Effects of Fitlight training on cognitive-motor performance in élite judo athletes.

Aims: The aims of this study were to verify if a 5-week cognitive-motor training (CMT) using FitlightsTM induced changes in young adult judo athletes compared to a non-intervention group. Specifically, it was verified if CMT influenced executive functions (EFs), physical fitness and brain-derived neurotrophic factor (BDNF) levels. Additionally, athletes' competitive results were compared between groups. Method: Twenty-seven athletes (14 males and 13 females; age = 19.5 ± 2.0 years) were assigned to the Fitlight (FG) and control (CG) groups which performed 5 weeks of CMT, respectively, including 25 min per day of Fitlight training or traditional judo practice. All participants performed cognitive (flanker task and forward/backward digit span) and fitness tests (counter movement jump, handgrip test, dynamic and isometric chin up). In addition, BDNF was collected by saliva sampling and competitive results after the intervention period were considered. Results: RM-ANOVA showed significant differences in FG for the accuracy of flanker (p = 0.028) and backward digit span (p < 0.001). Moreover, significant differences in FG were found for relative dynamic chin up (p = 0.027) and counter movement jump (p = 0.05). In addition, a significant difference in FG was found for competitive results after the intervention period (p < 0.01).No significant differences were found for BDNF and other cognitive and fitness measures (p > 0.05). Conclusion: A 5-week judo-specific CMT improved EFs and motor performance in élite judo athletes. It seems that CMT with Fitlight™ could be considered an additional support to coaches during the training period.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro.

PURPOSE: Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. METHODS: C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. RESULTS: The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. CONCLUSIONS: Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

Refracture following vertebral fragility fracture when bone fragility is not recognized: summarizing findings from comparator arms of randomized clinical trials.

PURPOSE: Since vertebral fragility fractures (VFFs) might increase the risk of subsequent fractures, we evaluated the incidence rate and the refracture risk of subsequent vertebral and non-vertebral fragility fractures (nVFFs) in untreated patients with a previous VFF. METHODS: We systematically searched PubMed, Embase, and Cochrane Library up to February 2022 for randomized clinical trials (RCTs) that analyzed the occurrence of subsequent fractures in untreated patients with prior VFFs. Two authors independently extracted data and appraised the risk of bias in the selected studies. Primary outcomes were subsequent VFFs, while secondary outcomes were further nVFFs. The outcome of refracture within ≥ 2 years after the index fracture was measured as (i) rate, expressed per 100 person-years (PYs), and (ii) risk, expressed in percentage. RESULTS: Forty RCTs met our inclusion criteria, ranging from medium to high quality. Among untreated patients with prior VFFs, the rate of subsequent VFFs and nVFFs was 12 [95% confidence interval (CI) 9-16] and 6 (95% CI 5-8%) per 100 PYs, respectively. The higher the number of previous VFFs, the higher the incidence. Moreover, the risk of VFFs and nVFFs increased within 2 (16.6% and 8%) and 4 years (35.1% and 17.4%) based on the index VFF. CONCLUSION: The highest risk of subsequent VFFs or nVFFs was already detected within 2 years following the initial VFF. Thus, prompt interventions should be designed to improve the detection and treatment of VFFs, aiming to reduce the risk of future FFs and properly implement secondary preventive measures.

The integrated structure of care: evidence for the efficacy of models of clinical governance in the prevention of fragility fractures after recent sentinel fracture after the age of 50 years.

