Wyniki wyszukiwania - Biblioteka Nauki

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Charakterystyka i znaczenie proteinaz cysteinowych w procesie nowotworzenia

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Młudzik P. , Mirowski M.

Folia Medica Lodziensia

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2015

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tom 42

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nr 2

93-106

EN

Cysteine proteases also known as thiol or sulfhydryl proteases are enzymes responsible for catalyzing the hydrolysis of peptide bonds in proteins. They take part in many physiological and pathological processes. Their abnormal activity can lead to a number of disease states including tumor growth. They are involved in the process of carcinogenesis at multiple levels– they participate in the invasion, transformation, angiogenesis, apoptosis and metastasis. The best characterised cysteine proteases are the lysosomal cathepsins, that belong to the papain family. So far 11 cysteine cathepsins have been identified: B, L, H, S, K, F, V, X, W, O and C. They take part in the activation of many proenzymes and prohormones, MHC–II–mediated antigen presentation, bone remodeling, reproduction and apoptosis. Research on the role of cysteine proteases in carcinogenesis showed elevated expression of mRNA or enzymatic activity of cathepsins in many human cancers, eg. breast, lung, brain, gastrointestinal tract, head and neck and melanoma. Cancer procoagulant also belongs to the group of cysteine proteases, however its structure and functions are still the subject of research for many scientists. Elevated levels of activity and concentrations of cancer procoagulant in the serum and tissues from patients with cancer disease compared to those observed in healthy people, provides the possibility of using this factor in the diagnosis of cancer. Many preclinical studies have shown that achieving a stop proliferation and reducing the metastatic potential of tumor cells is possible with the use of cysteine proteinases inhibitors. That gives great hope for the possibility of their application in anticancer therapy.

PL

Proteinazy cysteinowe, nazywane również proteinazami tiolowymi lub sulfhydrolowymi, to enzymy odpowiedzialne za katalizowanie reakcji hydrolizy wiązań peptydowych w białkach. Biorą udział w licznych procesach fizjologicznych oraz patologicznych. Ich nieprawidłowa aktywność może prowadzić do wielu stanów chorobowych, w tym rozwoju nowotworów. Zaangażowane są one w proces kancerogenezy na wielu poziomach – uczestniczą w inwazji, transformacji nowotworowej, angiogenenezie, apoptozie i powstawaniu przerzutów. Najlepiej scharakteryzowanymi proteinazami cysteinowymi są, należące do rodziny papainy, lizosomalne katepsyny. Dotychczas poznano 11 ludzkich katepsyn cysteinowych: B, L, H, S, K, F, V, X, W, O i C. Biorą one udział w aktywacji wielu proenzymów i prohormonów, pośredniczą w prezentacji antygenu MHC–II, przebudowie kości, procesie reprodukcji oraz apoptozie. Badania nad udziałem proteinaz cysteinowych w procesie kancerogenezy wykazały podwyższoną ekspresję mRNA lub aktywność enzymatyczną katepsyn w wielu ludzkich nowotworach np. raku piersi, płuc, mózgu, żołądkowo–jelitowym, głowy, szyi oraz czerniaku. Do grupy proteinaz cysteinowych należy również prokoagulant nowotworowy, którego struktura, jak i pełnione przez niego funkcje są wciąż przedmiotem badań wielu naukowców. Podwyższony poziom aktywności, jak i stężenia antygenu prokoagulanta nowotworowego w surowicy krwi osób z chorobą nowotworową oraz w pooperacyjnym materiale tkankowym w stosunku do wartości obserwowanych u ludzi zdrowych, świadczy o możliwości wykorzystania tego czynnika w diagnostyce onkologicznej. Liczne badania przedkliniczne dowiodły, że zatrzymanie proliferacji oraz obniżenie potencjału metastatycznego komórek nowotworowych jest prawdopodobne przy użyciu inhibitorów proteinaz cysteinowych. Daje to duże nadzieje na możliwość zastosowania ich w terapii przeciwnowotworowej.

2

Specific inhibitors of the

100%

Mirowski M. , Wierzbicki R.

