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Article: Context-Specific Genome-Scale Metabolic Modelling and Its Application to the Analysis of COVID-19 Metabolic Signatures.

Moškon, Miha / Režen, Tadeja

2023 Volume 13, Issue 1

Abstract: Genome-scale metabolic models (GEMs) have found numerous applications in different domains, ranging from biotechnology to systems medicine. Herein, we overview the most popular algorithms for the automated reconstruction of context-specific GEMs using ... ...

Abstract	Genome-scale metabolic models (GEMs) have found numerous applications in different domains, ranging from biotechnology to systems medicine. Herein, we overview the most popular algorithms for the automated reconstruction of context-specific GEMs using high-throughput experimental data. Moreover, we describe different datasets applied in the process, and protocols that can be used to further automate the model reconstruction and validation. Finally, we describe recent COVID-19 applications of context-specific GEMs, focusing on the analysis of metabolic implications, identification of biomarkers and potential drug targets.
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo13010126
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Article ; Online: Molekularne povezave med cirkadianim ritmom in mikro RNA v hepatocelularnem karcinomu

Rok Struna / Jan Tehovnik / Rok Razpotnik / Tadeja Režen

Zdravniški Vestnik, Vol 92, Iss 1-2, Pp 11-

2023 Volume 19

Abstract: Izhodišča: Cirkadiani ritem se uravnava na centralni in celični ravni preko transkripcijsko-translacijskih povratnih zank, ki so natančno uravnavane. Vpliv na uravnavanje cirkadianega ritma imajo miRNA molekule, ki skupaj s proteinskimi kompleksi ... ...

Abstract	Izhodišča: Cirkadiani ritem se uravnava na centralni in celični ravni preko transkripcijsko-translacijskih povratnih zank, ki so natančno uravnavane. Vpliv na uravnavanje cirkadianega ritma imajo miRNA molekule, ki skupaj s proteinskimi kompleksi privedejo do utišanja prevajanja določenih celičnih proteinov. Kronična motnja v cirkadianem ritmu lahko privede do maligne transformacije celic. Hepatocelularni karcinom je eden najpogostejših vrst raka pri človeku, pri katerem še vedno ni pojasnjen vpliv različnih signalnih poti na karcinogenezo. Namen študije je bil ugotoviti vpliv transkripcijskih dejavnikov cirkadianega ritma in miRNA na izražanje mRNA in krožnih RNA iz istega genskega lokusa, tj. gena LDLR (LDL receptor). Metode: Poskus smo izvedli na celičnih linijah Hep G2 in Huh7. Sprva smo v celice s postopkom transfekcije vnesli želene molekule (hsa-miR-17 in cirkadiane transkripcijske faktorje), s katerimi smo želeli vplivati na izražanje genov, ki so nas zanimali. Iz celic smo nato osamili RNA, ki smo jo nato prepisali v komplementarno DNA in izvedli qPCR (kvantitativno verižno reakcijo s polimerazo), na podlagi katere smo sklepali na raven izražanja želenih genov. Rezultate smo računalniško obdelali in jih grafično predstavili. Rezultati: Z obdelavo rezultatov smo ugotovili, da nobene od treh hipotez nismo uspeli potrditi, saj pri nobenem rezultatu v stopnji izražanja želenih genov nismo ugotovili statistično pomembne razlike (α=0,05). Zaključki: Kljub temu da sprememb v izražanju genov nismo uspeli potrditi, bi bilo raziskovano področje vredno nadaljnjih raziskav, ki bi trdneje prikazale povezavo. Osrediniti bi se morali na konkretne molekule, s čimer bi pridobili nove tarče za zdravljenje jetrnih bolezni, s katerimi bi izboljšali kakovost življenja bolnikov s HCC. Ugotovili bi lahko tudi nove dejavnike tveganja, na podlagi katerih bi lahko bolje ozaveščali prebivalstvo o preventivi, ki bi zmanjšala incidenco HCC.
Keywords	karcinogeneza ; izražanje genov ; molekularna genetika ; povratne zanke ; medcelično signaliziranje ; Medicine ; R
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Slovenian Medical Association
Document type	Article ; Online
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Article ; Online: Integrative Analysis of Rhythmicity: From Biology to Urban Environments and Sustainability.

