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  1. AU="Castell, Jose"
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  1. Book: In vitro methods in pharmaceutical research

    Castell, José V.

    1997  

    Author's details ed. by José V. Castell
    Keywords Technology, Pharmaceutical
    Language English
    Size IX, 467 S. : Ill., graph. Darst.
    Publisher Acad. Press
    Publishing place San Diego u.a.
    Publishing country United States
    Document type Book
    HBZ-ID HT007518445
    ISBN 0-12-163390-X ; 978-0-12-163390-5
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    1997 A 3616 order for loan Magazin

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  2. Article: The assessment of the potential hepatotoxicity of new drugs by

    Quintás, Guillermo / Castell, José V / Moreno-Torres, Marta

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1155271

    Abstract: Drug hepatotoxicity assessment is a relevant issue both in the course of drug development as well as in the post marketing phase. The use of human ... ...

    Abstract Drug hepatotoxicity assessment is a relevant issue both in the course of drug development as well as in the post marketing phase. The use of human relevant
    Language English
    Publishing date 2023-05-05
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1155271
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  3. Article ; Online: Exploring Individual Variability in Drug-Induced Liver Injury (DILI) Responses through Metabolomic Analysis.

    Moreno-Torres, Marta / Quintás, Guillermo / Martínez-Sena, Teresa / Jover, Ramiro / Castell, José V

    International journal of molecular sciences

    2024  Volume 25, Issue 5

    Abstract: Drug-induced liver injury (DILI) is a serious adverse hepatic event presenting diagnostic and prognostic challenges. The clinical categorization of DILI into hepatocellular, cholestatic, or mixed phenotype is based on serum alanine aminotransferase (ALT) ...

    Abstract Drug-induced liver injury (DILI) is a serious adverse hepatic event presenting diagnostic and prognostic challenges. The clinical categorization of DILI into hepatocellular, cholestatic, or mixed phenotype is based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values; however, this classification may not capture the full spectrum of DILI subtypes. With this aim, we explored the utility of assessing changes in the plasma metabolomic profiles of 79 DILI patients assessed by the RUCAM (Roussel Uclaf Causality Assessment Method) score to better characterize this condition and compare results obtained with the standard clinical characterization. Through the identification of various metabolites in the plasma (including free and conjugated bile acids and glycerophospholipids), and the integration of this information into predictive models, we were able to evaluate the extent of the hepatocellular or cholestatic phenotype and to assign a numeric value with the contribution of each specific DILI sub-phenotype into the patient's general condition. Additionally, our results showed that metabolomic analysis enabled the monitoring of DILI variability responses to the same drug, the transitions between sub-phenotypes during disease progression, and identified a spectrum of residual DILI metabolic features, which can be overlooked using standard clinical diagnosis during patient follow-up.
    MeSH term(s) Humans ; Chemical and Drug Induced Liver Injury ; Cholestasis ; Risk Factors ; Alanine Transaminase
    Chemical Substances Alanine Transaminase (EC 2.6.1.2)
    Language English
    Publishing date 2024-03-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25053003
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  4. Article: The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment.

    Moreno-Torres, Marta / Quintás, Guillermo / Castell, José V

    Metabolites

    2022  Volume 12, Issue 6

    Abstract: Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, ... ...

    Abstract Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, representing a major concern to the pharmaceutical industry. The current biochemical parameters for the detection of DILI are based on enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP)) and bilirubin serum levels that are not specific of DILI and therefore there is an increasing interest on novel, specific, DILI biomarkers discovery. Metabolomics has emerged as a tool with a great potential for biomarker discovery, especially in disease diagnosis, and assessment of drug toxicity or efficacy. This review summarizes the multistep approaches in DILI biomarker research and discovery based on metabolomics and the principal outcomes from the research performed in this field. For that purpose, we have reviewed the recent scientific literature from PubMed, Web of Science, EMBASE, and PubTator using the terms "metabolomics", "DILI", and "humans". Despite the undoubted contribution of metabolomics to our understanding of the underlying mechanisms of DILI and the identification of promising novel metabolite biomarkers, there are still some inconsistencies and limitations that hinder the translation of these research findings into general clinical practice, probably due to the variability of the methods used as well to the different mechanisms elicited by the DILI causing agent.
    Language English
    Publishing date 2022-06-19
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662251-8
    ISSN 2218-1989
    ISSN 2218-1989
    DOI 10.3390/metabo12060564
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  5. Article ; Online: Uncovering the toxicity mechanisms of a series of carboxylic acids in liver cells through computational and experimental approaches.

