Dataset Information

The peroxisome proliferator-activated receptor gamma (PPAR?) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

ABSTRACT: BACKGROUND:Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPAR? agonist, rosiglitazone (ROSI). METHODS:Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI. RESULTS:Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities. CONCLUSION:This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.

SUBMITTER: Keledjian K

PROVIDER: S-EPMC7665704 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

Keledjian Kaspar K Tsymbalyuk Orest O Semick Stephen S Moyer Mitchell M Negoita Serban S Kim Kevin K Ivanova Svetlana S Gerzanich Volodymyr V Simard J Marc JM

PloS one 20201113 11

<h4>Background</h4>Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an ines ...[more]

PMID: 33186383

Similar Datasets

Project description:Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) gamma agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARgamma directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Project description:Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

Dataset Information

The peroxisome proliferator-activated receptor gamma (PPAR?) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

Publications

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets