Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA361533 | ENA |
REPOSITORIES: ENA
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Project description:CAD-31 has potent neuroprotective properties in six distinct nerve cell assays that mimic toxicities observed in the old brain. Pharmacological and preliminary toxicology studies show that CAD-31 is brain penetrant and likely safe. When fed to old, symptomatic transgenic Alzheimer's disease (AD) mice starting at ten months of age for three additional months in a therapeutic model of the disease, there was a reduction in the memory deficit and brain inflammation, and an increase in the expression of synaptic proteins. Small molecule metabolic data from the brain and plasma showed that the major effect of CAD-31 is centered on fatty acid metabolism and inflammation. Pathway analysis of gene expression data showed that CAD-31 had major effects on synapse formation, AD and energy metabolism.
2017-08-11 | GSE93678 | GEO
Project description:Cancer is a systemic disease that includes several noted features, such as pre-metastatic niche formation, cachexia, and immune dysregulation. However, the mechanisms underlying multi-organ failure remain to be further investigated. Here, we show that inflammation, fatty liver, and dysregulated metabolism are hallmarks of systemically affected livers in various animal tumor models and cancer patients in the absence of hepatic metastasis. We identify that tumor-derived extracellular vesicles and particles (EVPs) are crucial mediators of cancer-induced hepatic functional reprogramming. Tumor EVPs package multiple fatty acids, such as palmitic acid, and target Kupffer cells upregulating TNFα via Toll-like receptor 4, which in turn promotes a pro-inflammatory microenvironment leading to fatty liver disease and downregulates metabolic pathways, such as fatty acid metabolism and oxidative phosphorylation. Strikingly, ablation of Kupffer cells or TNFα blockade markedly abrogates the tumor-induced excess hepatic lipid droplet accumulation. We show that tumor implantation or pre-treatment with tumor EVPs decreases the expression of Cytochrome P450 genes and attenuates drug metabolism in mice. Notably, increased fatty livers and decreased Cytochrome P450 genes are observed in tumor-free livers in cancer patients. Thus, tumor-derived EVP uptake in the liver may lead to reduced tolerance of drug toxicity in cancer patients. Our results highlight the role of tumor EVPs in dysregulating hepatic functions and its potential to serve as therapeutic targets along with Kupffer cell-induced TNFα inhibition to prevent fatty liver disease and enhance anti-cancer chemotherapy.
2023-03-09 | GSE220446 | GEO
Project description:We report the effects of exposure to the endocrine disruptor nonylphenol (NP) on transcriptome modification in the livers of in vivo Zebrafish. Our data indicate changes in fatty acid metabolism and inflammation, pathways associated with the development of Non-Alcoholic Fatty Liver Disease (NAFLD).
2020-06-03 | GSE100369 | GEO
Project description:Although human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) have emerged as a novel platform for heart regeneration, disease modeling, and drug screening, their immaturity significantly hinders their application. A hallmark of postnatal cardiomyocyte maturation is the metabolic substrate switch from glucose to fatty acids. We hypothesized that fatty acid supplementation would enhance hPSC-CM maturation. Fatty acid treatment induces cardiomyocyte hypertrophy and significantly increases cardiomyocyte force production. The improvement in force generation is accompanied by enhanced calcium transient peak height and kinetics, and by increased action potential upstroke velocity. Fatty acids enhance mitochondrial respiratory reserve capacity. RNA sequencing showed fatty acid treatment upregulates genes involved in fatty acid β-oxidation and downregulates genes in lipid synthesis. Signal pathway analyses reveal that fatty acid treatment results in phosphorylation of multiple intracellular kinases. Thus, fatty acids increase human cardiomyocyte hypertrophy, force generation, calcium dynamics, action potential upstroke velocity, and oxidative capacity. This enhanced maturation should facilitate hPSC-CMs usage for cell therapy, disease modeling, and drug/toxicity screens.
2018-12-19 | GSE124057 | GEO
Project description:Systematic analyses of the temporal dynamics of transcriptomes and chromatin landscapes of macrophages during timecourse of TLR4-mediated inflammatory response. As a multifunctional effector cell, macrophages play pivotal roles in both the induction and resolution components of varied inflammatory processes. During the course of an inflammation response, macrophages engage in a homeostatic program characterized by tightly coordinated modulation of temporal outputs of both lipid metabolism and inflammation. We demonstrate inversely biphasic temporal dynamics of specific fatty acid metabolic and inflammatory gene expression profiles, associated with concordant temporal reprogramming of macrophage fatty acid profiles. In part, the late phase of the macrophage inflammatory response is characterized by tailoring of fatty acid related gene expressions, facilitating both significant induction of anti-inflammatory unsaturated fatty acid production and associated resolution of inflammation. We demonstrate the biphasic temporal dynamics of macrophage inflammation, specifically anti-inflammatory omega-3 and omega-9 unsaturated fatty acid levels, are transcriptionally driven genome-wide by an unexpected shift from an LXR to SREBP1-dominant regulatory program in the late phase inflammatory response. Collectively, our findings reveal a novel Srebp1-driven mechanism allowing the intimate inverse temporal relationship between the transcriptional regulation of inflammatory and fatty acid metabolic outputs; whereby modulation key transcriptional regulators (LXR, SREBP1 and NF-kB) of these pathways coordinate appropriate temporal tailoring of local enhancer associated reprogramming and eventual pathway regulatory interactions, during the course of TLR4-dependent inflammatory response in macrophages. This specific Srebp-driven, temporal reprogramming of macrophage fatty acid metabolism, characterized by late phase induction of anti-inflammatory unsaturated fatty acid production, is necessary for appropriate resolution of inflammation. Thus, this study suggests that selective reprogramming of macrophage lipid metabolism can serve as a viable therapeutic intervention aimed at ameliorating chronic inflammation and varied metabolic syndrome associated states.
