- Publikační typ
- abstrakt z konference MeSH
Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia-reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small-molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.
- MeSH
- lidé MeSH
- mitochondriální nemoci * farmakoterapie MeSH
- mitochondrie metabolismus MeSH
- peptidylprolylisomerasa F * antagonisté a inhibitory MeSH
- přechodový pór mitochondriální permeability MeSH
- transportní proteiny mitochondriální membrány * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- antikoagulancia aplikace a dávkování terapeutické užití MeSH
- dolní končetina diagnostické zobrazování patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- opožděná diagnóza MeSH
- pyrazoly terapeutické užití MeSH
- tromboembolie * diagnostické zobrazování farmakoterapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- antiarytmika farmakologie terapeutické užití MeSH
- fibrilace síní * farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- propafenon farmakologie terapeutické užití MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
V kazuistice chceme ukázat léčbu arteriální hypertenze fixní kombinací trandolapril/verapamil; tato terapie byla u našeho pacienta zahájena před více než 12 lety, v době nástupu fixních dvojkombinací inhibitorů angiotenzin konvertujícího enzymu (ACE) a kalciových blokátorů. Trandolapril je zavedeným inhibitorem ACE s dlouhým poločasem účinku. Při zahájení léčby u hypertonika preferujeme tento typ blokátorů před blokátory AT pro výhodnou současnou blokádu bradykininu. Podobně verapamil je ověřen studiemi a praxí za více než tři desetiletí. Navíc ve skupině kalciových blokátorů má specifické postavení, kromě vazodilatačního má i bradykardizující účinek. Jeho použití je výhodné tam, kde jsou betablokátory kontraindikovány. U obou léků je dále výhodný neutrální vedlejší metabolický účinek na glykemii a lipidy, na rozdíl například od diuretik a betablokátorů.
In the case report, we want to show the treatment of arterial hypertension with a fixed combination of trandalopril / verapamil, which was used in this patient more than 12 years ago, at the time of the onset of fixed dual combinations of ACE inhibitors and calcium blockers. Trandalopril is an established ACE inhibitor, with a long half‑life. When initiating treatment in hypertensive patients, we prefer this type of blocker over AT blockers for the advantageous concomitant blockade of bradykinin. Similarly, verapamil has been validated in studies and practice for more than three decades. Above that, it has a specific position in the group of calcium blockers, in addition to the vasodilating effect, it also has a bradycarging effect. It is preferred where the beta‑blockers are contraindicated. Both drugs also have a neutral metabolic side effect on glycemia and lipids, in contrast to, for example, diuretics and beta‑blockers.
- Klíčová slova
- trandolapril,
- MeSH
- antihypertenziva MeSH
- arteriální tlak MeSH
- fixní kombinace léků MeSH
- hypertenze farmakoterapie MeSH
- inhibitory ACE MeSH
- lidé středního věku MeSH
- lidé MeSH
- verapamil MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Human cyclophilin D is a mitochondrial peptidyl-prolyl isomerase that plays a role in regulating the opening of the mitochondrial permeability transition pore. It is considered a viable and promising molecular target for the treatment of diseases for which disease development is associated with pore opening, e.g., Alzheimer's disease or ischemia/reperfusion injury. Currently available and widely used in vitro methods based on Kofron's assay for determining cyclophilin D activity suffer from serious drawbacks and limitations. In this study, a completely novel approach for an in vitro assay of cyclophilin D activity using RNase T1 refolding is introduced. The method is simple and is more in line with the presumed physiological role of cyclophilin D in protein folding than Kofron's assay, which relies on a peptide substrate. The method is applicable for identifying novel inhibitors of cyclophilin D as potential drugs for the treatment of the diseases mentioned above. Moreover, the description of CypD activity in the in vitro RNase T1 refolding assay reveals new possibilities for investigating the role of cyclophilin D in protein folding in cells and may lead to a better understanding of its pathological and physiological roles.