Randomized clinical trials and observational studies on the implementation of clinical governance models, in patients who had experienced a fragility fracture, were examined. Literature was systematically reviewed and summarized by a panel of experts who formulated recommendations for the Italian guideline. PURPOSE: After experiencing a fracture, several strategies may be adopted to reduce the risk of recurrent fragility fractures and associated morbidity and mortality. Clinical governance models, such as the fracture liaison service (FLS), have been introduced for the identification, treatment, and monitoring of patients with secondary fragility fractures. A systematic review was conducted to evaluate the association between multidisciplinary care systems and several outcomes in patients with a fragility fracture in the context of the development of the Italian Guidelines. METHODS: PubMed, Embase, and the Cochrane Library were investigated up to December 2020 to update the search of the Scottish Intercollegiate Guidelines Network. Randomized clinical trials (RCTs) and observational studies that analyzed clinical governance models in patients who had experienced a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random-effects models. Primary outcomes were bone mineral density values, antiosteoporotic therapy initiation, adherence to antiosteoporotic medications, subsequent fracture, and mortality risk, while secondary outcomes were quality of life and physical performance. RESULTS: Fifteen RCTs and 62 observational studies, ranging from very low to low quality for bone mineral density values, antiosteoporotic initiation, adherence to antiosteoporotic medications, subsequent fracture, mortality, met our inclusion criteria. The implementation of clinical governance models compared to their pre-implementation or standard care/non-attenders significantly improved BMD testing rate, and increased the number of patients who initiated antiosteoporotic therapy and enhanced their adherence to the medications. Moreover, the treatment by clinical governance model respect to standard care/non-attenders significantly reduced the risk of subsequent fracture and mortality. The integrated structure of care enhanced the quality of life and physical function among patients with fragility fractures. CONCLUSIONS: Based on our findings, clinicians should promote the management of patients experiencing a fragility fracture through structured and integrated models of care. The task force has formulated appropriate recommendations on the implementation of multidisciplinary care systems in patients with, or at risk of, fragility fractures.

A systematic review on the performance of fracture risk assessment tools: FRAX, DeFRA, FRA-HS.

PURPOSE: Preventing fragility fractures by treating osteoporosis may reduce disability and mortality worldwide. Algorithms combining clinical risk factors with bone mineral density have been developed to better estimate fracture risk and possible treatment thresholds. This systematic review supported panel members of the Italian Fragility Fracture Guidelines in recommending the use of best-performant tool. The clinical performance of the three most used fracture risk assessment tools (DeFRA, FRAX, and FRA-HS) was assessed in at-risk patients. METHODS: PubMed, Embase, and Cochrane Library were searched till December 2020 for studies investigating risk assessment tools for predicting major osteoporotic or hip fractures in patients with osteoporosis or fragility fractures. Sensitivity (Sn), specificity (Sp), and areas under the curve (AUCs) were evaluated for all tools at different thresholds. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2; certainty of evidence (CoE) was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Forty-three articles were considered (40, 1, and 2 for FRAX, FRA-HS, and DeFRA, respectively), with the CoE ranging from very low to high quality. A reduction of Sn and increase of Sp for major osteoporotic fractures were observed among women and the entire population with cut-off augmentation. No significant differences were found on comparing FRAX to DeFRA in women (AUC 59-88% vs. 74%) and diabetics (AUC 73% vs. 89%). FRAX demonstrated non-significantly better discriminatory power than FRA-HS among men. CONCLUSION: The task force formulated appropriate recommendations on the use of any fracture risk assessment tools in patients with or at risk of fragility fractures, since no statistically significant differences emerged across different prediction tools.

Which physical activity in patients affected by hypoparathyroidism? A review of the literature and practical recommendations.

