH
- roztroušená skleróza * farmakoterapie patofyziologie virologie MeSH
- virus Epsteinův-Barrové metabolismus patogenita MeSH
- virus varicella zoster metabolismus patogenita MeSH
- Check Tag
- lidé MeSH
Rhabdomyosarcoma (RMS) is a malignant tumour of soft tissues, occurring mainly in children and young adults. RMS cells derive from muscle cells, which due to mutations and epigenetic modifications have lost their ability to differentiate. Epigenetic modifications regulate expression of genes responsible for cell proliferation, maturation, differentiation and apoptosis. HDAC inhibitors suppress histone acetylation; therefore, they are a promising tool used in cancer therapy. Trichostatin A (TsA) is a pan-inhibitor of HDAC. In our study, we investigated the effect of TsA on RMS cell biology. Our findings strongly suggest that TsA inhibits RMS cell proliferation, induces cell apoptosis, and reactivates tumour cell differentiation. TsA up-regulates miR-27b expression, which is involved in the process of myogenesis. Moreover, TsA increases susceptibility of RMS cells to routinely used chemotherapeutics. In conclusion, TsA exhibits anti-cancer properties, triggers differentiation, and thereby can complement an existing spectrum of chemotherapeutics used in RMS therapy.
- MeSH
- acetylace účinky léků MeSH
- apoptóza účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- epigeneze genetická účinky léků genetika MeSH
- inhibitory histondeacetylas farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- lidé MeSH
- mikro RNA metabolismus MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- rhabdomyosarkom metabolismus MeSH
- vývoj svalů účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
We lack a holistic understanding of the genetic programs orchestrating embryonic colon morphogenesis and governing damage response in the adult. A window into these programs is the transcriptomes of the epithelial and mesenchymal cell populations in the colon. Performing unbiased single-cell transcriptomic analyses of the developing mouse colon at different embryonic stages (embryonic day 14.5 [E14.5], E15.5, and E18.5), we capture cellular and molecular profiles of the stages before, during, and after the appearance of crypt structures, as well as in a model of adult colitis. The data suggest most adult lineages are established by E18.5. We find embryonic-specific gene expression profiles and cell populations that reappear in response to tissue damage. Comparison of the datasets from mice and human colitis suggests the processes are conserved. In this study, we provide a comprehensive single-cell atlas of the developing mouse colon and evidence for the reactivation of embryonic genes in disease.
- MeSH
- analýza jednotlivých buněk MeSH
- buněčná diferenciace MeSH
- embryo savčí metabolismus MeSH
- idiopatické střevní záněty genetika patologie MeSH
- kolitida genetika MeSH
- kolon embryologie patologie MeSH
- lidé MeSH
- mezoderm embryologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- stanovení celkové genové exprese * MeSH
- střevní sliznice embryologie metabolismus patologie MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
