Jan Barciszewski

Publications (81)200.95 Total impact

• Article: Prediction of hammerhead ribozyme intracellular activity with the catalytic core fingerprint.

  Marta Magdalena Gabryelska, Eliza Wyszko, Maciej Szymański, Mariusz Popenda, Jan Barciszewski
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  ABSTRACT: Hammerhead ribozyme is a versatile tool for down-regulation of gene expression in vivo. Due to its small size and high activity, it is used as a model for RNA structure-function relationship studies. Here we describe a new extended hammerhead ribozyme HH-2 with a tertiary stabilizing motif constructed on the basis of the tetraloop receptor sequence. This ribozyme is very active in living cells but shows low activity in vitro. To understand it, we analyzed tertiary structure models of substrate:ribozyme complexes. We calculated six unique catalytic core geometry parameters as distances and angles between particular atoms that we call the ribozyme fingerprint. A flanking sequence and tertiary motif change the geometry of the general base, general acid, nucleophile and the leaving group. We found almost complete correlation between these parameters and the decrease of target gene expression in the cells. The tertiary structure model calculations allow us to predict ribozyme intracellular activity. Our approach could be widely adapted to characterize catalytic properties of other RNAs.
  Biochemical Journal 02/2013; · 4.90 Impact Factor
• Article: Spiegelzymes: Sequence Specific Hydrolysis of L-RNA with Mirror Image Hammerhead Ribozymes and DNAzymes.

  Eliza Wyszko, Maciej Szymański, Heinz Zeichhardt, Florian Müller, Jan Barciszewski, Volker A Erdmann
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  ABSTRACT: In this manuscript we describe for the first time mirror image catalytic nucleic acids (Spiegelzymes), which hydrolyze sequence specifically L-ribonucleic acid molecules. The mirror image nucleic acid ribozymes designed are based upon the known hammerhead ribozyme and DNAzyme structures that contain L-ribose or L-deoxyribose instead of the naturally occurring D-ribose or D-deoxyribose, respectively. Both Spiegelzymes show similar hydrolytic activities with the same L-RNA target molecules and they also exhibit extra ordinary stabilities when tested with three different human sera. In this respect they are very similar to Spiegelmers (mirror image aptamers), which we had previously developed and for which it has been shown that they are non-toxic and non-immunogenic. Since we are also able to demonstrate that the hammerhead and DNAzyme Spiegelzymes can also hydrolyze mirror image oligonucleotide sequences, like they occur in Spiegelmers, in vivo, it seems reasonable to assume that Spiegelzymes may in principle be used as an antidote against Spiegelmers. Since the Spiegelzymes contain the same building blocks as the Spiegelmers, it can be expected that they will have similar favorable biological characteristics concerning toxicity and immunogenety. In trying to understand the mechanism of action of the Spiegelzymes described in this study, we have initiated for the first time a model building system with L-nucleic acids. The models for L-hammerhead ribozyme and L-DNAzyme interaction with the same L-RNA target will be presented.
  PLoS ONE 01/2013; 8(1):e54741. · 4.09 Impact Factor
• Article: Convenient and Efficient Syntheses of N (6)- and N (4)- Substituted Adenines and Cytosines and their 2'-Deoxyribosides.

  Ewelina Adamska, Jan Barciszewski, Wojciech T Markiewicz
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  ABSTRACT: Convenient and efficient methods of the synthesis of N(6)- and N(4)-substituted derivatives of adenine and cytosine and their 2'-deoxyribosides were developed. The reactions of either unprotected nucleobases (adenine, cytosine) or unprotected 2'-deoxyribosides with aryl or alkyl aldehydes give corresponding Schiff bases that can be reduced to the target title compounds with high overall yields. In the case of aryl aldehydes the imine derivatives are obtained in the presence of methoxides in methanol and reduced with sodium borohydride. The corresponding reactions with alkyl aldehydes require the use of acetic acid and borane dimethyl sulfide complex instead.
  Nucleosides Nucleotides &amp Nucleic Acids 12/2012; 31(12):861-871. · 0.90 Impact Factor
• Article: New cytosine derivatives as inhibitors of DNA methylation.

  Beata Plitta, Ewelina Adamska, Małgorzata Giel-Pietraszuk, Agnieszka Fedoruk-Wyszomirska, Mirosława Naskręt-Barciszewska, Wojciech T Markiewicz, Jan Barciszewski
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  ABSTRACT: DNA cytosine methylation catalyzed by DNA methyltransferase 1 (DNMT1) is an epigenetic method of gene expression regulation and development. Changes in methylation pattern lead to carcinogenesis. Inhibition of DNMT1 activity could be a good strategy of safe and efficient epigenetic therapy. In this work, we present a novel group of cytosine analogs as inhibitors of DNA methylation. We show new methods of synthesis and their effect on in vitro reaction of DNA methylation. Almost all of analyzed compounds inhibit DNA methyltransferase activity in the competitive manner. K(i) values for the most potent compound 4-N-furfuryl-5,6-dihydroazacytosines is 0.7 μM. These compounds cause also a decrease of 5-methylcytosine (m(5)C) level in DNA of mammalian HeLa and HEK293 cells.
  European journal of medicinal chemistry 07/2012; 55:243-54. · 3.27 Impact Factor
• Source

  Available from: Małgorzata Giel-Pietraszuk

  Article: Hydrostatic and osmotic pressure study of the RNA hydration.

  Małgorzata Giel-Pietraszuk, Jan Barciszewski
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  ABSTRACT: The tertiary structure of nucleic acids results from an equilibrium between electrostatic interactions of phosphates, stacking interactions of bases, hydrogen bonds between polar atoms and water molecules. Water interactions with ribonucleic acid play a key role in its structure formation, stabilization and dynamics. We used high hydrostatic pressure and osmotic pressure to analyze changes in RNA hydration. We analyzed the lead catalyzed hydrolysis of tRNAPhe from S. cerevisiae as well as hydrolytic activity of leadzyme. Pb(II) induced hydrolysis of the single phosphodiester bond in tRNAPhe is accompanied by release of 98 water molecules, while other molecule, leadzyme releases 86.
  Molecular Biology Reports 02/2012; 39(5):6309-18. · 2.93 Impact Factor
• Article: [Effect of cigarette smoking on blood lead levels in pregnant women.]

  Magdalena Chełchowska, Katarzyna Jabłonka-Salach, Jadwiga Ambroszkiewicz, Tomasz Maciejewski, Joanna Gajewska, Ewa Bulska, Teresa Laskowska-Klita, Jerzy Leibschang, Jan Barciszewski
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  ABSTRACT: Tobacco smoking creates health problems which apply not only to individuals and the family but also to different ages and social groups, as well as the national economy. Epidemiologic studies conducted at the Institute of Mother and Child indicated that in Poland 25-30% women smoke during pregnancy. Lead exposure from cigarette smoke may have a negative effect on the transplacental flow of micronutrients and have an adverse influence on the growth and development of the fetus, and then on children. The aim of this study was to estimate the effect of smoking cigarettes on plasma and whole blood lead levels in pregnant women. Material and methods: Eighty healthy pregnant women, patients of the Clinical Department of the Obstetrics and Gynecology Institute of Mother and Child and Warsaw Medical University, were divided into two groups: group I - tobacco smokers and group II- tobacco abstainers according to questionnaire declaration and serum cotinine concentration. Current smokers were defined as those who had smoked 5 cigarettes per day for 2 years before conception and continued smoking during pregnancy. The women exposed to environmental tobacco smoke (smoking spouse or other family members, co-workers) were excluded from the non-smoking group. All pregnant volunteers signed a written, informed consent form, approved by the Institute's Ethical Committee. The concentrations of lead in plasma and whole blood were analyzed using inductively coupled plasma mass spectrometry on spectrometer analyzer ICP MS Elan 6100 (Perking Elmer, Germany). Levels of cotinine in serum were determined by Cotinine Direct ELISA test (Calbiotech Inc. Canada). Results: In the group of smoking mothers the mean serum cotinine concentration was 69.1 μg/L, whereas in the group of tobacco abstainers it was present only in trace amount. In group I we observed a significant positive correlation between serum cotinine and the number of cigarettes smoked daily (r=0.74; p<0.001), as well as the period of smoking before conception (r=0.60; p<0.001). The concentrations of lead in the plasma of smoking women were significantly higher than in the group of tobacco abstainers in each trimester of pregnancy (I trimester: 0.22 μg/dL vs 0.12 μg/dL p<0.01; II trimester: 0.19 μg/L vs 0.10 μg/L p<0.001; III trimester 0.28 μg/ dL vs 0.13 μg/dL p<0.0001). Tobacco smoking mothers also had a higher concentration of lead in whole blood as compared to pregnant non-smoking women. These differences were statistically significant and amounted to 2.15 μg/dL vs 1.28 μg/L in the first, 1.99 μg/dL vs 1.19 μg/dL in the second and 2.11 μg/dL vs 1.58 μg/dL in the third trimester of pregnancy. We observed that the level of lead was correlated with cotinine in blood, as well as with the number of cigarettes and the length of time women smoked before conception. Such an effect was observed in every trimester of gestation. A strong correlation between the number of cigarettes/day and lead concentration in plasma (r=0.57; p<0.001) and whole blood (r=0.54; p<0.001) was found in the third trimester of pregnancy. Conclusions: Tobacco smoking during pregnancy increased the concentrations in maternal blood lead. The level of lead in plasma and whole blood correlated with the degree of intensity of cigarette smoking in the pregnant women studied. It may be a result of influencing the mobilization of calcium from the bone with simultaneous release of lead deposited in the bone. Further studies are required to characterize the effect of higher lead level in the blood of mothers on the risk of premature labor, low birth weight of newborns and their inferior development.
  Medycyna wieku rozwojowego 01/2012; 16(3):196-204.
• Article: Squalene monooxygenase - a target for hypercholesterolemic therapy.