BACKGROUND: Hypoparathyroidism (HypoP) is a rare endocrine condition characterized by hypocalcaemia and hyperphosphatemia, as a consequence of absent or improperly low parathyroid hormone (PTH) levels. Patients affected by HypoP have a clinical condition often characterized by paresthesias and muscle spasms, as well as long-term consequences as nephrolithiasis, extraskeletal calcification, and fractures. In the literature, likely due to these symptoms, few data exist regarding the appropriate physical activity (PA) in subjects suffering from HypoP. PURPOSE: This review evaluates the literature on exercise-based approaches to the management of individuals affected by HypoP and evaluates: (1) the effects of physical exercise on muscle cramps and other clinical symptoms; (2) the effects of exercise on PTH and calcium level; (3) the most suitable clinical exercise testing; and (4) the most suitable exercise combination. METHODS AND RESULTS: A systematic search was conducted using the databases MEDLINE, Google Scholar using "hypoparathyroidism AND Physical Activity", "Training AND hypoparathyroidism", "Exercise AND muscle cramps", "Exercise AND Fatigue" as keywords. In addition, references list from the included articles were searched and cross-checked to identify any further potentially eligible studies. A total of 50 manuscripts were found among which 39 manuscripts were selected. A few clinical studies have been performed in HypoP patients to evaluate PA training protocols. CONCLUSION: Although further research is needed to draw solid conclusions regarding best PA protocols in subjects affected by HypoP, a PA protocol has been proposed within the manuscript to encourage patients to attempt exercise to improve their clinical conditions and their quality of life.

The endocrine disruptor cadmium: a new player in the pathophysiology of metabolic diseases.

Cadmium (Cd), a highly toxic heavy metal, is found in soil, environment and contaminated water and food. Moreover, Cd is used in various industrial activities, such as electroplating, batteries production, fertilizers, while an important non-occupational source is represented by cigarette smoking, as Cd deposits in tobacco leaves. Since many years it is clear a strong correlation between Cd body accumulation and incidence of many diseases. Indeed, acute exposure to Cd can cause inflammation and affect many organs such as kidneys and liver. Furthermore, the attention has focused on its activity as environmental pollutant and endocrine disruptor able to interfere with metabolic and energy balance of living beings. Both in vitro and in vivo experiments have demonstrated that the Cd-exposure is related to metabolic diseases such as obesity, diabetes and osteoporosis even if human studies are still controversial. Recent data show that Cd-exposure is associated with atherosclerosis, hypertension and endothelial damage that are responsible for cardiovascular diseases. Due to the large environmental diffusion of Cd, in this review, we summarize the current knowledge concerning the role of Cd in the incidence of metabolic and cardiovascular diseases.

Tissue and circulating microRNAs as biomarkers of response to obesity treatment strategies.

BACKGROUND: Obesity, characterized by an increased amount of adipose tissue, is a metabolic chronic alteration which has reached pandemic proportion. Lifestyle changes are the first line therapy for obesity and a large variety of dietary approaches have demonstrated efficacy in promoting weight loss and improving obesity-related metabolic alterations. Besides diet and physical activity, bariatric surgery might be an effective therapeutic strategy for morbid obese patients. Response to weight-loss interventions is characterised by high inter-individual variability, which might involve epigenetic factors. microRNAs have critical roles in metabolic processes and their dysregulated expression has been reported in obesity. AIM: The aim of this review is to provide a comprehensive overview of current studies evaluating changes in microRNA expression in obese patients undergoing lifestyle interventions or bariatric surgery. RESULTS: A considerable number of studies have reported a differential expression of circulating microRNAs before and after various dietary and bariatric surgery approaches, identifying several candidate biomarkers of response to weight loss. Significant changes in microRNA expression have been observed at a tissue level as well, with entirely different patterns between visceral and subcutaneous adipose tissue. Interestingly, relevant differences in microRNA expression have emerged between responders and non-responders to dietary or surgical interventions. A wide variety of dysregulated microRNA target pathways have also been identified, helping to understand the pathophysiological mechanisms underlying obesity and obesity-related metabolic diseases. CONCLUSIONS: Although further research is needed to draw firm conclusions, there is increasing evidence about microRNAs as potential biomarkers for weight loss and response to intervention strategies in obesity.

Role of vitamin K2 in bone metabolism: a point of view and a short reappraisal of the literature.