Postępy Higieny i Medycyny Doświadczalnej

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1993

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tom 47

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nr 2

147-157

EN

The article contains a survay of the recent papers on the which regulate the process of - PAI-1 and PAI-2. Both of them belong to serine family and are specific for tPA as well as uPA, forming stable complexes in molar ratio 1 : 1 with them. PAI-1, secreted mainly by and , is the main plasmic inhibitor of plasminogen activation. PAI-2, originated essentially from , appears in during .

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Charakterystyka elektroforetyczna aktywności metaloproteinazowej surowicy pacjentów z przewlekłą białaczką limfocytową – badania wstępne

80%

Pietrzak J. , Wodziński D. , Franiak-Pietryga I. , Mirowski M.

Folia Medica Lodziensia

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2015

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tom 42

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nr 1

49-62

EN

Metalloproteinases play an important role in the development and metastasis of many cancers. Their activity is also an important component of tumorgenesis associated processes such as angiogenesis, decreased apoptosis, or unlimited proliferation of pathological cells. In this study we tried to estimate a differences of metalloproteinase activity digesting the gelatin in the sera of patients with chronic lymphocytic leukemia and healthy people, by the zymographic technique. To confirm that the gelatinolytic activity originated from the metalloproteinases their specific inhibitors: phenanthroline and ethylene– diaminetetraacetic acid were used. In patient’s sera a zymographic analysis revealed the presence of additional activity. The first of them are located in a region corresponding to a molecular weight of approximately 240 kDa, probably corresponds to the dimer of proMMP–9. Another two active fractions present in the sera of patients suffering from leukemia corresponded to a molecular weight of about 110 and 130 kDa probably represents a complex of proMMP–9 with lipocain. In a control sera, only one activity could be observed exhibiting a molecular weight of about 110 kDa, which is stronger than corresponding fraction in patient’s sera. The biggest difference between the two investigated sera was gelatynolytic activity located in the region of a molecular weight of about 94 kDa, which probably corresponded to proMMP–9. In some leukemic sera this activity was several times higher compared to the control samples, in which there was a constant and relatively low level of it. Despite significant activity of proMMP–9 in sera of patients with CLL no biologically active equivalent band of molecular weight 84 kDa were detected. The fractions which corresponded to different forms of MMP–2 (72, 64 kDa) were present in the sera of tumor and control, although proMMP–2 was more strongly expressed in the control samples.

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The effect of hydrazine derivatives of 3-formylchromones on angiogenic basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanoma cell line WM-115

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Łazarenkow A. , Michalska M. , Mirowski M. , Słomiak K. , Nawrot-Modranka J.

Acta Biochimica Polonica

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2017

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tom 64

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nr 3

585-590

EN

The hydrazine derivatives of benzopyrones remain an unexplored group of chemical compounds. This preliminary study investigates the influence of A-5, CH-3 and K-2 derivatives at concentrations of 1, 10, 100 nM and 1 μM on selected biochemical factors of a melanoma cell line WM-115, with regard to their potential angiogenic properties. The studied compounds were found to influence cell proliferation, as well as total protein, bFGF and FGFR1 concentration.

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The influence of chromone based hydrazones on lipid peroxidation and bFGF concentration in the HL-60 cell line

61%

Łazarenkow A. , Michalska M. , Gorąca A. , Mirowski M. , Nawrot-Modranka J. , Piechota-Polanczyk A.

Acta Biochimica Polonica

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2013

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tom 60

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nr 2

259-262

EN

Natural and synthetic derivatives of benzo-γ-pyrones (i.e. flavones, chromones, and coumarins) and their synthetic analogues possess a wide range of biological properties in vitro and in vivo. In this paper we investigated the influence of two hydrazone compounds of chromones, 3-{[(2-dimethoxytiophosphoryl)-2-methylhydrazono]-methyl}-chromen-4-one (CH-3) and 2-amino-6-chloro-3-[(2-hydroxyethyl)-hydrazonomethyl]-chromen-4-one (A-12), on lipid peroxidation and bFGF concentration in the HL-60 cells. Both of the studied compounds had a significant influence on bFGF and TBARS in ranges -137.20 ~ 380.26% and -81.66 ~ -28.68%, respectively, in comparison with the control (counted as 0 %).

