Publications by authors named "Stefania Mai"

25 Publications

  • Page 1 of 1

Circulating Inhibitory Factor 1 levels in adult patients with Prader-Willi syndrome.

Horm Mol Biol Clin Investig 2021 Mar 5. Epub 2021 Mar 5.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.

Objectives: Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters.

Methods: We recruited 35 adult patients with genetically confirmed PWS.

Results: IF serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p<0.001) showed a statistically significant correlation with IF. Cholesterol and its fractions did not present any correlation with IF

Conclusions: In this study we do not confirm that HDL-cholesterol and IF are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.
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http://dx.doi.org/10.1515/hmbci-2020-0097DOI Listing
March 2021

Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations.

Front Endocrinol (Lausanne) 2020 18;11:591501. Epub 2020 Nov 18.

Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.
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http://dx.doi.org/10.3389/fendo.2020.591501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708377PMC
November 2020

Exploring extra dimensions to capture saliva metabolite fingerprints from metabolically healthy and unhealthy obese patients by comprehensive two-dimensional gas chromatography featuring Tandem Ionization mass spectrometry.

Anal Bioanal Chem 2021 Jan 3;413(2):403-418. Epub 2020 Nov 3.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125, Torino, Italy.

This study examines the information potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOF MS) and variable ionization energy (i.e., Tandem Ionization™) to study changes in saliva metabolic signatures from a small group of obese individuals. The study presents a proof of concept for an effective exploitation of the complementary nature of tandem ionization data. Samples are taken from two sub-populations of severely obese (BMI > 40 kg/m) patients, named metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Untargeted fingerprinting, based on pattern recognition by template matching, is applied on single data streams and on fused data, obtained by combining raw signals from the two ionization energies (12 and 70 eV). Results indicate that at lower energy (i.e., 12 eV), the total signal intensity is one order of magnitude lower compared to the reference signal at 70 eV, but the ranges of variations for 2D peak responses is larger, extending the dynamic range. Fused data combine benefits from 70 eV and 12 eV resulting in more comprehensive coverage by sample fingerprints. Multivariate statistics, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) show quite good patient clustering, with total explained variance by the first two principal components (PCs) that increases from 54% at 70 eV to 59% at 12 eV and up to 71% for fused data. With PLS-DA, discriminant components are highlighted and putatively identified by comparing retention data and 70 eV spectral signatures. Within the most informative analytes, lactose is present in higher relative amount in saliva from MHO patients, whereas N-acetyl-D-glucosamine, urea, glucuronic acid γ-lactone, 2-deoxyribose, N-acetylneuraminic acid methyl ester, and 5-aminovaleric acid are more abundant in MUO patients. Visual feature fingerprinting is combined with pattern recognition algorithms to highlight metabolite variations between composite per-class images obtained by combining raw data from individuals belonging to different classes, i.e., MUO vs. MHO.Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-03008-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806578PMC
January 2021

Evaluation of an Amino Acid Mix on the Secretion of Gastrointestinal Peptides, Glucometabolic Homeostasis, and Appetite in Obese Adolescents Administered with a Fixed-Dose or ad Libitum Meal.

J Clin Med 2020 Sep 22;9(9). Epub 2020 Sep 22.

Experimental Laboratory for Auxo-endocrinological Research, Istituto Auxologico Italiano, IRCCS, 28824 Verbania, Italy.

