Objective: Malignant gliomas are aggressive neoplasms with a dismal prognosis despite optimal treatment, i.e. surgery combined with radiotherapy. Systemic chemotherapy is less effective. However, temozolomide (TMZ) has been shown to... more
Objective: Malignant gliomas are aggressive neoplasms with a dismal prognosis despite optimal treatment, i.e. surgery combined with radiotherapy. Systemic chemotherapy is less effective. However, temozolomide (TMZ) has been shown to increase overall survival in glioblastoma patients. Its active metabolite[for full text, please go to the a.m. URL]
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Die Erfindung betrifft die Verwendung eines L-Ribozymes, welches zur Spaltung einer L-RNA im Bereich einer Targetsequenz der L-RNA befahigt ist, zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von unerwunschten... more
Die Erfindung betrifft die Verwendung eines L-Ribozymes, welches zur Spaltung einer L-RNA im Bereich einer Targetsequenz der L-RNA befahigt ist, zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von unerwunschten physiologischen Nebenreaktionen aufgrund der Gabe eines therapeutischen Molekuls enthaltend die L-RNA. Mit dem L-Ribozym kann aber auch alternativ eine endogene Target RNA gespalten werden.
RNA-based tools are frequently used to modulate gene expression in living cells. However, the stability and effectiveness of such RNA-based tools is limited by cellular nuclease activity. One way to increase RNA’s resistance to nucleases... more
RNA-based tools are frequently used to modulate gene expression in living cells. However, the stability and effectiveness of such RNA-based tools is limited by cellular nuclease activity. One way to increase RNA’s resistance to nucleases is to replace its D-ribose backbone with L-ribose isomers. This modification changes chirality of an entire RNA molecule to L-form giving it more chance of survival when introduced into cells. Recently, we have described the activity of left-handed hammerhead ribozyme (L-Rz, L-HH) that can specifically hydrolyse RNA with the opposite chirality at a predetermined location. To understand the structural background of the RNA specific cleavage in a heterochiral complex, we used circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy as well as performed molecular modelling and dynamics simulations of homo- and heterochiral RNA complexes. The active ribozyme-target heterochiral complex showed a mixed chirality as well as low field imino...
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Purification and properties of transcription factor IIIA (TF IIIA) from maize pollen (Zea mays L.) are presented for the first time. The purified protein has a molecular mass of about 35 kDa and exhibits binding affinity toward both 5S... more
Purification and properties of transcription factor IIIA (TF IIIA) from maize pollen (Zea mays L.) are presented for the first time. The purified protein has a molecular mass of about 35 kDa and exhibits binding affinity toward both 5S rRNA and 5S rRNA gene. It also facilitates transcription of the 5S rRNA gene in a HeLa cell extract.
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Despite the wealth of data on RNA secondary structure, conformational dynamics and tertiary structure in vitro and in vivo, predicting RNA biological activity in cellular environments remains difficult. Here we describe a method of in... more
Despite the wealth of data on RNA secondary structure, conformational dynamics and tertiary structure in vitro and in vivo, predicting RNA biological activity in cellular environments remains difficult. Here we describe a method of in silico RNA fingerprinting that allows efficient design of hammerhead ribozyme molecules with a high intracellular efficiency. Our method, which we call RNA dactyloscopy, is a reliable tool for assessing catalytic properties, modeling and design of RNA.
