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7. (082) The Effect of Sex Steroids on RhoA/ROCK Pathway in Rat Distal Vagina

Author

Cellai, I, primary, Comeglio, P, additional, Filippi, S, additional, Martinelli, S, additional, Amore, F, additional, Rapizzi, E, additional, Maseroli, E, additional, Raddi, C, additional, Guarnieri, G, additional, Cipriani, S, additional, Sarchielli, E, additional, Morelli, A, additional, Rastrelli, G, additional, Maggi, M, additional, and Vignozzi, L, additional

Published
2023
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8. Distal Vagina Smooth Muscle Contractility Mechanisms: Effects of in Vivo Sex Steroids Treatment in an Animal Experimental Model of Ovariectomy

Author

Cipriani, S, primary, Cellai, I, additional, Comeglio, P, additional, Filippi, S, additional, Martinelli, S, additional, Amore, F, additional, Rapizzi, E, additional, Maseroli, E, additional, Raddi, C, additional, Guarnieri, G, additional, Sarchielli, E, additional, Morelli, A, additional, Rastrelli, G, additional, Maggi, M, additional, and Vignozzi, L, additional

Published
2022
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9. 054 Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina

Author

Comeglio, P., primary, Maseroli, E., additional, Cellai, I., additional, Di Stasi, V., additional, Todisco, T., additional, Filippi, S., additional, Sorbi, F., additional, Fambrini, M., additional, Petraglia, F., additional, Scavello, I., additional, Rastrelli, G., additional, Villanelli, F., additional, Danza, G., additional, Guarnieri, G., additional, Morelli, A., additional, Maggi, M., additional, and Vignozzi, L., additional

Published
2022
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14. (046) THE ROLE OF ADENOSINE IN THE RELAXANT MECHANISM OF RAT DISTAL VAGINA.

Author

Cipriani, S, Cellai, I, Filippi, S, Comeglio, P, Guarnieri, G, Maseroli, E, Rastrelli, G, Morelli, A, Maggi, M, and Vignozzi, L

Subjects
*VAGINA, *MESSENGER RNA, *CYCLIC adenylic acid, *ADENOSINES, *VASCULAR smooth muscle
Abstract

Introduction: Adenosine (ADO) is a purinergic neuromodulator that in the male exerts a positive effect on penile erection by controlling smooth muscle (SM) relaxation. However, its role in the relaxant/contractile pathways in the vagina is yet to be investigated. Objective: The aim of this study was to characterize the effect of ADO stimulation on SM activity in distal vagina, evaluating its possible effect on the regulation of nitric oxide (NO) pathway using a validated animal model of female Sprague-Dawley rats. Methods: The immunolocalization of ADORA2A and ADORA2B in distal vagina tissues was detected by immunohistological staining. In vitro contractility studies on noradrenaline (NA)-precontracted vaginal strips from intact Sprague-Dawley rats were performed; rat smooth muscle cells (rvSMCs) from distal vagina of intact animals were stimulated with ADO for cyclic adenosine monophosphate (cAMP) quantification. mRNA (messenger ribonucleic acid) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: All ADORAs mRNA were expressed in the vaginal tissue, with a significant prevalence of ADORA2B; furthermore, ADORA2A and ADORA2B immunolocalization highlighted that both receptors are highly expressed in the epithelium, in blood capillaries of the vascular bed and in the smooth muscle bundles of vagina wall. In vitro ADO stimulation induced a dose-dependent relaxation (IC50=31.9±2.38 μM), which was significantly reduced by the administration of NO-synthase inhibitor L-NAME; similar effects were observed after the mechanical ablation of endothelium and in vitro administration of the soluble guanylate cyclase inhibitor ODQ, highlighting the pivotal contribution of NO signaling to the ADO relaxant activity. In vitro stimulation with increasing doses of the selective ADO receptor ADORA2A agonist CGS2-1680 induced a dose-dependent relaxation (IC50=132.6±3.47 nM); a similar but less potent relaxant effect was observed with ADORA2B selective agonist BAY60-6583. The relaxing effect induced by ADO on NA-precontracted vaginal strips was completely counteracted by the stimulation with the re-spectively selective ADORA2A and ADORA2B antagonists SHC-442416 and PSB603; a similar effect was induced by ADORA1 selective antagonist SLV320, but not by ADORA3 selective antagonists VUF5574. The mRNA relative expression of enzymes regulating the ADO turnover [adenosine deami-nase (ADA), 5′-nucleotidase (5NTD), AMP deaminase type 1 and type 2 (AMPD1, AMPD2) and adenosine kinase (ADK)] showed a higher expression of genes regulating the de novo ADO/cAMP syn-thesis (ADK, 5NTD), compared to those acting on ADO degradation (ADA, AMPD1, AMPD2). Finally, stimulation of rvSMCs with increasing doses of ADO induced a significant production of intracellular cAMP after 3 minutes (1 and 10 μM). Conclusions: These data show that ADO acts as an important relaxant modulator of the vagina through the activation of its receptors, specifically ADORA2A, and the consequent cAMP-dependent adenylate cyclase re-sponse. However, in vitro studies show that ADO also acts trough the NO-dependent pathway. These results therefore demonstrate for the first time a new relaxant pathway in distal vagina, ADO signaling, that results deeply intertwined with the well-known NO pathway. This finding unravels new biological mechanisms underlying vagina physiology that need to be further studied in future research. Disclosure: No. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men