Proteins have been demonstrated to reduce food intake in animals and humans via peripheral and central mechanisms. Supplementation of a dietetic regimen with single or mixed amino acids might represent an approach to improve the effectiveness of any body weight reduction program in obese subjects. The aim of the present study was to evaluate the effects of an amino acid mix (L-arginine + L-leucine + L-glutamine + L-tryptophan) on the secretion of some gastrointestinal peptides (i.e., ghrelin and glucagon-like peptide type 1, GLP-1), glucometabolic homeostasis (i.e., glucose, insulin, and glucagon), and appetite (hunger/satiety scored by visual analogue scale, VAS) in obese adolescents ( = 14; 10 females and 4 males; age: 16.6 ± 1.0 years; body mass index (BMI): 36.4 ± 4.6 kg/m²; fat-free mass (FFM): 54.9 ± 4.7%; fat mass (FM): 45.1 ± 4.4%) administered with a fixed-dose (lunch) or ad libitum (dinner) meal. Isocaloric maltodextrins were used as control treatment. During the lunch test, a significant increase in circulating levels of GLP-1, but not of ghrelin, was observed in the amino acid-treated group, which was congruent with significant changes in appetite, i.e., increase in satiety and decrease in hunger. A significant hyperglycemia was found in the maltodextrin-treated group during the prelunch period, without any significant changes in insulin and glucagon between the two groups. During the dinner test, there were no significant differences in appetite (hunger/satiety) and intake of calories. In conclusion, L-arginine, L-leucine, L-glutamine, and L-tryptophan, when administered to obese adolescents with a fixed-dose meal, are capable of evoking an anorexigenic response, which is, at least in part, mediated by an increase in GLP-1 released in circulation by L cells, which are capable of chemosensing specific amino acids present in the intestinal lumen. Further additional studies are requested to understand whether higher doses are necessary to inhibit ad libitum feeding.
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http://dx.doi.org/10.3390/jcm9093054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564111PMC
September 2020

Fat-Free Mass Is Better Related to Serum Uric Acid Than Metabolic Homeostasis in Prader-Willi Syndrome.

Nutrients 2020 08 25;12(9). Epub 2020 Aug 25.

Division of Auxology, IRCCS Istituto Auxologico Italiano, 28824 Piancavallo (VB), Italy.

: Prader-Willi syndrome (PWS) is conventionally regarded as a model of genetic obesity carrying a metabolically healthier profile and fat compartmentalization than subjects with non-syndromic obesity. Serum uric acid (sUA) is a recognized surrogate marker of metabolic derangement. As no information is currently available on sUA levels in adults with PWS, we aimed to analyze sUA in a large cohort of adult patients with PWS in comparison to a control counterpart; secondly, we aimed to investigate the metabolic and non-metabolic determinants of sUA in PWS. : A cross-sectional study was conducted on 89 consecutive adult patients with genetically confirmed PWS spanning a wide BMI range (17.2-56.7 kg/m). As controls, 180 age-, sex- and BMI-matched healthy controls were included. sUA levels were analyzed in relation to the PWS status, metabolic variables, hormone status, body composition, and resting energy expenditure (REE). Bivariate correlation and multivariable regression studies were used to test for predictors of sUA in PWS. : Despite having similar BMI values, patients with PWS presented with higher FM ( < 0.0001), lower FFM ( < 0.0001) and REE values than controls ( < 0.0001). In PWS, sUA levels were non-significantly different between subjects with and without obesity (5.4 ± 1.3 vs. 4.9 ± 1.1 mg/dL, = 0.09), and did not vary significantly in relation to genotype, sex steroid or GH replacement, as well as psychiatric treatments. Rates of hyperuricaemia (19.1% vs. 33.7%, < 0.01) and absolute sUA levels were lower in patients with PWS compared to controls owing to significant differences between subgroups with obesity (5.5 ± 1.4 vs. 6.6 ± 1.6 mg/dL, < 0.0001). In merged populations, sUA increased in parallel with age, BMI, FM, FFM, REE, glucolipid homeostasis, and inflammatory markers. In a separate analysis in PWS, however, sUA correlations with BMI, FM, and inflammatory markers were null. Stepwise multivariable regression analysis in the PWS group adjusted for karyotype, age, sex, FM, FFM, obesity, triglycerides, and HDL cholesterol, showed that sUA levels were independently associated with FFM (β = 0.35, < 0.0001) and, albeit less significantly, with triglycerides (β = 0.23, < 0.05). The introduction of height-normalized FFM (FFM index) in the regression model, however, abrogated the predictive role of FFM on sUA. : FFM mass is a strong predictor of sUA. PWS is associated to lower sUA levels than controls likely due to genetic predisposition to different body composition and healthier metabolic phenotype. Further studies are warranted to assess purine metabolism and the clinical significance of the FFM index in PWS.
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http://dx.doi.org/10.3390/nu12092583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551470PMC
August 2020

Irisin levels in genetic and essential obesity: clues for a potential dual role.