2017-01-04 | GSE79423 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immunometabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is associated with diverse features including oxidative stress, impaired mitochondrial function andlipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and investigation into a potential drug target that has overarching effects on these features will provide benefits towards discovering effective treatments for NAFLD. Here, we examined the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in in vitro fatty liver model. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic condition, and our transcriptome analysis revealed that PON2 deficiency disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, liver fibrosis, and hepatic inflammation. PON2 promoted the activation of overall autophagy pathway, especially mitophagy cargo sequestration, which may be considered as an underlying mechanism that contributed to the role of PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide mechanistic foundation on the prospect of targeting PON2 for the development of novel therapeutics for NAFLD in the future.
2022-09-26 | GSE213653 | GEO
Project description:Alteration in metabolic repertoire is commonly associated with resistance phenotype. Although it’s a common phenotype, not much efforts have been undertaken to design effective strategies to target the metabolic drift in such cancerous cells and especially with drug resistant properties. In our study, we identified that drug resistant AML cell line HL-60/MX2 do not follow classical Warburg effect, instead these cells exhibit drastically low levels of aerobic glycolysis. Biochemical analysis confirms reduced glucose consumption and lactic acid production by resistant population with no differences in glutamine consumption. Raman spectroscopy revealed increased lipid and cytochrome content in resistant cells which were also visualized in the form of lipid droplets by Raman mapping, electron microscopy and lipid specific staining. Gene set enrichment analysis data from both the cell lines revealed significant enrichment of lipid metabolic pathways in HL-60/MX2 cells. Further drug resistant cells possess higher mitochondrial activity and increased OXPHOS suggested the role of fatty acid metabolism as energy source which was confirmed by increased rate of fatty acid oxidation. Pharmacological inhibition of fatty acid oxidation using Etomoxir affected the colony formation ability of resistant cells and inhibition of OXPHOS using Antimycin-A increased the sensitivity of resistant cells to chemotherapeutic drug, demonstrating requirement of fatty acid metabolism and increased dependency on OXPHOS by resistant leukemic cells for tumorigenicity.
2021-01-01 | E-MTAB-8981 | biostudies-arrayexpress
Project description:Cancer is a systemic disease that includes several noted features, such as pre-metastatic niche formation, cachexia, and immune dysregulation. However, the mechanisms underlying multi-organ failure remain to be further investigated. Here, we show that inflammation, fatty liver, and dysregulated metabolism are hallmarks of systemically affected livers in various animal tumor models and cancer patients in the absence of hepatic metastasis. We identify that tumor-derived extracellular vesicles and particles (EVPs) are crucial mediators of cancer-induced hepatic functional reprogramming. Tumor EVPs package multiple fatty acids, such as palmitic acid, and target Kupffer cells upregulating tumor necrosis factor alpha (TNFα) via Toll-like receptor 4 (Tlr4), which in turn promotes a pro-inflammatory microenvironment leading to fatty liver formation and downregulates metabolic pathways, such as fatty acid metabolism and oxidative phosphorylation. Strikingly, ablation of Kupffer cells or TNFα blockade markedly abrogates the tumor-induced excess hepatic lipid droplet accumulation. We show that tumor implantation or pre-treatment with tumor EVPs decreases the expression of Cytochrome P450 genes and attenuates drug metabolism in mice. Notably, increased fatty livers and decreased Cytochrome P450 genes are observed in tumor-free livers in cancer patients. Thus, tumor-derived EVP uptake in the liver may lead to reduced tolerance of drug toxicity in cancer patients. Our results highlight the role of tumor EVPs in dysregulating hepatic functions and its potential to serve as therapeutic targets along with Kupffer cell-induced TNFα inhibition to prevent fatty liver formation and enhance anti-cancer chemotherapy.
2023-03-09 | GSE199863 | GEO
Project description:We analyzed the transcriptome for drug metabolism genes of 35 human (17 healthy control (HC), and 18 nonalcoholic fatty liver disease (NAFLD)) liver tissues, obtained during laparoscopic cholecystectomy. The aim of our study is to identify the drug metabolism genes significantly regulated by NAFLD at the transcriptome level.
2022-12-19 | E-MTAB-12445 | biostudies-arrayexpress
Project description:Many acquired traits related to fat metabolism are inherited, and nutritional factors can induce fatty liver in chickens. We found that the paternal fatty livers induced by high-fat diet in Jingxing-Huang chickens were inherited, but the molecular mechanisms of inherited fatty liver in chickens are far from clear. The goals of this study are to compare liver transcriptome profiling (RNA-seq) in F1 generation to screen candidate genes for acquired fatty liver. Compared to birds without fatty liver in the control group, the paternal group exhibited altered hepatic gene expression profiles, including up-regulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.
2018-04-09 | GSE111909 | GEO