Mechanisms Driving Fasting-Induced Protection from Genotoxic Injury in the Small Intestine
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ABSTRACT:
PROVIDER: PRJNA1028562 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26396675_1.fastq.gz | Fastqsanger.gz | |||
| SRR26396675_2.fastq.gz | Fastqsanger.gz | |||
| SRR26396676_1.fastq.gz | Fastqsanger.gz | |||
| SRR26396676_2.fastq.gz | Fastqsanger.gz | |||
| SRR26396677_1.fastq.gz | Fastqsanger.gz |
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Project description:To elucidate the mechanisms required for short-term fasting to protect healthy intestinal cells from chemotherapy injury, we conducted an investigation comparing the effects of altered mTORC1 modulation in DDIT4 knockout male mice to wild-type male mice at various timepoints following doxorubicin treatment.
2024-01-01 | GSE245477 | GEO
Project description:Background The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting. Results Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut’s structural components, so that the microarrays’ tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed. Conclusion The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover. Keywords: fasting response, time course
2007-11-12 | GSE8019 | GEO
Project description:Gene expression regulation of transporters and phase I/II metabolic enzymes in murine small intestine during fasting Keywords: metabolic state analysis
2007-07-04 | GSE6864 | GEO
Project description:Background; The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting. Results; Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gutâs structural components, so that the microarraysâ tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed. Conclusion; The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover. Experiment Overall Design: Male FVB mice (Charles River, Maastricht, The Netherlands) were housed at 20-22°C, 50-60% humidity, a 12 hours light/dark cycle, and food and water ad libitum. At 6 weeks of age, mice were fasted by removing chow for up to 72 hours before sacrifice (n = 6 per group). The animals were kept in metabolic cages to prevent the consumption of beddings and were kept warm with an infrared lamp starting at 24h. Experiment Overall Design: All animals were sacrificed between 9:00 and 10:00 a.m. by cervical dislocation. The small intestine was removed quickly in such a way that adherent tissue remained behind. It was opened longitudinally, rinsed in phosphate-buffered saline, blotted, weighed, snap-frozen in liquid N2, and stored at -80°C. We opted to use extracts of full-thickness intestine for gene-expression profiling, because the epithelial component of the murine small intestine comprises over 70% of its volume The suitability of this strategy is underscored by a recent microarray study of transporters in the mouse intestine [Anderle P et al., BMC Genomics 2005, 6: 69.]. In addition, isolation of enterocytes is time-consuming and, hence, entails a risk of mRNA degradation, while mucosal scraping harvests villi more efficiently than crypts , whereas many mRNAs are most abundant in the crypts. Experiment Overall Design: Total intestinal RNA was extracted from frozen tissue with guanidiniumthiocyanate [Chomczynski P, Sacchi N: Analytical Biochemistry 1987, 162: 156-159.], followed by cesium-chloride centrifugation [Glisin V, Crkvenjakov R BC: Biochemistry 1974, 13: 2633-2637.] to avoid contamination with mucus. The quality of RNA was assessed with the RNA 6000 Nano LabChip® Kit in an Agilent 2100 bioanalyzer (Agilent Technologies, Palo Alto, USA). Microarray-based quantification of 8 mRNAs with a 1.3-9.2-fold change in expression was validated by qPCR, as described [58]. mRNA concentration was calculated using the LinReg program [59]. In the absence of reverse transcriptase, the signal was < 0.1% of that in its presence for each primer pair (not shown). Experiment Overall Design: Microarrays. The 60-mer Mouse Development (22K) Oligo Microarray G4120A (Agilent) was used. Three arrays per experimental condition were used. Per microarray, 20 μg mRNA, pooled from 2 intestines, was reverse transcribed with Cy3-labelled dCTP (Perkin Elmer, Boston, USA), using the Agilent Fluorescent Direct Label Kit. Cy5-labeled cDNA produced from RNA pooled from 6 fed animals served as the common reference across all arrays (Figure 1A). Hybridized cDNAs were detected with Agilentâs dual-laser microarray slide scanner. The data were retrieved with Agilentâs Feature Extraction software 6.1.1.
2009-05-13 | E-GEOD-8019 | biostudies-arrayexpress
Project description:Short-term fasting elicits beneficial effects in mice and humans, including protection from chemotherapy toxicity, but the involved mechanisms are not well understood. We collected blood samples from healthy human volunteers and mice before and after 36 or 24 hours of fasting, respectively, to measure fatty acid composition of erythrocyte membranes, circulating miRNAs, and RNA expression at PBMCs. In both mice and humans, fasting affected the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane. Also, fasting significantly reduced the expression at PBMCs of insulin signaling-related genes, including the SREBP lipid-metabolizing pathway, in correlation with changes in membrane fatty acids. We tested the relevance of these fatty acid homeostasis parameters using a complete platform to monitor chemotherapy toxicity in mice. When fasted for 24 hours before and 24 hours after administration of the chemotherapeutic drug oxaliplatin, mice showed a strong protection from kidney, liver, heart and bone marrow toxicity. Importantly, the newly discovered fasting parameters defined two clearly separated groups of individuals that accurately predicted a differential protection from chemotherapy toxicity. Our results reveal a novel mechanism of fasting associated with fatty acids homeostasis, and provide novel biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.
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Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis. 6 week-old male FVB mice were fasted for 0, 12, 24, 48 or 72 hours before sacrifice (N = 5 per group). From each mouse total RNA was isolated from five organs - liver, small intestine, kidney, brain, and calf muscle. Five microarrays per experimental condition (five tissues, five timepoints) were performed. We used a common reference design. The single common-reference sample was a pool of equal amounts of RNA from all the samples investigated, including additional samples from 5 mice that were fasted for 48 hours and supplemented with vitamin B complex after 24 and 36 hours of fasting.
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Project description:Intermittent fasting is previously reported to exhibit neuroprotection against experimental ischemic stroke. However, the detailed understanding of protection mechanisms are lacking. By observing the overall transcriptomic changes in each timepoint of ischemic stroke would benefit the understanding of underlying active pathways and mechanisms. Here, we conduct experimental MCAO ischemic stroke on mice exposed to different daily intermittent fasting method to compare not only among the ischemic stroke timepoints but also the efficacy of different intermittent fasting interventions. Our current study presented the transcriptomic changes for the first time in specific timepoints of ischemic stroke as well as under the condition of intermittent fasting. A number of neuroprotective mechanisms-related genes were significantly affected by intermittent fasting conditions in differential manners.
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Project description:Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at Ser336 sustains mitochondrial fission and respiratory sufficiency. Timelapse imaging shows that NDRG1, but not phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in both control and Drp1-deficient cells, reflecting independency from Drp1. Using proteomics, an siRNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase Cdc42 and effectors and regulators of Cdc42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants, and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.
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Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis.
2011-03-09 | GSE24504 | GEO