  Agnieszka Belter, Miroslawa Skupinska, Malgorzata Giel-Pietraszuk, Tomasz Grabarkiewicz, Leszek Rychlewski, Jan Barciszewski
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  ABSTRACT: Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both sufficient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.
  Biological Chemistry 12/2011; 392(12):1053-75. · 2.96 Impact Factor
• Article: Binding of the plant hormone kinetin in the active site of Mistletoe Lectin I from Viscum album.

  Piotr H Małecki, Wojciech Rypniewski, Maciej Szymański, Jan Barciszewski, Arne Meyer
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  ABSTRACT: The crystal structure of the ribosome inhibiting protein Mistletoe Lectin I (ML-I) derived from the European mistletoe, Viscum album, in complex with kinetin has been refined at 2.7Å resolution. Suitably large crystals of ML-I were obtained applying the counter diffusion method using the Gel Tube R Crystallization Kit (GT-R) on board the Russian Service Module on the international space station ISS within the GCF mission No. 6, arranged by the Japanese aerospace exploration agency (JAXA). Hexagonal bi-pyramidal crystals were grown during three months under microgravity. Before data collection the crystals were soaked in a saturated solution of kinetin and diffraction data to 2.7Å were collected using synchrotron radiation and cryogenic techniques. The atomic model was refined and revealed a single kinetin molecule in the ribosome inactivation site of ML-I. The complex demonstrates the feasibility of mistletoe to bind plant hormones out of the host regulation system as part of a self protection mechanism.
  Biochimica et Biophysica Acta 10/2011; 1824(2):334-8. · 4.66 Impact Factor
• Article: Squalene monooxygenase - a target for hypercholesterolemic therapy.

  Agnieszka Belter, Miroslawa Skupinska, Malgorzata Giel-Pietraszuk, Tomasz Grabarkiewicz, Leszek Rychlewski, Jan Barciszewski
  [show abstract] [hide abstract]
  ABSTRACT: Abstract Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in Eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regularory point in their synthesis. Squalene monooxygenase down regulation in vertebras and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase the potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes' inhibitors are still under investigation. An enormous scale of hypercholesterolemia and a lack of both sufficient and safe remedies make researches on new squalene monooxygenase inhibitors so urgent and up-to-date. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors (iii) compare current strategies of lowering cholesterol level in blood with a selection of the most promising, (iv) underline advantages of squalene monooxygenase as a good target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use statin there are some clinical evidences for their adverse effects and only partial effectiveness. Currently they are drugs of choice used with many restrictions especially in case of children, old patients, women of childbearing potential. Certainly, for the next few years, statins will continue to be suitable tool for cost-effective cardiovascular prevention, however researches on new hypolipidemic drugs are highly desirable. We suggest that squalene monooxygenase inhibitors have a big chance to become the hypocholesterolemic agents of the future.
  Biological Chemistry 10/2011; · 2.96 Impact Factor
• Article: 2011: 50th anniversary of the discovery of the genetic code.

  Volker A Erdmann, Jan Barciszewski
  Angewandte Chemie International Edition 09/2011; 50(41):9546-52. · 13.45 Impact Factor
• Article: Nucleic acid-based technologies in therapy of malignant gliomas.

