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

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

• MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• chromatografie kapalinová MeSH
• krysa rodu rattus MeSH
• oximy MeSH
• reaktivátory cholinesterázy * MeSH
• tandemová hmotnostní spektrometrie MeSH
• tělesné tekutiny * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The purpose of this review is to discuss rare neurological disorders with respect to communication difficulties typical of children. Firstly, communication disorders with special focus on rare communication neurological disorders are discussed. Secondly, on the basis of literature review, the authors explore clinical studies on the most typical rare children's communication neurological disorders. Thirdly, on the basis of the findings from the clinical studies, they set a few recommendations for their medical therapies and management. The methodology was based on the literature review of research studies exploring the research issue. The findings show that the intervention strategies appear to have positive effects on the improvement of speech and language production among children suffering from Landau– Kleffner syndrome and childhood apraxia of speech. Nevertheless, randomized control trials are needed in order to accelerate and facilitate an early and relevant diagnosis and treatment management. In addition, a multidisciplinary approach seems to be the most appropriate for the accurate diagnosis and comprehensive treatment.

• MeSH
• afázie farmakoterapie   klasifikace   rehabilitace   MeSH
• antikonvulziva aplikace a dávkování   MeSH
• diferenciální diagnóza MeSH
• diskriminační učení MeSH
• dítě MeSH
• glukokortikoidy aplikace a dávkování   MeSH
• komunikační poruchy diagnóza   farmakoterapie   rehabilitace   MeSH
• Landau-Kleffnerův syndrom * diagnóza   psychologie   terapie   MeSH
• levetiracetam aplikace a dávkování   MeSH
• lidé MeSH
• mladiství MeSH
• neurovývojové poruchy MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The aim of this study was to compare the effects of DNA repair inhibitors in the context of radio-sensitization of human lung cells. The radio-sensitizing effects of NU7441 (1 mM), an inhibitor of DNA-dependent protein kinase (DNA-PK); KU55933 (10 μM), an inhibitor of ataxia-telangiectasia mutated kinase (ATM); and VE-821 (10 μM), an inhibitor of ATM-related kinase (ATR) were tested by the xCELLigence system for monitoring proliferation, fluorescence microscopy for DNA damage detection, flow-cytometry for cell cycle and apoptosis analysis and western blotting and ELISA for determination of DNA repair proteins. We employed normal human lung fibroblasts (NHLF, p53-wild-type) and non-small cell lung cancer cells (H1299, p53-negative). DNA-PK inhibition (by NU7441) in combination with ionizing radiation (IR) increased the number of double strand breaks (DSB), which persisted 72 h after irradiation in both cell lines. Additionally, NU7441 and KU55933 in combination with IR caused G2-arrest. ATR inhibitor (VE-821) together with IR markedly inhibited proliferation and induced G2/M arrest accompanied by apoptosis in H1299, but not in NHLF cells, and thus diminished DNA-repair of tumour cells but not normal lung fibroblasts. Our findings indicate that ATR inhibition could be a promising therapeutic strategy in p53-deficient lung tumours.

• MeSH
• enzymy opravy DNA antagonisté a inhibitory   genetika   MeSH
• fibroblasty účinky záření   MeSH
• kultivované buňky účinky záření   MeSH
• nádorové buňky kultivované účinky léků   účinky záření   MeSH
• nemalobuněčný karcinom plic genetika   radioterapie   MeSH
• oprava DNA účinky léků   MeSH
• proliferace buněk účinky záření   MeSH
• radiosenzibilizující látky farmakologie   izolace a purifikace   terapeutické užití   MeSH
• techniky in vitro MeSH
• Publikační typ
• práce podpořená grantem MeSH

Uterine lymphoma is rare in the dog, in other animal species, and in humans. The lymphoma in the two female dogs presented as a primary tumour of uterine tissue and was classified as diffuse centroblastic B cell lymphoma. Terminally, the uterine lymphoma metastasized to various organs in one of the dogs, despite chemotherapy. This case study describes a very rare form of canine lymphoma and suggests to include lymphoma in the differential diagnoses in bitches with uterine masses.

• MeSH
• B-buněčný lymfom * MeSH
• nádory močového měchýře MeSH
• nemoci psů * MeSH
• Publikační typ
• kazuistiky MeSH