Sci Rep 2020 01 23;10(1):1020. Epub 2020 Jan 23.

Istituto Auxologico Italiano, IRCCS, Division of General Medicine, Ospedale S. Giuseppe, via Cadorna 90, 28824, Piancavallo di Oggebbio, (VB), Italy.

Irisin is conventionally regarded as a myokine involved in the browning of white adipose tissue, energy expenditure and glucose tolerance. Its potential link to fat accumulation and metabolic dysfunction is debated. We sought to explore the relationship between circulating irisin and components of body composition in two different phenotypes of severe obesity. For this purpose, 30 obese adults with Prader-Will syndrome (PWS) (age 35.7 ± 1.5 y, BMI 45.5 ± 1.5 kg/m) and 30 adult controls with common obesity (age 34.9 ± 1.7 y, BMI 46.8 ± 1.4 kg/m) underwent analysis of irisin levels, metabolic profile, body composition and resting energy expenditure (REE). Normal irisin levels were obtained from a group of 20 lean donors (age 32.4 ± 1.5 y, BMI 23.8 ± 0.8 kg/m). Expected differences in body composition and metabolic profile existed between study groups. PWS exhibited lower muscle mass (p < 0.001), FFM (p < 0.001), REE (p < 0.001), as well as insulin (p < 0.05), HOMA-IR (p < 0.05) and triglycerides levels (p < 0.05) than controls with common obesity. In PWS, irisin levels were significantly lower and overall less dispersed than in controls with common obesity (p < 0.05), while being similar to values recorded in lean subjects. To explore the relation between irisin and body composition in obesity, univariate correlation analysis in the obese populations as a whole showed positive associations between irisin and muscle mass (p = 0.03) as well as REE (p = 0.01), which disappeared when controlled for the PWS status. Noticeably, a positive association became evident between irisin and %FM after controlling for the PWS status (p = 0.02). Also positive were associations between irisin and insulin (p = 0.02), HOMA-IR (p = 0.02) and triglycerides (p = 0.04). In stepwise multivariable regression analysis, irisin levels were independently predicted by the PWS status (p = 0.001), %FM (p = 0.004) and triglycerides (p = 0.008). Current results suggest that obese adults with PWS harbor lower irisin levels than individuals with common obesity. The divergent models of obesity herein studied suggest a potential link between circulating irisin and muscle mass and metabolic dysfunction relating to adiposity.
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http://dx.doi.org/10.1038/s41598-020-57855-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978420PMC
January 2020

Effect of Short-Term Dietary Intervention and Probiotic Mix Supplementation on the Gut Microbiota of Elderly Obese Women.

Nutrients 2019 Dec 10;11(12). Epub 2019 Dec 10.

Department of Medical Sciences and Rehabilitation, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy.

Accumulating literature is providing evidence that the gut microbiota is involved in metabolic disorders, but the question of how to effectively modulate it to restore homeostasis, especially in the elderly, is still under debate. In this study, we profiled the intestinal microbiota of 20 elderly obese women (EO) at the baseline (T0), after 15 days of hypocaloric Mediterranean diet administered as part of a nutritional-metabolic rehabilitation program for obesity (T1), and after a further 15 days of the same diet supplemented with a probiotic mix (T2). Fecal samples were characterized by Illumina MiSeq sequencing of the 16S rRNA gene. The EO microbiota showed the typical alterations found in obesity, namely, an increase in potential pro-inflammatory components (i.e., ) and a decrease in health-promoting, short-chain fatty acid producers (i.e., and members), with a tendency to reduced biodiversity. After 15 days of the rehabilitation program, weight decreased by (2.7 ± 1.5)% and the gut microbiota dysbiosis was partially reversed, with a decline of and an increase in leanness-related taxa. During the next 15 days of diet and probiotics, weight dropped further by (1.2 ± 1.1)%, markers of oxidative stress improved, and , a mucin degrader with beneficial effects on host metabolism, increased significantly. These findings support the relevant role of a correct dietetic approach, even in the short term, to modulate the EO gut microbiota towards a metabolic health-related configuration, counteracting the increased risk of morbidity in these patients.
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http://dx.doi.org/10.3390/nu11123011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950529PMC
December 2019

