Upon their translocation into the mitochondrial matrix, the N-terminal pre-sequence of nuclear-encoded proteins undergoes cleavage by mitochondrial processing peptidases. Some proteins require more than a single processing step, which involves several peptidases. Down-regulation of the putative Trypanosoma brucei mitochondrial intermediate peptidase (MIP) homolog by RNAi renders the cells unable to grow after 48 hours of induction. Ablation of MIP results in the accumulation of the precursor of the trypanosomatid-specific trCOIV protein, the largest nuclear-encoded subunit of the cytochrome c oxidase complex in this flagellate. However, the trCOIV precursor of the same size accumulates also in trypanosomes in which either alpha or beta subunits of the mitochondrial processing peptidase (MPP) have been depleted. Using a chimeric protein that consists of the N-terminal sequence of a putative subunit of respiratory complex I fused to a yellow fluorescent protein, we assessed the accumulation of the precursor protein in trypanosomes, in which RNAi was induced against the alpha or beta subunits of MPP or MIP. The observed accumulation of precursors indicates MIP depletion affects the activity of the cannonical MPP, or at least one of its subunits.
- MeSH
- down regulace MeSH
- fluorescenční mikroskopie MeSH
- fylogeneze MeSH
- malá interferující RNA metabolismus MeSH
- metaloendopeptidasy antagonisté a inhibitory klasifikace genetika metabolismus MeSH
- mitochondrie enzymologie MeSH
- podjednotky proteinů antagonisté a inhibitory genetika metabolismus MeSH
- respirační komplex IV metabolismus MeSH
- RNA interference MeSH
- sekvence aminokyselin MeSH
- substrátová specifita MeSH
- Trypanosoma brucei brucei metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- LCZ696,
- MeSH
- antagonisté receptorů pro angiotenzin * aplikace a dávkování terapeutické užití MeSH
- chemie farmaceutická MeSH
- inhibitory ACE farmakologie MeSH
- lidé MeSH
- metaloendopeptidasy antagonisté a inhibitory farmakologie MeSH
- neprilysin * antagonisté a inhibitory farmakologie MeSH
- randomizované kontrolované studie jako téma MeSH
- receptor typu 2 angiotensinu II - blokátory farmakologie MeSH
- renin-angiotensin systém účinky léků MeSH
- Check Tag
- lidé MeSH
Vliv natriuretických peptidů na kardiovaskulární a renální systém představuje potenciální možnosti využít tyto působky v léčbě hypertenze a srdečního selhání, i když současné výsledky klinických studií nejsou povzbudivé. Syntetický B-natriuretický peptid sice prokázal krátkodobé hemodynamické zlepšení pacientů, nicméně z pohledu renálních funkcí a dlouhodobé prognózy pacientů byl účinek sporný. Naopak novou nadějí je ularitid a duální inhibitor neprilyzinu a ARB: LCZ 696, u nejž probíhají klinické studie a předchozí data z pilotních studií se jeví slibná.
The effect of natriuretic peptides on cardiovascular and renal system offers a potential benefit in therapy of hypertension and heart failure; however the current results of clinical trials are not encouraging. Synthetic B natriuretic peptide has demonstrated short-term hemodynamic improvement in patients, but in terms of renal function and long-term prognosis the effect was questionable. Nevertheless, new hope is ularitid a dual inhibitor of neprilysin and ARB: LCZ 696, the ongoing clinical studies and previous data from pilot studies appear promising.
- MeSH
- angioedém chemicky indukované MeSH
- atriální natriuretický faktor * škodlivé účinky terapeutické užití MeSH
- bezpečnost MeSH
- dvojitá slepá metoda MeSH
- lidé MeSH
- metaloendopeptidasy antagonisté a inhibitory MeSH
- multicentrické studie jako téma MeSH
- natriuretický peptid typu B * škodlivé účinky terapeutické užití MeSH
- nemoci ledvin MeSH
- neprilysin antagonisté a inhibitory MeSH
- randomizované kontrolované studie jako téma MeSH
- srdeční selhání * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
We previously found that endothelin-1(1-31) (ET-1(1-31)) exhibited a pro-arrhythmogenic effect in isolated rat hearts. In this study, we further investigated the effects of ET-1(1-31) on a cell viability and observed [Ca(2+)](i) in cultured cardiomyocytes. Cultured neonatal rat cardiomyocytes were treated with 0.1, 1, and 10 nM ET-1(1-31) for 24h in the presence or absence of ET(A) receptor antagonist (BQ(123)) or phosphoramidon, a NEP/ECE inhibitor. Cell injury was evaluated by supernatant lactate dehydrogenase (LDH) assay, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content. Cell viability was assessed by MTT assay. [Ca(2+)](i) was measured with Fluo-3/AM under a laser confocal microscope. 1) ET-1(1-31) dose-dependently increased LDH release and decreased cell viability. 2) LDH and MDA levels were significantly elevated and SOD activity decreased after administration of 1 nM ET-1(1-31) for 24h, and these changes were markedly attenuated by 1 uM BQ(123). 3) Exposure to 10 nM ET 1(1-31) caused a continuous increase in [Ca(2+)](i) to cultured beating cardiomyocytes and termination of [Ca(2+)](i) transient within 6 min, and this change was reversed by 1 uM BQ(123) and attenuated by 0.5 mM phosphoramidon. These results suggest that ET-1(1-31) could cause cell injury, and that the effect of ET-1(1-31) on [Ca(2+)](i) transients is mainly mediated by ET(A) receptor and partially attributed to the conversion of ET-1(1-31) to ET-1(1-21).
- MeSH
- aspartátové endopeptidasy antagonisté a inhibitory metabolismus MeSH
- časové faktory MeSH
- cyklické peptidy farmakologie MeSH
- endotelin-1 analogy a deriváty farmakologie MeSH
- financování organizované MeSH
- glykopeptidy farmakologie MeSH
- inhibitory proteas farmakologie MeSH
- kardiomyocyty enzymologie metabolismus účinky léků MeSH
- konfokální mikroskopie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- L-laktátdehydrogenasa metabolismus MeSH
- malondialdehyd metabolismus MeSH
- metaloendopeptidasy antagonisté a inhibitory metabolismus MeSH
- novorozená zvířata MeSH
- peptidové fragmenty farmakologie MeSH
- potkani Sprague-Dawley MeSH
- receptor endotelinu A antagonisté a inhibitory metabolismus MeSH
- superoxiddismutasa metabolismus MeSH
- vápníková signalizace účinky léků MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- fenylalanin farmakologie MeSH
- hypoxie farmakoterapie metabolismus MeSH
- inhibitory proteas farmakologie MeSH
- kolagen metabolismus MeSH
- krysa rodu rattus MeSH
- metaloendopeptidasy antagonisté a inhibitory MeSH
- plicní hypertenze farmakoterapie metabolismus MeSH
- thiofeny farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