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Locked nucleic acids (LNAs) and double-stranded small interfering RNAs (siRNAs) are rather new promising antisense molecules for cell culture and in vivo applications. Here, we compare LNA-DNA-LNA gapmer oligonucleotides and siRNAs with a... more
Locked nucleic acids (LNAs) and double-stranded small interfering RNAs (siRNAs) are rather new promising antisense molecules for cell culture and in vivo applications. Here, we compare LNA-DNA-LNA gapmer oligonucleotides and siRNAs with a phosphorothioate and a chimeric 2'-O-methyl RNA-DNA gapmer with respect to their capacities to knock down the expression of the vanilloid receptor subtype 1 (VR1). LNA-DNA-LNA gapmers with four or five LNAs on either side and a central stretch of 10 or 8 DNA monomers in the center were found to be active gapmers that inhibit gene expression. A comparative co-transfection study showed that siRNA is the most potent inhibitor of VR1-green fluorescent protein (GFP) expression. A specific inhibition was observed with an estimated IC50 of 0.06 nM. An LNA gapmer was found to be the most efficient single-stranded antisense oligonucleotide, with an IC50 of 0.4 nM being 175-fold lower than that of commonly used phosphorothioates (IC50 approximately 70 nM...
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Hammerhead ribozyme is the smallest naturally occurring catalytic RNA. It is a perfect model for structure-function relation studies. Initially, it was identified as an autocatalytic part of viroid and virusoid genomic RNA. It exists... more
Hammerhead ribozyme is the smallest naturally occurring catalytic RNA. It is a perfect model for structure-function relation studies. Initially, it was identified as an autocatalytic part of viroid and virusoid genomic RNA. It exists within the genomes of many organisms including human, which makes it the most common autocatalytic motif in the nature. After 25 years of intensive research, there are a lot of data considering its structure, conformational dynamics and an influence of tertiary stabilizing motifs on its stability and properties. Structure of the hammerhead ribozyme is a system of elements that influence each other. The knowledge of ribozyme architecture is outstandingly interesting in the context of rules and logic of design, construction and application of such molecules as spatial molecular constructions. Presence of additional structural motifs distinguishes extended hammerhead ribozyme from the minimal one. Hammerhead ribozyme recognizes complementary RNA and cataly...
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Hypertension is a common disease of the cardiovascular system and one of the main causes of mortality in the world. Its etiopathogenesis and molecular mechanisms are unknown. Epigenetic changes may play a role in its development.... more
Hypertension is a common disease of the cardiovascular system and one of the main causes of mortality in the world. Its etiopathogenesis and molecular mechanisms are unknown. Epigenetic changes may play a role in its development. Therefore the level of 5-methylcytosine (5mC), a well-known epigenetic marker, was analyzed in DNA from the blood of essential hypertension patients. TLC chromatographic analysis of the DNA nucleotide composition was used to determine 5mC levels in blood DNA samples from 60 patients suffering from essential hypertension (30 with stage 1 and 30 with stage 2 hypertension) and 30 control subjects. The mean levels of 5mC were 1.80 + or - 0.69 in the healthy subjects, 1.14 + or - 0.48 in all the patients with essential hypertension, 1.29 + or - 0.50 in those with stage 1, and 0.99 + or - 0.42 in those with stage 2 of hypertension. Statistically significant differences in 5mC amount in DNA were observed between the control group and the whole patient group, the c...
Research Interests: Biology, Epigenetics, Adolescent, Medicine, Humans, and 15 moreInternal Medicine, Hypertension, Blood Pressure, Female, Male, DNA methylation, Young Adult, Middle Aged, Deamination, Adult, Quntitative Thin Layer Chromatography, Case Control Studies, 5-Methylcytosine, Essential Hypertension, and Medical and Health Sciences
Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. Malignant gliomas express preferentially a... more
Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. Malignant gliomas express preferentially a number of surface markers that may be exploited as therapeutic targets, such as tenascin-C, an extracellular matrix glycoprotein contributes to tumor cell adhesion, invasion, migration and proliferation. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fuelled a search for new treatment modalities. Here we present the data for 46 patients suffering from brain tumor. They were resected and treated with dsRNA (ATN-RNA) complementary to the sequence of tenascin-C mRNA. MRI and CT follow up studies showed growth tumor delay or lack of its recurrence symptoms, due to inhibition of TN-C synthesis. A significant improvement in overall survival (OS) was observed without loosing of the quality of life (QOL) of pa...
