High-fat diet promotion of endometriosis in an immunocompetent mouse model is associated with altered peripheral and ectopic lesion redox and inflammatory status
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE80603 | GEO | 2017/04/23
SECONDARY ACCESSION(S): PRJNA319477
REPOSITORIES: GEO
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Project description:Endometriosis is a common gynecological disease of women in reproductive age, and is primarily thought to arise from retrograde menstruation and implantation of endometrium, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process, within which oxidative stress likely plays a critical role. Although elevated reactive oxygen species (ROS) and oxidative stress have previously been postulated as being involved in endometriosis pathogenesis, we set out for a more systematic study to identify novel factors defining oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets, including upregulated pro-oxidative enzymes such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1), as well as downregulated protective factors such as alkenal reductase PTGR1 or methionine sulfoxide reductase, supporting the observation of increased oxidative protein modification in ectopic lesions and peritoneal fluid. The observed ROS-derived 4-hydroxy-2-nonenal-induced interleukin (IL)-8 release from monocytes indicates a further pathomechanism, whereby elevated IL-8 levels promote further immune cell infiltration and angiogenesis in lesions.
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Project description:Endometriosis is a prevalent health condition in women of reproductive age characterized by ectopic growth of endometrial tissue in the extrauterine environment. Thorough understanding of the molecular mechanisms underlying the disease are still lacking and incomplete. We dissect eutopic and ectopic endometrial primary stromal cell proteomes to a depth of nearly 6900 proteins using quantitative mass-spectrometry with a spike-in SILAC standard. Acquired data reveal metabolic reprogramming of ectopic stromal cells of endometriosis with extensive upregulation of glycolysis and down-regulation of oxidative respiration – a wide-spread metabolic phenotype previously described in many cancers. Our results also underlie other molecular changes of ectopic endometriotic stromal cells indicating reduced apoptotic potential, increased cellular adhesiveness/invasiveness and altered immune function. The changes related to metabolism are additionally reflected by attenuated aerobic respiration of ectopic endometrial stromal cells measured by live cell oximetry and by altered mRNA levels. These comprehensive proteomics data refine the current understanding of endometriosis presenting potential new avenues for therapies.
2016-10-22 | MSV000080276 | MassIVE
Project description:Endometriosis is a prevalent health condition in women of reproductive age characterized by ectopic growth of endometrial tissue in the extrauterine environment. Thorough understanding of the molecular mechanisms underlying the disease are still lacking and incomplete. We dissect eutopic and ectopic endometrial primary stromal cell proteomes to a depth of nearly 6900 proteins using quantitative mass-spectrometry with a spike-in SILAC standard. Acquired data reveal metabolic reprogramming of ectopic stromal cells of endometriosis with extensive upregulation of glycolysis and down-regulation of oxidative respiration – a wide-spread metabolic phenotype previously described in many cancers. Our results also underlie other molecular changes of ectopic endometriotic stromal cells indicating reduced apoptotic potential, increased cellular adhesiveness/invasiveness and altered immune function. The changes related to metabolism are additionally reflected by attenuated aerobic respiration of ectopic endometrial stromal cells measured by live cell oximetry and by altered mRNA levels. These comprehensive proteomics data refine the current understanding of endometriosis presenting potential new avenues for therapies.
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Project description:We performed gene expression analysis human peritoneal endometriosis lesions, eutopic endometrium from endometriosis patients and peritoneum form endometriosis patients.The goal of the study was to analyse gene expression differences between peritoneal endometriosis lesion and eutopic endometrium and peritoneal endometriosis lesion and peritoneum.
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Project description:We primary cultured ectopic endometrial cells from patients with endometriosis (2 cases) and without endometriosis(2 cases) and collected cell culture supernatants（P0). We isolated exosomes from cell culture supernatants by differential centrifugation and then performed proteome analysis on the two groups of exosomes to investigate the role of ectopic endometrial cell-derived exosomes in the development of endometriosis.
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Project description:In this survey we effectively combined transcriptomics, proteomics and targeted-metabolomics to analyse the temporal relationship of alterations in liver preceding and accompanying the development of HFD-mediated hepatic insulin resistance. To assess HFD-mediated alterations in physiological parameters, insulin sensitivity, and molecular adaptations in liver male C3HeB/FeJ mice treated with a high-fat diet (HFD) for 7, 14, or 21 days and compared to age- matched controls fed low-fat diet (LFD). Data indicate early systemic increases in pro-inflammatory signals, in hepatic DAG but not hepatic TAG concentrations prior to development of hepatic insulin resistance. We propose a hypothesis via which a HFD-mediated increase in the hepatic long-chain acyl-carnitine moiety in liver alters mitochondrial membrane physiology and beta-oxidation rates, thereby contributing to oxidative stress and the development of insulin resistance in liver. Alterations in the enrichment of respiratory chain complex proteins, substrate transporters, VDACs, and long-chain carnitines in mitochondrial membranes likely affect mitochondrial membrane topology, membrane dynamics (fission and fusion) and bioenergetics as well as the cross-talk between the mitochondria and other cellular compartments. In conclusion, we emphasize a tight association between HFD-induced early modifications in the organisation of mitochondrial membranes paving the road for hepatic insulin resistance.