Vitamin K2 (vit K2) belongs to a large group of fat-soluble compounds whose formulation is MK (menaquinone) (MK-2 to MK-14), that seem to be involved in different biological functions. In particular, vit K2 has been recently recognized as efficacious and safe in treatment of bone loss, as it contributes to structural integrity of osteocalcin (OC), the major non-collagenous protein typically found in bone matrix. Several studies proved low vit K2 intake is linked to bone loss and to increased fracture risk in both sexes. Nowadays, vit K2 supplementation is considered a significant manner to enhance the association of calcium and vitamin D whose role on bone health is largely recognized. On the other hand, vit K2 may be used alone or with other drugs to preserve bone quality/strength from skeletal degradation after menopause and/or in patients affected by secondary osteoporosis. In this paper, we review the most recent data about vit K2 on skeleton.

Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE).

BACKGROUND: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. PURPOSE: We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect.

BACKGROUND: Cadmium (Cd) is a widespread environmental pollutant that causes alterations in human health acting as endocrine disruptor. Recent data suggest that cardiovascular system might be a contamination target tissue, since Cd is found in atheromatic plaques. Thus, the purpose of this study was to evaluate the consequence of Cd exposure of endothelial cells in vitro to evaluate detrimental effect in vascular system by a potential sex-steroid hormone receptor-dependent mechanism(s). METHODS: To this aim, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured and exposed to several concentrations of cadmium chloride (CdCl2) for different interval times. RESULTS: CdCl2 exposure of HUVECs induced a significant increase of ERß and Cyp19a1 at both mRNA and protein levels, while a drastic dose-dependent decrease of AR expression level was observed after 24 h of exposure. On the contrary, an increase of PhARser308 as well as a reduction of PhGSK-3ßser9 and PhAKTser473 was detected after 1 h treatment. This effect was consistently reduced by GSK inhibition. Furthermore, CdCl2 abolished DHT-induced cell proliferation in HUVECs suggesting an antagonist-like effect of Cd on AR-mediated signaling. Remarkable, after 6 h CdCl2-treatment, a relevant increase in TNF-α, IL-6 and IL-8 mRNA was observed and this effect was blocked by the presence of an ERß-selective antagonist. Moreover, Cd-induced TxR1 overexpression, likely, correlated with the activation of p38 MAPK/NF-κB pathway. CONCLUSION: In conclusion, our study demonstrates for the first time that Cd alters sex-steroid hormone receptors level and activity likely affecting intracellular signaling linked to a proinflammatory state in endothelial cells. This alteration might possibly lead to endothelial cell injury and vascular dysfunction and could be a mechanism of gender-specific atherogenic damages induced by endocrine disruptors and, thus, induce atherogenic events with increased risk of cardiovascular diseases in individuals exposed to this endocrine disruptor.

Correction to: Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect.

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The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism.

PURPOSE: Tadalafil seems to ameliorate insulin resistance and glucose homeostasis in humans. We have previously reported that tadalafil targets human skeletal muscle cells with an insulin (I)-like effect. We aim to evaluate in human fetal skeletal muscle cells after tadalafil or I: (i) expression profile of I-regulated genes dedicated to cellular energy control, glycolitic activity or microtubule formation/vesicle transport, as GLUT4, PPARγ, HK2, IRS-1, KIF1C, and KIFAP3; (ii) GLUT4, Flotillin-1, and Caveolin-1 localization, all proteins involved in energy-dependent cell trafficking; (iii) activation of I-targeted paths, as IRS-1, PKB/AKT, mTOR, P70/S6K. Free fatty acids intracellular level was measured. Sildenafil or a cGMP synthetic analog were used for comparison; PDE5 and PDE11 gene expression was evaluated in human fetal skeletal muscle cells. METHODS: RTq-PCR, PCR, western blot, free fatty acid assay commercial kit, and lipid stain non-fluorescent assay were used. RESULTS: Tadalafil upregulated I-targeted investigated genes with the same temporal pattern as I (GLUT4, PPARγ, and IRS-1 at 3 h; HK2, KIF1C, KIFAP3 at 12 h), re-localized GLUT4 in cell sites positively immune-decorated for Caveolin-1 and Flotillin-1, suggesting the involvement of lipid rafts, induced specific residue phosphorylation of IRS-1/AKT/mTOR complex in association with free fatty acid de novo synthesis. Sildenafil or GMP analog did not affect GLUT4 trafficking or free fatty acid levels. CONCLUSION: In human fetal skeletal muscle cells tadalafil likely favors energy storage by modulating lipid homeostasis via IRS-1-mediated mechanisms, involving activation of I-targeted genes and intracellular cascade related to metabolic control. Those data provide some biomolecular evidences explaining, in part, tadalafil-induced favorable control of human metabolism shown by clinical studies.