- MeSH
- Aspergillus oryzae enzymologie MeSH
- guanyloribonukleasa chemie MeSH
- konformace proteinů MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- molekulární modely MeSH
- objevování léků * MeSH
- peptidylprolylisomerasa F chemie metabolismus MeSH
- refolding proteinů * MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory chemie MeSH
- aktivace enzymů MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- benzothiazoly chemie MeSH
- inhibitory enzymů chemie farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- močovina chemie farmakologie MeSH
- molekulární struktura MeSH
- rekombinantní proteiny MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Wood chips ash coming from biomass heating plant is studied as an eco-friendly mineral admixture in mortar mix design. The raw material was mechanically activated by milling in a vibratory disc mill to a degree of fineness comparable to cement. For the mortars with ash dosage, basic physical, mechanical, hygric, and thermal properties is accessed. The mortars with partial Portland cement replacement with wood chips ash exhibited good functional properties for all studied ash dosages. With increasing amount of the ash used, the average pore diameter decreased due to the partial filler effect of WCHA in mortar mix. The strength activity index was very high for all studied mortars and gave evidence of the wood chips ash pozzolanity. The pozzolan effectiveness coefficient varied from 1.52 to 0.59, which proved the pozzolanity of the studied ash and synergic effects in the Portland cement-ash-water system. The results of leaching tests showed, the chlorides contained in ash were safely immobilized in the silicate matrix. The environmental evaluation revealed decrease in both carbon dioxide production and energy consumption by the use of wood chips ash in mortar mix. For the mortar with 20% substitution of Portland cement with wood chips ash, it represents 15% of CO2 and 16% of energy, as compared with the reference mortar mix. As the developed mortars possess good functional and environmental parameters the analyzed wood chips ash can be considered as an eco-efficient low-cost alternative to other pozzolans for production of blended binders.
- MeSH
- biomasa MeSH
- dřevo * MeSH
- konstrukční materiály MeSH
- minerály MeSH
- popel uhelný * MeSH
- Publikační typ
- časopisecké články MeSH
Many enzymes from the short-chain dehydrogenase/reductase superfamily (SDR) have already been well characterized, particularly those that participate in crucial biochemical reactions in the human body (e.g. 11β-hydroxysteroid dehydrogenase 1, 17β-hydroxysteroid dehydrogenase 1 or carbonyl reductase 1). Several other SDR enzymes are completely or almost completely uncharacterized, such as DHRS1 (also known as SDR19C1). Based on our in silico and experimental approaches, DHRS1 is described as a likely monotopic protein that interacts with the membrane of the endoplasmic reticulum. The highest expression level of DHRS1 protein was observed in human liver and adrenals. The recombinant form of DHRS1 was purified using the detergent n-dodecyl-β-D-maltoside, and DHRS1 was proven to be an NADPH-dependent reductase that is able to catalyse the in vitro reductive conversion of some steroids (estrone, androstene-3,17-dione and cortisone), as well as other endogenous substances and xenobiotics. The expression pattern and enzyme activities fit to a role in steroid and/or xenobiotic metabolism; however, more research is needed to fully clarify the exact biological function of DHRS1.
- MeSH
- dehydrogenasy/reduktasy s krátkým řetězcem metabolismus MeSH
- endoplazmatické retikulum metabolismus MeSH
- estron metabolismus MeSH
- HeLa buňky MeSH
- játra metabolismus MeSH
- kortison metabolismus MeSH
- lidé MeSH
- nadledviny metabolismus MeSH
- nádorové buněčné linie MeSH
- oxidoreduktasy genetika metabolismus MeSH
- rekombinantní proteiny biosyntéza genetika MeSH
- sekvence aminokyselin MeSH
- Sf9 buňky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Human DHRS7 (SDR34C1) is one of insufficiently described enzymes of the short-chain dehydrogenase/reductase superfamily. The members of this superfamily often play an important pato/physiological role in the human body, participating in the metabolism of diverse substrates (e.g. retinoids, steroids, xenobiotics). A systematic approach to the identification of novel, physiological substrates of DHRS7 based on a combination of homology modeling, structure-based virtual screening and experimental evaluation has been used. Three novel substrates of DHRS7 (dihydrotestosterone, benzil and 4,4'-dimetylbenzil) have been described.
