6 results on '"human organoid models"'
Search Results
2. New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids.
- Author
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Rodrigues, Daniela, de Souza, Terezinha, Coyle, Luke, Di Piazza, Matteo, Herpers, Bram, Ferreira, Sofia, Zhang, Mian, Vappiani, Johanna, Sévin, Daniel C., Gabor, Attila, Lynch, Anthony, Chung, Seung-Wook, Saez-Rodriguez, Julio, Jennen, Danyel G. J., Kleinjans, Jos C. S., and de Kok, Theo M.
- Subjects
- *
INTESTINES , *LARGE intestine , *RHO GTPases , *METABOLOMICS , *ORGANOIDS , *SMALL intestine - Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids
- Author
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Daniela Rodrigues, Luke Coyle, Barbara Füzi, Sofia Ferreira, Heeseung Jo, Bram Herpers, Seung-Wook Chung, Ciarán Fisher, Jos C. S. Kleinjans, Danyel Jennen, and Theo M. de Kok
- Subjects
doxorubicin ,toxicity ,human organoid models ,molecular mechanisms ,transcriptomics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.
- Published
- 2022
- Full Text
- View/download PDF
4. New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids
- Author
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Johanna Vappiani, Terezinha de Souza, Theo M. de Kok, Luke Coyle, Julio Saez-Rodriguez, Danyel Jennen, Daniel C. Sévin, D. F. Rodrigues, Seung-Wook Chung, Matteo Di Piazza, Bram Herpers, Attila Gábor, Mian Zhang, Anthony M. Lynch, Jos C. S. Kleinjans, Sofia Ferreira, Toxicogenomics, RS: GROW - R1 - Prevention, RS: FSE MaCSBio, RS: FPN MaCSBio, and RS: FHML MaCSBio
- Subjects
0301 basic medicine ,Male ,PHARMACOKINETICS ,Health, Toxicology and Mutagenesis ,Cell ,Apoptosis ,Toxicology ,Toxicogenomics and Omics Technologies ,COLORECTAL-CANCER ,Transcriptome ,0302 clinical medicine ,Intestine, Small ,E2F1 ,TISSUE DISTRIBUTION ,GENE-EXPRESSION ,Cell Cycle ,General Medicine ,Cell cycle ,STEM ,5-FU toxicity ,3. Good health ,Cell biology ,Organoids ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Antimetabolites, Antineoplastic ,Cell Survival ,Colon ,Human organoid models ,Biology ,HIGH-THROUGHPUT ,Models, Biological ,03 medical and health sciences ,Metabolomics ,Organoid ,Metabolome ,medicine ,Humans ,Transcriptomics ,MUCOSAL INJURY ,Transcription factor ,Dose-Response Relationship, Drug ,Molecular mechanisms ,IN-VITRO ,FLUOROURACIL ,MODEL ,Oxidative Stress ,030104 developmental biology - Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03092-2.
- Published
- 2021
5. Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids.
- Author
-
Rodrigues, Daniela, Coyle, Luke, Füzi, Barbara, Ferreira, Sofia, Jo, Heeseung, Herpers, Bram, Chung, Seung-Wook, Fisher, Ciarán, Kleinjans, Jos C. S., Jennen, Danyel, and de Kok, Theo M.
- Subjects
- *
INTESTINES , *ORGANOIDS , *CELL morphology , *CELLULAR aging , *DOXORUBICIN , *SMALL intestine - Abstract
Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
6. Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids
- Author
-
Daniela Rodrigues, Luke Coyle, Barbara Füzi, Sofia Ferreira, Heeseung Jo, Bram Herpers, Seung-Wook Chung, Ciarán Fisher, Jos C. S. Kleinjans, Danyel Jennen, Theo M. de Kok, Toxicogenomics, RS: GROW - R1 - Prevention, RS: FSE MaCSBio, RS: FPN MaCSBio, and RS: FHML MaCSBio
- Subjects
Proteomics ,PHARMACOKINETICS ,Colon ,PHARMACOGENOMICS ,QH301-705.5 ,human organoid models ,molecular mechanisms ,Gene Expression ,Apoptosis ,METABOLISM ,Models, Biological ,doxorubicin ,Catalysis ,Inorganic Chemistry ,transcriptomics ,Intestine, Small ,Humans ,ADRIAMYCIN ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,TISSUE DISTRIBUTION ,Spectroscopy ,GENE-EXPRESSION ,IDENTIFICATION ,Gene Expression Profiling ,Cell Cycle ,Organic Chemistry ,PLATFORM ,PATHWAYS ,toxicity ,IN-VITRO ,General Medicine ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Intestines ,Organoids ,Chemistry ,Transcriptome - Abstract
Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.
- Full Text
- View/download PDF
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