Proliferator-activated Receptor Gamma Agonist Pioglitazone Research Articles

Peroxisome proliferator-activated receptor gamma regulates interleukin-6 induced lipoprotein(a) gene expression in human HepG2 cells

Abstract Background Lipoprotein(a)[Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and outcomes. The LPA gene promoter contains an interleukin 6 (IL-6) responsive binding site. IL-6 is a pro-inflammatory cytokine and data from patients with inflammatory diseases indicate an impact of the inflammatory milieu on LPA gene regulation and Lp(a) production. In a clinical study, the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone was associated with decreased Lp(a) levels. Publicly accessible ChIP-sequencing of human hepatocytes and measures of Lp(a) production by HepG2 cells provide an opportunity to explore PPARγ regulation of hepatic Lp(a) production. Purpose To investigate the role of PPARγ as a regulator of hepatic Lp(a) production. Methods Public ChIP-sequencing of human hepatocytes was analyzed. Commercially available HepG2 cells were incubated with one of the following: (1) scrambled small interfering RNA (siRNA) alone (control); (2) IL-6 (20ng/mL) and scrambled siRNA ; (3) IL-6 and PPARγ siRNA ; and (4) IL-6 and pioglitazone (25uM). LPA transcription was measured using the quantitative polymerase chain reaction. Results Analysis of the ChIP-sequencing data demonstrated that the LPA locus variant rs56393506, which is associated with increased Lp(a) levels and ASCVD risk in the general population, was within the location of the PPARγ binding site in the LPA promoter (Figure 1). IL-6 significantly increased LPA transcription in the HepG2 cells, compared to control (1.65±0.44 vs. 0.66±0.45, p=0.0027). In the presence of siRNA-mediated knock-down of PPARγ (58±17% PPARγ reduction, p<0.0001 vs. scrambled control), the effect of IL-6 on LPA transcription was significantly amplified (6.78±2.4 vs. 1.65±0.44, p=0.0009). IL-6 did not increase LPA transcription in the presence of the PPARγ agonist pioglitazone compared to control (0.16±0.03 vs. 0.66+0.45, p=0.11, Figure 2). Conclusion PPARγ is a negative regulator of IL-6 induced hepatic Lp(a) production and may represent a new therapeutic target in patients with inflammatory conditions.Figure 1Figure 2

Peroxisome proliferator-activated receptor gamma agonist pioglitazone alleviates hemorrhage-induced thalamic pain and neuroinflammation

BackgroundThalamic pain frequently occurs after stroke and is a challenging clinical issue. However, the mechanisms underlying thalamic pain remain unclear. Neuroinflammation is a key determining factor in the occurrence and maintenance of hemorrhage-induced thalamic pain. Pioglitazone is an agonist of peroxisome proliferator-activated receptor gamma (PPARγ) and shows anti-inflammatory effects in multiple diseases. The present work focused on exploring whether PPARγ is related to hemorrhage-induced thalamic pain. MethodsImmunostaining was conducted to analyze the cellular localization of PPARγ and co-localization was evaluated with NeuN, ionized calcium-binding adapter molecular 1 (IBA1), and glia fibrillary acidic protein (GFAP). Western blot analyses were used to evaluate MyD88, pNF-κB/NF-κB, pSTAT6/STAT6, IL-1β, TNF-α, iNOS, Arg-1, IL-4, IL-6, and IL-10 expression. Behavioral tests in mice were conducted to evaluate continuous pain hypersensitivity. ResultsWe found that pioglitazone appeared to mitigate the contralateral hemorrhage-induced thalamic pain while inhibiting inflammatory responses. Additionally, Pioglitazone induced phosphorylation of STAT6 and suppressed the phosphorylation NF-κB in our model of thalamic pain. These effects could be partially reversed with the PPARγ antagonist GW9662. ConclusionThe PPARγ agonist pioglitazone can mitigate mechanical allodynia by suppressing the NF-κB inflammasome while activating the STAT6 signal pathway, which are well-known to be associated with inflammation.

Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus

ObjectivesPremature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent...

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition.