Moškon, Miha / Režen, Tadeja / Juvančič, Matevž / Verovšek, Špela

International journal of environmental research and public health

2022 Volume 20, Issue 1

Abstract: From biological to socio-technical systems, rhythmic processes are pervasive in our environment. However, methods for their comprehensive analysis are prevalent only in specific fields that limit the transfer of knowledge across scientific disciplines. ... ...

Abstract	From biological to socio-technical systems, rhythmic processes are pervasive in our environment. However, methods for their comprehensive analysis are prevalent only in specific fields that limit the transfer of knowledge across scientific disciplines. This hinders interdisciplinary research and integrative analyses of rhythms across different domains and datasets. In this paper, we review recent developments in cross-disciplinary rhythmicity research, with a focus on the importance of rhythmic analyses in urban planning and biomedical research. Furthermore, we describe the current state of the art of (integrative) computational methods for the investigation of rhythmic data. Finally, we discuss the further potential and propose necessary future developments for cross-disciplinary rhythmicity analysis to foster integration of heterogeneous datasets across different domains, as well as guide data-driven decision making beyond the boundaries of traditional intradisciplinary research, especially in the context of sustainable and healthy cities.
MeSH term(s)	Circadian Rhythm ; Biomedical Research ; Cities ; Biology
Language	English
Publishing date	2022-12-31
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph20010764
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Article: Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma.

Razpotnik, Rok / Vidmar, Robert / Fonović, Marko / Rozman, Damjana / Režen, Tadeja

Cancers

2022 Volume 14, Issue 18

Abstract: Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable ... ...

Abstract	Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced colony formation, migration, cell proliferation, sorafenib sensitivity, and additionally induced morphological changes in cell lines, indicating an important role of hsa_circ_0062682 in oncogenesis. Pathway enrichment analysis and gene set enrichment analysis of the transcriptome data from hsa_circ_0062682 knockdown explained the observed phenotypes and exposed transcription factors E2F1, Sp1, HIF-1α, and NFκB1 as potential downstream targets. Biotinylated oligonucleotide pulldown combined with proteomic analyses identified protein interaction partners of which YBX1, a known oncogene, was confirmed by RNA immunoprecipitation. Furthermore, we discovered a complex cell-type-specific phenotype in response to the oncogenic potential of hsa_circ_0062682. This finding is in line with different classes of HCC tumours, and more studies are needed to shed a light on the molecular complexity of liver cancer.
Language	English
Publishing date	2022-09-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14184524
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Article ; Online: Integrative computational modeling to unravel novel potential biomarkers in hepatocellular carcinoma.

Walakira, Andrew / Skubic, Cene / Nadižar, Nejc / Rozman, Damjana / Režen, Tadeja / Mraz, Miha / Moškon, Miha

Computers in biology and medicine

2023 Volume 159, Page(s) 106957

Abstract: Hepatocellular carcinoma (HCC) is a major health problem around the world. The management of this disease is complicated by the lack of noninvasive diagnostic tools and the few treatment options available. Better clinical outcomes can be achieved if HCC ... ...

