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• Klíčová slova
• studie VICTORION-INITIATE, Inklisiran,
• MeSH
• arterioskleróza * farmakoterapie   MeSH
• dyslipidemie farmakoterapie   MeSH
• hypolipidemika * farmakokinetika   terapeutické užití   MeSH
• LDL-cholesterol účinky léků   MeSH
• lidé MeSH
• malá interferující RNA farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Cyclophilin D (CypD) is a mitochondrial enzyme widely accepted as a regulator of the mitochondrial permeability transition pore (mPTP). Excessive opening of mPTP is associated with mitochondrial dysfunction and the development of various diseases; thus, suppression of mPTP opening through CypD inhibition presents a promising therapeutic approach. However, only a limited number of selective CypD inhibitors are currently available. In this study, 10 derivatives of 2-(benzyloxy)arylurea similar or identical to previously published CypD/mPTP inhibitors were synthesized. Unlike the original reports that assessed the opening of mPTP at the cellular level, the compounds were tested directly on the purified CypD enzyme to validate their putative mechanism of action. Additionally, the effect of the selected compounds was tested on isolated mitochondria. The obtained results show that the compounds are only weak inhibitors of CypD and mPTP opening, which is in contrast to previous conclusions drawn from the unspecific cellular JC-1 assay.

• Publikační typ
• časopisecké články MeSH

• 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