We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice (N = 23; baseline age: 8 months) and AppNL–G–F mice (N = 37; baseline age: 5 months) using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aβ-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.

Update on cardiovascular risk in nonalcoholic fatty liver disease.

To summarize recent evidence demonstrating increased cardiovascular disease (CVD) risk, and how CVD risk may be reduced, in patients with nonalcoholic fatty liver disease (NAFLD). NAFLD is a multisystem disease, defined by a spectrum of liver fat-associated conditions extending from simple steatosis, to inflammation, fibrosis and cirrhosis. NAFLD not only increases the risk of liver morbidity and mortality but also increases the risk of CVD morbidity and mortality and is associated with recognized CVD risk factors such as hypertension, atherogenic dyslipidaemia, type 2 diabetes mellitus and chronic kidney disease. Evidence suggests that the liver fibrosis stage may be a strong CVD risk factor. Lifestyle measures (e.g. weight loss and increased physical activity) are effective in improving CVD risk factors. Hypoglycaemic agents, such as the peroxisome proliferator-activated receptor gamma agonist pioglitazone and the glucagon-like peptide-1 receptor agonist liraglutide, reduce cardiovascular risk and may improve liver histology. Statin and antihypertensive treatments are well tolerated and currently it is unclear whether novel antifibrotic drugs will reduce CVD risk. Assessment and treatment of increased cardiovascular risk is important in patients with NAFLD. If not contra-indicated, pioglitazone or a glucagon-like peptide 1 agonist should be considered and may benefit both CVD risk and early liver disease.

Effects of Cardiac Sympathetic Neurodegeneration and PPARγ Activation on Rhesus Macaque Whole Blood miRNA and mRNA Expression Profiles.

Degeneration of sympathetic innervation of the heart occurs in numerous diseases, including diabetes, idiopathic REM sleep disorder, and Parkinson's disease (PD). In PD, cardiac sympathetic denervation occurs in 80-90% of patients and can begin before the onset of motor symptoms. Today, there are no disease-modifying therapies for cardiac sympathetic neurodegeneration, and biomarkers are limited to radioimaging techniques. Analysis of expression levels of coding mRNA and noncoding RNAs, such as microRNAs (miRNAs), can uncover pathways involved in disease, leading to the discovery of biomarkers, pathological mechanisms, and potential drug targets. Whole blood in particular is a clinically relevant source of biomarkers, as blood sampling is inexpensive and simple to perform. Our research group has previously developed a nonhuman primate model of cardiac sympathetic denervation by intravenous administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA). In this rhesus macaque (Macaca mulatta) model, imaging with positron emission tomography showed that oral administration of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5 mg/kg daily) significantly decreased cardiac inflammation and oxidative stress compared to placebo (n = 5). Here, we report our analysis of miRNA and mRNA expression levels over time in the whole blood of these monkeys. Differential expression of three miRNAs was induced by 6-OHDA (mml-miR-16-2-3p, mml-miR-133d-3p, and mml-miR-1262-5p) and two miRNAs by pioglitazone (mml-miR-204-5p and mml-miR-146b-5p) at 12 weeks posttoxin, while expression of mRNAs involved in inflammatory cytokines and receptors was not significantly affected. Overall, this study contributes to the characterization of rhesus coding and noncoding RNA profiles in normal and disease-like conditions, which may facilitate the identification and clinical translation of biomarkers of cardiac neurodegeneration and neuroprotection.

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration.

Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid decarboxylase) and circulating levels of norepinephrine, which were attenuated by PPARγ-activation. Overall, these results validate in vivo PET findings of cardiac sympathetic innervation, oxidative stress, and inflammation and illustrate cardiomyocyte CD36 upregulation as a marker of PPARγ target engagement.

Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist.

Identification of molecular mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-month-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied separately. Biochemical assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Amyloid precursor protein and amyloid-β levels in plasma, brain cortex tissue and mitochondria fractions isolated from brain cortex were measured to assess the amyloid pathology. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metabolism and perturbation of amino acid metabolism in these mice. APP/PS1 mice also exhibited higher amyloid-β40 and amyloid-β42 in their cortex, accumulation of mitochondria APP in their cortex, and presented an altered oxidative state in their brain. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-β levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.

