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Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industrial and consumer products. The environmental spreading of PFASs raises concerns for their impact on ...human health. In particular, the bioaccumulation in humans due to environmental exposure has been reported also in total brain samples and PFAS exposure has been associated with neurodevelopmental disorders. In this study we aimed to investigate the specific PFAS bioaccumulation in different brain areas. Our data reported major accumulation in the brainstem region, which is richly populated by dopaminergic neurons (DNs), in brain autopsy samples from people resident in a PFAS-polluted area of Italy.
Since DNs are the main source of dopamine (DA) in the mammalian central nervous system (CNS), we evaluated the possible functional consequences of perfluoro-octanoic acid (PFOA) exposure in a human model of DNs obtained by differentiation of human induced pluripotent stem cells (hiPSCs). Particularly, we analyzed the specific effect of the exposure to PFOA for 24 h, at the concentration of 10 ng/ml, at 3 different steps of dopaminergic differentiation: the neuronal commitment phase (DP1), the neuronal precursor phase (DP2) and the mature dopaminergic differentiation phase (DP3). Interestingly, compared to untreated cells, exposure to PFOA was associated with a reduced expression of Tyrosine Hydroxylase (TH) and Neurofilament Heavy (NFH), both markers of dopaminergic maturation at DP2 phase. In addition, cells at DP3 phase exposed to PFOA showed a severe reduction in the expression of the Dopamine Transporter (DAT), functionally involved in pre-synaptic dopamine reuptake.
In this proof-of-concept study we show a significant impact of PFOA exposure, mainly on the most sensitive stage of neural dopaminergic differentiation, prompting the way for further investigations more directly relevant to risk assessment of these chemicals.
The molecular bases of sperm thermotaxis, the temperature-oriented cell motility, are currently under investigation. Thermal perception relies on a subclass of the transient receptor potential TRP ...channels, whose member TRPV1 is acknowledged as the heat sensing receptor. Here we investigated the involvement of TRPV1 in human sperm thermotaxis. We obtained semen samples from 16 normozoospermic subjects attending an infertility survey programme, testis biopsies from 6 patients with testicular germ cell cancer and testis fine needle aspirates from 6 patients with obstructive azoospermia undergoing assisted reproductive technologies. Expression of TRPV1 mRNA was assessed by RT-PCR. Protein expression of TRPV1 was determined by western blot, flow cytometry and immunofluorescence. Sperm motility was assessed by Sperm Class Analyser. Acrosome reaction, apoptosis and intracellular-Ca2+ content were assessed by flow cytometry. We found that TRPV1 mRNA and protein were highly expressed in the testis, in both Sertoli cells and germ-line cells. Moreover, compared to no-gradient controls at 31°C or 37°C (Ctrl 31°C and Ctrl 37°C respectively), sperm migration towards a temperature gradient of 31-37°C (T gradient) in non-capacitated conditions selected a higher number of cells (14,9 ± 4,2×106 cells T gradient vs 5,1± 0,3×106 cells Ctrl 31°C and 5,71±0,74×106 cells Ctrl 37°C; P = 0,039). Capacitation amplified the migrating capability towards the T gradient. Sperms migrated towards the T gradient showed enriched levels of both TRPV1 protein and mRNA. In addition, sperm cells were able to migrate toward a gradient of capsaicin, a specific agonist of TRPV1, whilst capsazepine, a specific agonist of TRPV1, blocked this effect. Finally, capsazepine severely blunted migration towards T gradient without abolishing. These results suggest that TRPV1 may represent a facilitating mediator of sperm thermotaxis.
OBJECTIVE: To evaluate prevalence, association, and clearance of human papillomavirus (HPV) and antisperm antibodies (ASAs) in infected semen samples from infertile patients. DESIGN: Cross-sectional ...clinical study. SETTING: Andrology and microbiology sections at a university hospital. PATIENT(S): Three groups of subjects: 61 infertile patients with HPV semen infection, 104 noninfected infertile subjects, and 92 control subjects. INTERVENTION(S): Semen analysis, spermMar test, fluorescence in situ hybridization for sperm aneuploidy and for HPV, and immunofluorescence for HPV 16-L1 and immunoglobulins (IgA, IgG, and IgM) determination. MAIN OUTCOME MEASURE(S): Association of sperm procedures, HPV sperm infection, sperm aneuploidies, and sperm ASAs. RESULT(S): Infertile patients with HPV semen infection showed high percentages of ASAs. In these patients HPV sperm infection was associated with lower sperm motility, which was worse in subjects with ASAs. No alterations of sperm chromosomes were observed. To obtain a significant clearance of both HPV sperm infection and ASAs at least 24 months of follow-up were needed. CONCLUSION(S): Human papillomavirus has been recently suggested to have an important role in male infertility. This study demonstrated that HPV sperm infection can be long lasting and frequently associated with ASAs that may further reduce male fertility. Infertile patients with positive spermMar test results should be considered for investigation for HPV, especially if they are candidates for assisted reproduction.