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New benzimidazole derivatives with potential cytotoxic activity - study of their stability by RP-HPLC

61%

Błaszczak-Świątkiewicz K. , Mirowski M. , Kaplińska K. , Kruszyński R. , Trzęsowska-Kruszyńska A. , Mikiciuk-Olasik E.

Acta Biochimica Polonica

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2012

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tom 59

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nr 2

279-288

EN

Obtained benzimidazole derivatives, our next synthesized heterocyclic compounds, belong to a new group of chemical bondings with potential anticancer properties (Błaszczak-Świątkiewicz & Mikiciuk-Olasik, 2006, J Liguid Chrom Rel Tech 29: 2367-2385; Błaszczak-Świątkiewicz & Mikiciuk-Olasik, 2008, Wiad Chem 62: 11-12, in Polish; Błaszczak-Świątkiewicz & Mikiciuk-Olasik, 2011, J Liguid Chrom Rel Tech 34: 1901-1912). We used HPLC analysis to determine stability of these compounds in 0.2% DMSO (dimethyl sulfoxide). Optimisation of the chromatographic system and validation of the established analytical method were performed. Reversed phases (RP-18) and a 1:1 mixture of acetate buffer (pH 4.5) and acetonitrile as a mobile phase were used for all the analysed compounds at a flow rate 1.0 mL/min. The eluted compounds were monitored using a UV detector, the wavelength was specific for compounds 6 and 9 and compounds 7 and 10. The retention time was specific for all four compounds. The used method was found to have linearity in the concentration range of (0.1 mg/mL-0.1 μg/mL) with a correlation coefficient not less than r2=0.9995. Statistical validation of the method proved it to be a simple, highly precise and accurate way to determine the stability of benzimidazole derivatives in 0.2% DMSO. The recoveries of all four compounds examined were in the range 99.24-100.00%. The developed HPLC analysis revealed that the compounds studied remain homogeneous in 0.2% DMSO for up to 96 h and that the analysed N-oxide benzimidazole derivatives do not disintegrate into their analogues - benzimidazole derivatives. Compounds 8, 6 and 9 exhibit the best cytotoxic properties under normoxic conditions when tested against cells of human malignant melanoma WM 115.

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Elektroforetyczna identyfikacja proteinaz cysteinowych w surowicach pacjentów z przewlekłą białaczką limfocytową (PBL) z wykorzystaniem biotynylowanego jodoacetamidu

61%

Młudzik P. , Pietrzak J. , Saed L. , Wodziński D. , Franiak–Pietryga I. , Mirowski M.

Folia Medica Lodziensia

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2016

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tom 43

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nr 1

35-55

EN

Introduction: Cysteine proteases are enzymes that regulate numerous physiological and pathological processes in the human body. Disorders of their activity can lead to a number of diseases. They play an important role in the process of carcinogenesis, participating in the invasion, transformation, angiogenesis, apoptosis and metastasis. The aim of this study was to elaborate the electrophoretic method of cysteine proteinases identification in the sera of patients suffering from chronic lymphocytic leukemia based on biotinylated iodoacetamide. Material and methods: Preliminary studies were carried out on the commercially available papain (EC 3.4.22.2) well known and widely used plant cysteine protease with a molecular weight 23,4 kDa. The study was conducted on the blood samples taken from patients with chronic lymphocytic leukemia (CLL) and control sera from healthy donors. The sera after the preincubation with iodoacetamide were mixed with the sample buffer followed by electrophoresis on polyacrylamide gel containing sodium dodecyl sulfate (SDS–PAGE). The separated proteins were electrophoretically transferred to the nitrocellulose membranes and subjected to the further analysis using streptavidin conjugated with horseradish peroxidase (HRP). The use of substrate for HRP 3,3’- diaminobenzidine tetrachloride (DAB) allows the biotinylated iodoacetamide and thereby cysteine proteinase identification. Results: The comparative analysis of the sera from the patients with chronic lymphocytic leukemia and the control sera led to the identification of additional protein with a cysteine protease characteristic having a molecular weight of about 37 kDa, which did not occur or was present in a smaller amount of the control sera. Conclusions: The developed method allows the detection of cysteine proteases which are present in the control sera and the sera of patients with chronic lymphocytic leukemia.