Deregulation of PPARß/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.

The nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARß/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARß/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARß/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARß/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARß/δ ligands. These observations suggest that the deregulation of PPARß/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.

Changes in plasma PPARs levels in migraine patients.

BACKGROUND: The aim of this study was to observe the change in plasma PPARs (peroxisome proliferator-activated receptors) level during various periods and in different subtypes in migraine patients. MATERIAL AND METHODS: We divided 227 patients with migraine into 2 main groups: the attack period group (n=98) and the attack-free period group (n=129). Patients were further divided into 4 subgroups according to whether they had aura symptoms. The control group consisted of 100 healthy subjects. We collected the clinical data of patients and measured the plasma levels of PPARs using enzyme-linked immunoassay (ELISA). We used SPSS software for statistical analysis. RESULTS: We found no significant difference in age, BMI, blood pressure, or blood lipid level among migraine patients during the headache attack period and during the headache-free period compared with the control group. The PPARα and PPARß/δ levels during the headache attack period were significantly higher than during the headache free period and in healthy controls. The PPARγ levels during the headache attack period were significantly lower than those during the headache-free period and in the healthy control group. The PPARs levels during the headache attack period were significantly different from those during the headache-free period, regardless of presence or absence of aura. The PPARs levels during the headache-free period were not significantly different from those of the healthy control group. The level of PPARs has no significant differences between migraine with aura group and without aura group, regardless of whether headache attack. CONCLUSIONS: PPARs involved in the pathogenesis of migraine. Presence of absence of aura had no obvious effect on PPARs level.

[Expression of peroxisome proliferator-activated receptor alpha and beta in peripheral blood mononuclear cells of non-vavular hypertensive atrial fibrillation patients].

OBJECTIVE: To determine the mRNA expressions of PPARalpha and PPARbeta in peripheral blood mononuclear cells of non-vavular hypertensive atrial fibrillation (AF) patients and elucidate its possible role in the pathogenesis of AF. METHODS: Peripheral blood samples were collected from 103 patients with hypertensive AF (persistent AF: 55, paroxysmal AF: 48) and 50 age-adjusted hypertension patients without AF. The mRNA expressions of PPARalpha, PPARbeta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in monocytes were detected by using a Real time polymerase chain reaction. The concentrations of high sensitive C-reactive protein (CRP) and interleukin-1 (IL-1) were measured by immunoenzymetric method. RESULTS: The PPARalpha mRNA expression level was persistently decreased in hypertensive non-AF group, paroxysmal AF group, and persistent AF group (1.34 +/- 0.17, 1.09 +/- 0.23, 0.85 +/- 0.22), while the difference was statistically significant (P < 0.001; respectively). TNF-alpha mRNA, IL-6 mRNA,CRP and IL-1 persistently increased in hypertensive non-AF group, paroxysmal AF group, persistent AF group, also the difference was statistically significant (P < 0. 001; respectively). The difference of PPARbeta mRNA was not statistically significant between non-AF group, paroxysmal AF group and persistent AF group. Left atrial diameter (LAD) was in positive correlation with CRP, IL-1, IL-6 mRNA and TNF-alpha mRNA (P < 0.05). PPARalpha mRNA level was in negative correlation with CRP, IL-1, IL-6 mRNA and TNF-alpha mRNA, the correlation coefficient was -0.519, -0.532, -0.491 and -0.528, respectively (P < 0.05). CONCLUSION: In hypertensive patients with AF, increased inflammatory cytokines were associated with atrial remodeling and lead to the development of atrial fibrillation; PPARalpha was negatively correlated with these inflammatory cytokines and may play a vital role in the process of atrial fibrillation development.

The antiplatelet activity of magnolol is mediated by PPAR-ß/γ.

Activation of peroxisome proliferator-activated receptor (PPAR) isoforms (α, ß/δ, and γ) is known to inhibit platelet aggregation. In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20-60 µM) dose-dependently enhanced the activity and intracellular level of PPAR-ß/γ in platelets. In the presence of selective PPAR-ß antagonist (GSK0660) or PPAR-γ antagonist (GW9662), the inhibition of magnolol on collagen-induced platelet aggregation and intracellular Ca(2+) mobilization was significantly reversed. Moreover, magnolol-mediated up-regulation of NO/cyclic GMP/PKG pathway and Akt phosphorylation leading to increase of eNOS activity were markedly abolished by blocking PPAR-ß/γ activity. Additionally, magnolol significantly inhibited collagen-induced PKCα activation through a PPAR-ß/γ and PKCα interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B(2) formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol. However, these above effects of magnolol on platelet responses were strongly reduced by simultaneous addition of GSK0660 or GW9662, suggesting that PPAR-ß/γ-mediated processes may account for magnolol-regulated antiplatelet mechanisms. Similarly, administration of PPAR-ß/γ antagonists remarkably abolished the actions of magnolol in preventing platelet plug formation and prolonging bleeding time in mice. Taken together, we demonstrate for the first time that the antiplatelet and anti-thrombotic activities of magnolol are modulated by up-regulation of PPAR-ß/γ-dependent pathways.

Peroxisome proliferator receptor (PPAR) ß/δ in psoriatic patients before and after two conventional therapeutic modalities: methotrexate and PUVA.

Peroxisome proliferator-activated receptor ß/δ is a member of the nuclear hormone receptor superfamily suggested to contribute to psoriasis pathogenesis. Methotrexate and PUVA mainly target the T cell-mediated immunopathology of psoriasis. Our work aimed at estimating PPARß/δ in psoriatic patients and investigating whether the standard therapeutic modalities (methotrexate and PUVA) exert their anti-psoriatic activity partially through altering PPARß/δ levels. RT-PCR was used to measure PPAR ß/δ mRNA levels in twenty four chronic plaque psoriasis patients. Patients were divided into two groups (12 patients each); group A received intramuscular methotrexate and group B was treated by PUVA 3 times/week in a PUVA 1000 cabin for ten weeks each, followed by measurement of PPAR ß/δ mRNA levels. Twelve healthy volunteers served as controls. PPAR ß/δ mRNA levels were significantly elevated in all patients and significantly decreased ten weeks after treatment, however, post treatment levels were still significantly elevated in comparison with those of controls. PPAR ß/δ mRNA levels showed a significant positive correlation with disease duration.