Abstract	Hepatocellular carcinoma (HCC) is a major health problem around the world. The management of this disease is complicated by the lack of noninvasive diagnostic tools and the few treatment options available. Better clinical outcomes can be achieved if HCC is detected early, but unfortunately, clinical signs appear when the disease is in its late stages. We aim to identify novel genes that can be targeted for the diagnosis and therapy of HCC. We performed a meta-analysis of transcriptomics data to identify differentially expressed genes and applied network analysis to identify hub genes. Fatty acid metabolism, complement and coagulation cascade, chemical carcinogenesis and retinol metabolism were identified as key pathways in HCC. Furthermore, we integrated transcriptomics data into a reference human genome-scale metabolic model to identify key reactions and subsystems relevant in HCC. We conclude that fatty acid activation, purine metabolism, vitamin D, and E metabolism are key processes in the development of HCC and therefore need to be further explored for the development of new therapies. We provide the first evidence that GABRP, HBG1 and DAK (TKFC) genes are important in HCC in humans and warrant further studies.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Gene Regulatory Networks ; Gene Expression Profiling ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Computer Simulation ; Computational Biology ; Gene Expression Regulation, Neoplastic
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	127557-4
ISSN	1879-0534 ; 0010-4825
ISSN (online)	1879-0534
ISSN	0010-4825
DOI	10.1016/j.compbiomed.2023.106957
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Article ; Online: Correction to: Effect of In Vitro Maturation of Human Oocytes Obtained After Controlled Ovarian Hormonal Stimulation on the Expression of Development- and Zona Pellucida-Related Genes and Their Interactions.

Bedenk, Jure / Režen, Tadeja / Jančar, Nina / Geršak, Ksenija / Virant Klun, Irma

Reproductive sciences (Thousand Oaks, Calif.)

2022 Volume 30, Issue 3, Page(s) 995

Language	English
Publishing date	2022-08-08
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2276411-2
ISSN	1933-7205 ; 1933-7191
ISSN (online)	1933-7205
ISSN	1933-7191
DOI	10.1007/s43032-022-01058-y
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Article ; Online: Factors affecting RNA quantification from tissue long-term stored in formalin.

Malnar, Mirjana / Režen, Tadeja

Journal of pharmacological and toxicological methods

2019 Volume 96, Page(s) 61–66

Abstract: Introduction: FFPE samples represent a rich pool of tissue samples for retrospective analyses of mRNA and miRNA analyses. However, the initial formalin fixation introduces a chemical modification of RNA and causes its degradation, therefore, a longer ... ...

Abstract	Introduction: FFPE samples represent a rich pool of tissue samples for retrospective analyses of mRNA and miRNA analyses. However, the initial formalin fixation introduces a chemical modification of RNA and causes its degradation, therefore, a longer storage of tissue in formalin is predicted to render ribonucleic acids lost for isolation and subsequent analyses. Methods: Herein, we tested the impact of several factors on isolation of total RNA and detection with RT-qPCR from mouse liver tissue stored for over two years in formalin at room temperature. Results: The incubation of tissue in TAE buffer before RNA isolation yielded higher concentration and purity of RNA and also improved subsequent analyses. Using gene-specific primers for cDNA synthesis and shorter PCR products (under 70 bp) significantly improved RT-qPCR analyses. We also compared the level of expression and differential expression of mRNA and miRNA with matched fresh frozen liver tissue, and observed similar changes in differential expression of selected mRNA and miRNA as in matched fresh frozen tissue. Discussion: Conclusion is that adjustments of the protocol can substantially improve analyses of mRNA and miRNA from tissues stored in formalin for longer time.
MeSH term(s)	Animals ; Formaldehyde ; Frozen Sections ; Liver ; Mice ; Mice, Knockout ; MicroRNAs/analysis ; MicroRNAs/isolation & purification ; RNA, Messenger/analysis ; RNA, Messenger/isolation & purification ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Reverse Transcriptase Polymerase Chain Reaction ; Sterol 14-Demethylase/deficiency ; Tissue Fixation/methods
Chemical Substances	MicroRNAs ; RNA, Messenger ; Formaldehyde (1HG84L3525) ; Sterol 14-Demethylase (EC 1.14.13.70)
Language	English
Publishing date	2019-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2019.02.002
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Article: Guided extraction of genome-scale metabolic models for the integration and analysis of omics data.