In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration

Loss of cardiac postganglionic sympathetic innervation is a characteristic pathology of Parkinson’s disease (PD). It progresses over time independently of motor symptoms and is not responsive to typical anti-parkinsonian therapies. Cardiac sympathetic neurodegeneration can be mimicked in animals using systemic dosing of the neurotoxin 6-hydroxydopamine (6-OHDA). As in PD, 6-OHDA-induced neuronal loss is associated with increased inflammation and oxidative stress. To assess the feasibility of detecting changes over time in cardiac catecholaminergic innervation, inflammation, and oxidative stress, myocardial positron emission tomography with the radioligands [11C]meta-hydroxyephedrine (MHED), [11C]PBR28 (PBR28), and [61Cu]diacetyl-bis(N(4))-methylthiosemicarbazone (ATSM) was performed in 6-OHDA-intoxicated adult, male rhesus macaques (n = 10; 50 mg/kg i.v.). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, which is known to have anti-inflammatory and anti-oxidative stress properties, was administered to five animals (5 mg/kg, PO); the other five were placebo-treated. One week after 6-OHDA, cardiac MHED uptake was significantly reduced in both groups (placebo, 86% decrease; pioglitazone, 82%); PBR28 and ATSM uptake increased in both groups but were attenuated in pioglitazone-treated animals (PBR28 Treatment × Level ANOVA p < 0.002; ATSM Mann–Whitney p = 0.032). At 12 weeks, partial recovery of MHED uptake was significantly greater in the pioglitazone-treated group, dependent on left ventricle circumferential region and axial level (Treatment × Region × Level ANOVA p = 0.034); 12-week MHED uptake significantly correlated with tyrosine hydroxylase immunoreactivity across cardiac anatomy (p < 0.000002). PBR28 and ATSM uptake returned to baseline levels by 12 weeks. These radioligands thus hold potential as in vivo biomarkers of mechanisms of cardiac neurodegeneration and neuroprotection.

The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves nitric oxide availability, renin-angiotensin system and aberrant redox regulation in the kidney of pre-hypertensive rats.

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear receptor. It plays an important role in kidney physiology, where it might contribute to arterial blood pressure regulation and hypertension development by modulation of several signaling pathways. In our study we focused on the effect of PPARγ agonist pioglitazone on changes in the nitric oxide synthase (NOS) expression and activity, the renin-angiotensin system (RAS) cascade, and redox homeostasis signaling pathways in the renal cortex of young pre hypertensive rat models. Young (5-weeks old) spontaneously hypertensive (SHR) and borderline hypertensive (BHR) rats were treated by pioglitazone (PIO, 10 mg/kg/day) during 10 days. Blood pressure (BP) was determined by plethysmography method. Changes in lipid profile were detected in plasma with standard kits using biochemical analyser. Gene expression has been detected by qRT-PCR and protein level was determined using Western blot analysis. Superoxide dismutase (SOD) and catalase (CAT) activities were determined spectrophotometrically and the total enzyme activity of NOS was measured using a radioactive assay based on conversion of [3H] L-arginine to [3H] L- citrulline. Administration of pioglitazone decreased BP in BHR and slowed down the development of BP increase in young SHR animals. For NOS, activation by PPARγ correlated with increase in gene and protein expression of NOS isoforms and in total enzyme activity both in BHR and SHR. In the AT1R/Nox pathway, the treatment did not significantly influence mRNA expression of the p22phox subunit of NADPH oxidase (Nox) and AT1R, but up-regulated the 'pro-vasodilatatory' Mas and AT2R receptors in both BHR and SHR groups. Pioglitazone treatment affected redox regulation. Increase in gene expression of nuclear factor E2-related factor 2 (Nrf2) and SOD isoforms correlated with SOD and CAT enzyme activities. The group treatment-to-control ratios, BHR Pioglitazone to BHR control and SHR Pioglitazone to SHR control for gene expression increased by 10% to 230%. The largest effect of PPARγ has been observed in SOD1, SOD3 and the Mas receptor gene treatment-to-control ratios. The most prominent differences between BHR and SHR were observed in SOD1 and Mas receptor expressions, with large effects of opposite sign in BHR versus SHR. Our data indicate that an increase of NO release activates signaling in the renal cortex of pre-hypertensive rats after pioglitazone treatment. Improvement of NO availability, AT2R, Mas receptors and aberrant redox regulation is thought to be the major correlated mechanisms mediating the BP decrease affected by the PPARγ agonist treatment. We also observed that the most sensitive tissue responses to PPARγ-dependent activation of Nrf2 have been primarily found in the kidney of young hypertensive animals.