  Monika Piwecka, Katarzyna Rolle, Eliza Wyszko, Ryszard Żukiel, Stanisław Nowak, Mirosława Z Barciszewska, Jan Barciszewski
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  ABSTRACT: Malignant gliomas are the deadliest brain tumors, which are characterized by highly invasive growth, a rampant genetic instability and intense resistance to apoptosis. Such an aggressive behavior of malignant gliomas is reflected in the resistance to chemo- and radiotherapy and weak prognosis in spite of cytoreduction through surgery. Brain tumors preferentially express a number of specific protein and RNA markers, that may be exploited as potential therapeutic targets in design of the new treatment modalities based on nucleic acids. For almost three decades, a possibility to apply DNA and RNA molecules as anticancer therapeutics have been studied. A variety of antisense oligonucleotides, ribozymes, DNAzymes, and aptamers can be designed to trigger the sequence-specific inhibition of particular mRNA of interest. RNA interference (RNAi) is the latest and the most promising technique in the long line of nucleic acid-based therapeutic technologies. Recently, we designed and implemented the experimental therapy of patients suffering from malignant brain tumors based on application of double-stranded RNA (dsRNA) specific for tenascin-C (TN-C) mRNA. That therapeutic agent, called ATN-RNA, induces RNAi pathway to inhibit the synthesis of TN-C, the extracellular matrix protein which is highly overexpressed in brain tumor tissue. In the chapter specific problems of application of nucleic acid-based technologies in glioma tumors treatment will be discussed.
  Current pharmaceutical biotechnology 09/2011; 12(11):1805-22. · 3.40 Impact Factor
• Source

  Available from: PubMed Central

  Article: Organelle trafficking of chimeric ribozymes and genetic manipulation of mitochondria.

  Romain Val, Eliza Wyszko, Clarisse Valentin, Maciej Szymanski, Anne Cosset, Malek Alioua, Theo W Dreher, Jan Barciszewski, André Dietrich
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  ABSTRACT: With the expansion of the RNA world, antisense strategies have become widespread to manipulate nuclear gene expression but organelle genetic systems have remained aside. The present work opens the field to mitochondria. We demonstrate that customized RNAs expressed from a nuclear transgene and driven by a transfer RNA-like (tRNA-like) moiety are taken up by mitochondria in plant cells. The process appears to follow the natural tRNA import specificity, suggesting that translocation indeed occurs through the regular tRNA uptake pathway. Upon validation of the strategy with a reporter sequence, we developed a chimeric catalytic RNA composed of a specially designed trans-cleaving hammerhead ribozyme and a tRNA mimic. Organelle import of the chimeric ribozyme and specific target cleavage within mitochondria were demonstrated in transgenic tobacco cell cultures and Arabidopsis thaliana plants, providing the first directed knockdown of a mitochondrial RNA in a multicellular eukaryote. Further observations point to mitochondrial messenger RNA control mechanisms related to the plant developmental stage and culture conditions. Transformation of mitochondria is only accessible in yeast and in the unicellular alga Chlamydomonas. Based on the widespread tRNA import pathway, our data thus make a breakthrough for direct investigation and manipulation of mitochondrial genetics.
  Nucleic Acids Research 07/2011; 39(21):9262-74. · 8.03 Impact Factor
• Source

  Available from: Agnieszka Rybarczyk

  Article: 2D-PAGE as an effective method of RNA degradome analysis.

  Martyna Nowacka, Paulina Jackowiak, Agnieszka Rybarczyk, Tomasz Magacz, Pawel M Strozycki, Jan Barciszewski, Marek Figlerowicz
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  ABSTRACT: The continuously growing interest in small regulatory RNA exploration is one of the important factors that have inspired the recent development of new high throughput techniques such as DNA microarrays or next generation sequencing. Each of these methods offers some significant advantages but at the same time each of them is expensive, laborious and challenging especially in terms of data analysis. Therefore, there is still a need to develop new analytical methods enabling the fast, simple and cost-effective examination of the complex RNA mixtures. Recently, increasing attention has been focused on the RNA degradome as a potential source of riboregulators. Accordingly, we attempted to employ a two-dimensional gel electrophoresis as a quick and uncomplicated method of profiling RNA degradome in plant or human cells. This technique has been successfully used in proteome analysis. However, its application in nucleic acids studies has been very limited. Here we demonstrate that two dimensional electrophoresis is a technique which allows one to quickly and cost-effectively identify and compare the profiles of 10-90 nucleotide long RNA accumulation in various cells and organs.
  Molecular Biology Reports 05/2011; 39(1):139-46. · 2.93 Impact Factor
• Article: Effects of kinetin riboside on proliferation and proapoptotic activities in human normal and cancer cell lines.

  Paulina Dudzik, Joanna Dulińska-Litewka, Eliza Wyszko, Patrycja Jędrychowska, Maciej Opałka, Jan Barciszewski, Piotr Laidler
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  ABSTRACT: Kinetin riboside (KR) is a N6-substituted derivative of adenosine. It is a natural compound which occurs in the milk of coconuts on the nanomole level. KR was initially shown to selectively inhibit proliferation of cancer cells and induce their apoptosis. We observed that KR inhibited growth (20-80%) of not only human cancer, but also normal cells and that this effect strongly depended on the type of cells. The anti-apoptotic Bcl-2 protein was downregulated, while proapoptotic Bax was upregulated in normal as well as in cancer cell lines, upon exposure to KR. Cytochrome c level increased in the cytosol upon treatment of cells with KR. The activity of caspases (ApoFluor®Green Caspase Activity Assay), as well as caspase-3 (caspase-3 activation assay) were increased mainly in cancer cells. The expression of procaspase 9 and its active form in the nucleus as well as in cytosol of KR-treated cells was elevated. In contrast, no effect of KR on caspase 8 expression was noted. The results indicated that non-malignant cells were less sensitive to KR then their cancer analogs and that KR most likely stimulated apoptosis mechanism of cancer cells through the intrinsic pathway.
  Journal of Cellular Biochemistry 04/2011; 112(8):2115-24. · 2.87 Impact Factor
• Article: [Lycopene--occurrence, properties and applications].

  Agnieszka Belter, Małgorzata Giel-Pietraszuk, Stefan Oziewicz, Piotr Chomczyński, Jan Barciszewski
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  ABSTRACT: Natural products from plants, fungi and higher animals are valuable sources of attractive alternatives for therapeutics. One of them, lycopene is a bright red carotene found in several fruits and vegetables. Tomato, tomato-based sauces and juices are the most abundant sources of this compound for human. There is a positive correlation between lycopene intake and health. It plays an important role in preventing several diseases, inclusing cancers. Lycopene is the most efficient oxygen and free radicals scavenger. Moreover it controls cell cycle and activates phase II detoxification enzymes. Epidemiological studies confirm its significant role in preventing diseases. Constant progress on this field makes lycopene an interesting object of researches.
  Postepy biochemii 01/2011; 57(4):372-80.
• Article: [Cytosine methylation in DNA and its role in cancer therapy].

  Beata Plitta, Małgorzata Giel-Pietraszuk, Wojciech T Markiewicz, Jan Barciszewski
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  ABSTRACT: DNA methyltransferase 1 (DNMT1) is one of three enzymes independently coded in mammalian cells. It catalyses postreplicative synthesis of 5-methylcytosine in DNA. The aim of this modification is regulation of gene expression characteristic for the given organism. DNMT1 maintains methylation pattern by copying it from maternal to daughter stand. S-adenosylo-L-methionina is a donor of methyl group in his process. Disturbance in methylation level results in changes in cell differentiation and finally to tumor transformation. Hypermethylation of promotor or first exon of tumor suppression gene results in silencing of its transcription. While hypomethylation of regulatory sequence of protooncogene and retrotransposon make them transcriptionally active. DNMT1 as a key enzyme in maintaing of proper methylation pattern is a attractive target in anti-tumor therapy.
  Postepy biochemii 01/2011; 57(1):24-32.
• Chapter: Noncoding RNAs as Therapeutic Targets

  Maciej Szymański, Jan Barciszewski
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  ABSTRACT: Noncoding RNAs are key players in the regulation of complex cellular processes. Over the years, it has been demonstrated that their abnormal expression is associated with many human pathologies including developmental and neurobehavioral disorders, diabetes, obesity, and cancer. A wide spectrum of activities and a large number of genes that are regulated by RNA-dependent mechanisms makes the ncRNA molecules attractive targets for developing next generation therapeutic agents. This chapter outlines the principles of RNA regulation, the involvement of various RNAs in human diseases, and the strategies of application of ncRNA-targeted therapeutic approaches. KeywordsCancer-Noncoding RNAs-Therapy
  09/2010: pages 393-418;
• Article: Effect of high hydrostatic pressure on hydration and activity of ribozymes.

