Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Effects of Brazilian propolis on gene expression of stromal cells in mesenteric adipose tissue of ob/ob mice

ABSTRACT: A hive product propolis has been used for folk medicine for more than 4, 000 years. So far, several line of studies demonstrated that propolis improved glucose metabolism in obese models. In this study, we inverstigated whether propolis modulates stromal cells of mesenteric adipose tissue of ob/ob mice. Male ob/ob mice were inhjected with Brazilian propolis ethanol extract (100mg/kg ip, twice a week) or vehicle for 12 weeks. Subsequently, vasucular stromal fraction was prepared from mesenteric adipose tissue. Total cellular RNA extracted from the fraction was used for microarray analysis. Biological triplicates were subjected.

ORGANISM(S): Mus musculus

SUBMITTER: Hiroshi Kitamura

PROVIDER: E-GEOD-46110 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:BACKGOUND: Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can have harmful consequences for the liver, especially in the context of obesity. OBJECTIVES: To determine whether chronic, low dose exposure to pharmaceuticals could have deleterious effects in livers of lean and obese mice. METHODS: Lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs (acetaminophen, caffeine, carbamazepine, cotinine, diclofenac, erythromycin, ibuprofen, phenazone, roxithromycin, salicylic acid and sulfamethoxazole) provided in drinking water at a concentration of 1 mg/L (for each drug). At the end of the treatment, investigations were performed in liver and plasma. RESULTS: Some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 1 mg/L of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals indicated that expression of 8 different circadian genes was significantly modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 100-1,000 ng/L. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were confirmed in an independent study performed in female mice. CONCLUSIONS: Chronic, low dose exposure to pharmaceuticals disturbed hepatic expression of circadian genes, especially in obese mice. Because some of the 11 drugs can be found in the drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, in particular for obese individuals exposed to these contaminants. C57BL/6J lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs provided in drinking water at a concentration of 1 mg/L (for each drug). 4 groups were designed: untreated versus treated WT and ob/ob mice (n=6 mice per group).

Project description:Proteomic modifications linked to non-enzymatic glycation and glycoxidation are common in all tissues under hyperglycemic conditions, as present in metabolic syndrome, type 2 diabetes (T2D), mice bearing a homozygous mutation in leptin (so-called Ob/Ob mice, a common model of obesity and T2D) and mice subjected to a high fat diet (HFD). It has been already shown that the circulating levels of glycated or glycoxidated proteins (e.g., glycated hemoglobin or albumin) are commonly employed as a reliable indicator of overall glycemic status. Albeit these initial non-enzymatic reactions are reversible, following a series of chemical rearrangements protein glycation and glycoxidation become irreversible, generating the so-called advanced glycation end-products (AGEs). AGEs are commonly detected in tissue proteins with an extended half-life, including dermal collagens as well as extracellular matrix proteins. In these proteins, Nϵ-carboxymethyllysine (CML), pentosidins, and glucosepane represent the most prevalent AGEs. As an additional, novel mechanism linking protein PTMs to altered immunity, the research presented herein highlights that several components of the MHC class II antigen processing and presentation machinery are glycated in metabolic conditions associated with increased oxidative stress, leading to qualitative and quantitative changes in the MHC class II immunopeptidome. To investigate the impact of T2D and metabolic syndrome on the proteome of antigen presenting cells (APCs) we isolated dendritic cells (DCs, which are key for the initiation of antigen-specific immunity) from the lymph nodes of Ob/Ob mice and syngeneic, age-matched control C57BL/6 (B6) mice and mapped the oxidized proteins at the molecular and cellular level by employing label-free mass spectrometry using at least three biologically independent whole lysates of DCs. Analysis of the type of post-translational modifications (PTMs) accumulated in the proteome from the combined three biological Ob/Ob samples ranked the formyl-lysine and site-specific carboxymethylation on lysine (CML) as the most abundant AGEs found in the glycated proteome; with CML having about two-fold increase in their total PTM-modified spectral counts in the Ob/Ob vs control dendritic cell proteome. Additional glycoxidation-specific PTMs, that mapped only on the Ob/Ob proteome, albeit at a smaller amount than CML and formyl lysine, were glyceryl lysine and 3-deoxyglucosone. Finally, a separate proteomic analysis, performed on gradient purified late endosomes also mapped an increased number of PTM-modified proteins in the Ob/Ob organelles. Ingenuity pathway analysis (IPA) analysis identified metabolic pathways as well as phagocytosis, antigen processing and presentation and phagosome maturation amongst the top pathways including a higher number of proteins modified by AGEs or carbonylation in primary DCs from Ob/Ob vs. control mice. The site-specific amide-AGE modifications that we detected also mapped to proteins involved in response to DC signaling, immune cell trafficking, actin and cytoskeleton signaling, cell movement, and carbohydrate, nucleic acids and protein metabolism. Overall, these findings indicate that the DC proteome of Ob/Ob mice has an increased number of carbonyl PTMs and AGEs as compared to DC of C57BL/6 mice. The results presented herein are one of the first to map the redox mediated PTM in the primary mouse DC in healthy vs T2DM type syndrome physiological conditions.

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Effects of Brazilian propolis on gene expression of stromal cells in mesenteric adipose tissue of ob/ob mice

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