Background: Weight control through lifestyle interventions represents a suitable strategy to avoid the metabolic, endocrine, and reproductive comorbidities associated with overweight and obesity. ...Reduced testosterone (T) levels are a worsening factor in overweight males. However, prognostic parameters of long-term weight loss are not readily available. Here, we tested the prognostic value of early variations of anthropometric and hormonal parameters, with a focus on ultrasound stratigraphy (US) and the reduction in body mass index (BMI) associated with nutritional counseling/lifestyle interventions at 6-month follow-up. Methods: Ninety-five male subjects (BMI 25–34.9 kg/m 2 ) who had undergone nutritional/lifestyle interventions, were retrospectively analyzed for: body weight and composition; US evaluation at the triceps (TRC), abdominal (ABD), and thigh (THI) areas; and circulating levels of T, luteinizing hormone, and follicle-stimulating hormone. Sixty patients (63.2%) completed the 6-month follow-up program. Results: At 6 months, a significant reduction in BMI (26.38 ± 1.55 vs. 31.5 ± 5.0 basal, p < 0.001) and increase in T levels (18 ± 5.4 vs. 9.5 ± 2.3 nmol/L basal, p = 0.04) were observed. Subjects in the highest quartile of the BMI reduction at 6 months (ΔBMI 6 mo), compared to the lowest, showed a significant difference at the 2-month follow-up variation of BMI (p = 0.025), and fat and muscle thickness at the TRC (both p < 0.001) and ABD (p < 0.001 and p = 0.002, respectively) areas. Variation of TRC muscle thickness at 2 months was the only independent predictor of ΔBMI 6 mo in the multiple stepwise regression analysis. Conclusions: BMI evaluation and US represent useful monitoring tools in the follow-up of nutritional/lifestyle interventions for overweight-to-mildly obese patients. The important effects on motivation and adherence to the intervention program are to be considered.
Skeletal muscles and bones form a joined functional unit sharing a complex mechanical, biochemical and hormonal crosstalk. A number of factors, including sex hormones, physiologically regulate the ...musculoskeletal system. Striking gender differences in muscle and bone mass, and function are mainly caused by distinct actions exerted by oestrogens and androgens. However, relaxin and relaxin‐related peptides, such as insulin‐like peptide 3 (INSL3), might contribute to these sex‐associated differences in physiological and pathological conditions (such as osteoporosis and sarcopenia). Relaxin is a ‘pregnancy’ hormone, but it is also produced from the prostate gland, and has recently attracted attention as a potential drug for cardiovascular disorders and fibrosis. In contrast, INSL3 is a male‐specific hormone produced by the Leydig cells of the testis with a fundamental role in testicular descent during fetal life. Recent evidence suggests that both hormones have interesting roles in the musculoskeletal system. Relaxin and INSL3, by finely tuning bone formation and resorption, are involved in bone remodelling processes, and relaxin contributes to the healing of injured ligaments and promotes skeletal muscle regeneration. Here, we review the most recent findings on the effects of relaxin and INSL3 on skeletal muscle and the cell components of bone. In the light of the experimental evidence available and animal models, their clinical implications are also discussed.
Linked Articles
This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc
From seminal evidence in the early 2000s, the opportunity to drive the specific knockdown of a protein of interest (POI) through pharmacological entities called Proteolysis Targeting Chimeric ...molecules, or PROTACs, has become a possible therapeutic option with the involvement of these compounds in clinical trials for cancers and autoimmune diseases. The fulcrum of PROTACs pharmacodynamics is to favor the juxtaposition between an E3 ligase activity and the POI, followed by the ubiquitination of the latter and its degradation by the proteasome system. In the face of an apparently modular design of these drugs, being constituted by an E3 ligase binding moiety and a POI-binding moiety connected by a linker, the final structure of an efficient PROTAC degradation enhancer often goes beyond the molecular descriptors known to influence the biological activity, specificity, and pharmacokinetics, requiring a rational improvement through appropriate molecular strategies. Starting from the description of the basic principles underlying the activity of the PROTACs to the evaluation of the strategies for the improvement of pharmacodynamics and pharmacokinetics and rational design, this review examines the molecular elements that have been shown to be effective in allowing the evolution of these compounds from interesting proof of concepts to potential aids of clinical interest.
Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid
, among others. Since its approval in the early 80s, GEM has been largely applied ...to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free, active concentration of some co-administered drugs, leading to adverse effects. Most of them appear to be related to the ability of GEM to bind with high affinity human serum albumin (HSA), the major drug-carrier protein in blood plasma. Here, we report the crystal structure of HSA in complex with GEM. Two binding sites have been identified, namely Sudlow's binding sites I (FA7) and II (FA3-FA4). A comparison of the crystal structure of HSA in complex with GEM with those of other previously described HSA-drug complexes enabled us to appreciate the analogies and differences in their respective binding modes. The elucidation of the molecular interaction between GEM and HSA might offer the basis for the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, enabling augmented therapeutic efficacies.
Abstract
Infection by human papillomavirus (HPV) represents one of the most common sexually transmitted diseases in both men and women worldwide. Recently, the detection of HPV virions in the semen ...of a large percentage of sexually active men has been associated with detrimental effects on both sperm parameters and on assisted reproductive technologies (ART) treatment outcomes. Conventional semen washing procedure used in ART have proved to be ineffective in removing HPV bound to sperm, requiring the identification of more effective and specific methods.
In the present study, we assessed the possible use of hyaluronidase for the detachment of HPV from sperm cell surface. Semen samples from five normozoospermic control subjects (CTRL) were incubated with HPV virus-like particles (HPV-VLP) and treated with hyaluronidase by both a modified swim-up procedure (M-SU) and single-cell approach (SCA). The treatment with hyaluronidase was associated with the complete loss of HPV-VLP signal on sperms by both M-SU and SCA. In addition, semen samples from 12 HPV-positive infertile patients were treated with hyaluronidase 80 IU/mL by M-SU, resulting in the complete loss of HPV-DNA signal from sperm surface.
Finally, the possible impact of hyaluronidase treatment on sperm parameters was assessed on both sperms from the five CTRL subjects and on further five oligo-astheno-terato-zoospermic (OAT) patients, both HPV negative. The treatment with hyaluronidase was equally associated with a slight reduction of sperm viability and progressive motility in both CTRL and OAT. In conclusion, the treatment with hyaluronidase removed efficiently and safely HPV virions bound to spermatozoa.
Summary Sentence The treatment of semen with hyaluronidase associates with total removal of HPV virions bound to spermatozoa, suggesting possible application in assisted reproduction techniques.
Infertility is an important health problem that affects up to 16% of couples worldwide. Male infertility is responsible for about 50% of the cases, and the various causes of male infertility may be ...classified in pre-testicular (for example hypothalamic diseases), testicular, and post-testicular (for example obstructive pathologies of seminal ducts) causes. Sexually transmitted infections (STI) are increasingly widely accepted by researchers and clinicians as etiological factors of male infertility. In particular, several recent reports have documented the presence of HPV in seminal fluid and observed that sperm infection can also be present in sexually active asymptomatic male and infertile patients. In this review, we aimed to perform a systematic review of the whole body of literature exploring the impact of HPV infection in natural and assisted fertility outcomes, from both an experimental and a clinical point of view. Starting from
studies in animals up to
studies in humans, we aimed to study and evaluate the weight of this infection as a possible cause of idiopathic infertility in males with any known cause of conception failure.
•Exposure to legacy PFAS associates with endocrine disruption and health concerns.•Legacy PFOA was demonstrated to increase basal platelet pro-aggregation profile.•Supposed with a lower accumulation ...profile, novel C6O4 is expected to be with safer.•C6O4 equally accumulates on platelets membrane likely altering their properties.•C6O4 increases in vitro platelets aggregation profile and micro-particles production.
Health concerns associated with the exposure to legacy perfluoro-alkyl substances (PFAS) led to the development of new-generation PFAS, such as C6O4. Here we investigated the possible effects of C6O4 on the platelet’s activation profile, by incubating human platelets from healthy donors with C6O4 at different concentrations and evaluating the effects on activation, production and phenotype of platelets micro-particles (MPV) and aggregation under-flow. Based on the eventual platelet pro-aggregation profile detected, the preventive effect of acetylsalicylic acid (ASA) was also explored.
Adhesion-induced platelet aggregation of platelet rich plasma (PRP) under flow was evaluated on collagen-coated microchip at a shear stress of 10 Dyne. The turbidimetric method was used to investigate platelet aggregation. Finally, the in vitro generation of pro-coagulant MPV in PRP was evaluated by flow cytometry, as characterized by CD41 and annexin V positive events, under resting conditions and after stimulation with agonists at low shear stress.
The generation of platelet aggregates under flow was significantly increased by the pretreatment of PRP with 100–200 ng/mL C6O4, compared to both the control condition and the experiment performed in presence of ASA. Arachidonic acid (AA), ADP and collagen induced an higher maximal aggregation, at turbidimetric evaluation, when PRP was pretreated with 100–500 ng/mL C6O4. In addition, PRP stimulated with AA also showed a steeper slope of the aggregation curve. The aggregation induced by the tested agonists was almost abolished by ASA. Finally, pretreatment with C6O4 increased the number of MPV in resting conditions and in presence of ADP and TRAP. ASA tended to reduce MPV generation.
Exposure to C6O4 associates with an increased platelet response to agonists, translating into a possible increased risk of cardiovascular events. Pending a further clarification on the toxicokinetics of this compound, our results claim the possible prophylactic use of ASA.
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