(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.

• MeSH
• Cisplatin pharmacology   MeSH
• Diphosphates pharmacology   MeSH
• DNA metabolism   MeSH
• Neoplasms * MeSH
• Organoplatinum Compounds pharmacology   metabolism   MeSH
• Oxaliplatin pharmacology   MeSH
• Platinum pharmacology   MeSH
• Antineoplastic Agents * pharmacology   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Podle definice života – množivost (replikace), metabolismus a energetická potřeba a schopnost reagovat na adekvátní podněty mají základní stavební molekuly života společnou hlavní nosnou strukturu: purinovou bázi – adenin, ribózu a dvě fosfátové skupiny. V tomto smyslu může molekula ATP představovat nosič a donor energie a organizátor molekulární výstavby, obnovy a replikace i signální molekulu v mechanismech reaktivity.

According to the definition of life – reproduction (replication), metabolism and energy requirements and the ability to respond to adequate stimuli, the basic building molecules of life have a common principal structure: the purine base - adenine, ribose and two phosphate groups. In this sense, the ATP molecule can represent a carrier and donor of energy and an organizer of molecular construction, renewal and replication, as well as a signalling molecule in reactivity mechanisms.

• MeSH
• Citric Acid Cycle * physiology   MeSH
• Diphosphates chemistry   MeSH
• Genome MeSH
• Origin of Life * MeSH
• Life MeSH

• MeSH
• Chondrocalcinosis * diagnosis   etiology   therapy   MeSH
• Humans MeSH
• Calcium Pyrophosphate MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Cíl: Popsat nález neobvyklého močového konkrementu u pětiletého pacienta s kongenitální hypofosfatázií. Typ studie: Kazuistika se zhodnocením laboratorních nálezů. Název a sídlo pracoviště: Ústav lékařské chemie a klinické biochemie 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice Motol, Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice Motol, V Úvalu 84, 150 06 Praha 5 Materiál a metody: Popis kazuistiky se zaměřením se především na analýzy močových konkrementů pomocí polarizační mikroskopie a infračervené spektrometrie. Výsledky: U pětiletého pacienta s kongenitální hypofosfatázií efektivně léčeného rekombinantní alkalickou fosfatázou (jejíž hodnota v séru představovala desetinásobek horní hranice referenčního rozmezí) byl prokázán raritní pyrofosfátový močový konkrement s příměsí sulfátu. K jeho tvorbě došlo v období, kdy byla u pacienta terapeuticky alkalizována moč (jejímž důvodem byla metafylaxe urátové urolitiázy), a pacient užíval profylakticky sulfonamidy před plánovanou litotrypsí. Závěr: Ačkoliv sérová koncentrace alkalické fosfatázy, jejíž funkcí je přeměna pyrofosfátu na fosfát, byla vysoká, byl u pacienta s kongenitální hypofosfatázií identifikován pyrofosfátový močový konkrement. Sulfátová složka konkrementu vznikla pravděpodobně na podkladě profylaktického podávání sulfonamidů.

Objectives: Identification of unusual renal pyrophosphate stone in 5 years old patient with congenital hypophosphatasia. Design: Case report and evaluation of laboratory results. Settings: Department of Medical Chemistry and Clinical Biochemistry, University Hospital Motol, Charles University, Second Faculty of Medicine, Department of Paediatrics, University Hospital Motol, Charles University, Second Faculty of Medicine, V Úvalu 84, 150 06 Prague 5 (Czech Republic). Material and methods: Case report focusing on determination of urinary stone composition by polarized light microscopy and infra-red spectrometry. Results: In 5 years old patient with effectively treated congenital hypophosphatasia by recombinant alkaline phosphatase (the serum value of which was ten times the upper limit of the reference range), rare pyrophosphate renal stone with addition of sulphate was demonstrated. The formation of the stone occurred in the period when the patient´s urine was therapeutically alkalized (due to the history of urate stones) and the patient used prophylactically sulfonamides prior to planned lithotripsy. Conclusion: Despite the high serum alkaline phosphatase concentration, the function of which is the conversion of pyrophosphate to phosphate, pyrophosphate renal stone was identified in a patient with congenital hypophosphatasia. The sulphate component of the stone is probably due to the prophylactic administration of sulfonamides.

