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Follicle-stimulating hormone (FSH) administration is applied in the management of subjects affected by hypogonadotropic hypogonadism. Whilst this application is widely recognized and established alone or in combination with human chorionic gonadotropin (hCG), a similar strategy is empirically advocated in idiopathic male factor infertility (MFI). In this setting, FSH therapy has been used to increase sperm quantity, quality, and pregnancy rate when FSH plasma concentrations are below 8 IU/L and when the seminal tract is not obstructed. In the literature, several studies suggested that giving FSH to patients with idiopathic MFI increases sperm count and motility, raising the overall pregnancy rate. However, this efficacy seems to be limited, and about 10–18 men should be treated to achieve one pregnancy. Thus, several papers suggest the need to move from a replacement approach to an overstimulating approach in the management of FSH therapy in idiopathic MFI. To this aim, it is imperative to determine some pharmacologic markers of FSH efficacy. Furthermore, it should be useful in clinical practice to distinguish, before starting the treatment, among patients who might respond or not to FSH treatment. Indeed, previous studies suggest that infertile men who have normal levels of gonadotropins in plasma might not respond to FSH treatment and about 50% of patients might be defined as “non-responders”. For these reasons, identifying predictive markers of FSH action in spermatogenesis and clinical markers of response to FSH treatment is a fascinating area of study that might lead to new developments with the aim of achieving personalization of the treatment of male infertility. From this perspective, seminal parameters (i.e., spermatid count), testicular cytology, genetic assessment, and miRNA or protein markers in the future might be used to create a tailored FSH therapy plan. The personalization of FSH treatment is mandatory to minimize side effects, to avoid lost time with ineffective treatments, and to improve the efficacy, predicting the most efficient dose and the duration of the treatment. This narrative review’s objective is to discuss the role of the different putative factors which have been proposed to predict the response to FSH treatment in idiopathic infertile men.

In recent years, several studies have analyzed the composition of the male genital tract microbiota and its changes in infertility or in different situations associated with infertility. The aim of this narrative review is to obtain more insight on this topic; in particular, to describe actual evidence about changes in the semen microbiota in patients with infertility, male tract infections, or HPV infections. In semen, an increase in semen Prevotella spp. is associated with oligozoospermia and with obesity-associated asthenozoospermia; an increase in Pseudomonas is more frequently associated with asthenozoospermia and oligozoospermia; a reduction in Lactobacilli spp. (namely in Lactobacillus crispatus) may represent a marker of low semen quality. However, an increase in Lactobacillus iners is considered a risk factor for a reduced sperm concentration. In patients with prostatitis, there is a reduction in Lactobacillus spp. and an increase in Streptococcus spp., opening important perspectives about the role of probiotic treatments in these patients. Finally, an increase in Fusobacteria spp. was observed in patients with an HPV infection. In the conclusion, we underline the interactions between the seminal and vaginal microbiota, so that further studies should focus on the “couple genital microbiota”.

Cold recycling techniques in road construction have been of rising interest because of huge environmental benefits in terms of energy saving, emission reduction, and preservation of natural resources. The improvement on selection and quality of the raw materials and binders as well as the enhancement of the knowledge on mixture performance are leading to the intensive use of cold recycling techniques in place of traditional ones. One of the main differences between cold and hot techniques is the evolutive development of performance, generally identified as curing process, due to the presence of water and hydraulic binders in the cold mixtures. Environmental-related factors such as temperature, humidity, wind, and rainfall significantly influence the curing process and, as consequence, the mixture properties over time. Several laboratory curing protocols have been developed by universities, research centers, and agencies, but a clear relationship between simulative procedures in laboratory and the field is still an open challenge. This paper aims at characterizing the short-term and midterm curing behavior of a cold recycled material (CRM) mixture. A CRM mixture was selected and characterized in laboratory, and the in-plant production procedure was validated. The CRM mixture was used to build the binder course of an instrumented pavement in the Republic of San Marino. Volumetric and mechanical testing on laboratory-produced specimens and cores were analyzed considering the temperature and moisture sensor measurements in field. Results address to a new insight for laboratory procedures and prediction models matching laboratory conditions and the real curing condition in field.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is defined as urologic pain or discomfort in the pelvic region, associated with urinary symptoms and/or sexual dysfunction, lasting for at least 3 of the previous 6 months. The rate of symptoms related to prostatitis has a mean prevalence of 8–8.2%. CP/CPPS is most frequent in men younger than 50 years, among whom it is the most common urologic diagnosis. In the last decades, many studies have been published on CP/CPPS and its association with male infertility. The pathophysiologic relation between CP/CPPS and male infertility involves several aspects, which are not well studied yet. A reduction in semen parameters has been demonstrated in patients with CP/CPPS, and several mechanisms have been proposed to represent putative pathophysiological links between CP/CPPS and infertility, including male accessory gland inflammation, metabolic syndrome, inflammatory bowel disease, HPV co-infection and autoimmunity. In light of this evidence, a multidisciplinary approach is advocated for patients with known CP/CPPS, and particular attention is needed for male patients of infertile couples in order to evaluate male accessory glands correctly. In addition, it is advisable that future studies dealing with the treatment of CP/CPPS take into consideration all the different pathophysiological aspects implicated.

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

Unacylated ghrelin (UnGhr) exerts several beneficial actions on vascular function. The aim of this study was to assess the effects of UnGhr on high-fat induced endothelial dysfunction and its underlying mechanisms. Thoracic aortas from transgenic mice, which were overexpressing UnGhr and being control fed either a standard control diet (CD) or a high-fat diet (HFD) for 16 weeks, were harvested and used for the assessment of vascular reactivity, endothelial nitric oxide synthase (eNOS) expression and activity, thiobarbituric acid reactive substances (TBARS) and glutathione levels, and aortic lipid accumulation by Oil Red O staining. Relaxations due to acetylcholine and to DEA-NONOate were reduced (p < 0.05) in the HFD control aortas compared to vessels from the CD animals. Overexpression of UnGhr prevented HFD-induced vascular dysfunction, while eNOS expression and activity were similar in all vessels. HFD-induced vascular oxidative stress was demonstrated by increased (p < 0.05) aortic TBARS and glutathione in wild type (Wt) mice; however, this was not seen in UnGhr mice. Moreover, increased (p < 0.05) HFD-induced lipid accumulation in vessels from Wt mice was prevented by UnGhr overexpression. In conclusion, chronic UnGhr overexpression results in improved vascular function and reduced plaque formation through decreased vascular oxidative stress, without affecting the eNOS pathway. This research may provide new insight into the mechanisms underlying the beneficial effects of UnGhr on the vascular dysfunction associated with obesity and the metabolic syndrome.

Phosphomannomutase-2 (PMM2) deficiency represents the most common congenital disorder of glycosylation (CDG). Currently, little is known about cell metabolic alterations occurring in these patients. Here, we quantified compounds connected to protein glycosylation (GDP-mannose, UDP-derivatives), energy metabolism (high-energy phosphates, nicotinic coenzymes, oxypurines), oxidative/nitrosative stress (GSH, nitrite, nitrate) and free amino acids in extracts of peripheral blood mononucleated cells (PBMCs), of seven PMM2-CDG patients and ten control healthy donors. Besides marked GDP-mannose decrease, PBMCs of PMM2-CDG patients had higher UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal) and UDP-Glucuronic levels, lower ATP, GTP and UTP levels, abnormal ATP/ADP, ATP/AMP and NAD + /NADH ratios, increased xanthine, uric acid and nitrite + nitrate levels, and decreased GSH and free amino acids concentrations. These results suggest a new, conceivable metabolic route leading to the increase of specific UDP-derivatives (UDP-Glc, UDP-Gal and UDP-Glucuronic), also potentially explaining the glycogen abnormalities recently found in PMM2-CDG patients. Altogether, this study highlighted various metabolic changes caused by PMM2 deficiency, illustrating the widespread effects of PMM2 mutations (beyond N-glycan biosynthesis) that may significantly vary depending on the cell line considered. Using PBMCs, as a cellular model of lower invasiveness than skin fibroblast, may advantage cell metabolism studies to investigate new therapies specifically targeted to PMM2 deficiency.

Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy. Cell-based screening assays allow functional testing of chemicals but do not mimic the in vivo situation well. Here, the authors report a method for the discovery of secreted cytoprotective factors in mice and use it to demonstrate that the hormone ghrelin protects cardiac muscle from ischaemic damage.

Male tract infections (MTIs) are a common clinical condition, often presenting without any signs nor symptoms of disease. As advised by the European Urology Guidelines dealing with this topic, patients are typically treated with antibiotics alone. Nevertheless, in between 40% and 50% of cases, antibiotic therapy is not effective in eradicating the semen infection. Therefore, persistent semen infection is frequently found upon semen culture evaluation following antibiotic therapy. In this study, we aimed to analyze the fecal microbiota of male infertile patients with persistent MTI in order to verify the prevalence of gut dysbiosis in these patients. We therefore enrolled 20 infertile patients with persistent MTIs after a proper cycle of antibiotic treatment. All patients performed the study for gut microbiota analysis after about 30 days after the last dose of antibiotic treatment. Gut microbiota analysis revealed that 50% of patients with persistent MTI presented a reduction in microbial biodiversity. Indeed, a situation of gut dysbiosis was reported in 75% of patients. In details, the Firmicutes–Bacteroidetes ratio was reduced in 70% of such patients, including 40% of patients where a severe reduction was observed due to an elevated abundance of Bacteroidetes (putrefactive dysbiosis). The most frequent enterotype was Prevotella-dominant (43%). We demonstrated for the first time that patients with recurrent MTIs have enterotypes associated with increased gut permeability and systemic inflammation. Further studies are required to analyze the molecular machinery by which gut dysbiosis exerts its role in patients with MTIs, in particular persistent MTIs, and how supplementation with probiotics might impact in terms of restoring eubiosis, in terms of eradicating the infection, and reducing prostate inflammation and eventually in terms of improving semen evaluation in male infertile patients.

Although precision medicine took its first steps from genomic medicine, it has gone far beyond genomics, considering the full complexity of cellular physiology. Therefore, the present time can be considered as the “post-genomic era”. In detail, proteomics captures the overall protein profile of an analyzed sample, whilst metabolomics has the purpose of studying the molecular aspects of a known medical condition through the measurement of metabolites with low molecular weight in biological specimens. In this review, the role of post-genomic platforms, namely proteomics and metabolomics, is evaluated with a specific interest in their application for the identification of novel biomarkers in male hypogonadism and in the identification of new perspectives of knowledge on the pathophysiological function of testosterone. Post-genomic platforms, including MS-based proteomics and metabolomics based on ultra-high-performance liquid chromatography-HRMS, have been applied to find solutions to clinical questions related to the diagnosis and treatment of male hypogonadism. In detail, seminal proteomics helped us in identifying novel non-invasive markers of androgen activity to be translated into clinical practice, sperm proteomics revealed the role of testosterone in spermatogenesis, while serum metabolomics helped identify the different metabolic pathways associated with testosterone deficiency and replacement treatment, both in patients with insulin sensitivity and patients with insulin resistance.