    Ortega-Vallbona, Rita / Méndez, Rebeca / Tolosa, Laia / Escher, Sylvia E / Castell, José V / Gozalbes, Rafael / Serrano-Candelas, Eva

    Toxicology

    2024  Volume 504, Page(s) 153764

    Abstract: Hepatotoxicity poses a significant concern in drug design due to the potential liver damage that can be caused by new drugs. Among common manifestations of hepatotoxic damage is lipid accumulation in hepatic tissue, resulting in liver steatosis or ... ...

    Abstract Hepatotoxicity poses a significant concern in drug design due to the potential liver damage that can be caused by new drugs. Among common manifestations of hepatotoxic damage is lipid accumulation in hepatic tissue, resulting in liver steatosis or phospholipidosis. Carboxylic derivatives are prone to interfere with fatty acid metabolism and cause lipid accumulation in hepatocytes. This study investigates the toxic behaviour of 24 structurally related carboxylic acids in hepatocytes, specifically their ability to cause accumulation of fatty acids and phospholipids. Using high-content screening (HCS) assays, we identified two distinct lipid accumulation patterns. Subsequently, we developed structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models to determine relevant molecular substructures and descriptors contributing to these adverse effects. Additionally, we calculated physicochemical properties associated with lipid accumulation in hepatocytes and examined their correlation with our chemical structure characteristics. To assess the applicability of our findings to a wide range of chemical compounds, we employed two external datasets to evaluate the distribution of our QSAR descriptors. Our study highlights the significance of subtle molecular structural variations in triggering hepatotoxicity, such as the presence of nitrogen or the specific arrangement of substitutions within the carbon chain. By employing our comprehensive approach, we pinpointed specific molecules and elucidated their mechanisms of toxicity, thus offering valuable insights to guide future toxicology investigations.
    MeSH term(s) Carboxylic Acids/toxicity ; Carboxylic Acids/chemistry ; Quantitative Structure-Activity Relationship ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Humans ; Chemical and Drug Induced Liver Injury/etiology ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/metabolism ; Phospholipids/metabolism ; Phospholipids/chemistry ; Fatty Acids/metabolism ; Lipid Metabolism/drug effects ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Hep G2 Cells
    Chemical Substances Carboxylic Acids ; Phospholipids ; Fatty Acids
    Language English
    Publishing date 2024-02-28
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 184557-3
    ISSN 1879-3185 ; 0300-483X
    ISSN (online) 1879-3185
    ISSN 0300-483X
    DOI 10.1016/j.tox.2024.153764
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 888: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  6. Article ; Online: Hepatocyte transplantation, a step forward?

    Ott, Michael / Castell, Jose V

    Journal of hepatology

    2019  Volume 70, Issue 6, Page(s) 1049–1050

    MeSH term(s) Animals ; Atherosclerosis ; Cholesterol ; Dyslipidemias ; Hepatocytes ; Liver ; Mice
    Chemical Substances Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2019-04-17
    Publishing country Netherlands
    Document type Editorial ; Comment
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2019.03.022
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  7. Article: Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.

    Garcia-Llorens, Guillem / Lopez-Navarro, Sergi / Jaijo, Teresa / Castell, Jose V / Bort, Roque

    Journal of personalized medicine

    2022  Volume 12, Issue 7

    Abstract: The diagnosis of inherited metabolic disorders is a long and tedious process. The matching of clinical data with a genomic variant in a specific metabolic pathway is an essential step, but the link between a genome and the clinical data is normally ... ...