• Keywords
• infračervená spektrometrie,
• MeSH
• Urinalysis methods   MeSH
• Chemistry Techniques, Analytical methods   MeSH
• Diphosphates analysis   MeSH
• Hypophosphatasia * complications   pathology   MeSH
• Clinical Laboratory Techniques methods   MeSH
• Kidney Calculi * etiology   chemistry   therapy   MeSH
• Humans MeSH
• Lithotripsy methods   MeSH
• Child, Preschool MeSH
• Sulfonamides therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Case Reports MeSH

Mitochondrial evolution entailed the origin of protein import machinery that allows nuclear-encoded proteins to be targeted to the organelle, as well as the origin of cleavable N-terminal targeting sequences (NTS) that allow efficient sorting and import of matrix proteins. In hydrogenosomes and mitosomes, reduced forms of mitochondria with reduced proteomes, NTS-independent targeting of matrix proteins is known. Here, we studied the cellular localization of two glycolytic enzymes in the anaerobic pathogen Trichomonas vaginalis: PPi-dependent phosphofructokinase (TvPPi-PFK), which is the main glycolytic PFK activity of the protist, and ATP-dependent PFK (TvATP-PFK), the function of which is less clear. TvPPi-PFK was detected predominantly in the cytosol, as expected, while all four TvATP-PFK paralogues were imported into T. vaginalis hydrogenosomes, although none of them possesses an NTS. The heterologous expression of TvATP-PFK in Saccharomyces cerevisiae revealed an intrinsic capability of the protein to be recognized and imported into yeast mitochondria, whereas yeast ATP-PFK resides in the cytosol. TvATP-PFK consists of only a catalytic domain, similarly to "short" bacterial enzymes, while ScATP-PFK includes an N-terminal extension, a catalytic domain, and a C-terminal regulatory domain. Expression of the catalytic domain of ScATP-PFK and short Escherichia coli ATP-PFK in T. vaginalis resulted in their partial delivery to hydrogenosomes. These results indicate that TvATP-PFK and the homologous ATP-PFKs possess internal structural targeting information that is recognized by the hydrogenosomal import machinery. From an evolutionary perspective, the predisposition of ancient ATP-PFK to be recognized and imported into hydrogenosomes might be a relict from the early phases of organelle evolution.

• MeSH
• Adenosine Triphosphate pharmacology   MeSH
• Diphosphates metabolism   MeSH
• Ferredoxins metabolism   MeSH
• Phosphofructokinases chemistry   metabolism   MeSH
• Phylogeny MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Sequence Data MeSH
• Organelles drug effects   metabolism   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Saccharomyces cerevisiae drug effects   metabolism   MeSH
• Amino Acid Sequence MeSH
• Sequence Alignment MeSH
• Protein Transport drug effects   MeSH
• Trichomonas vaginalis drug effects   enzymology   MeSH
• Hydrogen metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 μM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.