Altered temporal sensitivity in obesity is linked to pro-inflammatory state.

Sci Rep 2019 10 29;9(1):15508. Epub 2019 Oct 29.

Department of Psychological, Health, and Territorial Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.

Temporal sensitivity to multisensory stimuli has been shown to be reduced in obesity. We sought to investigate the possible role of the pro-inflammatory state on such alteration, considering the effect of the expression of markers, such as leptin and IL6, which are notably high in obesity. The performance of 15 male individuals affected by obesity and 15 normal-weight males was compared using two audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Analyses of serum levels of inflammatory markers of leptin and IL6, and of neurotrophic factors of BDNF and S100SB were quantified. At the behavioral level we confirmed previous evidence showing poorer temporal sensitivity in obesity compared to normal-weight participants. Furthermore, leptin, that is a cytokine overexpressed in obesity, represented the best predictor of behavioral differences between groups in both tasks. The hypothesis we put forward is that the immune system, rather than overall cerebral dysfunction, might contribute to explain the altered temporal sensitivity in obesity. The present finding is discussed within the context of the role of cytokines on the brain mechanisms supporting temporal sensitivity.
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http://dx.doi.org/10.1038/s41598-019-51660-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820747PMC
October 2019

Preclinical and Clinical Evidence for a Distinct Regulation of Mu Opioid and Type 1 Cannabinoid Receptor Genes Expression in Obesity.

Front Genet 2019 14;10:523. Epub 2019 Jun 14.

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene () expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene () expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of and genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest and epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention.
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http://dx.doi.org/10.3389/fgene.2019.00523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588048PMC
June 2019

Circulating adipokines and metabolic setting in differentiated thyroid cancer.

Endocr Connect 2019 Jul;8(7):997-1006

Division of Endocrinology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

The associative link relating insulin resistance (IR) and adipokines to the occurrence and phenotype of differentiated thyroid cancer (DTC) is unknown. The aim of this study was to evaluate the relationship between IR and adipokines in DTC patients, as compared with carriers of benign thyroid diseases (BTD) and healthy controls. This observational study enrolled 77 subjects phenotyped as DTC (N = 30), BTD (N = 27) and healthy subjects (N = 20). Each subject underwent preoperative analysis of anthropometric parameters, thyroid function and autoimmunity, insulin resistance (HOMA-IR) and levels of unacylated (UAG) and acylated ghrelin (AG), obestatin, leptin and adiponectin. Multivariate regression models were used to test the predictive role of metabolic correlates on thyroid phenotypes and DTC extension. The three groups showed similar age, gender distribution, smoking habit, BMI and thyroid parameters. Obestatin was significantly higher in DTC group compared to BTD (P < 0.05) and control subjects (P < 0.0001). DTC and BTD groups showed higher levels of UAG (P < 0.01) and AG (P < 0.05). Leptin levels were comparable between groups, whereas adiponectin levels were lower in DTC compared to BTD group (P < 0.0001) and controls (P < 0.01). In parallel, HOMA-IR was higher in DTC than BTD (P < 0.05) and control group (P < 0.01). Stepwise multivariable regression analysis showed that obestatin and UAG were independent predictors of DTC (P = 0.01 for both). In an analysis restricted to the DTC group, obestatin levels were associated with the absence of lymph node metastases (P < 0.05). Our results highlight a potential association between metabolic setting, circulating adipokines and thyroid cancer phenotype.
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http://dx.doi.org/10.1530/EC-19-0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652238PMC
July 2019

Plasma Oxytocin Concentration in Pre- and Postmenopausal Women: Its Relationship with Obesity, Body Composition and Metabolic Variables.

