Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that regulates lipid metabolism and glucose homeostasis. PPARγ is not only highly expressed in adipose tissue but also in cells involved in the immune system, and it exerts anti-inflammatory activities. We showed that eosinophils, a major inflammatory cell in allergic inflammation, express PPARγ. PPARγ negatively modulates eosinophil functions, such as survival, chemotaxis, antibody-dependent cellular cytotoxicity and degranulation. Recently, three independent groups have demonstrated that PPARγ agonists inhibit airway inflammation in an animal model of asthma. This evidence suggests that PPARγ agonists may be a new therapeutic modality for the treatment of allergic diseases including asthma.

p53 suppresses the genomic instability provoked by genotoxic agents. Ultraviolet (UV) B induces skin cancers by producing DNA damage and mutations in the skin genome, whereas the skin tissue responds to the UVB insult with cell cycle arrest and apoptosis as well as damage exclusion by DNA repair. To address the p53 contribution to these skin responses in vivo, we analyzed the time course of DNA damage removal, apoptosis induction and hyperplasia in the skin after UVB irradiation in p53-knockout mice. We also examined UVB-induced mutations in the skin. We found that p53 deficiency does not abolish the UVB-induced apoptotic response in the epidermis but delays the process and the following hyperplasia 12-24 h. Regardless of the p53 genotype, 1 kJ/m(2) UVB induced a total replacement of the epidermal layer by destroying the damaged epidermis by apoptosis and rebuilding a new one through hyperplasia. We failed to detect a clear defect in removal of UVB-induced DNA photolesions from the genome of the p53-deficient skin except for a delay in the epidermis, which seemed to result from the delay in the apoptotic response. However, we found that p53 deficiency enhanced UVB-induced mutagenesis. Furthermore, in a genetic study using Xpa-knockout mice, we showed that the enhanced mutagenic response depends on the activity of nucleotide excision repair (NER), which was also supported by the mutation spectrum observed in the UVB-exposed p53-knockout mice. These results indicate that p53 protects the skin genome from the UVB genotoxicity by facilitating NER, whereas its contribution to the UVB-induced apoptosis is limited.

-equol, which is enantioselectively produced from daidzein by gut microbiota, has been suggested as a chemopreventive agent against type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear. We investigated the effects of -equol on pancreatic β-cell function. β-Cell growth and insulin secretion were evaluated with male Institute of Cancer Research mice and isolated pancreatic islets from the mice, respectively. The mechanisms by which -equol stimulated β-cell response were examined in INS-1 β-cells. The effect of-equol treatment on β-cell function was assessed in low-dose streptozotocin-treated mice. -equol was used at 10 μmol/L for in vitro and ex vivo studies and was administered by oral gavage (20 mg/kg, 2 times/d throughout the experimental period) for in vivo studies.-equol administration for 7 d increased Ki67-positive β-cells by 27% ( < 0.01) in mice. -equol enantioselectively enhanced glucose-stimulated insulin secretion in mouse pancreatic islets by 41% ( < 0.001). In INS-1 cells, -equol exerted stronger effects than daidzein on cell growth, insulin secretion, and cAMP-response element (CRE)-mediated transcription. These-equol effects were diminished by inhibiting protein kinase A. The effective concentration of -equol for stimulating cAMP production at the plasma membrane was lower than that for phosphodiesterase inhibition.-equol-stimulated CRE activation was negatively controlled by the knockdown of G-protein α subunit group S (stimulatory) and positively controlled by that of G-protein-coupled receptor kinase-3 and -6. Compared with vehicle-treated controls, -equol gavage treatment resulted in an increase in β-cell mass of 104% ( < 0.05), a trend toward high plasma insulin concentrations (by 118%; = 0.06), and resistance to hyperglycemia after streptozotocin treatment (78% of AUC after glucose challenge; < 0.01). -equol administration significantly increased the number of Ki67-positive proliferating β-cells by 62% ( < 0.01) and decreased that of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic β-cells by 75% ( < 0.05). Our results show that -equol boosts β-cell function and prevents hypoglycemia in mice, suggesting its potential for T2DM prevention.

A BSTRACTBackground: Recently, a second prostaglandin D 2 (PGD 2 ) receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), was identified. Because PGD 2 was reported to have chemotactic activity on eosinophils, CRTH2 expressed on eosinophils attracted interest as a receptor associated with eosinophil migration to, and accumulation at, inflammatory sites. To elucidate the mechanism regulating the expression of CRTH2 on eosinophils, the effects of PGD 2 , interleukin (IL)-4, IL-5 and interferon (IFN)-γ on CRTH2 expression were investigated. Methods: Blood eosinophils were purified using Percoll and anti-CD16 antibody coated magnetic beads. Eosinophils were incubated with PGD 2 and/or IL-4, IL-5 and IFN-γ . The expression of CRTH2 on eosinophils was measured using a FACScan cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA). Results: Prostaglandin D 2 and IL-5, but not IL-4 and IFN-γ , downregulated the expression of CRTH2 on eosinophils. Furthermore, PGD 2 -and IL-5-induced downregulation of CRTH2 on human eosinophils was inhibited by phenylarsine oxide, a receptor internalization inhibitor. Conclusions: These results suggest that PGD 2 and IL-5 regulate CRTH2 expression on eosinophils through

Eosinophils are major effector cells in allergic diseases including asthma. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that regulates immune reaction. We have previously demonstrated that human eosinophils express PPARγ and that stimulation with a synthetic agonist for PPARγ attenuated the factor-induced eosinophil survival and chemotaxis. However, the modulator of the eosinophil PPARγ expression has not yet been studied. In this study, we investigated the effect of theophylline and dexamethasone (widely used drugs in the treatment of asthma) on PPARγ expression in eosinophils. Purified human peripheral blood eosinophils were cultured, and therapeutic concentrations of theophylline and dexamethasone were added. Subsequently, PPARγ was measured using quantitative real-time RT-PCR and flow cytometry. Theophylline and dexamethasone markedly enhanced both mRNA and protein levels of PPARγ. These findings suggest that the increase in PPARγ expression on eosinophils may play a role in the anti-inflammatory effects of theophylline and dexamethasone.