• MeSH
• Antitubercular Agents chemistry   pharmacology   MeSH
• Diphosphates chemistry   metabolism   MeSH
• Hypoxanthine Phosphoribosyltransferase chemistry   metabolism   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Crystallography, X-Ray MeSH
• Guanosine Monophosphate chemistry   metabolism   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Molecular Sequence Data MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis drug effects   enzymology   MeSH
• Tumor Cells, Cultured MeSH
• Lung Neoplasms drug therapy   pathology   MeSH
• Organophosphonates chemistry   metabolism   MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Amino Acid Sequence MeSH
• Sequence Homology, Amino Acid MeSH
• Tuberculosis drug therapy   microbiology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The objective of this study was to describe the dependence of textural properties (hardness, cohesiveness, and relative adhesiveness) of processed cheese spreads on the proportion of disodium phosphate (DSP), tetrasodium diphosphate (TSPP), and sodium salts of polyphosphate in ternary mixtures of emulsifying salts. Sodium salts of polyphosphate with different mean lengths (n ≈ 5, 9, 13, 20, and 28) were used. Pentasodium triphosphate (PSTP) was used instead of TSPP in the second part of the study. Products with and without pH adjustment were tested (the target pH value was 5.60-5.80). Textural properties of the processed cheese were observed after 2, 9, and 30 d of storage at 6°C. Hardness of the processed cheese with a low content of polyphosphate increased at a specific DSP:TSPP ratio (~1:1 to 3:4). This trend was the same for all the polyphosphates used; only the absolute values of texture parameters were different. The same trends were observed in the ternary mixtures with PSTP, showing lower final values of hardness compared with samples containing TSPP. Hardness and cohesiveness decreased and relative adhesiveness increased in the samples with increased pH values and vice versa; the main trend remained unchanged.

• MeSH
• Diphosphates chemistry   MeSH
• Emulsions MeSH
• Phosphates chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Food Handling methods   MeSH
• Polyphosphates chemistry   MeSH
• Food Storage MeSH
• Salts chemistry   MeSH
• Cheese analysis   MeSH
• Hardness MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• Keywords
• butyrofilin 3A1 (CD277),
• MeSH
• Antigen-Presenting Cells MeSH
• Antigens, CD * MeSH
• Diphosphates metabolism   MeSH
• Immune System * MeSH
• Humans MeSH
• Chromosomes, Human, Pair 6 MeSH
• Receptors, Antigen, T-Cell, gamma-delta * MeSH
• T-Lymphocytes MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH

Úvod: Krystaly indukované artropatie jsou častým onemocněním kloubů. Dochází ke tvorbě depozit krystalů v kloubních nebo periartikulárních tkáních. Ukládání krystalů v temporomandibulárním kloubu se vyskytuje velmi vzácně. Cíl práce: Cílem práce je demonstrovat ojedinělý výskyt vzácné krystalové artropatie v temporomandibulárním kloubu, prezentovat vyšetřovací metody a terapeutické možnosti. Materiál, metodika, výsledky: Autoři popisují případ 77leté ženy s chondrokalcinózou pravého čelistního kloubu. Po absolvování zobrazovacího vyšetření pomocí magnetické rezonance podstoupila nejprve biopsii, potom, vzhledem k nejasnému závěru histopatologického vyšetření, chirurgické odstranění pseudotumoru. Podrobnějším histopatologickým vyšetřením byly zjištěny romboidní krystaly kalciumpyrofosfátu. Závěr: Nebývá lehké stanovit přesnou diagnózu onemocnění pro různorodost klinických symptomů. Často imituje různé nádory či zánětlivé stavy. V diagnostice se využívá hlavně histopatologické vyšetření v polarizačním mikroskopu a CT a MRI zobrazení. Hlavní terapeutickou metodou je chirurgické odstranění depozit krystalů.

Introduction: Crystal-induced arthropathies are a frequent inflammatory joint disease. These diseases are characterized by the formation of crystal deposits in joint tissues or in periarticular structures. Calcium pyrophosphate crystal deposition in the temporomandibular joint occurs very rarely. Aim: The aim of this case report is to demonstrate the occurrence of the rare crystal arthropathy in temporomandibular joint, examination methods and therapeutic options. Material and method, results: In this report, we present the case of a 77-year-old woman with chondrocalcinosis of right temporomandibular joint. She underwent removal of pseudotumor after MRI examination. Evaluation of the specimen revealed the presence of rhomboid positively birefringent crystals. Conclusion: It is not easy to make an accurate diagnosis of the disease due to the heterogeneity in the clinical symptoms. Frequently, it imitates various tumours or inflammatory conditions. Histopathological examination with a polarizing microscope and CT and MRI scans are the mainstays of the diagnostics. The principal therapeutic method is the surgical removal of the depositions of crystals.