Obes Facts 2018 30;11(5):429-439. Epub 2018 Oct 30.

Objective: To investigate the relationship between oxytocin, menopause and obesity.

Methods: A cross-sectional analysis on 56 obese (OB; 28 premenopausal) and 53 normal-weight women (NW; 27 premenopausal) was performed by measurement of oxytocin, leptin, adiponectin, gonadotropins, sex steroids, glucose, and lipid homeostasis as well as DXA assessment of fat mass (%FM) and fat-free mass (FFM).

Results: Women from NW and OB groups were comparable for age but differed in anthropometric measures. In our cohorts, menopause was not associated with changes in gluco-lipid homeostasis and %FM, while FFM was lower in postmenopausal women from both study groups (p < 0.05). In each group, leptin was unaltered, and adiponectin only marginally changed across menopause, while oxytocin levels were lower in post- than in premenopausal women (NW: p < 0.05; OB: p < 0.005), and lower in OB than NW women, either when assessed as whole groups or if stratified by menopause (p < 0.001). In correlation analysis, inverse associations related oxytocin to menopause, obesity, and adiposity-related measures. BMI (p < 0.0001) and menopause independently predicted oxytocin levels (p < 0.001), but their interaction was null (p = 0.5).

Conclusions: Obesity and menopause are independent negative predictors of plasma oxytocin. Longitudinal studies should clarify the role of oxytocin on weight modifications experienced around and after menopause.
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http://dx.doi.org/10.1159/000492001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257199PMC
September 2019

Analysis of Predictive Equations for Estimating Resting Energy Expenditure in a Large Cohort of Morbidly Obese Patients.

Front Endocrinol (Lausanne) 2018 25;9:367. Epub 2018 Jul 25.

Obesity Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy.

The treatment of obesity requires creating an energy deficit through caloric restriction and physical activity. Energy needs are estimated assessing the resting energy expenditure (REE) that in the clinical practice is estimated using predictive equations. In the present cross sectional study, we compared, in a large cohort of morbidly obese patients, the accuracy of REE predictive equations recommended by current obesity guidelines [Harris-Benedict, WHO/FAO/ONU and Mifflin-St Jeor (MJ)] and/or developed for obese patients (Muller, Muller BC, Lazzer, Lazzer BC), focusing on the effect of comorbidities on the accuracy of the equations. Data on REE measured by indirect calorimetry and body composition were collected in 4,247 obese patients (69% women, mean age 48 ± 19 years, mean BMI 44 ± 7 Kg/m) admitted to the Istituto Auxologico Italiano from 1999 to 2014. The performance of the equations was assessed in the whole cohort, in 4 groups with 0, 1, 2, or ≥ 3 comorbidities and in a subgroup of 1,598 patients with 1 comorbidity (47.1% hypertension, 16.7% psychiatric disorders, 13.3% binge eating disorders, 6.1% endocrine disorders, 6.4% type 2 diabetes, 3.5% sleep apnoea, 3.1% dyslipidemia, 2.5% coronary disease). In the whole cohort of obese patients, as well as in each stratum of comorbidity number, the MJ equation had the highest performance for agreement measures and bias. The MJ equation had the best performance in obese patients with ≥3 comorbidities (accuracy of 61.1%, bias of -89.87) and in patients with type 2 diabetes and sleep apnoea (accuracy/bias 69%/-19.17 and 66%/-21.67 respectively), who also have the highest levels of measured REE. In conclusion, MJ equation should be preferred to other equations to estimate the energy needs of Caucasian morbidly obese patients when measurement of the REE cannot be performed. As even MJ equation does not precisely predict REE, it should be better to plan the diet intervention by measuring rather than estimating REE. Future studies focusing on the clinical differences that determine the high inter-individual variability of the precision of the REE predictive equations (e.g., on the organ-tissue metabolic rate), could help to develop predictive equations with a better performance.
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http://dx.doi.org/10.3389/fendo.2018.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068274PMC
July 2018

Effect of continuous positive airway pressure in hypertensive patients with obstructive sleep apnea and high urinary metanephrines.