Research Interests: Magnetic Resonance Imaging, Quality of life, Cancer Research, Medicine, Multivariate Analysis, and 15 moreRNA interference, Humans, Glioma, Glioblastoma, Female, Male, Aged, Middle Aged, Adult, Survival Rate, Base Sequence, X ray Computed Tomography, Brain Neoplasms, Tenascin, and Pharmacology and pharmaceutical sciences
Riboswitches are RNA structures able to bind small molecules and regulate gene expression at both, transcriptional and translational level. They are present in a wide variety of bacterial species. In Bacillus subtilis more than 2% of the... more
Riboswitches are RNA structures able to bind small molecules and regulate gene expression at both, transcriptional and translational level. They are present in a wide variety of bacterial species. In Bacillus subtilis more than 2% of the genome is regulated by riboswitches. Metabolite binding is highly specific and can be provided in cooperative manner. Several riboswitches has been identified and characterized to be specific for flavin mononucleotide, thiamine, thiamine pyrophosphate, adenosylcobalamin, S-adenosylmethionine, lysine, glycine, adenine, guanine and glucosamine-6-phosphate. Some of them have been found also in fungi (Neurospora crassa) and plants (Oryza sativa, Arabidopsis thaliana). In human only one riboswitch with binding capacity for 2-aminopurine, has been found. Occurrence of riboswitches in all of the phylogenetic groups suggests that they are one of the oldest regulatory systems. It provokes also the question about their involvement in regulation of gene expres...
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Eukaryotic transcription factor IIIA (TF IIIA) is know to activate specifically transcription of 5S rRNA gene. It also interacts with mature 5S rRNA. The best known TF IIIA has been purified from Xenopus laevis. Up to know this protein... more
Eukaryotic transcription factor IIIA (TF IIIA) is know to activate specifically transcription of 5S rRNA gene. It also interacts with mature 5S rRNA. The best known TF IIIA has been purified from Xenopus laevis. Up to know this protein has not been isolated from plants. In this paper we show for the first time purification and properties of TF IIIA like protein from tulip (Tulipa whittalli). It shows 5S rRNA and 5S rRNA gene binding activity.
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Trinucleotide repeats are microsatellite sequences that are polymorphic in length. Their expansion in specific genes underlies a number of neurodegenerative disorders. Using ultraviolet-visible, circular dichroism, nuclear magnetic... more
Trinucleotide repeats are microsatellite sequences that are polymorphic in length. Their expansion in specific genes underlies a number of neurodegenerative disorders. Using ultraviolet-visible, circular dichroism, nuclear magnetic resonance (NMR) spectroscopies and electrospray ionization mass spectrometry, the structural preferences of RNA molecules composed of two and four repeats of AGG, CGG and UGG in the presence of K+, Na+ and NH4+ were analysed. (AGG)2A, (AGG)4A, p(UGG)2U and p(UGG)4U strongly prefer folding into G-quadruplexes, whereas CGG-containing sequences can adopt different types of structure depending on the cation and on the number of repeats. In particular, the two-repeat CGG sequence folds into a G-quadruplex in potassium buffer. We also found that each G-quadruplex fold is different: A:(G:G:G:G)A hexads were found for (AGG)2A, whereas mixed G:C:G:C tetrads and U-tetrads were observed in the NMR spectra of G(CGG)2C and p(UGG)2U, respectively. Finally, our NMR stud...
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Malignant gliomas preferentially express a number of surface markers that may be exploited as therapeutic targets, such as tenascin-C, an extracellular matrix glycoprotein which contributes to tumor cell adhesion, invasion, migration, and... more
Malignant gliomas preferentially express a number of surface markers that may be exploited as therapeutic targets, such as tenascin-C, an extracellular matrix glycoprotein which contributes to tumor cell adhesion, invasion, migration, and proliferation. Glioblastoma ...