• MeSH
• Biopsy MeSH
• Chondrocalcinosis * diagnosis   surgery   pathology   MeSH
• Diagnosis, Differential MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Temporomandibular Joint Disorders * diagnosis   surgery   pathology   MeSH
• Tomography, X-Ray Computed MeSH
• Calcium Pyrophosphate metabolism   MeSH
• Aged MeSH
• Temporomandibular Joint pathology   MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Řadu onemocnění vyvolaných herpetickými viry lze kauzálně léčit antivirotiky. Článek přináší přehled základních poznatků o používaných antiviroticích, vysvětluje mechanismy účinku užitečné pro chápání dalších souvislostí, připomíná nežádoucí účinky léků a upozorňuje na skutečnosti důležité pro volbu antivirotik a jejich dávkování. Acyklovir je základním lékem většiny infekcí vyvolaných herpes simplex virem (HSV) a virem varicely a zosteru (VZV). Dávky se liší podle diagnózy, obecně u infekcí vyvolaných VZV se podávají dvojnásobné dávky než u infekcí vyvolaných HSV, volba aplikační formy se odvíjí od závažnosti stavu, délka léčby závisí především na imunokompetenci. Acyklovir je dobře tolerován. Valacyklovir má lepší biologickou dostupnost a v jistých indikacích je výhodnější. Brivudin, famcyklovir a pencyklovir jsou používány výjimečně. Gancyklovir je základním lékem cytomegalovirových (CMV) infekcí. Jeho nevýhodou je významná hematotoxicita. Cidofovir a foskarnet jsou další antivirotika používaná v léčbě CMV infekce imunosuprimovaných osob a vykazují účinek proti dalším virům. Použití je limitováno četnými nežádoucími účinky - zejména nefrotoxicitou, myelosupresí a iontovými disbalancemi. Fomivirsen je antisense oligonukleotid určený k intravitreální aplikaci jako alternativa léčby CMV retinitidy.

A range of diseases caused by herpetic viruses can be causally treated with antivirotics. The article brings an overview of the basic findings regarding the generally used antivirotics, explains the mechanisms of effects useful for understanding other related information, reviews the adverse effects of these drugs and highlights the factors important for choosing an antivirotic and its dosage. Acyclovir is the basic drug used against all infections caused by the herpes simplex virus (HSV) and the varicella zoster and herpes zoster viruses (VZV). The doses vary according to the diagnosis; in general, infections caused by VZV require double the doses as infections caused by HSV. The choice of the form of application is made on the basis of the seriousness of the patient’s condition; the length of the treatment depends mostly on immuno-competence. Acyclovir is well-tolerated. Valacyclovir has a better biological availability and it is more beneficial in certain indications. Brivudin, famcyclovir and pencyclovir are used rarely. Gancyclovir is the primary drug for cytomegalovirus (CMV) infections. Its main disadvantage is strong haematotoxicity. Cidofovir and foscarnet are antivirotics used for treatment of CMV infections in immunosuppressed patients and they show efficacy against other viruses as well. Their use is limited by frequent adverse effects - nephrotoxicity, myelosuppression and ion disbalances. Fomivirsen is a synthetic oligonucleotide designated for intravitreal application, as an alternative treatment of CMV retinitis.

• Keywords
• valacyklovir, valgancyklovir, gancyklovir, pencyklovir, famcyklovir, brivudin,
• MeSH
• Acyclovir * analogs & derivatives   pharmacology   classification   therapeutic use   MeSH
• Antiviral Agents * pharmacology   classification   therapeutic use   MeSH
• Cidofovir MeSH
• Diphosphates pharmacology   MeSH
• Foscarnet MeSH
• Herpesviridae Infections * drug therapy   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH