Adenosine relaxes vagina smooth muscle through the cyclic guanosine monophosphate- and cyclic guanosine monophosphate-dependent pathways.

Background: In males, adenosine (ADO) is known to relax penile smooth muscles, although its role in the vagina is not yet fully elucidated.

Aim: This study investigated the effect of ADO on vagina smooth muscle activity, using a validated female Sprague-Dawley rat model.

Methods: Contractility studies, using noradrenaline-precontracted vaginal strips, tested the effects of ADORA1/3 antagonists and ADORA2A/2B antagonists and agonists.

The galectin-3 inhibitor selvigaltin reduces liver inflammation and fibrosis in a high fat diet rabbit model of metabolic-associated steatohepatitis.

Introduction: Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human K = 25 nM; rabbit K = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).

The regulatory effect of sex steroids on the RhoA/ROCK pathway in the rat distal vagina.

Background: Sex steroids have been demonstrated as important modulators of vaginal function. The RhoA/ROCK calcium-sensitizing pathway plays a role in genital smooth muscle contractile mechanism, but its regulation has never been elucidated.

Aim: This study investigated the sex steroid regulation of the vaginal smooth muscle RhoA/ROCK pathway using a validated animal model.

Consequences of Anabolic-Androgenic Steroid Abuse in Males; Sexual and Reproductive Perspective.

The real epidemiology and the possible consequences of anabolic-androgenic steroids (AAS) use still represent a very tricky task due to the difficulties in the quantification and detection of these drugs. Chronic use of AAS, frequently combined with other illicit substances, can induce tremendous negative effects on the reproductive system, but it is also associated with an increased overall and cardiovascular mortality risk. In the present review we summarize and discuss the available evidence regarding the negative impact of AAS on the male reproductive system, providing practical suggestions to manage these problems.

Neuroprotective Effects of Testosterone in the Hypothalamus of an Animal Model of Metabolic Syndrome.

Metabolic syndrome (MetS) is known to be associated to inflammation and alteration in the hypothalamus, a brain region implicated in the control of several physiological functions, including energy homeostasis and reproduction. Previous studies demonstrated the beneficial effects of testosterone treatment (TTh) in counteracting some MetS symptoms in both animal models and clinical studies. This study investigated the effect of TTh (30 mg/kg/week for 12 weeks) on the hypothalamus in a high-fat diet (HFD)-induced animal model of MetS, utilizing quantitative RT-PCR and immunohistochemical analyses.

Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina.

In this study, we investigated steroidogenic gene mRNA expression in human vaginas and verified the ability of human vagina smooth muscle cells (hvSMCs) to synthesize androgens from upstream precursor dehydroepiandrosterone (DHEA). As a readout for androgen receptor (AR) activation, we evaluated the mRNA expression of various androgen-dependent markers. hvSMCs were isolated from vagina tissues of women undergoing surgery for benign gynecological diseases.

Cardiovascular Risks of Androgen Deprivation Therapy for Prostate Cancer.

Androgen deprivation therapy (ADT) is the gold standard treatment in patients with locally advanced or metastatic prostate cancer (PC). Emerging evidence has documented a association between ADT and body composition, along with metabolic profile impairment. These alterations might underpin the observed ADT-related increase in cardiovascular (CV) and thromboembolic (venous thromboembolism, VTE) mortality and morbidity.

Anti-inflammatory effects of androgens in the human vagina.

Chronic inflammation is involved in the genitourinary syndrome of menopause (GSM) and beneficial effects of androgens in the vagina have been described. We investigated the potential involvement of human vagina smooth muscle cells (hvSMCs) in the inflammatory response and the immunomodulatory effect of androgen receptor (AR) agonist dihydrotestosterone (DHT). HvSMCs isolated from menopausal women were evaluated for sex steroids receptors and toll-like receptors mRNA expression, and left untreated or treated in vitro with lipopolysaccharide (LPS) or IFNγ, in the presence or absence of DHT.

Controversial aspects of testosterone in the regulation of sexual function in late-onset hypogonadism.

Background: Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful.

Testosterone improves muscle fiber asset and exercise performance in a metabolic syndrome model.

Lifestyle modifications, including physical exercise (PhyEx), are well-known treatments for metabolic syndrome (MetS), a cluster of metabolic and cardiovascular risk factors often associated to hypogonadism. Given the trophic role of testosterone on skeletal muscle (SkM), this study was aimed at evaluating the effects of testosterone treatment on SkM metabolism and exercise performance in male rabbits with high-fat diet (HFD)-induced MetS. HFD rabbits, treated or not with testosterone (30 mg/kg/week) for 12 weeks, were compared to regular diet animals (RD).

Co-carcinogenic effects of vitamin E in prostate.