Research Interests: Quality of life, Radiation Therapy, Cancer Research, Medicine, Extracellular Matrix, and 13 moreRNA interference, Brain Tumor, Glioma, Glioblastoma, P-glycoprotein, Glioblastoma Multiforme, Genetic Instability, Malignant Glioma, Human Disease, Tumor Growth, Overall Survival, Tenascin, and Springer Ebooks
Research Interests: Molecular Biology, RNA, Kinetics, Biology, Medicine, and 15 moreBiological Sciences, DNA, Environmental Sciences, Humans, Drug Design, Nucleic Acids, RNAse P, Antisense Oligonucleotide Drugs, Human Serum, Ribonucleotides, Drug Stability, Nucleotides, Nucleic Acid, Melting Temperature, and Oligonucleotide
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DsrA RNA is an 87-nucleotide regulatory non-protein-coding RNA of Escherichia coli for which two secondary structure models (I and II) have been proposed. We have compared these models by the energy calculations, which revealed that the... more
DsrA RNA is an 87-nucleotide regulatory non-protein-coding RNA of Escherichia coli for which two secondary structure models (I and II) have been proposed. We have compared these models by the energy calculations, which revealed that the currently accepted model II should be rejected on the basis of thermodynamics. Here we provide new results of nuclease footprinting analysis and the application of RNA technologies that have not previously been used for DsrA RNA structural studies, such as hydrolysis with RNase H, DNAzyme, hydroxyl radicals and lead. These approaches together with bioinformatics calculations provided strong arguments for a new model III. This model clearly shows that the long U-rich region between hairpins 1 and 2 is double-stranded. These findings shed new light on DsrA RNA-Hfq interactions.
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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... more
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.
Research Interests: RNA, Biology, Cancer Research, Transcription Factors, Apoptosis, and 14 moreMedicine, RNA interference, Humans, Glioma, Medical Biotechnology, Animals, microRNAs, Current, Brain Neoplasms, Nucleic Acid, Extracellular Matrix Proteins, Oligonucleotide, Tenascin, and Pharmacology and pharmaceutical sciences
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Streszczenie Oprócz białek oraz niskocząsteczkowych regulatorów, istotną rolę kontrolną w mózgu odgrywają kwasy rybonukleinowe (RNA), aw szczególności te niekodujące białek (ang. non-coding RNA, ncRNA). Występują one we wszystkich... more
Streszczenie Oprócz białek oraz niskocząsteczkowych regulatorów, istotną rolę kontrolną w mózgu odgrywają kwasy rybonukleinowe (RNA), aw szczególności te niekodujące białek (ang. non-coding RNA, ncRNA). Występują one we wszystkich komórkach od bakterii po ...
Small compounds are a large group of chemicals characterized by various biological properties. Some of them also have antiaging potential, which is mainly attributed to their antioxidant activity. In this study, we examined the antiaging... more
Small compounds are a large group of chemicals characterized by various biological properties. Some of them also have antiaging potential, which is mainly attributed to their antioxidant activity. In this study, we examined the antiaging effect of 4-N-Furfurylcytosine (FC), a cytosine derivative belonging to a group of small compounds, on budding yeast Saccharomyces cerevisiae. We chose this yeast model as it is known to contain multiple conserved genes and mechanisms identical to that of humans and has been proven to be successful in aging research. The chronological lifespan assay performed in the study revealed that FC improved the viability of yeast cells in a concentration-dependent manner. Furthermore, enhanced mitochondrial activity, together with reduced intracellular ROS level, was observed in FC-treated yeast cells. The gene expression analysis confirmed that FC treatment resulted in the restriction of the TORC1 signaling pathway. These results indicate that FC has antiagi...
