imagine (Institute of molecular genetics and genetic engineering)
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Selenium activates components of iron acquisition machinery in oilseed rape roots
No full textAims Beneficial elements may stimulate plant growth by favoring the availability of essential nutrients for metabolic processes. This study addresses the still unexplored question whether the beneficial action of selenium (Se) on plants can be due to its interaction with iron (Fe). Methods Oilseed rape (Brassica napus) plants were grown hydroponically without (-Se) or with 10 mu M Na2SeO4(+Se) and exposed to either Fe adequate (+Fe) or starvation (-Fe) treatments. Results Selenium enhanced leaf chlorophyll concentration, photochemical parameters and CO(2)fixation. Although Se did not significantly increase total leaf Fe concentration, the concentration of cytoplasmic Fe(II)pool was enhanced under -Fe + Se conditions. However, the most conspicuous Se effects occurred in Fe-deficient roots. Selenium upregulated both the root expression levels of genes encodingFERRIC-REDUCTION OXIDASE (FRO1)and the activity of FRO and exacerbated the stimulatory effect of -Fe on the exudation rate of organic acids and phenolic compounds. Both -Se and + Se plants used Fe(III)EDTA in similar way, while only +Se plants were able to take advantage of the sparingly soluble Fe(OH)(3). In order to explore the mechanism of Se action, we recorded higher endogenous level of NO and upregulation ofETHYLENE RESPONSE FACTOR 2(ERF2) by Se irrespective of Fe conditions. Conclusions Our results show that Se augments root machinery for Fe acquisition mainly through activation of Fe signaling components
Antioxidant and Antiproliferative Activity of Allium ursinum and Their Associated Microbiota During Simulated in vitro Digestion in the Presence of Food Matrix
Get PDFIn this study, for the first time, the comprehensive analysis of antiproliferative and antioxidant activities of ramson, followed by the analysis of its associated microbiota and health-promoting effects of lactic acid bacteria (LAB), was performed. Ramson (Allium ursinum) is recognized as a medicinal plant with a long history of use in traditional medicine due to its antimicrobial and antioxidant activity. In this study the influence of in vitro gastrointestinal digestion on the cytotoxic activity of A. ursinum extracts against human malignant cell lines was demonstrated. Seven sulfur compounds, the degradation products of thiosulfinates, including diallyl disulfide were shown to inhibit proliferation of malignant cells by inducing accumulation within G2/M phase as well as to induce apoptosis through activation of caspase-3 and mitochondrial signaling pathway. Further, the A. ursinum microbiota, particularly LAB with potential probiotic effects, was analyzed by culture-dependent method and culture-independent method [denaturing gradient gel electrophoresis (DGGE)]. The obtained results revealed that the most abundant genera were Streptococcus, Lactobacillus, and Bacillus. The Lactobacillus genus was mainly represented by L. fermentum. The pulsed-field gel electrophoresis (PFGE) analysis revealed the presence of two PFGE pulsotypes. The probiotic potential of the strain L. fermentum BGSR163 belonging to PFGE pulsotype 1 and the strain L. fermentum BGSR227 belonging to the PFGE pulsotype 2 was characterized. The results revealed that both strains are safe for human use, successfully survive the simulated gastrointestinal conditions, have potential to transiently colonize the gastrointestinal tract (GIT) and have a protective immunomodulatory effect, inducing the production of proinflammatory cytokine IL17 and regulatory cytokine IL10, while decreasing the production of proinflammatory cytokine IFN-gamma. In conclusion, the results of this study suggest that consumption of A. ursinum might have health-promoting properties, including anticancer effects, while L. fermentum strains isolated from A. ursinum leaves could be used as probiotics for human consumption
Hydrolytic degradation of star-shaped poly(epsilon-caprolactone)s with different number of arms and their cytotoxic effects