Effects of an individualized home-based unsupervised aerobic training on body composition and physiological parameters in obese adults are independent of gender.

PURPOSE: Evaluation of the effects of an individualized home-based unsupervised aerobic training on body composition, physical and physiological parameters in female and male obese adults. METHODS: Two hundred and twenty obese adults (age 47.9 ± 12.4 years; BMI 38.0 ± 7.2 kg/m2) entered the 4-month training program. Body composition, physiological and functional capacities were assessed pre- and post-intervention. All subjects were requested to perform unsupervised aerobic training with the intensity based on heart rate, walking speed and OMNI-RPE score corresponding to the individual ventilatory threshold for at least 5 days/week. RESULTS: After 4-month study period, 40% of patients completed the protocol, 24% had high compliance (HC) (exercise ≥ 3 days/week), while 16% had low compliance (LC) to exercise prescription (exercise < than 3 days/week). In HC group, a significant improvement of body composition variables after training was performed. Moreover, oxygen uptake and metabolic equivalent at peak significantly increased after training. Six-minute walking test (6MWT) distance significantly increased while heart rate during 6MWT was significantly lower after training. No significant differences were found in LC group between pre- and post-intervention in all variables. Interestingly, gender does not influence the effects of training. CONCLUSIONS: Our results indicate that subjects, independent of gender, with high compliance to the aerobic training based on a new individualized method can achieve a significant reduction in weight loss and also an improvement in physical and physiological parameters. This innovative personalized prescription could be a valuable tool for exercise physiologist, endocrinologists, and nutritionists to approach and correct life style of obese subjects.

Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy.

BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Are Dietary Supplements and Nutraceuticals Effective for Musculoskeletal Health and Cognitive Function? A Scoping Review.