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In the present study, we continue our work related to the synthesis of 1,8-naphthalimide and carborane conjugates and the investigation of their anticancer activity and DNA-binding ability. For this purpose, a series of... more
In the present study, we continue our work related to the synthesis of 1,8-naphthalimide and carborane conjugates and the investigation of their anticancer activity and DNA-binding ability. For this purpose, a series of 4-carboranyl-1,8-naphthalimide derivatives, mitonafide, and pinafide analogs were synthesized using click chemistry, reductive amination, amidation, and Mitsunobu reactions. The calf thymus DNA (ct-DNA)-binding properties of the synthesized compounds were investigated by circular dichroism (CD), UV–vis spectroscopy, and thermal denaturation experiments. Conjugates 54–61 interacted very strongly with ct-DNA (∆Tm = 7.67–12.33 °C), suggesting their intercalation with DNA. They were also investigated for their in vitro effects on cytotoxicity, cell migration, cell death, cell cycle, and production of reactive oxygen species (ROS) in a HepG2 cancer cell line as well as inhibition of topoisomerase IIα activity (Topo II). The cytotoxicity of these eight conjugates was in th...
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Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the... more
Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). A series of isoniazid-carborane derivatives containing 1,2-dicarba-closo-dodecaborane, 1,7-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, or 7,8-dicarba-nido-undecaborate anion were synthesized for the first time. The compounds were tested in vitro against the Mycobacterium tuberculosis (Mtb) H37Rv strain and its mutant (ΔkatG) defective in the synthesis of catalase-peroxidase (KatG). N′-((7,8-dicarba-nido-undecaboranyl)methylidene)isonicotinohydrazide (16) showed the highest activity against the wild-type Mtb strain. All hybrids could inhibit the growth of the ΔkatG mutant in lower concentrations than INH. N′-([(1,12-dicarba-closo-dodecaboran-1yl)ethyl)isonicotinohydra...
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An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely... more
An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR)... more
Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative—7-deaza...
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Small-molecule compound-based therapies have provided new insights into cancer treatment against mitochondrial impairment. N6-furfuryladenosine (kinetin riboside, KR) is a purine derivative and an anticancer agent that selectively affects... more
Small-molecule compound-based therapies have provided new insights into cancer treatment against mitochondrial impairment. N6-furfuryladenosine (kinetin riboside, KR) is a purine derivative and an anticancer agent that selectively affects the molecular pathways crucial for cell growth and apoptosis by interfering with mitochondrial functions and thus might be a potential mitotoxicant. Metabolism of cancer cells is predominantly based on the Crabtree effect that relies on glucose-induced inhibition of cell respiration and thus on oxidative phosphorylation (OXPHOS), which supports the survival of cancer cells in metabolic stress conditions. The simplest way to circumvent this phenomenon is to replace glucose with galactose in the culture environment. Consequently, cells become more sensitive to mitochondrial perturbations caused by mitotoxicants. In the present study, we evaluated several cellular parameters and investigated the effect of KR on mitochondrial functions in HepG2 cells f...
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We synthesized a series of novel 3-carboranyl-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, using click chemistry, reductive amination and amidation reactions and investigated their in vitro effects on cytotoxicity, cell... more
We synthesized a series of novel 3-carboranyl-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, using click chemistry, reductive amination and amidation reactions and investigated their in vitro effects on cytotoxicity, cell death, cell cycle, and the production of reactive oxygen species in a HepG2 cancer cell line. The analyses showed that modified naphthalic anhydrides and naphthalimides bearing ortho- or meta-carboranes exhibited diversified activity. Naphthalimides were more cytotoxic than naphthalic anhydrides, with the highest IC50 value determined for compound 9 (3.10 µM). These compounds were capable of inducing cell cycle arrest at G0/G1 or G2M phase and promoting apoptosis, autophagy or ferroptosis. The most promising conjugate 35 caused strong apoptosis and induced ROS production, which was proven by the increased level of 2′-deoxy-8-oxoguanosine in DNA. The tested conjugates were found to be weak topoisomerase II inhibitors and classical DNA intercalators....