No full textStar-shaped polymers of biodegradable aliphatic polyester, poly(epsilon-caprolactone), PCL, with different number of arms (three, four, and six) were synthesized by ring-opening polymerization initiated by multifunctional alcohols used as cores. As potential biomaterials, synthesized star-shaped poly(epsilon-caprolactone)s,sPCL, were thoroughly characterized in terms of their degradation under different pH conditions and in respect to their cytotoxicity. The in vitro degradation was performed in phosphate buffer (pH 7.4) and hydrochloric acid solution (pH 1.0) over 5 weeks. Degradation ofsPCL films was followed by the weight loss measurements, GPC, FTIR, and AFM analysis. While the most of the samples were stable against the abiotic hydrolysis at pH 7.4 after 5 weeks of degradation, degradation was significantly accelerated in the acidic medium. Degradation rate of polymer films was affected by the polymer architecture and molecular weight. The molecular weight profiles during the degradation revealed random chain scission of the ester bonds indicating bulk degradation mechanism of hydrolysis at pH 7.4, while acidic hydrolysis proceeded through the bulk degradation associated with surface erosion, confirmed by AFM. The in vitro toxicity tests, cytotoxicity applying normal human fibroblasts (MRC5) and embryotoxicity assessment (using zebra fish model,Danio rerio), suggested those polymeric materials as suitable for biomedical application
Genetic basis of otosclerosis
Get PDFUvod Otoskleroza je poremećaj koštane kapsule lavirinta i slušnih koščica uva, koji dovodi do gubitka sluha zbog nemogućnosti provođenja zvuka. Genetički uzrok otoskleroze je nepoznat. Cilj ovog rada je bio da se sačini sveobuhvatni pregled savremenih saznanja o genetičkoj osnovi otoskleroze. Metode Za prikaz podataka o genetici otoskleroze korišćen je narativni pregled literature. Rezultati Genetika otoskleroze nije mnogo izučavana i literaturni podaci o genetičkoj osnovi otoskleroze su oskudni. Međutim, u novije vreme, proširuju se znanja o genetičkoj osnovi otoskleroze. Ovde je prikazan pregled znanja o asocijaciji genetičkih markera i otoskleroze, koja su rezultat analiza genetičke povezanosti, kao i asocijativnih studija gena kandidata i sveobuhvatnih analiza genoma. Zaključak Otoskleroza zbog svoje kompleksnosti nije bolest čija će genetička osnova biti lako rasvetljena. Analize omika i bioinformatika će doprineti razumevanju genetičke osnove otoskleroze.Introduction Otosclerosis is a disorder of the bone labyrinth and stapes resulting in conductive hearing loss. The genetic basis of otosclerosis still remains unknown. We aimed at reporting a comprehensive review of up-to-date knowledge on genetic basis of otosclerosis. Methods Narrative literature review was undertaken to summarize the data about genetics of otosclerosis. Results Genetics of otosclerosis has not been studied extensively and the literature on this topic is scarce. However, knowledge of genetic basis of otosclerosis is recently increasing. We have presented an overview of the knowledge of association of genetic markers with otosclerosis, gained from linkage analyses, candidate-gene studies, and modern high-throughput genomic studies. Conclusion Due to its complex pathophysiology, otosclerosis is not a disease whose genetic base will be easily understood. Multiple omics analysis and bioinformatics will lead to elucidation of genetic basis of otosclerosis
Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients
No full textMaturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genesGCK,HNF1A,HNF4AandHNF1Bin our cohort of 29 MODY patients. We identified one genetic variant in theHNF1Agene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in theGCKgene, -282C gt T; -194A gt G; 402C gt G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in theHNF1Agene could be associated with the patient's diabetes. As for theGCKvariant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in theHNF1Agene is presumed to be disease-causing and theGCKpromoter variant set could be a phenotype modifier
The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor
No full textBACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt T transfected cells. Our ex vivo study of FII c.1824C gt T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests
Lectin from Laetiporus sulphureus effectively inhibits angiogenesis and tumor development in the zebrafish xenograft models of colorectal carcinoma and melanoma
