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Metabolic Syndrome (MetS) is a cluster of clinical conditions, associated to an increased cardiovascular risk, as well as to hypogonadism in males. Lifestyle modification (including physical exercise, PhyEx) may be beneficial for the condition. Skeletal muscles (SkM) are some of the most highly plastic tissues, able of remodeling in response to use, disuse and disease. In particular, transformations of fiber type may occur in response to physiological milieu to induce functional adaptations. This study is aimed at investigating in experimental MetS, high fat diet-induced in male rabbits [1], the effect of PhyEx on hormonal and metabolic parameters, as well as on SkM composition. Control and MetS rabbits were exercise-trained to run on a treadmill for 12 weeks. Quadriceps femoris samples were collected for histomorphological and gene expression analyses. We found that exercise resistance was significantly reduced in MetS rabbits, as demonstrated by the significant reduction of both running time and distance, compared to control group. MetS rabbits also exhibited the lowest quadriceps mass. Fiber typing by PAS-staining showed a pronounced shift from slower type I to faster type II fibers in MetS group in response to PhysEx, suggesting that MetS condition addressed SkM function towards anaerobic metabolism. Accordingly, extracellular lactate levels were significantly increased and mitochondrial respiration-related genes reduced in SkM of MetS rabbits respect to controls. Interestingly, PhyEx significantly counteracted MetS-related testosterone deficiency and hypercholesterolemia. In conclusion, our results indicate that dysmetabolic milieu induces a reduced proportion of fatigue-resistant type I fibers in response to PhysEx, which however resulted beneficial for MetS condition., Italian Journal of Anatomy and Embryology, Vol. 122, No. 1 (Supplement) 2017

Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus (Filippi et al., 2009). This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropins levels decreased as a function of MetS severity, glucose intolerance, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD significantly induced mRNA expression and hypothalamic immunopositivity of GLUT4 and IL-6, as well as a low-grade hypothalamic inflammation (microglial activation with unchanged astroglia morphology), while reduced hypothalamic immunopositivity for KiSS-1 receptor (KiSS-1R), whose mRNA expression negatively correlated with glucose intolerance. Moreover, high glucose exposure down-regulated KiSS-1/KiSS-1R system and GnRH expression in human GnRH-secreting neuroblasts. A subset of HFD rabbits was treated with the farnesoid-X receptor agonist obeticholic acid, able to ameliorate glucose metabolism (Morelli et al., 2012). This treatment significantly increased GnRH mRNA and reduced GLUT4 and IL-6 immunopositivity. Our results suggest that HFD-induced glucose dysregulation negatively affects GnRH neuron function through an inflammatory injury at the hypothalamic level., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013

Morbidelli L, Pyriochou A, Filippi S, Vasileiadis I, Roussos C, Zhou Z, Loutrari H, Waltenberger J, Stossel A, Giannis A, Ziche M, Papapetropoulos A. The soluble guanylyl cyclase inhibitor NS-2028 reduces vascular endothelial growth factor-induced angiogenesis and permeability. Am J Physiol Regul Integr Comp Physiol 298: R824-R832, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00222.2009.-Nitric oxide (NO) is known to promote vascular endothelial growth factor (VEGF)stimulated permeability and angiogenesis. However, effector molecules that operate downstream of NO in this pathway remain poorly characterized. Herein, we determined the effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in vitro and in vivo. Treatment of endothelial cells (EC) with VEGF stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with the sGC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028) blunted cGMP levels without affecting VEGF-receptor phosphorylation. Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF. In addition, cells in which sGC was inhibited exhibited no migration and sprouting in response to VEGF. To study the mechanisms through which NS-2028 inhibits EC migration, we determined the effects of alterations in cGMP levels on p38 MAPK. Initially, we observed that inhibition of sGC attenuated VEGF-stimulated activation of p38. In contrast, the addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC migration. To test whether sGC also mediated the angiogenic effects of VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028 orally displayed a reduced angiogenic response to VEGF. As increased vascular permeability occurs prior to new blood vessel formation, we determined the effect of NS-2028 in vascular leakage. Using a modified Miles assay, we observed that NS-2028 attenuated VEGF-induced permeability. Overall, we provide evidence that sGC mediates the angiogenic and permeability-promoting activities of VEGF, indicating the significance of sGC as a downstream effector of VEGF-triggered responses.