J Hypertens 2018 01;36(1):199-204

Department of Medical Sciences and Rehabilitation.

Objective: Some cases of pseudopheochromocytoma have been described among hypertensive patients with obstructive sleep apnea (OSA). This study examined whether a pathological rise of urinary metanephrines is a common feature in hypertensive OSA patients and, in such a case, whether the ventilation treatment during sleep (continuous or biphasic positive airway pressure) may normalize high metanephrines levels.

Methods: Patients with endocrine diseases, drug abuse, therapy with TCA and cardiovascular events in the previous 6 months were excluded. Thirty-four hypertensive patients with OSA (BMI 40.6 ± 8.7 kg/m(2)) performed three 24-h urine collections for metanephrine assessment, before and after 1 month of ventilation therapy.

Results: Urinary normetanephrine (uNMT) was above the normal limit in 21 of 34 of the patients. In the 16 to 21 patients with high uNMT who were compliant to ventilation treatment, uNMT decreased in 13 by 26% and normalized in six of 13. uNMT levels were associated with apnea hypopnea index (AHI) (r = 0.799, P < 0.0001) and minimal SaO2 (r = -0.700, P < 0.01). The ventilation therapy-induced changes in AHI were associated with those in uNMT (r = 0.689, P < 0.005). In the multivariate analysis with uNMT changes as dependent variable and changes in AHI, BMI, SBP as independent variables, only AHI changes were independently associated with uNMT changes (β = 0.738, P < 0.01).

Conclusion: Two-thirds of OSA hypertensive patients have uNMT values above the normal limit. The early identification of these patients is important as ventilation therapy can correct the pathological sympathoadrenal activation. Patients who do not normalize uNMT with ventilation therapy deserve a strict follow-up as this lack of normalization may indicate insufficient ventilation therapy or resistance of sympathetic hyperactivity to this treatment, not excluding an early stage of a chromaffin tumor.
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http://dx.doi.org/10.1097/HJH.0000000000001507DOI Listing
January 2018

Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome.

Sci Rep 2017 06 9;7(1):3186. Epub 2017 Jun 9.

Division of General Medicine, Ospedale S. Giuseppe, Istituto Auxologico Italiano, via Cadorna 90, 28824, Piancavallo di Oggebbio (VB), Italy.

ANGPTL8 is a liver-derived protein related to insulin-sensitivity. Its relationship with obesity and liver function in Prader-Willi syndrome (PWS) is unknown. The present study investigated circulating ANGPTL8 in PWS and controls with common obesity, assessing its association to liver steatosis. For this purpose, 20 obese PWS and 20 controls matched for body mass index (BMI), sex and age underwent analysis of ANGPTL8 levels, glucose and lipid metabolism. Liver function tests and degree of liver steatosis by ultrasonography (US), fat-free mass (FFM) and fat mass (FM) by dual-energy x-ray absorptiometry (DEXA) were also assessed. In comparison to controls, obese PWS showed lower values of FFM (p < 0.0001) and higher FM (p = 0.01), while harbouring higher HDL cholesterol, lower triglycerides and OGTT-derived insulin levels, as well as a lower prevalence and severity of liver steatosis. With respect to obese controls, ANGPTL8 levels were significantly lower in PWS (p = 0.007) and overall correlated with transaminase levels and the severity of liver steatosis, as well as FFM (p < 0.05 for all). By a stepwise multivariable regression analysis, ANGPTL8 levels were independently predicted by PWS status (p = 0.01) and liver steatosis (p < 0.05). In conclusion, ANGPTL8 levels are lower in PWS than obese controls and are inversely associated with the severity of liver steatosis. Further studies should investigate the potential genetic basis for this observation.
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http://dx.doi.org/10.1038/s41598-017-03538-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466606PMC
June 2017

Acute Vitamin D₃ Supplementation in Severe Obesity: Evaluation of Multimeric Adiponectin.