No full textIn spite of extensive usage of Laetiporus sulphureus (sulphur polypore) in traditional European and Asian ethnomedicine for centuries, its anticancer therapeutic potential and toxicity profile remained explored in animal models. Herein, using zebrafish (Danio rerio), as a preclinical animal model, we demonstrated that L sulphureus lectin (LSL) and ethanol extract (LSE) are non-toxic at high doses up to 400-500 mu g/mL, while they effectively inhibited angiogenesis and cancer development at much lower doses. Lectin showed 74-fold higher antiangiogenic potency than the extract, and even 378-fold higher therapeutic potential than sunitinib-malate, cardiotoxic and myelosupressive anti-angiogenic drug of clinical relevance. Using wound healing and MTT assays, we proved LSL's strong anti-migratory effect and selective endothelial cytotoxidty in relation to lung fibro-blasts. In addition, employing the zebrafish xenograft models, we demonstrated that LSL almost completely reduced growth, neovascularization and metastasis of human colorectal carcinoma and mouse melanoma. Even more, LSL exerted 8-fold higher potency towards colorectal carcinoma than melanoma, showing markedly higher activity than cisplatin, while LSE failed to express any anticancer activity. Accompanied with non-toxic response, including neutropenia and inflammation, the results of this study strongly imply that LSL could be used as safe adjuvant in chemotherapy against colorectal carcinoma and melanoma
Insights into platinum-induced peripheral neuropathy-current perspective
Get PDFCancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment
Antimicrobial Activity and DNA/BSA Binding Affinity of Polynuclear Silver(I) Complexes with 1,2-Bis(4-pyridyl)ethane/ethene as Bridging Ligands
Get PDF1,2-Bis(4-pyridyl)ethane (bpa) and 1,2-bis(4-pyridyl)ethene (bpe) were used for the synthesis of polynuclear silver(I) complexes, {[Ag(bpa)]NO3}(n) (1), {[Ag(bpa)(2)](CF3SO3H2O)-H-.}(n) (2) and {[Ag(bpe)]CF3SO3}(n) (3). In complexes 1-3, the corresponding nitrogen-containing heterocycle acts as a bridging ligand between two Ag(I) ions. In vitro antimicrobial activity of these complexes, along with the ligands used for their synthesis, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi. The silver(I) complexes 1-3 showed selectivity towards Candida spp. and Gram-negative Escherichia coli in comparison to the other investigated bacterial strains, effectively inhibiting the growth of four different Candida species with minimal inhibitory concentrations (MICs) between 2.5 and 25 mu g/mL and the growth of E. coli, with MIC value being 12.5 mu g/mL. Importantly, complex 2 significantly reduced C. albicans filamentation, an essential process for its pathogenesis. Antiproliferative effect on the normal human lung fibroblast cell line MRC-5 was also evaluated with the aim of determining the therapeutic potential of the complexes 1-3. The interactions of these complexes with calf thymus DNA (ctDNA) and bovine serum albumin (BSA) were studied to evaluate their binding activities towards these biomolecules for possible insights on their mode of action
Clinical Application of Thiopurine Pharmacogenomics in Pediatrics
No full textBackground: Thiopurine drugs are used for the treatment of pediatric diseases. Inter-individual differences in the metabolism of these drugs greatly influence the risk of thiopurine induced toxicity and therapy failure. These differences are the consequence of genomic, epigenomic and transcriptomic variability among patients. Pharmacogenomics aims to individualize therapy according to the specific genetic signature of a patient. Treatment protocols based on thiopurine drugs have already been improved by applying pharmacogenomics in pediatric clinical practice. Objective: The aim of this review was to summarize the application of thiopurine pharmacogenomics in pediatric patients suffering from acute leukemias, different types of autoimmune and inflammatory diseases, as well as in posttransplant care. Methods: We searched PubMed/Medline database to identify thiopurine pharmacogenomic markers clinically relevant in pediatric diseases. Results: TPMT and NUDT15 pharmacogenomic testing is done in pediatric care, contributing to the reduction of thiopurine induced toxicity. Data on numerous novel potential pharmacogenomic markers relevant for optimization of thiopurine treatment are still controversial (ITPA, ABCC4, NT5C2, PRPS1, GSTM1, FTO gene variants). Majority of evidences regarding thiopurine pharmacogenomics in pediatrics have been acquired by studying acute lymphoblastic leukemia and inflammatory bowel disease. For other pediatric diseases, namely acute myeloid leukemia, non-Hodgkin lymphoma, juvenile idiopathic arthritis, atopic dermatitis, juvenile autoimmune hepatitis and renal allograft transplantation, data are still scarce. Conclusion: Thiopurine pharmacogenomics has shown to be one of the best examples of successful application of pharmacogenomics in pediatrics