Role of adipocyte mitochondria in inflammation, lipemia and insulin sensitivity in humans: effects of pioglitazone treatment.

To gain further insight into the role of adipocyte mitochondria in systemic lipid metabolism, inflammation and insulin sensitivity in humans and to provide a better understanding of the mechanisms of action of the peroxisome proliferator-activated receptor gamma agonist pioglitazone. Mitochondrial DNA (mtDNA) copy number, mitochondrial distribution, mitochondrial and overall cellular protein abundances as well as intrinsic mitochondrial function of subcutaneous adipocytes were assessed by real-time quantitative PCR, MitoTracker staining, global proteomics analyses and NADH cytochrome c reductase activity in insulin-sensitive, normal-glucose-tolerant (NGT) individuals and age, gender, adiposity-matched insulin-resistant individuals with abnormal glucose tolerant (AGT) before and after 3 months of pioglitazone treatment. mtDNA copy number/adipocyte and mtDNA copy number/adipocyte volume were ~55% and ~4-fold lower in AGT than in NGT, respectively, and correlated positively with the M-value of euglycemic clamps and high-density lipoprotein, and negatively with fasting plasma triglyceride, tumor necrosis factor-α and interleukin-6 levels in the entire cohort. mtDNA copy number/adipocyte volume also correlated positively with plasma adiponectin. Pioglitazone, which improved insulin sensitivity, plasma lipids and inflammation, increased the mitochondrial copy number, and led to a redistribution of mitochondria from a punctate to a more reticular pattern as observed in NGT. This was accompanied by disproportionately increased abundances of mitochondrial proteins, including those involved in fat oxidation and triglyceride synthesis. Pioglitazone also increased the abundance of collagen VI and decreased the abundance of cytoskeletal proteins. NADH cytochrome c reductase activity of isolated adipocyte mitochondria was similar in AGT and NGT and unaltered by pioglitazone. Adipocyte mitochondria are deficient in insulin-resistant individuals and correlate with systemic lipid metabolism, inflammation and insulin sensitivity. Pioglitazone induces mitochondrial biogenesis and reorganization as well as the synthesis of mitochondrial proteins including those critical for lipid metabolism. It also alters extracellular matrix and cytoskeletal proteins. The intrinsic function of adipocyte mitochondria appears unaffected in insulin resistance and by pioglitazone.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.192.

Neuroprotective Effects of Piracetam Versus Peroxisome Proliferator-Activated Receptor-Gamma Agonist Pioglitazone in Drug-Induced Parkinsonism

Parkinsonism is a common and disabling neurodegenerative disease. Drug-induced Parkinsonism is not uncommon. The neuroprotective actions of Piracetam and peroxisome proliferator–activated receptor gamma (PPAR I³) agonist pioglitazone have been reported. The aim of the current work was to investigate and compare the neuroprotective effect of piracetam versus pioglitazone on haloperidol-induced Parkinsonism. 36 male rats constituted the animal model for our study and had been divided into six groups (6 rats/group); control, Haloperidol, Piracetam, Piracetam with haloperidol, Pioglitazone, and Pioglitazone with Haloperidol groups. Hypokinesia was tested by stepping test and blood samples were collected for measurement of serum glucose, calcium, Creatine phosphokinase (CPK), Transforming growth factor beta 1 (TGF-I²1), Fibroblast growth factor 21(FGF-21), Glial cell-Derived Neurotrophic Factor (GDNF). Brains extracted for measurement of basal ganglia Tyrosin hydroxylase (TH) and Beclin gene expression. Haloperidol caused hypokinesia, increased serum glucose, CPK, TGF-I²1, FGF-21, GDNF, basal ganglia TH expression and decreased serum calcium and basal ganglia Beclin expression. Both piracetam and pioglitazone provided neuroprotection and improved hypokinesia and the biochemical markers measured in blood and brains of haloperidol-induced Parkinsonism when administered before haloperidol, however; Pioglitazone had a better effect regarding the improvement of serum glucose, CPK and brain expression of Beclin.

Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis

ObjectivesThe aim of this work is to study the possible mechanisms through which different immune-modulating agents can produce their beneficial effects on treatment of psoriasis and to determine whether the supplementation of these agents for psoriasis patients induces regression of psoriasis. Subjects and methodsOne hundred fifty participants were included in this study. The participants were divided into five groups: 1. Normal control group, 2. Psoriasis patients not taking any treatment, 3. Psoriasis patients treated with anti-psoriatic treatment (including coal tar, vitamin D3 analogues and corticosteroids). 4. Psoriasis patients treated with anti-psoriatic treatment and oral metformin (850mg twice daily) and 5. Psoriasis patients treated with anti-psoriatic treatment and oral pioglitazone (15mg once a day). Demographic characteristics, diabetic index, lipid profile and liver function tests were monitored. The CD4+ Tcells, CD8+ Tcells, CD4+/CD8+ ratio, interleukin-2 (IL-2), C-reactive protein (CRP) and ceruloplasmin (CP) were assayed. ResultsAfter treatment of psoriasis patients with a traditional anti-psoriatic drug in combination with metformin and peroxisome proliferator-activated receptor gamma (PPARɤ) agonist (pioglitazone), the CD4+ T cells, IL-2, CRP, CP, ALT and AST levels were statistically significantly decreased compared to psoriasis patients without treatment. Positive and significant correlations between CD4+ % and IL-2, CRP, CP, ALT and AST in psoriasis patients were recorded. ConclusionsThe activation of PPAR-γ receptors by pioglitazone results in reduced formation of the proinflammatory cytokines and infiltration by inflammatory cells. Additionally, metformin acts as a modulator of the immune system in psoriasis patients and has a remarkable effect on the early stages of psoriasis. Therefore, either pioglitazone or metformin in combination with traditional anti-psoriatic drugs provides better results in the treatment of psoriasis than does each alone.

Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution

BackgroundJunctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes. ObjectiveAlthough inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions. MethodsBy the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A–localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines. ResultsRNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone. ConclusionsThis study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.

PPAR-γ agonist pioglitazone affects rat gouty arthritis by regulating cytokines.

The objective was to study peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone regulation effect and its mechanism of expression of cytokines on acute gouty arthritis synovial in rats. Rats with unilateral ankle were injected with artificial monosodium urate (MSU) crystals to make the acute gouty arthritis model. Taking the synovium 48 h after the injection of MSU and using RT-PCR, we assessed the effect of pioglitazone (20 mg·kg(-1)·day(-1), oral administration) on synovial expression, by detecting tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ). The pioglitazone treatment group showed synovial expression of TNF-α, and IFN-γ was significantly lower than in the control group; the inhibition rates were 78.5 and 60.4%. The IL-1 expression difference was not statistically significant between the two groups. Pioglitazone has anti-inflammatory effects on acute gouty arthritis by inhibiting the expression of TNF-α and IFN-γ.

Pilot Study of Pioglitazone and Exercise Training Effects on Basal Myocardial Substrate Metabolism and Left Ventricular Function in HIV-Positive Individuals with Metabolic Complications

Background: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. Objective: In a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. Design: Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. Results: Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. Conclusions: PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.

Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology

Animal models of Alzheimer’s disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months) and aged (>18 months) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-β1 (TGF-β1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone’s efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

THU0036 PPAR gamma agonist rosiglitazone could inhibit RA-FLS induced osteoclastogenesis by down-regulating RANKL expression and suppression of ERK phosphorylation

BackgroundExperiments and clinical trial have shown that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist could inhibit inflammation in rheumatoid arthritis (RA)[1,2]. Recent reports also showed that PPAR-γ agonist could prevent inflammatory periodontal...

