Project description:Abnormal production of amyloid-beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease.
Project description:We performed gene expresion analysis of T cell treated with agonist of three isoform of PPAR. This analysis allowed us to explain why the activation of PPAR g is the best in boosting PD-1 blockade efficacy compared with other isoform activation. We demonstrated that activation of the PPAR-γ isoform specifically enhanced PD-1 blockade greater than activation of the other two PPAR isoforms (a and b) in mouse tumor model. Using the microarray assay we found genes that were most differentially regulated by PPAR agonist treatment were with a well-documented role in T cell biology, such as Ddx3y, Ifng, Il17c, Ccr3, Acrv1, Btk and metabolic process such as Pygl, P2rx1, Tph2, Kynu, and Ugt2b37. Therefore, microarray data has been useful to establish that activation of PPAR-g in T cell uniquely modulate genes, which include metabolic as well genes related to immune function.
Project description:To identify the key genes participating in the regulation of mast cell activation, we profiled the expression patterns of mRNAs associated with PPAR γ agonist,pioglitazone (PIO), treatment in RBL-2H3 cells.
Project description:Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) is a convenient and promising tactic for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonist of PPAR-γ exhibits severe side effects in animal model and clinical uses. Therefore, it is emerging to develop efficient and safe PPAR-γ modulators for metabolic disease treatment. Here, by utilizing comprehensive methods, we report a previously unidentified ligand binding pocket (LBP) in PPAR-γ and link it to beige adipocyte differentiation. Further virtual screening from 4097 natural compounds based on this novel LBP, we discover NJT-2, a terpenoid compound, can bind to PPAR-γ induce co-activator recruitment and effectively activate PPAR-γ mediated transcription of beige adipocyte program. Importantly, in mouse model, NJT-2 administration efficiently promotes beige adipocyte biogenesis and improve obesity-associated metabolic dysfunction with significant lower adverse effects than those observed in TZD. Our results not only provide an advanced molecular insight into the structural ligand binding details in PPARg, but also develop its linked selective and safe agonist for obesity treatment.
Project description:We found that bezafibrate, PPAR-alpha agonist, increased EEG delta oscillation throughout 24 hours and decreased body temperature especially in the later half of the dark period in mice. This DNA- microarray experiment was performed due to investigate the gene expression at ZT10, when body temperature showed no difference between nomal- and bezafibrate-treated mice, and ZT22, when body temperature showed the largest difference between the groups. Keywords: drug treatment, time course
Project description:To investigate how a natural product analog mitigates AD, cortical transcriptomes from WT and 5xFAD mice were analyzed. Comparing vehicle-treated groups revealed extensive differential expression associated with neuroinflammation in 5xFAD mice. This was attenuated in the 5xFAD mice treated with the natural product, whose profiles resembled WT controls. RNA seq suggested the natural product regulated the nervous and immune systems.
Project description:Transcriptional consequences of pharmacologic PPAR a, d, & g agonist administration in murine liver, heart, kidney, and skeletal muscle
Project description:Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited due to their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem brain tissue from AD patients and in the 5xFAD -amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected AD mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β-amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. Importantly, TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.
Project description:Liver gene expression was examined in male cynomolgus monkeys treated with ciprofibrate (PPAR-alpha agonist) for 4 days at 400 mg/kg/day and treated for 15 days at 0, 3, 30, 150 or 400 mg/kg/day. The untreated control group were given only the vehicle (0.5% hydroxypropyl methylcellulose). Two animals per group were used for the 4 day treatment and four animals per group were used for the 15 day treatment (except the 15 day control group, which had three animals). Selection of significantly changed probesets was done using Rosetta Resolver and the fold-change and p values as determined by Resolver are given below. Affymetrix CEL files and MAS5-processed data have been made availabe for convenience. Note that data processing reported in the Toxicological Sciences manuscript was done using Rosetta Resolver and the treated versus control group fold-change and p-value are appended to the Series entry. An article has been published in Toxicological Sciences regarding this dataset; the data interpretation was based on the Rosetta Resolver data. Keywords: repeat
Project description:Cardiac hypertrophy is characterized by increase in the size of the cardiomyocytes which is initially triggered as an adaptive response due to various kinds of stimuli but ultimately becomes maladaptive with chronic exposure. Peroxisome proliferator activated receptor alpha (PPAR α), which is critical for mitochondrial biogenesis and fatty acid oxidation, is known to be down regulated in hypertrophied cardiomyocytes. The aim of the study was to unveil the role of PPAR α in the mechanism that drives myocardium towards maladaptation in chronic hypertrophy. Wild-type C57BL/6 and PPAR α-/- mice were subjected to isoproterenol treatment for 2 weeks (n=8). Proteomic analysis using Orbitrap mass spectrometer revealed an unexpected down regulation of apoptotic markers, Annexin V and p53. PPAR α regulated and non-regulated genes were validated using RT-PCR. Specificity for α isoform was confirmed using PPAR α agonist, fenofibrate and pan-agonist bezafibrate. Fenofibrate failed to restore PPAR α target genes, whereas bezafibrate managed to ameliorate the effects of isoproterenol for a subset of genes even in the absence of PPAR α. Autophagy markers like p62, Beclin1 and LC3 A/B were up regulated in PPAR α-/-mice therefore indicating an upsurge in autophagy. The results demonstrate hindrance to intrinsic apoptotic pathway and activation of autophagy in the absence of PPAR α in hypertrophic cardiomyocytes. Therefore, PPAR α signalling might act as a molecular switch between apoptosis and autophagy thereby playing a critical role in adaptive process in stress induced cardiomyocytes.