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1.
Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies.
Bossio, S, Perri, A, Gallo, R, De Bartolo, A, Rago, V, La Russa, D, Di Dio, M, La Vignera, S, Calogero, AE, Vitale, G, et al
International journal of molecular sciences. 2023;(23)
Abstract
Alpha-lipoic acid (ALA) is a natural antioxidant dithiol compound, exerting antiproliferative and antimetastatic effects in various cancer cell lines. In our study, we demonstrated that ALA reduces the cell growth of prostate cancer cells LNCaP and DU-145. Western blot results revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3. Concomitantly, MTT assays showed that chloroquine (CQ) exposure, a well-known autophagy inhibitor, reduced cells' viability. This was more evident for treatment using the combination ALA + CQ, suggesting that ALA can reduce cells' viability by inhibiting autophagy. In addition, in DU-145 cells we observed that ALA affected the oxidative/redox balance system by deregulating the KEAP1/Nrf2/p62 signaling pathway. ALA decreased ROS production, SOD1 and GSTP1 protein expression, and significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2, concomitantly downregulating p62, suggesting that ALA disrupted p62-Nrf2 feedback loop. Conversely, in LNCaP cells, ALA exposure upregulated both SOD1 and p62 protein expression, but did not affect the KEAP1/Nrf2/p62 signaling pathway. In addition, wound-healing, Western blot, and immunofluorescence assays evidenced that ALA significantly reduced the motility of LNCaP and DU-145 cells and downregulated the protein expression of TGFβ1 and vimentin and the deposition of fibronectin. Finally, a soft agar assay revealed that ALA decreased the colony formation of both the prostate cancer cells by affecting the anchorage independent growth. Collectively, our in vitro evidence demonstrated that in prostate cancer cells, ALA reduces cell growth and counteracts both migration and invasion. Further studies are needed in order to achieve a better understanding of the underlined molecular mechanisms.
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2.
Effects of the ketogenic diet on bone health: A systematic review.
Garofalo, V, Barbagallo, F, Cannarella, R, Calogero, AE, La Vignera, S, Condorelli, RA
Frontiers in endocrinology. 2023;:1042744
Abstract
OBJECTIVE To carry out a systematic review of published studies to evaluate the relationship between different type of ketogenic diet (KD) and bone health as supported by the scientific literature. METHODS The study involved all articles that assessed the relationship between the use of KD for the treatment of overweight or obesity and bone health. The quality assessment was evaluated with using the Cambridge Quality Checklists. The search strategy included the following combination of Medical Subjects Headings terms and keywords: "osteoporosis", "bone health, "bone function", "bone mineral density", and "ketogenic diet". RESULTS Seven trials were identified and reviewed. No significant changes in bone mass density (BMD) were observed after KD. The results showed no significant effect on bone resorption by measuring urinary N-telopeptide levels, on bone formation by measuring bone-specific alkaline phosphatase, or alterations in overall bone turnover in patients who followed KD. Only in female subject after a 10% weight loss, bone resorption increases while new bone synthesis decreases, but without increasing the risk of osteoporosis. Finally, patients on KD lost significantly more weight than controls, associated with an increase in serum vitamin D levels and a reduction in plasma parathyroid hormone (PTH) levels. CONCLUSION No human studies have currently been conducted with adequate and powerful experimental designs to definitively understand the impact of KD therapy on bone health.
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3.
Lipidomic Profile of Human Sperm Membrane Identifies a Clustering of Lipids Associated with Semen Quality and Function.
Di Nisio, A, De Toni, L, Sabovic, I, Vignoli, A, Tenori, L, Dall'Acqua, S, Sut, S, La Vignera, S, Condorelli, RA, Giacone, F, et al
International journal of molecular sciences. 2023;(1)
Abstract
Reduced sperm motility and/or count are among the major causes of reduced fertility in men, and sperm membranes play an important role in the spermatogenesis and fertilization processes. However, the impact of sperm lipid composition on male fertility remains under-investigated. The aim of the present study was to perform a lipidomic analysis of human sperm membranes: we performed an untargeted analysis of membrane lipid composition in fertile (N = 33) and infertile subjects (N = 29). In parallel, we evaluated their serum lipid levels. Twenty-one lipids were identified by their mass/charge ratio and post-source decay spectra. Sulfogalactosylglycerolipid (SGG, seminolipid) was the most abundant lipid component in the membranes. In addition, we observed a significant proportion of PUFAs. Important differences have emerged between the fertile and infertile groups, leading to the identification of a lipid cluster that was associated with semen parameters. Among these, cholesterol sulfate, SGG, and PUFAs represented the most important predictors of semen quality. No association was found between the serum and sperm lipids. Dietary PUFAs and SGG have acknowledged antioxidant functions and could, therefore, represent sensitive markers of sperm quality and testicular function. Altogether, these results underline the important role of sperm membrane lipids, which act independently of serum lipids levels and may rather represent an independent marker of reproductive function.
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4.
Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.
Cannarella, R, Gusmano, C, Condorelli, RA, Bernini, A, Kaftalli, J, Maltese, PE, Paolacci, S, Dautaj, A, Marceddu, G, Bertelli, M, et al
International journal of molecular sciences. 2023;(8)
Abstract
Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.
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5.
Relationship between Iron Deficiency and Thyroid Function: A Systematic Review and Meta-Analysis.
Garofalo, V, Condorelli, RA, Cannarella, R, Aversa, A, Calogero, AE, La Vignera, S
Nutrients. 2023;(22)
Abstract
Objective: Iron deficiency (ID) is the most prevalent nutritional deficiency worldwide. Low levels of serum ferritin (SF) could affect the thyroid gland and its functioning. The purpose of this systematic review and meta-analysis is to summarize the main currently available evidence and analyze data on the relationship between ID and thyroid function. Methods: This study included all articles evaluating the relationship between ID and thyroid function. Quality assessment was performed using Cambridge Quality Checklists. The search strategy included the following combination of Medical Subjects Headings terms and keywords: "iron deficiency", "thyroid function", "thyroid disease", "thyroid dysfunction", and "hypothyroidism". A meta-analysis was performed to evaluate whether thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels differed between patients with ID and healthy controls without ID. For statistical comparison between cases and controls, the mean difference (MD) was calculated, and a subgroup analysis of pregnant and non-pregnant women was performed. Cochran's Q testing and heterogeneity indices (I2) were used to assess statistical heterogeneity. Sensitivity analysis and publication bias analyses were also performed, both qualitatively and quantitatively. Finally, a meta-regression analysis was performed to evaluate the correlation between serum TSH or FT4 levels and SF in the study population. Results: Ten cross-sectional studies were identified and reviewed. Patients with ID showed TSH (MD: -0.24 mIU/L; 95% CI -0.41, -0.07; I2 = 100%, p = 0.005), FT4 (MD: -1.18 pmol/L; 95% CI -1.43, -0.94; I2 = 99%, p < 0.000001), and FT3 (MD: -0.22 pmol/L; 95% CI -0.32, -0.12; I2 = 99%, p < 0.00001) levels that were significantly lower. Subgroup analysis confirmed significantly lower TSH, FT4, and FT3 levels in pregnant women. Non-pregnant women showed significantly lower serum FT4 and FT3 levels but no difference in TSH values. Meta-regression analysis showed that serum TSH and FT4 levels were positively correlated with SF levels. Our systematic review of the literature found that ID significantly increases the prevalence of thyroid autoantibody (anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies) positivity both individually and collectively. Conclusion: Studies currently published in the literature indicate a possible relationship between ID, thyroid function, and autoimmunity, especially in some patient groups. Data analysis shows that thyroid hormone levels are lower in patients with ID and, in particular, in pregnant women. Further studies are needed to understand the role played by iron in thyroid metabolism.
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6.
Red Wine and Sexual Function in Men: An Original Point of View.
Basile, L, Condorelli, RA, Calogero, AE, Cannarella, R, Barbagallo, F, Crafa, A, Aversa, A, La Vignera, S
Journal of clinical medicine. 2023;(12)
Abstract
Red wine is a rich source of nutrients whose biological properties have inspired numerous scientific studies. Indeed, it has been widely reported that there is a correlation between the positive health effects of moderate consumption of red wine and its phenolic content, which, due to its antioxidant activity, has proved to be useful in the improvement of various diseases, such as cardiovascular diseases, metabolic syndrome, cognitive disorders, depression, and cancer. It is a common opinion that the antioxidant activity of red wine is to be ascribed to its entire content of polyphenols, which act synergistically and not as a single component. Furthermore, this health-promoting effect of red wine can also be linked to its ethanol content, which has shown a wide array of biological properties. Beyond this evidence, very little is known about a possible correlation between moderate consumption of red wine and male sexual function. This brief review aimed to evaluate the effects of moderate consumption of red wine on erectile function. To accomplish this, Pubmed and Google Scholar databases were searched to retrieve the most relevant studies on this topic. The evidence so far collected has shown that red wine, if consumed in moderation, can be potentially beneficial for patients with erectile dysfunction as well as can positively influence reproductive function through mechanisms that depend on the vasorelaxant properties of red wine and its antioxidant properties.