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Project description:Obesity and diabetes associated visual impairment and vascular dysfunctions are increasing reasons for vision loss. The detailed mechanisms in these diseases are still largely unknown, but mice models have been useful to study these mechanisms and explore the detailed effects of potential compounds. Such compounds usually have antioxidant and anti-inflammatory properties. These properties are found in anthocyanins and a major source of dietary anthocyanins in Nordic diet is bilberries (European wild blueberries, Vaccinium myrtillus). In this explorative study we show results with differentially expressed genes in retina using a high-fat diet (HFD) mouse model. Our findings displayed differential regulation of genes in pathways for apoptosis, inflammation and oxidative stress, especially systemic lupus erythematosus (SLE), mitogen activated protein kinase (MAPK) and glutathione metabolism. Mice fed with HFD had increased retinal gene expression of several crystallins, which was reduced in the retina of mice fed with bilberries. Bilberries seem to reduce the expression of genes in MAPK and to increase the expression of genes in glutathione metabolism pathway. All together despite minor effects in the mouse phenotype, a diet rich in bilberries may prevent the retinal gene expression changes in the early stages of obesity. Mice were fed ad libitum with normal control diet (NCD, 10% kcal fat), high-fat diet (HFD, 45% kcal fat), 5% (w/w) freeze-dried biberries (Vaccinium myrtillus) in NCD (NCD+BB) or HFD (HFD+BB) for 12 weeks. Diets were prepared in Research Diets Inc. Feed consumption and weight gain were measured during the feeding trial, and blood pressure and serum markers of obesity at the end. Retinas were collected and RNA extracted from all 24 mice samples, and pooled retinas from 4 mice per group were hybridized with standard Illumina protocols. The expression in retinas was analyzed using R, Pathvisio and DAVID to screen for differences between high-fat and berry induced changes to control diets and further bilberry induced changes to HFD up- or downregulated transcripts. diet: NCD, HFD, NCD+BB, HFD+BB
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Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, the consequences of an alternate high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue concerning common situations where dietary habits change over time, we developed a novel protocol in athero-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, the overall period of time of exposure to HFD being similar between groups. We showed that alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared to continuous HFD. The pro-atherogenic effect of alternate HFD was also found in Apoe-/-Rag2-/- mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the observed phenotype. Using different complementary in vivo approaches, we found that lipid-rich diet discontinuation in alternate group downregulated Runx1, a negative regulator downstream of TLR-4 pathways. As a result, after re-exposure to HFD, myeloid progenitors were more sensitive to hypercholesterolemia leading to acute differentiation into IL-1b- producing immature neutrophils, which caused a state of emergency myelopoiesis. Consecutively, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1b receptor confirmed that the IL-1b signaling pathway was a major driver of the pro-inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1b neutralizing antibody or inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1b-dependent neutrophil progenitor reprogramming.
2024-04-14 | GSE252604 | GEO
Project description:Carotenoids are naturally occurring pigments in plants responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results depicted that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Carotenoid-rich foods may prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms.
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Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, it is common for individuals to change dietary habits over time. The consequences of an alternating high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue, we developed a novel protocol in atherosclerosis-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, while keeping the overall period of exposure to HFD similar between groups. We showed that an alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe 55 -/- mice compared to continuous HFD. This pro-atherogenic effect of alternate HFD was also observed in Apoe-/-Rag2 57 -/- mice lacking T, B, and NKT cells, ruling out the role of the adaptive immune system in the observed phenotype. Employing various complementary in vivo approaches, we discovered that discontinuing HFD in the alternate group downregulated Runx1, a negative regulator of inflammatory signaling pathways in the myeloid lineage. Consequently, after re61 exposure to HFD, myeloid progenitors were primed to respond to HFD re-exposure by differentiating into IL-1-producing immature neutrophils, and inducing a state of emergency myelopoiesis. Subsequently, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1 receptor confirmed that the IL-1 signaling pathway was a major driver of the pro67 inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1 neutralizing antibody or an inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1-dependent neutrophil progenitor reprogramming.
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