Nutrients 2017 May 5;9(5). Epub 2017 May 5.

Division of General Medicine, I.R.C.C.S. Istituto Auxologico Italiano, Ospedale S. Giuseppe, 28921 Piancavallo-Verbania, Italy.

Obesity predisposes to vitamin D deficiency (VDD) and glucose abnormalities. It is currently debated if vitamin D administration may improve glucose homeostasis by interacting with modulators of insulin sensitivity, such as adiponectin and its oligomers. In a 4-week inpatient study on a metabolic rehabilitation program, consisting of individualized caloric restriction and aerobic physical exercise in obese subjects with VDD, we assessed the acute effects of 600,000 IU cholecalciferol given per os VD group, 12 subjects; body mass index (BMI) 42.7 ± 1.3 kg/m²) or placebo per os (PL group, 12 subjects, BMI 39.8 ± 0.9 kg/m²) on high (HWM-A), medium (MMW-A), and low molecular weight adiponectin (LMW-A), as quantified by western immunoblot (WIB) and ELISA. During the 4-week study, dieting promoted a similar magnitude of weight loss in VD and PL groups. Compared to the PL group, cholecalciferol administration increased 25(OH)Vit D levels ( < 0.001) and promoted a significant increase of HMW-A expression analyzed by WIB ( = 0.02). In parallel, a significant decrease of leptin/HMW-A ratio ( < 0.05), a biomarker of metabolic homeostasis, was observed. During the study, changes of MMW-A and LMW-A occurred independently of cholecalciferol administration, and were likely explained by weight loss. At odds with these findings, the ELISA assessment of adiponectin oligomers showed no modifications in the VD group or PL group. Current findings suggest that acute cholecalciferol administration selectively modifies HMW-A and the leptin/HMW-A ratio.
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http://dx.doi.org/10.3390/nu9050459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452189PMC
May 2017

The impact of the metabolic phenotype on thyroid function in obesity.

Diabetol Metab Syndr 2016 24;8(1):59. Epub 2016 Aug 24.

Division of General Medicine, I.R.C.C.S. Istituto Auxologico Italiano, Ospedale S. Giuseppe, Casella Postale 1, 28921 Verbania, Italy ; Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.

Background: Obesity is known to promote mild hyperthyrotropinaemia by unknown metabolic mechanisms. This investigation aimed to explore the association between thyroid function and metabolic phenotype in euthyroid obese individuals. Retrospective, cross-sectional study. Tertiary care center.

Methods: 952 euthyroid obese individuals referred to our Institution for obesity. Serum levels of TSH, FT4, glucose, insulin and HbA1c levels, lipid profile, liver function and proinflammatory indices were measured. Resting energy expenditure was assessed by indirect calorimetry and body composition by bioimpedance analysis.

Results: On admission, 306 patients had previously diagnosed diabetes mellitus on treatment with metformin, while 113 patients were diagnosed with incident diabetes mellitus. Serum TSH levels were similar between metformin-treated diabetic subjects and metformin-untreated subjects, while FT4 was slightly but significantly higher in the former. Analysis stratified by TSH categories found no effect of metformin-treated diabetes mellitus on TSH levels. Interestingly, obese patients with incident diabetes showed lower TSH levels than normoglycaemic ones. In correlation studies on the whole dataset, an association related TSH to BMI and total cholesterol levels, which was lost upon adjustment for individual confounders. FT4 levels were found to be inversely related to BMI, insulin resistance and triglycerides, while being directly associated with HDL-cholesterol levels. These correlations remained unaltered after controlling for individual confounders. In multivariate linear regression analysis, TSH was associated with FT4, total cholesterol and BMI values. Significant predictors of FT4 were constituted by previously diagnosed diabetes mellitus, BMI, TSH and age.