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7.
Dietary Fats and Cardio-Metabolic Outcomes in a Cohort of Italian Adults.
Currenti, W, Godos, J, Alanazi, AM, Grosso, G, Cincione, RI, La Vignera, S, Buscemi, S, Galvano, F
Nutrients. 2022;(20)
Abstract
BACKGROUND Dietary fats, and especially saturated fatty acid (SFA), have been blamed for being the culprit in the dramatic increase in obesity and its associated diseases. However multiple systematic reviews and recent meta-analyses do not support the association between SFA and cardiovascular diseases. Thus, the objective of this study was to test whether specific types and subtypes of dietary fats are associated with metabolic outcomes in a cohort of Italian adults. METHODS Nutritional and demographic data of 1936 adults living in the south of Italy were examined. Food frequency questionnaires (FFQs) were administered to assess the intake of total dietary fat and each specific class of dietary fat, such as SFA, monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA). The intake of fatty acids was also examined according to the carbon-chain length of each individual class. Cases of hypertension, type-2 diabetes and dyslipidemias were collected from previous doctor-confirmed diagnosis records (or direct measurement of blood pressure). RESULTS After adjustment for potential confounding factors, individuals reporting higher intakes of total and saturated fats were associated with lower likelihood of having hypertension (odds ratio (OR) = 0.57, 95% CI: 0.35, 0.91 and OR = 0.55, 95% CI: 0.34, 0.89, respectively). Moreover, higher intake of short-chain saturated fatty acids (SCSFAs) and medium-chain saturated fatty acids (MCSFAs) was inversely associated with dyslipidemia and diabetes (OR = 0.43, 95% CI: 0.23, 0.82 and OR = 0.25, 95% CI: 0.09, 0.72, respectively). Among MUFAs, C18:1 was inversely associated with hypertension and diabetes (OR = 0.52, 95% CI: 0.30, 0.92 and OR = 0.21, 95% CI: 0.07, 0.67, respectively), while C14:1 intake was inversely associated only with hypertension (OR = 0.57, 95% CI: 0.37, 0.88). In contrast, C20:1 intake was associated with dyslipidemia (OR = 3.35, 95% CI: 1.33, 8.42). Regarding PUFA, C18:2 and 20:5 were inversely associated with hypertension (OR = 0.33, 95% CI: 0.18, 0.60 and OR = 0.30, 95% CI: 0.10, 0.89, respectively). CONCLUSIONS The consumption of SFA does not seem to be harmful to cardio-metabolic health and, on the contrary, SCSFA may exert beneficial effects. Further studies are needed to clearly validate the results of the present study.
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8.
Alcohol Consumption, Bone Mineral Density, and Risk of Osteoporotic Fractures: A Dose-Response Meta-Analysis.
Godos, J, Giampieri, F, Chisari, E, Micek, A, Paladino, N, Forbes-Hernández, TY, Quiles, JL, Battino, M, La Vignera, S, Musumeci, G, et al
International journal of environmental research and public health. 2022;(3)
Abstract
Excess alcohol consumption is known to be detrimental to human health. However, the role of light-to-moderate alcohol intake is under investigation for potential certain health benefits-mostly related to the cardiovascular system. Nevertheless, there is no univocal agreement on this matter, and research is still ongoing to clarify whether there might be other potential outcomes affected by alcohol intake. In this regard, there is evidence that excess alcohol intake may negatively influence the risk of osteoporotic fractures. However, there is no comprehensive evidence of literature assessing the role of alcohol consumption in bone mineral density (BMD) and the risk of osteoporotic fractures. Thus, the aim of this study was to quantitatively assess the dose-response relationship between alcohol intake and BMD and risk of osteoporotic fractures. The Embase and MEDLINE electronic databases were searched from their inception to December 2021 for articles providing a quantifiable measurement of alcohol consumption for at least three categories and (1) a measurement of BMD (and dispersion as continuous variables) in some area of the body or (2) risk of osteoporotic fracture provided as relative risk (RR) or hazard ratio (HR), with a 95% confidence interval (CI) as the measure of the association of each category with alcohol intake. A total of 11 studies including 46,916 individuals with BMD assessment and 8 studies including 240,871 individuals with risk of fracture analysis were included. Compared to non-drinkers, consumption of up to two standard drinks of alcohol per day was correlated with higher lumbar and femur neck BMD values, while up to one standard drink of alcohol was correlated with higher hip BMD compared to no alcohol consumption. Higher risk of hip fractures was found starting from three standard drinks of alcohol per day (RR = 1.33, 95% CI: 1.04; 1.69 for three alcoholic drinks/d, and RR = 1.59, 95% CI: 1.23; 2.05 for four alcoholic drinks/d) compared to no alcohol consumption, with no evidence of heterogeneity. Concerning the risk of any osteoporotic fractures, the risk steadily increased with higher intake of alcohol, although never reaching statistical significance. In conclusion, there is consistent evidence that increased alcohol consumption is associated with higher risk of osteoporotic hip fracture; however, the role of alcohol at lower doses is uncertain, as BMD was even higher in light drinkers compared to abstainers.