Author

Maseroli, E., primary, Comeglio, P., additional, Corno, C., additional, Cellai, I., additional, Filippi, S., additional, Mello, T., additional, Galli, A., additional, Rapizzi, E., additional, Presenti, L., additional, Truglia, M. C., additional, Lotti, F., additional, Facchiano, E., additional, Beltrame, B., additional, Lucchese, M., additional, Saad, F., additional, Rastrelli, G., additional, Maggi, M., additional, and Vignozzi, L., additional

Published
2020
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23. HP-1-1 Anti Inflammatory Effects of Androgenic Signaling in Human Vagina: A Potential Therapeutical Application for the Genitourinary Syndrome of Menopause

Author

Cipriani, S., primary, Maseroli, E., additional, Cellai, I., additional, Filippi, S., additional, Comeglio, P., additional, Frison, M., additional, Amoriello, R., additional, Ballerini, C., additional, Sarchielli, E., additional, Guarnieri, G., additional, Morelli, A., additional, Maggi, M., additional, and Vignozzi, L., additional

Published
2020
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29. (007) TESTOSTERONE POSITIVELY REGULATES ADENOSINE-INDUCED RELAXATION IN THE VAGINA: AN EXPERIMENTAL STUDY IN RATS.

Author

Cipriani, S, Cellai, I, Filippi, S, Comeglio, P, Guarnieri, G, Maseroli, E, Rastrelli, G, Morelli, A, Maggi, M, and Vignozzi, L

Subjects
*MESSENGER RNA, *CYCLIC adenylic acid, *VAGINA, *TESTOSTERONE, *PENILE erection
Abstract

Introduction: It has been previously demonstrated that testosterone (T) has a pivotal role in controlling vaginal relaxation through the related molecular machinery, i.e., improving the nitric oxide (NO)/protein kinase G (PKG)/cyclic guanosine monophosphate (cGMP) vaginal signaling and maintaining the integrity of the muscular wall. Adenosine (ADO) is a purinergic neuromodulator that, in the male, shows a positive effect on penile erection by controlling smooth muscle relaxation and local blood flow increase. However, the role, if any, of T on the ADO-induced relaxation signaling is yet to be investigated. Objective: The aim of this study was to evaluate the effect of sex steroids on ADO-mediated vaginal relaxation using a validated animal model of ovariectomized (OVX) and sex steroid supplemented Sprague-Dawley rats. Methods: Subgroups of OVX rats were treated with 17β-estradiol (E2; 10 mg/kg/die), testosterone (T; 30 mg/kg/week), or testosterone and letrozole (T+L, 2.5 mg/kg/die) for 6 weeks. The experimental groups were compared with a group of intact rats. In vitro contractility studies were performed on noradrenaline (NA) pre-contracted distal vaginal strips, isolated from each experimental group, stimulated with increasing doses of ADO (1 μM - 1 mM), with or without NO-synthase inhibitor L-NAME (100 μM) pretreatment, or treated with ADORA2A selective agonist CGS21680 (10 Pm-100 μM). Messenger ribonucleic acid (mRNA) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results: The results showed that OVX resulted in a decreased responsiveness to ADO, completely restored by T supplementation, with or without letrozole. In contrast, E2 did not affect the hyporesponsiveness to ADO in OVX rats. Likewise, ADO induced dose-dependent relaxation was significantly reduced by in vitro L-NAME (100 μM) only in the OVX animals treated with T or T+L. Accordingly, vagina expressed all ADO receptors (ADORA1, ADORA2A, ADORA2B, ADORA3) mRNAs, with pro-relaxant ADORA2A (ADO receptor coupled to adenylyl cyclase activation) being significantly modulated by hormonal treatments: OVX significantly reduced ADORA2A mRNA expression, an effect counteracted by either T or T+L administration, but not by E2. These data are supported by the observed T-induced upregulation of cyclic adenosine monophosphate (cAMP)-dependent genes, where T, but not E2, treatment upregulated the mRNA expression of the ubiquitous isoform of ADCY (ADCY4), protein kinase A (PKA) catalytic subunit b (PKAcb), PKA regulatory subunit 2b (PKAr2b) and cAMP responsive element modulator (CREM). Finally, as further demonstration of the functional activity of ADO signaling in distal vagina, stimulation by increasing doses of CGS21680, a selective agonist of ADORA2A receptor, enhanced the relaxant effect induced by T and T+L treatments but not by E2. Conclusions: Our data demonstrated for the first time a novel ADO-mediated relaxant mechanism in vagina and suggested that T positively modulates the responsiveness to ADO stimulation, thus confirming this process as a major player in the relaxant mechanism regulation of muscle contractility in vagina. Disclosure: No. [ABSTRACT FROM AUTHOR]

Published
2024
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36. 081 Testosterone Replacement Therapy is Able to Reduce Prostate Inflammation in Men with BPH, Metabolic Syndrome and Hypogonadism: Preliminary Results from a Randomized Placebo-controlled Clinical Trial

Author

Rastrelli, G., primary, Cipriani, S., additional, Lotti, F., additional, Cellai, I., additional, Comeglio, P., additional, Boddi, V., additional, Della Camera, P., additional, Palma, M., additional, Gacci, M., additional, Serni, S., additional, Maggi, M., additional, and Vignozzi, L., additional

Published
2018
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39. Testosterone replacement therapy is able to reduce prostate inflammation in men with BPH, metabolic syndrome and hypogonadism: Preliminary results from a randomized placebocontrolled clinical trial

Author

Rastrelli, G., primary, Cipriani, S., additional, Lotti, F., additional, Cellai, I., additional, Comeglio, P., additional, Boddi, V., additional, Della Camera, P., additional, Palma, M., additional, Gacci, M., additional, Serni, S., additional, Maggi, M., additional, and Vignozzi, L., additional

Published
2018
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48. 411 Metabolic syndrome is correlated with prostatic inflammation in men with severe LUTS related to benign prostatic hyperplasia: Results of a preclinical and clinical experimental study

Author

Vignozzi, L., primary, Gacci, M., additional, Cellai, I., additional, Sebastianelli, A., additional, Salvi, M., additional, Santi, R., additional, Morelli, A., additional, Rastrelli, G., additional, Comeglio, P., additional, Maneschi, E., additional, Corona, G., additional, Nesi, G., additional, De, Nunzio C., additional, Tubaro, A., additional, Carini, M., additional, and Maggi, M., additional

Published
2013
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50. In vivo effects of rosiglitazone in a human neuroblastoma xenograft

Author

Cellai, I, primary, Petrangolini, G, additional, Tortoreto, M, additional, Pratesi, G, additional, Luciani, P, additional, Deledda, C, additional, Benvenuti, S, additional, Ricordati, C, additional, Gelmini, S, additional, Ceni, E, additional, Galli, A, additional, Balzi, M, additional, Faraoni, P, additional, Serio, M, additional, and Peri, A, additional

Published
2010
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