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Some studies have ascribed a protective effect against neurodegenerative diseases to the β-carbolines harman (H) and norharman (NH), which occur mostly in coffee and coffee substitutes. We determined the concentrations of β-carbolines and... more
Some studies have ascribed a protective effect against neurodegenerative diseases to the β-carbolines harman (H) and norharman (NH), which occur mostly in coffee and coffee substitutes. We determined the concentrations of β-carbolines and undesirable compounds (such as acrylamide) in roasted coffee substitute ingredients and found that chicory coffee was optimal. Two in vivo experiments were conducted with seventeen-month-old male Sprague Dawley rats fed a diet with the addition of pure carboline standards in the first stage, and chicory in the second. We observed an increase in the level of H and NH in blood plasma, as well as higher activity of animals in the battery behavioral test, particularly in the second stage. The results of in vitro studies—particularly the level of the expression in brain tissue of genes associated with aging processes and neurodegenerative diseases—clearly show the benefits of a diet rich in β-carbolines.
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The development of 1,8-naphthalimide derivatives as DNA-targeting anticancer agents is a rapidly growing area and has resulted in several derivatives entering into clinical trials. One of original recent developments is the use of boron... more
The development of 1,8-naphthalimide derivatives as DNA-targeting anticancer agents is a rapidly growing area and has resulted in several derivatives entering into clinical trials. One of original recent developments is the use of boron clusters: carboranes and metallacarboranes in the design of pharmacologically active molecules. In this direction several naphthalimide-carborane and metallacarborane conjugates were synthesized in the present study. Their effect on a cancer cell line - cytotoxicity, type of cell death, cell cycle, and ROS production were investigated. The tested conjugates revealed different activities than the leading members of the naphthalimides family, namely mitonafide and pinafide. These derivatives could induce G0/G1 arrest and promote mainly apoptosis in HepG2 cell line. Our investigations demonstrated that the most promising molecule is N-{[2-(3,3'-commo-bis(1,2-dicarba-3-cobalta(III)-closo-dodecaborate-1-yl)ethyl]-1'-aminoethyl)}-1,8-naphthalimide] (17). It was shown that 17 exhibited cytotoxicity against HepG2 cells, activated cell apoptosis, and caused cell cycle arrest in HepG2 cells. Further investigations in HepG2 cells revealed that compound 17 can also induce ROS generation, particularly mitochondrial ROS (mtROS), which was also proved by increased 8-oxo-dG level in DNA. Additionally to biological assays the interaction of the new compounds with ct-DNA was studied by CD spectra and melting temperature, thus demonstrating that these compounds were rather weak classical DNA intercalators.
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Cardiovascular diseases (CD) are currently one of the most common causes of death of people during the past decade. Due to the enormous scale, heart diseases have already been given the title of the epidemic. Chronic and acute injury of... more
Cardiovascular diseases (CD) are currently one of the most common causes of death of people during the past decade. Due to the enormous scale, heart diseases have already been given the title of the epidemic. Chronic and acute injury of heart can be an effect of cardiac remodeling, which is a result of molecular, cellular and interstitial changes, influenced by hemodynamic load or neurohormonal activation (Cohn et al., 2000). These small deviations in cardiac function and morphology, may lead to enormous negative effect. Despite great progress, knowledge of classical risk factors for cardiovascular disease, becomes less and less effective, that is why, predicting and seeking for appropriate treatment is very challenging. Therefore, it has been observed growing interest in finding new markers of the CD.microRNAs (miRNAs), are short, non-coding RNAs responsible for regulation of gene expression at the post-transcriptional level. Among them, the greatest potential have microRNA molecu...