  Małgorzata Giel-Pietraszuk, Agnieszka Fedoruk-Wyszomirska, Jan Barciszewski
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  ABSTRACT: Formation and stabilization of RNA structure in the cell depends on its interaction with solvent and metal ions. High hydrostatic pressure (HHP) is a convenient tool in an analysis of the role of small molecules in the structure stabilization of biological macromolecules. Analysis of HHP effect and various concentrations of ions showed that water induce formation of the active ribozyme structure. So, it is clear that water is the driving force of conformational changes of nucleic acid.
  Molecular Biology Reports 03/2010; 37(8):3713-9. · 2.93 Impact Factor
• Source

  Available from: psychepharmaceuticals.com

  Article: Promising human brain tumors therapy with interference RNA intervention (iRNAi).

  Katarzyna Rolle, Stanislaw Nowak, Eliza Wyszko, Monika Nowak, Ryszard Zukiel, Rafal Piestrzeniewicz, Iwona Gawronska, Miroslawa Z Barciszewska, Jan Barciszewski
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  ABSTRACT: Glioblastoma multiforme (GBM) is the most common type of malignant gliomas, characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fuelled a search for new treatment modalities. Malignant gliomas express preferentially a number of surface markers that may be exploited as therapeutic targets, such as tenascin-C (TN-C), an extracellular matrix glycoprotein that contributes to tumor cell adhesion, invasion, migration and proliferation. In this paper we describe a novel strategy for human brain tumors therapy based on RNA interference (RNAi) and its application after surgery (intervention with RNAi) to inhibit TN-C synthesis. We present data of 46 patients suffering from brain tumors resected and treated with dsRNA with the sequence homology of tenascin-C mRNA (ATN-RNA). The specific effect of ATN-RNA on TN-C downregulation was proved with antibodies against TN-C in glioblastoma multiforme cultured cells. A significant improvement in overall survival (OS) without loosing the quality of life (QOL) of patients was observed. MRI and CT studies showed tumor growth delay or lack of tumor recurrence. This novel therapy based on RNA interference shows a hopeful therapeutical potential. To our knowledge the intervention with RNAi (iRNAi) method is the first protocol of RNAi application in human brain tumor treatment.
  Cancer biology & therapy 03/2010; 9(5):396-406. · 2.64 Impact Factor
• Article: A new family of ferritin genes from Lupinus luteus--comparative analysis of plant ferritins, their gene structure, and evolution.

  Pawel M Strozycki, Maciej Szymanski, Anna Szczurek, Jan Barciszewski, Marek Figlerowicz
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  ABSTRACT: Ferritins are one of the most important elements of cellular machinery involved in iron management. Despite extensive studies conducted during the last decade, many factors regulating the expression of ferritin genes in plants remain unknown. To broaden our knowledge about the mechanisms controlling ferritin production in plant cells, we have identified and characterized a new family of ferritin genes (from yellow lupine). We have also inventoried all available plant ferritins and their genes and subjected them to a complex bioinformatic analysis. It showed that the conservative structure of ferritin genes was established much earlier than it was thought before. The first introns in ferritin genes appeared already in green algae. The number and location of introns have been finally established in mosses, over 400 million years ago, and are strictly preserved in all plants from bryophytes to dicots. Comparison of ferritin gene promoters revealed that the 14-bp-long iron-dependent regulatory sequence (IDRS), identified earlier in Arabidopsis and maize, is characteristic for all higher plants. Moreover, we found that a highly conserved IDRS can be extended (extIDRS) up to 22 bp. Phylogenetic analysis of plant ferritins showed that polypeptides of the eudicot clade can be divided into two subclasses (eudicot-1 and eudicot-2). Interestingly, we found that genes encoding proteins classified as eudicot-1 and eudicot-2 are equipped with class-specific promoters. This suggests that eudicot ferritins are structurally and perhaps functionally diverse. Based on the above observations, we were able to identify conservative elements (ELEM1--6) other than extIDRS within plant ferritin gene promoters. We also found E-boxes and iron-responsive sequence elements FeRE1 and 2, characteristically distributed within ferritin promoters. Because most of the identified conserved sequences are located within or in close proximity of extIDRS, we named this fragment of the plant ferritin gene promoter the regulatory element rich region.
  Molecular Biology and Evolution 10/2009; 27(1):91-101. · 5.55 Impact Factor