Walakira, Andrew / Rozman, Damjana / Režen, Tadeja / Mraz, Miha / Moškon, Miha

Computational and structural biotechnology journal

2021 Volume 19, Page(s) 3521–3530

Abstract: Omics data can be integrated into a reference model using various model extraction methods (MEMs) to yield context-specific genome-scale metabolic models (GEMs). How to chose the appropriate MEM, thresholding rule and threshold remains a challenge. We ... ...

Abstract	Omics data can be integrated into a reference model using various model extraction methods (MEMs) to yield context-specific genome-scale metabolic models (GEMs). How to chose the appropriate MEM, thresholding rule and threshold remains a challenge. We integrated mouse transcriptomic data from a
Language	English
Publishing date	2021-06-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2021.06.009
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Article: The role of bile acids in carcinogenesis

Režen, Tadeja / Rozman, Damjana / Kovács, Tünde / Kovács, Patrik / Sipos, Adrienn / Bai, Péter / Mikó, Edit

Cellular and molecular life sciences. 2022 May, v. 79, no. 5

2022

Abstract: Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; ... ...

Abstract	Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
Keywords	antineoplastic activity ; bile ; bile acids ; biosynthesis ; blood serum ; breast neoplasms ; breasts ; carcinogenesis ; cholestasis ; cholesterol ; drug therapy ; drugs ; gene expression regulation ; large intestine ; liver ; metabolites ; ovarian neoplasms
Language	English
Dates of publication	2022-05
Size	p. 243.
Publishing place	Springer International Publishing
Document type	Article
Note	Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04278-2
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: VLDL and HDL attenuate endoplasmic reticulum and metabolic stress in HL-1 cardiomyocytes.

Tekavec, Sara / Sorčan, Tjaša / Giacca, Mauro / Režen, Tadeja

Biochimica et biophysica acta. Molecular and cell biology of lipids

2020 Volume 1865, Issue 8, Page(s) 158713

Abstract: Lipoproteins have a vital role in the development of metabolic and cardiovascular diseases ranging from protective to deleterious effects on target tissues. VLDL has been shown to induce lipotoxic lipid accumulation and exert a variety of negative ... ...

Abstract	Lipoproteins have a vital role in the development of metabolic and cardiovascular diseases ranging from protective to deleterious effects on target tissues. VLDL has been shown to induce lipotoxic lipid accumulation and exert a variety of negative effects on cardiomyocytes. Lipotoxicity and endoplasmic reticulum (ER) stress are proposed to be the mediators of damaging effects of metabolic diseases on cardiovascular system. We treated cardiomyocytes with lipoproteins to evaluate the adaptability of these cells to metabolic stress induced by starvation and excess of lipoproteins, and to evaluate the effect of lipoproteins and lipid accumulation on ER stress. VLDL reversed metabolic stress induced by starvation, while HDL did not. VLDL induced dose-dependent lipid accumulation in cardiomyocytes, which however did not result in reduced cell viability or induction of ER stress. Moreover, VLDL or HDL pre-treatment reduced ER stress in cardiomyocytes induced by tunicamycin and palmitic acid as measured by the expression of ER stress markers, even in conditions of increased lipid accumulation. VLDL and HDL induced activation of pro-survival ERK1/2 in cardiomyocytes; however, this activation was not involved in the protection against ER stress. Additionally, we observed that LDLR and VLDLR are regulated differently by lipoproteins and cellular stress, as lipoproteins induced VLDLR protein independently of the level of lipid accumulation. We conclude that VLDL is not a priori detrimental for cardiomyocytes and can even have beneficial effects, enabling cell survival under starvation and attenuating ER stress.
MeSH term(s)	Cell Line ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Humans ; Lipoproteins, HDL/metabolism ; Lipoproteins, VLDL/metabolism ; Myocytes, Cardiac/metabolism ; Stress, Physiological
Chemical Substances	Lipoproteins, HDL ; Lipoproteins, VLDL
Language	English
Publishing date	2020-04-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2020.158713
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