We have previously shown that hypoxia makes vascular smooth muscle cells (VSMCs) responsive to placental growth factor (PlGF) through the induction of functional fms-like tyrosine kinase (Flt-1) receptors. The aim of this study was to investigate the molecular mechanisms involved in the PlGF effects on proliferation and contraction of VSMCs previously exposed to hypoxia (3% O2). In cultured rat VSMCs exposed to hypoxia, PlGF increased the phosphorylation of protein kinase B (Akt), p38 and STAT3; activation of STAT3 was higher than that of other kinases. In agreement with this finding, the proliferation of hypoxia-treated VSMCs in response to PlGF was significantly impaired by the p38 and the phosphatidylinositol 3-kinase inhibitors SB202190 and LY294002, respectively, and was almost completely prevented by AG490, a janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor. Since hypoxia was able to reverse the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this latter effect was also investigated. Significant Flt-1 activity was measured in isolated preparations from rat aorta exposed to hypoxia. Inhibitors of mitogen-activated protein kinase kinase, Akt and STAT3 induced a modest inhibition of the vasoconstrictor response to PlGF, while the p38 inhibitor SB202190 markedly impaired the PlGF-induced contractile response. These effects were selectively mediated by Flt-1 without any involvement of foetal liver kinase-1 receptors. These data are the first evidence that different intracellular pathways activated by Flt-1 receptor in VSMCs are involved in diverse biological effects of PlGF: while mitogen activated protein kinase kinase/extracellular signal regulated kinase(1/2) and JAK/STAT play a role in VSMC proliferation, p38 is involved in VSMC contraction. These findings may highlight the role of PlGF in vascular pathology.

Introduction Phosphodiesterase type 5 inhibitors (PDE5-I) have acquired an established role in the treatment of post-prostatectomy erectile dysfunction (ED). Several trials in men with ED and lower urinary tract symptoms associated with benign prostatic hyperplasia suggest that PDE5-I could improve both erectile function and urinary symptoms. Aim To assess the role of vardenafil in continence recovery after bilateral nerve sparing radical prostatectomy (BNS-RP). Methods Thirty-nine patients with prostate cancer were recruited. After BNS-RP, patients were double-blinded assigned to three arms: a) vardenafil on demand; b) vardenafil nightly; and c) placebo. Main Outcomes Measures Urinary function (UF) and urinary bother (UB) of University of California–Los Angeles Prostate Cancer Index questionnaire were assessed preoperatively and at 1, 3, 6, 9, 10, and 12 months. Twelve-month outcomes were compared to 1 month with a t -test. The differences in UF and UB (at 3, 6, 9, 10, and 12 months) between the three treatment arms were calculated by an analysis of variance. With ALLFIT we estimated half-maximal recovery times (ER50) and maximal recovery ( R max ) in three groups. Results The improvement of UF and UB between 1 and 12 months was significant in all arms except for placebo (UF: P = 0.125; UB: P = 0.089). Nightly resulted in greater UF at 3, 6, and 9 months and greater UB at 6 months compared with placebo ( P = 0.042, P = 0.044 and P = 0.039); after nightly administration, patients presented higher UB than after on-demand use, 3 and 6 months postoperatively ( P = 0.036 and P = 0.017). ALLFIT demonstrated a similar ER50 in all groups (2.6 months for both UF and UB) and indicated that nightly administration induced significant improvements in R max compared with placebo (both Conclusions Vardenafil can improve continence recovery after BNS-RP compared with placebo. The daily use of vardenafil seems to provide better continence rate, although it does not seem to influence the timing needed to achieve full continence. Gacci M, Ierardi A, Delle Rose A, Tazzioli S, Scapaticci E, Filippi S, Maggi M, Nicita G, Carini M, and Montorsi F. Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: Results of a randomized, double blind, placebo-controlled pilot study.