OBJECTIVE: The aim of our scoping review was to summarize the state of the art regarding micronutrients in order to identify which of them might effectively improve health status in the areas typically impaired in older people: bone, skeletal muscle, and cognitive function. DESIGN: Scoping review. METHODS: The Italian Study Group on Healthy Aging by Nutraceuticals and Dietary Supplements (HANDS) performed this scoping review, based on the following steps: doing a list of micronutrients related with musculoskeletal or cognitive functions, included in dietary supplements and nutraceuticals commercialized in Italy; planning a research on PubMed, according to an evidence-based approach, in order to the most relevant positive study for each micronutrient into each of the three areas involved (bone, skeletal muscle and cognitive function); identifying the micronutrients effective in maintaining or achieving an adequate health status in older people, specifying the effective and safe daily doses, according to the selected studies. RESULTS: In literature we found 12 relevant positive studies (1 international society guidelines/recommendations, 1 systematic review, 7 randomized controlled trials, and 3 prospective cohort studies). We showed that only 16 micronutrients resulted to have appropriate scientific evidences in terms of improving musculoskeletal health and/or cognitive function in older people: beta-alanine, calcium, creatine, fluorides, leucine, magnesium, omega-3 fatty acids, potassium, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K2, and zinc. CONCLUSION: This scoping review showed that selected micronutrients in adequate doses might have an ancillary role in musculoskeletal health and cognitive functions in older people.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PURPOSE: Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). METHODS: Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. RESULTS: Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. CONCLUSIONS: Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Effect of personalized dietary intervention on nutritional, metabolic and vascular indices in patients with chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) present a markedly increased cardiovascular (CV) morbidity and mortality since the early stages of the disease and a high prevalence of malnutrition, inflammation, and accelerated atherosclerosis. Personalized nutritional intervention, with of a low-protein diet (LPD), since the early stages of CKD should be able to achieve significant metabolic improvements. In our study we have verified the effects of a personalized dietary intervention in patients in the CKD stages 3/4 KDOQI on nutritional, metabolic and vascular indices. PATIENTS AND METHODS: We have evaluated renal function, lipid profile, mineral metabolism, inflammatory indices, and acid-base balance of 16 patients with CKD (stages 3/4 KDOQI). Assessment of nutritional status, body composition, bone mineral density and muscle mass, using body mass index (BMI), handgrip strength, bioelectrical impedance analysis (BIA), and dual energy X-ray absorptiometry (DEXA) was performed. Vascular indices and endothelial dysfunction such as carotid intima-media thickness (cIMT) and the brachial artery flow-mediated dilation (baFMD) were also analyzed. RESULTS: After dietary interventions, we observed a significant increase in plasma bicarbonate (p = 0.004) and vitamin D levels (p = 0.03) and a concomitant significant reduction of phosphorus concentration (p = 0.001) and C-reactive protein (CRP) (p = 0.01). CONCLUSIONS: Nutritional intervention potentially plays a major role in reducing the progression of CKD and systemic complications of predialysis patients. A low-protein diet (LPD) ensuring vegetable protein intake and a reduced amount of specific micronutrients should be recommended to stage 3/4 CKD patients in order to ameliorate metabolic profile, renal outcome, and reduce cardiovascular risk factors.

The endocrine disruptor cadmium alters human osteoblast-like Saos-2 cells homeostasis in vitro by alteration of Wnt/ß-catenin pathway and activation of caspases.

PURPOSE: The pollutant Cadmium (Cd) is widespread in the environment and causes alterations of human health by acting as an endocrine disruptor. Bone tissue seems to be a crucial target of Cd contamination. Indeed, we have previously demonstrated that this endocrine disruptor induces osteoblast apoptosis and necrosis. Thus, aim of this study was to further evaluate the effect of Cd on osteoblasts homeostasis, investigating potential modification of the Wnt/ß-catenin intracellular pathway, the intracellular process involved in programmed cellular death and the cytoskeletal alterations. MATERIAL AND METHODS: To this purpose, human osteoblastic Saos-2 cells, a human osteosarcoma osteoblast-like cell line, were cultured and treated with Cd. RESULTS: Osteoblastic cells were treated for 6 h with 10µM Cd, which induced nuclear translocation of ß-catenin and increased expression of Wnt/ß-catenin target genes. Longer exposure to the same Cd concentration induced osteoblastic cell apoptosis. To better characterize the intracellular events involved in these Cd-induced alterations, we evaluated the effect of Cd exposure on actin filaments and proteins associated to cytoskeletal actin, characterized by the presence of LIM domains. Long (15, 24 h) exposure of osteoblasts to Cd reduced LIM proteins expression and induced actin filaments destruction and a significant caspase-3 activation after 24 h. In addition, to prove that Cd induces osteoblastic cells apoptosis after long exposure, we performed TUNEL assay which demonstrated increase of cell apoptosis after 24 h. CONCLUSION: In conclusion, our study shows that osteoblasts exposed to Cd for short intervals of time demonstrated an increase in cell proliferation through a Wnt/ß-catenin dependent mechanism, likely as a compensatory mechanism in response to cell injury. Longer exposure to the same Cd concentration induced cells apoptosis through cytoskeleton disruption-mediated mechanisms and caspase activation.