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9.
Beneficial Effects of the Very-Low-Calorie Ketogenic Diet on the Symptoms of Male Accessory Gland Inflammation.
Condorelli, RA, Aversa, A, Basile, L, Cannarella, R, Mongioì, LM, Cimino, L, Perelli, S, Caprio, M, Cimino, S, Calogero, AE, et al
Nutrients. 2022;(5)
Abstract
Introduction. Obesity exposes individuals to the risk of chronic inflammation of the prostate gland. Aim and design of the study. A longitudinal clinical study was conducted on selected overweight/obese patients with male accessory gland inflammation (MAGI) to evaluate the effects of body weight loss on their urogenital symptoms. Materials and methods. One hundred patients were selected and assigned to two groups undergoing two different nutritional programs. The first group (n = 50) started a Mediterranean diet (MedDiet) and the second (n = 50) a very-low-calorie ketogenic diet (VLCKD). Before and after three months on the diet, each patient was evaluated for body weight, waist circumference, and MAGI symptoms. The MAGI was assessed using the Structured Interview about MAGI (SI-MAGI), a questionnaire previously designed to assess the symptoms of MAGI. The questionnaire explores four domains, including urinary symptoms, ejaculatory pain or discomfort, sexual dysfunction, and impaired quality of life. Finally, in the two groups, the frequency of an α-blocker used to treat urinary tract symptoms was also evaluated. Results. Patients on MedDiet experienced significant amelioration in urinary symptoms and quality of life. Patients under VLCKD reported not only significant improvement of the same parameters, but also in ejaculatory pain/discomfort and sexual dysfunction. Finally, the percentage of patients on VLCKD taking the α-blocker decreased significantly. Moreover, patients under VLCKD showed a greater loss of body weight than those following the MedDiet. Discussion. The results of this study support the effectiveness of VLCKD in improving the symptoms of patients with MAGI. This improvement involved all of the domains of the SI-MAGI questionnaire and became manifest in a relatively short time. We suggest that a ketogenic nutritional approach can be used in overweight/obese patients with MAGI.
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10.
Is Chronic Varicocele a Risk Factor for Secondary Hyperparathyroidism?
Cannarella, R, Condorelli, RA, Perelli, S, Calogero, AE, Greco, E, Aversa, A, La Vignera, S
Journal of clinical medicine. 2022;(3)
Abstract
OBJECTIVE To assess whether varicocele affects testicular 25-hydroxylase activity. METHODS Twenty normozoospermic patients with bilateral varicocele (grade III according to the Dubin and Amelar classification) without indications to undergo varicocele repair (normal sperm parameters and testicular volume; no scrotal pain) were consecutively enrolled and followed-up for four years. Serum levels of parathyroid hormone (PTH), calcium, and 25-hydroxy-cholecalciferol [25(OH)D] along with serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), conventional sperm parameters, sperm DNA fragmentation (SDF) rate, and testicular volume (TV) were measured annually for three years. PTH, calcium, and 25(OH)D serum levels over time were compared with those of age- and body mass index (BMI)-matched control group of twenty varicocelectomized patients. MAIN RESULTS Both intra- and between-group analyses showed that serum PTH levels increased significantly over time in parallel with a significant decline in 25(OH)D levels. Serum calcium levels did not change significantly. At the same time, signs of mild Leydig and Sertoli cell dysfunction were found, such as an increase in gonadotropins and decreased TT and VT. However, conventional sperm parameters and SDF rate did not change significantly. CONCLUSION This prospective controlled study provides the first evidence of a negative impact of bilateral grade III varicocele on testicular 25-hydroxylase activity. Accordingly, the patients included in this study showed a significant increase in PTH and a decrease in 25(OH)D levels over time. Patients with varicocele deserve endocrinologic counseling.