    Abstract The diagnosis of inherited metabolic disorders is a long and tedious process. The matching of clinical data with a genomic variant in a specific metabolic pathway is an essential step, but the link between a genome and the clinical data is normally difficult, primarily for new missense variants or alterations in intron sequences. Notwithstanding, elucidation of the pathogenicity of a specific variant might be critical for an accurate diagnosis. In this study, we described a novel intronic variant c.2597 + 5G > T in the donor splice sequence of the PHKA2 gene. To investigate PHKA2 mRNA splicing, as well as the functional consequences on glycogen metabolism, we generated hepatocyte-like cells from a proband’s fibroblasts by direct reprogramming. We demonstrated an aberrant splicing of PHKA2, resulting in the incorporation of a 27 bp upstream of intron 23 into exon 23, which leads to an immediate premature STOP codon. The truncated protein was unable to phosphorylate the PYGL protein, causing a 4-fold increase in the accumulation of glycogen in hepatocyte-like cells. Collectively, the generation of personalized hepatocyte-like cells enabled an unequivocal molecular diagnosis and qualified the sister’s proband, a carrier of the same mutation, as a candidate for a preimplantation genetic diagnosis. Additionally, our direct reprogramming strategy allows for an unlimited source of “diseased” hepatocyte-like cells compatible with high-throughput platforms.
    Language English
    Publishing date 2022-07-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662248-8
    ISSN 2075-4426
    ISSN 2075-4426
    DOI 10.3390/jpm12071111
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  8. Article ; Online: A robust reprogramming strategy for generating hepatocyte-like cells usable in pharmaco-toxicological studies.

    Garcia-Llorens, Guillem / Martínez-Sena, Teresa / Pareja, Eugenia / Tolosa, Laia / Castell, José V / Bort, Roque

    Stem cell research & therapy

    2023  Volume 14, Issue 1, Page(s) 94

    Abstract: Background: High-throughput pharmaco-toxicological testing frequently relies on the use of established liver-derived cell lines, such as HepG2 cells. However, these cells often display limited hepatic phenotype and features of neoplastic transformation ... ...

    Abstract Background: High-throughput pharmaco-toxicological testing frequently relies on the use of established liver-derived cell lines, such as HepG2 cells. However, these cells often display limited hepatic phenotype and features of neoplastic transformation that may bias the interpretation of the results. Alternate models based on primary cultures or differentiated pluripotent stem cells are costly to handle and difficult to implement in high-throughput screening platforms. Thus, cells without malignant traits, optimal differentiation pattern, producible in large and homogeneous amounts and with patient-specific phenotypes would be desirable.
    Methods: We have designed and implemented a novel and robust approach to obtain hepatocytes from individuals by direct reprogramming, which is based on a combination of a single doxycycline-inducible polycistronic vector system expressing HNF4A, HNF1A and FOXA3, introduced in human fibroblasts previously transduced with human telomerase reverse transcriptase (hTERT). These cells can be maintained in fibroblast culture media, under standard cell culture conditions.
    Results: Clonal hTERT-transduced human fibroblast cell lines can be expanded at least to 110 population doublings without signs of transformation or senescence. They can be easily differentiated at any cell passage number to hepatocyte-like cells with the simple addition of doxycycline to culture media. Acquisition of a hepatocyte phenotype is achieved in just 10 days and requires a simple and non-expensive cell culture media and standard 2D culture conditions. Hepatocytes reprogrammed from low and high passage hTERT-transduced fibroblasts display very similar transcriptomic profiles, biotransformation activities and show analogous pattern behavior in toxicometabolomic studies. Results indicate that this cell model outperforms HepG2 in toxicological screening. The procedure also allows generation of hepatocyte-like cells from patients with given pathological phenotypes. In fact, we succeeded in generating hepatocyte-like cells from a patient with alpha-1 antitrypsin deficiency, which recapitulated accumulation of intracellular alpha-1 antitrypsin polymers and deregulation of unfolded protein response and inflammatory networks.
    Conclusion: Our strategy allows the generation of an unlimited source of clonal, homogeneous, non-transformed induced hepatocyte-like cells, capable of performing typical hepatic functions and suitable for pharmaco-toxicological high-throughput testing. Moreover, as far as hepatocyte-like cells derived from fibroblasts isolated from patients suffering hepatic dysfunctions, retain the disease traits, as demonstrated for alpha-1-antitrypsin deficiency, this strategy can be applied to the study of other cases of anomalous hepatocyte functionality.
    MeSH term(s) Humans ; Doxycycline/pharmacology ; Hepatocytes/metabolism ; Liver ; Cell Line ; Cell Differentiation/genetics
    Chemical Substances Doxycycline (N12000U13O)
    Language English
    Publishing date 2023-04-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2548671-8
    ISSN 1757-6512 ; 1757-6512
    ISSN (online) 1757-6512
    ISSN 1757-6512
    DOI 10.1186/s13287-023-03311-w
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  9. Article ; Online: Metabolomics-based strategy to assess drug hepatotoxicity and uncover the mechanisms of hepatotoxicity involved.