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species.

Physical activity counteracts metabolic syndrome-induced hypogonadotropic hypogonadism and erectile dysfunction in the rabbit.

Metabolic syndrome (MetS) clusters cardiovascular and metabolic risk factors along with hypogonadism and erectile dysfunction. Lifestyle modifications including physical exercise (PhyEx) are well-known treatments for this condition. In this study, we analyzed the effect of PhyEx on hypothalamic-pituitary-testis axis and erectile function by use of an animal MetS model, previously established in rabbits fed a high-fat diet (HFD).

INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function.

The bile acid receptors, farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), regulate multiple pathways, including glucose and lipid metabolism. In a rabbit model of high-fat diet (HFD)-induced metabolic syndrome, long-term treatment with the dual FXR/TGR5 agonist INT-767 reduces visceral adipose tissue accumulation, hypercholesterolemia and nonalcoholic steatohepatitis. INT-767 significantly improves the hallmarks of insulin resistance in visceral adipose tissue (VAT) and induces mitochondrial and brown fat-specific markers.

Metabolic Syndrome in Male Hypogonadism.

Metabolic syndrome (MetS) and hypogonadism (HG) are frequently comorbid. In this review, we summarize interconnections between the construct of MetS and the presence of HG, as well as the effect of specific treatments for each condition on this association. Data from meta-analytic studies suggest a bidirectional pathogenic relationship.

Anti-fibrotic effects of chronic treatment with the selective FXR agonist obeticholic acid in the bleomycin-induced rat model of pulmonary fibrosis.

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model.

Differential Effects of Testosterone and Estradiol on Clitoral Function: An Experimental Study in Rats.

Introduction: Female sexual response is a complex phenomenon in which psychological, neurologic, and vascular mechanisms and hormonal factors interact. During the arousal phase, they cooperate to increase genital blood flow, thus inducing engorgement of the clitoris and lubrication of the vagina. Regulation of vascular and non-vascular smooth muscle tone is the crucial event in the erectile process.

Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension.

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury.

Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits.

Development of metabolically healthy adipocytes within dysfunctional adipose tissue may represent an attractive way to counteract metabolic syndrome (MetS). In an experimental animal model of high fat diet (HFD)-induced MetS, in vivo, long- and short-term tadalafil treatments were able to reduce visceral adipose tissue (VAT) accumulation and hypertriglyceridemia, and to induce the expression in VAT of the brown fat-specific marker, uncoupling protein 1 (UCP1). VAT preadipocytes (PAD), isolated from the tadalafil-treated HFD rabbits, showed: i) a multilocular morphology; ii) an increased expression of brown fat-specific genes (such as UCP1 and CIDEA); iii) improved mitochondrial structure and dynamic and reduced superoxide production; iv) improved insulin sensitivity.

Metabolic syndrome-associated sperm alterations in an experimental rabbit model: relation with metabolic profile, testis and epididymis gene expression and effect of tamoxifen treatment.

The influence of metabolic syndrome (MetS) on sperm quality and function is debated. Using a well-established high fat diet (HFD) rabbit model resembling human MetS, including development of hypogonadism, we demonstrate that HFD decreased sperm motility, morphology and acrosome reaction in response to progesterone and increased sperm cholesterol content. All the above parameters were associated with most MetS features, its severity and plasma testosterone (T) at univariate analysis.

Estrogen mediates metabolic syndrome-induced erectile dysfunction: a study in the rabbit.

Introduction: Estrogen receptor (ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood.

Aim: To investigate the effect of estrogens on metabolic syndrome (MetS)-associated erectile dysfunction (ED).

Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa.

Introduction: In subjects with erectile dysfunction responding poorly to sildenafil, metformin was reported to improve erections.

Aims: The aim of this study is to investigate metformin's mechanism of action on erectile function, particularly focusing on adenosine (ADO) and nitric oxide (NO) signaling in an animal model of high-fat diet (HFD)-induced metabolic syndrome.

Methods: In vitro contractility studies of penile strips.

Erectile dysfunction and central obesity: an Italian perspective.

Erectile dysfunction (ED) is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone (T) levels.

Tadalafil effect on metabolic syndrome-associated bladder alterations: an experimental study in a rabbit model.

Introduction: Metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) are often associated. Bladder detrusor hyper-contractility-a major LUTS determinant-is characterized by increased Ras homolog gene family, member A/Rho-associated protein kinase (RhoA/ROCK) signaling, which is often upregulated in MetS.

Aim: This study investigated the effects of tadalafil dosing on RhoA/ROCK signaling in bladder, in a rabbit model of high-fat diet (HFD)-induced MetS.

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit.

A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction.

Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits.

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. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6).