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5-methylcytosine (m5C, 5mC) is a nucleotide occurring naturally in genomic DNA and play an important role in regulation of genes expression. Methylation of cytosine in DNA is an epigenetic modification and different intrinsic and... more
5-methylcytosine (m5C, 5mC) is a nucleotide occurring naturally in genomic DNA and play an important role in regulation of genes expression. Methylation of cytosine in DNA is an epigenetic modification and different intrinsic and extrinsic factors can influence on its level. For example, it is subject to modification and/or degradation by the free radicals which are commonly present in environment of human, among others the cigarette smoke. The reactions of m5C with free radicals lead to origination of many products which effect is decrease of level of m5C in DNA (hypomethylation) and excessive expression of genes inducing development of different diseases, especially cardiovascular system diseases. The aim of the study was statement if exist differences of level of 5-methylcytosine in DNA between smoking and non-smoking patients suffering from mild essential hypertension. The study group was composed of 30 patients suffering from mild essential hypertension (21 females and 40 males...
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Research Interests: Chemistry, Organic Chemistry, Fluorescence, Medicine, DNA, and 15 moreHumans, Silver, Escherichia coli, Staphylococcus aureus, Intercalation Chemistry, Pyridines, Microbial Sensitivity Tests, HeLa, Cell Proliferation, Structure activity Relationship, Organometallic Compounds, Antineoplastic Agents, Counterion, Molecular Structure, and Pharmacology and pharmaceutical sciences
We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants.... more
We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans-cleaving hammerhead ribozymes into the organelles, to knock down specific mitochondrial RNAs and analyze the regulatory impact. In a similar approach, the tRNA mimic was used to import into mitochondria in Arabidopsis thaliana the orf77, an RNA associated with cytoplasmic male sterility in maize and possessing sequence identities with the atp9 mitochondrial RNA. In both cases, inducible expression of the transgenes allowed to characterise early regulation and signaling responses triggered by these respective manipulations of the organellar transcriptome. The results imply that the mitochondrial transcriptome is tightly controlled by a “buffering” mechanism at the early and intermediate stage...
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Despite great progress in the treatment of AIDS, HIV-1 remains one of the major concerns as a human pathogen. One of the therapeutic strategies against viral infections is the application of catalytic ribonucleic acids (ribozymes) that... more
Despite great progress in the treatment of AIDS, HIV-1 remains one of the major concerns as a human pathogen. One of the therapeutic strategies against viral infections is the application of catalytic ribonucleic acids (ribozymes) that can significantly reduce expression of a target gene by site-specific hydrolysis of its mRNA. In the present paper, we report a study on the activity of several variants of hammerhead ribozymes targeting a conserved region within mRNA encoding HIV-1 envelope glycoprotein gp41. On the basis of the data from in vitro assays and gene silencing in the cultured cells, we propose a new hammerhead ribozyme targeting the gp41-encoding sequence that can be potentially used as a therapeutic agent in AIDS treatment. Moreover, we demonstrate that the hydrolytic activity of the ribozyme in the intracellular environment cannot be inferred solely from the results of in vitro experiments.
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No conventional approach has been validated to transform mitochondria in plant and animal cells. This restricts fundamental investigations on organelles and prevents development of mitochondrial biotechnology or complementation of... more
No conventional approach has been validated to transform mitochondria in plant and animal cells. This restricts fundamental investigations on organelles and prevents development of mitochondrial biotechnology or complementation of pathogenic mutations in the mitochondrial DNA (mtDNA). In that context, we develop alternative strategies based on physiological mechanisms of nucleic acid transport. Plant mitochondria import one third to one half of their transfer RNAs (tRNAs) from the cytosol. In a first approach, we exploit this pathway to transport into the organelles RNAs of interest expressed from nuclear transgenes. We demonstrated that a tRNA mimic can drive a 5'-trailor cargo RNA into mitochondria in plant cells and whole plants. Using as a cargo RNA a trans-cleaving hammerhead ribozyme targeting the atp9 messenger RNA allowed to obtain the first directed knockdown of a mitochondrial RNA in a multicellular eukaryote. This strategy opens the way for RNA-directed manipulation o...