    Martínez-Sena, Teresa / Moro, Erika / Moreno-Torres, Marta / Quintás, Guillermo / Hengstler, Jan / Castell, José V

    Archives of toxicology

    2023  Volume 97, Issue 6, Page(s) 1723–1738

    Abstract: Toxicity studies, among them hepatotoxicity, are key throughout preclinical stages of drug development to minimise undesired toxic effects that might eventually appear in the course of the clinical use of the new drug. Understanding the mechanism of ... ...

    Abstract Toxicity studies, among them hepatotoxicity, are key throughout preclinical stages of drug development to minimise undesired toxic effects that might eventually appear in the course of the clinical use of the new drug. Understanding the mechanism of injury of hepatotoxins is essential to efficiently anticipate their potential risk of toxicity in humans. The use of in vitro models and particularly cultured hepatocytes represents an easy and robust alternative to animal drug hepatotoxicity testing for predicting human risk. Here, we envisage an innovative strategy to identify potential hepatotoxic drugs, quantify the magnitude of the alterations caused, and uncover the mechanisms of toxicity. This strategy is based on the comparative analysis of metabolome changes induced by hepatotoxic and non-hepatotoxic compounds on HepG2 cells, assessed by untargeted mass spectrometry. As a training set, we used 25 hepatotoxic and 4 non-hepatotoxic compounds and incubated HepG2 cells for 24 h at a low and a high concentration (IC10 and IC50) to identify mechanism-related and cytotoxicity related metabolomic biomarkers and to elaborate prediction models accounting for global hepatotoxicity and mechanisms-related toxicity. Thereafter, a second set of 69 chemicals with known predominant mechanisms of toxicity and 18 non-hepatotoxic compounds were analysed at 1, 10, 100 and 1000 µM concentrations from which and based on the magnitude of the alterations caused as compared with non-toxic compounds, we defined a "toxicity index" for each compound. In addition, we extracted from the metabolome data the characteristic signatures for each mechanism of hepatotoxicity. The integration of all this information allowed us to identify specific metabolic patterns and, based on the occurrence of that specific metabolome changes, the models predicted the likeliness of a compound to behave as hepatotoxic and to act through a given toxicity mechanism (i.e., oxidative stress, mitochondrial disruption, apoptosis and steatosis) for each compound and concentration.
    MeSH term(s) Animals ; Humans ; Chemical and Drug Induced Liver Injury/etiology ; Chemical and Drug Induced Liver Injury/metabolism ; Drug-Related Side Effects and Adverse Reactions/metabolism ; Hepatocytes ; Hep G2 Cells ; Fatty Liver/metabolism
    Language English
    Publishing date 2023-04-06
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-023-03474-8
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  10. Book ; Online: Hepatocyte transplantation, a step forward?

    Ott, Michael / Castell, Jose V

    Journal of hepatology

    2019  

    Abstract: ... ...

    Abstract Editorial
    Publishing date 2019-06-01
    Publisher Elsevier
    Publishing country de
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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