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Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3′,4′,5,7-pentahydroxyflavone) and of one of its derivatives, Q2 in which the OH groups have been replaced by acetyl groups. In 3 T3-L1 preadipocytes, Quercetin and Q2 treatment induce chromatin remodeling and histone modifications at the 5′ regulatory region of the two main adipogenic genes, c/EBPα and PPARγ. Chromatin immunoprecipitation assays revealed a concomitant increase of histone H3 di-methylation at Lys9, a typical mark of repressed gene promoters, and a decrease of histone H3 di-methylation at Lys 4, a mark of active transcription. At the same time, both compounds inhibited histone demethylase LSD1 recruitment to the 5′ region of c/EBPα and PPARγ genes, a necessary step for adipogenesis. The final effect is a significant reduction in c/EBPα and PPARγ gene expression and attenuated adipogenesis. Q2 supplementation in rats reduced the gain in body weight and in white adipose tissue, as well as the increase in adipocyte size determined by high fat diet. Moreover, Q2 improved dyslipidemia, glucose tolerance and decreased the hepatic lipid accumulation by activating the expression of beta-oxidation related genes. Our data suggest that Q2, as well as Quercetin, has the potential to revert the unfavorable epigenomic profiles associated with obesity onset. This opens the possibility to use these compounds in targeted prevention strategies against obesity.

BACKGROUND: Prostate health index (phi) and prostate cancer antigen 3 (PCA3) have been recently proposed as novel biomarkers for prostate cancer (PCa). We assessed the diagnostic performance of these biomarkers, alone or in combination, in men undergoing first prostate biopsy for suspicion of PCa. METHODS: One hundred sixty male subjects were enrolled in this prospective observational study. PSA molecular forms, phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay), and other established biomarkers (tPSA, fPSA, and %fPSA) were assessed before patients underwent a 18-core first prostate biopsy. The discriminating ability between PCa-negative and PCa-positive biopsies of Beckman coulter phi and PCA3 score and other used biomarkers were determined. RESULTS: One hundred sixty patients met inclusion criteria. %p2PSA (p2PSA/fPSA × 100), phi and PCA3 were significantly higher in patients with PCa compared to PCa-negative group (median values: 1.92 vs. 1.55, 49.97 vs. 36.84, and 50 vs. 32, respectively, P ≤ 0.001). ROC curve analysis showed that %p2PSA, phi, and PCA3 are good indicator of malignancy (AUCs = 0.68, 0.71, and 0.66, respectively). A multivariable logistic regression model consisting of both the phi index and PCA3 score allowed to reach an overall diagnostic accuracy of 0.77. Decision curve analysis revealed that this "combined" marker achieved the highest net benefit over the examined range of the threshold probability. CONCLUSIONS: phi and PCA3 showed no significant difference in the ability to predict PCa diagnosis in men undergoing first prostate biopsy. However, diagnostic performance is significantly improved by combining phi and PCA3.

Background: Approximately 40% of males with low Gleason grade clinically localized prostate cancer (PCa) at biopsy were finally diagnosed with high Gleason grade PCa at radical prostatectomy (RP). Therefore, a more reliable assessment of the Gleason grade prior to RP is required. Readily available modalities such as circulating biomarkers may be useful for this purpose. The aim of this study was to evaluate the ability of preoperative interleukin 6 (IL-6) and its soluble receptor (sIL-6R), as well as urokinase-type plasminogen activator (u- PA), its receptor (u-PAR) and the inhibitor (PAI-1) to predict Gleason score upgrading. Patients and Methods: A total of 51 PCa patients with biopsy Gleason score ≤7 were studied. Preoperative serum samples were collected prior to digital rectal examination (DRE) and TRUS. Blood was collected into non-heparinized tubes and serum was separated within 1 h of blood collection. The serum was stored at –80˚C and then thawed just prior to testing. Serum levels of PSA, free-PSA and IL-6 were measured using the Immulite 2000 automated assay (DPC, Los Angeles, CA, USA). The concentrations of sIL-6R (R&D Systems, Minneapolis, MN, USA), uPA, uPAR and PAI- 1 (Assaypro, Winfield, MO, USA) in serum were determined according to the manufacturer’s instructions using the ELISA test. Every sample was run in duplicate and the mean was used. The differences between the two measurements were minimal. Results: GS upgrading was defined as a Gleason sum increase between biopsy and RP from ≤7 to >7, since this is important for the therapeutic strategy. On this basis, an upgrade was noted in 5 (10%) samples. Median sIL-6R values were found to be significantly higher in patients with GS upgrading (difference in medians, 28.40 ng/ml; 95% CI, 5.60-49.44; p=0.024). The association between sIL-6R and GS upgrading became more significant by using the sIL-6R/IL-6 ratio (difference in medians, 7.77; 95% CI, 1.72-11.28; p=0.011). Sensitivity and specificity of sIL-6R and the sIL-6R/IL-6 ratio were explored by ROC curve analysis (Figure 1). Figure 1. ROC analysis comparing sIL-6R (--) and sIL-6R/IL-6 ratio (–). The results indicated an extremely good ability to predict the probability of biopsy Gleason sum upgrading of the two parameters (sIL-6R: AUC=0.80; 95% CI, 0.63-0.97; p=0.026. sIL-6R/IL-6 ratio: AUC=0.84; 95% CI, 0.69-0.98; p=0.014). The optimal cut-off point for sIL-6R was 76.5 ng/ml, providing a sensitivity of 80% and a specificity of 76%, whereas for the sIL-6R/IL-6 ratio the optimal cut-off point was 13.5 with comparable sensitivity (80%), but higher specificity (83%). Discussion and Conclusion: sIL-6R may be a significant circulating biomarker employed to predict GS upgrading in patients with a biopsy GS ≤7. Moreover, this ability appears to be enhanced by calculating the sIL-6R/IL-6 ratio. These findings may provide an additional ‘staging tool’ for PCa patients, which may be of great significance in guiding clinicians’ treatment choices, according to current guidelines. 1 Shariat SF, Andrews B, Kattan MW, Kim J, Wheeler TM and Slawin KM: Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58: 1008-1015, 2001. 2 Spiotto MT and Chung TD: STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 42: 186-195, 2000. 3 Deeble PD, Murphy DJ, Parsons SJ and Cox ME: Interleukin-6-and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. Mol Cell Biol 21: 84718482, 2001.

Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1). Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4) restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15) by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance.

In this study, we evaluated the ability of preoperative IGFBP-2, IGFBP-3, IL-6, and SIL-6R serum levels to predict Gleason score upgrade in 52 PCa patients.