Abstract TP167: Suppression of High-mobility Group Protein Box-1 Signaling by Eicosapentaenoic Acid Ameliorates Brain Ischemic Damage in Oophorectomized Rats

Background and Purpose— Cerebral ischemia triggers the acute inflammation that has been associated with an increase in brain damage. In male rats exposed to ischemic insult, high-mobility group protein box-1 (HMGB1) activates inflammatory pathways via its receptor for advanced glycation products (RAGE) and its toll-like receptors (TLRs). We examined the role of these molecules in female rats with experimental ischemic brain damage. We further investigated the efficacy of eicosapentaenoic acid (EPA) against cerebral ischemia and its effect on HMGB1 signaling. Methods— Before 90-min middle cerebral artery occlusion-reperfusion, 5-week-old female Sprague-Dawley rats were subjected to bilateral oophorectomy (OVX + ) and pretreated with 500mg/kg/day EPA for 4 weeks. The relationship between the efficacy of EPA and the regulation of HMGB1 signaling were investigated using peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, PPARγ inhibitor GW9662, and vehicle-control. Results— In parallel with the expansion of the cortical infarct size, HMGB1 signaling after cerebral ischemia was increased in OVX + rats. The mRNA level of TLR9 and RAGE but not TLR2 and TLR4 was moderately increased by cerebral ischemia and significantly higher in OVX + - than OVX - rats. The HMGB1 signal in the OVX + rats pretreated with EPA was inhibited in a PPARγ-dependent and independent manner. These effects were associated with a reduction in the infarct size. Conclusions— We first demonstrate that cortical infarct facilitated by OVX is associated with augmented HMGB1 signaling and that the augmented HMGB1 signaling was suppressed by EPA. To assess whether EPA treatment is a promising strategy further clinical studies are required in postmenopausal women.

Effects of peroxisome proliferator-activated receptor gamma agonist pioglitazone on neurocyte apoptosis and expression of ICAM-1 after traumatic brain injury

Objective To investigate the effects of peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone on delayed neuronal death,apoptosis of neurocytes,and expression of intercellular adhesion molecule-1 ( ICAM-1 ) following traumatic brain injury (TBI) in rats.Methods Thirty-six Sprague-Dawley rats were randomized into sham injury group,control group and pioglitazone treatment group,with 12 rats in each group.TBI model was established by modified Feeney method.Treatment grouP received intragastric administration of pioglitazone at a dosage of 10 mg/kg,and the sham injury group and the control group were lavaged with isometric 0.2％ dimethyl sulphoxide.Paraffin sections of brain tissues collected at 48 hours after TBI were employed to observe delayed neuronal death,apoptosis of neurocytes and expression of ICAM-1 by Nissl staining,TUNEL staining and immunochemistry respectively.Results ( 1 ) Cell loss rate of Nissl body in the treatment group [ ( 38.59 ± 1.97 ) ％ ]was significantly lower than that of the control group [ (51.25 ± 4.01 ) ％ ] ( P ＜ 0.05 ),but was higher than that of the sham injury group [ (8.65 ± 1.23 ) ％ ] ( P ＜ 0.01 ).(2) The number of apoptotic neurocytes of the treatment group (31.67 ± 4.76) was significantly lower than that of the control group (45.33 ± 4.68 ) ( P ＜ 0.05),but was higher than that of the sham injury group ( 16.83 ± 2.04 ) ( P ＜ 0.01 ).(3) The mean optical degree of ICAM-1 positive expression of the treatment group (0.26 ± 0.04) was significantly lower than that of the control group (0.31 ± 0.04) ( P ＜ 0.05 ),but was higher than that of the sham injury group (0.10 ± 0.02 ) ( P ＜ 0.01 ).Conclusions The PPARγagonist pioglitazone can reduce the apoptosis of neurocytes and protect neurons after TBI.Meanwhile,its suppression of ICAM-1 expression is probably a mechanism of the suppression of inflammatory reaction and neural protection. Key words: Peroxisome proliferator-activated receptor; Brain injuries; Apoptosis; Cell adhesion molecules