Conclusions: In euthyroid obese subjects, FT4 seems more closely related than TSH levels to parameters of cardiometabolic risk. TSH levels did not differ between metformin-treated and untreated subjects, while they were lower in patients with incident diabetes mellitus compared to normoglycaemic ones.
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http://dx.doi.org/10.1186/s13098-016-0177-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995618PMC
August 2016

Inherent insulin sensitivity is a major determinant of multimeric adiponectin responsiveness to short-term weight loss in extreme obesity.

Sci Rep 2014 Jul 24;4:5803. Epub 2014 Jul 24.

1] Division of General Medicine, Ospedale S. Giuseppe, I.R.C.S.S. Istituto Auxologico Italiano, Strada Cadorna 90, 28921, Piancavallo-Verbania [2] Department of Translational Medicine, Università del Piemonte Orientale "Amedeo Avogadro", Via Solaroli 17, 28100, Novara.

High molecular weight (HMW-A) adiponectin levels mirror alterations in glucose homeostasis better than medium (MMW-A) and low molecular weight (LMW-A) components. In 25 patients with wide-range extreme obesity (BMI 40-77 kg/m(2)), we aimed to explore if improvements of multimeric adiponectin following 4-wk weight loss reflect baseline OGTT-derived insulin sensitivity (ISIOGTT) and disposition index (DIOGTT). Compared to 40 lean controls, adiponectin oligomers were lower in extreme obesity (p < 0.001) and, within this group, HMW-A levels were higher in insulin-sensitive (p < 0.05) than -resistant patients. In obese patients, short-term weight loss did not change total adiponectin levels and insulin resistance, while the distribution pattern of adiponectin oligomers changed due to significant increment of HMW-A (p < 0.01) and reduction of MMW-A (p < 0.05). By multivariate analysis, final HMW-A levels were significantly related to baseline ISIOGTT and final body weight (adjusted R(2) = 0.41). Our data suggest that HMW adiponectin may reflect baseline insulin sensitivity appropriately in the context of extreme obesity. Especially, we documented that HMW-A is promptly responsive to short-term weight loss prior to changes in insulin resistance, by a magnitude that is proportioned to whole body insulin sensitivity. This may suggest an insulin sensitivity-dependent control operated by HMW-A on metabolic dynamics of patients with extreme obesity.
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http://dx.doi.org/10.1038/srep05803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109026PMC
July 2014

GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies.

Endocr Rev 2012 Oct 9;33(5):784-811. Epub 2012 Jul 9.

Section of Biomedicine and Endocrinology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.

The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a G(αi)-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.
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http://dx.doi.org/10.1210/er.2012-1014DOI Listing
October 2012

Molecular mechanisms of the antimetastatic activity of nuclear clusterin in prostate cancer cells.

Int J Oncol 2011 Jul 3;39(1):225-34. Epub 2011 May 3.

Department of Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, I-20133 Milan, Italy.

The proapoptotic activity of nuclear clusterin (nCLU) in cancer cells is now well established. We previously showed that nCLU decreases the motility of prostate cancer cells by triggering a dramatic dismantling of the actin cytoskeleton. Here, we sought to unravel the molecular mechanisms of the antimetastatic activity of nCLU. We found that nCLU: i) decreases LIMK1 expression, thus increasing the levels of the active (unphosphorylated) form of cofilin, the well known actin depolymerizing factor; ii) binds to vimentin, sequestering the protein from its adhesion sites at the cell periphery, thus interfering with its role in cell motility and adhesion; iii) affects the intracellular distribution of E-cadherin (the major component of epithelial adherens junctions) which appears to be diffusely distributed in the cells. Through these mechanisms nCLU reduces the migratory/invasive behavior of PC3 cells; this effect is further demonstrated by a decreased secretion of active MMP-2 from the cells. Thus, in addition to its proapoptotic function, nCLU also exerts a strong anti-migratory/anti-invasive activity in prostate cancer cells, by interfering with the cytoskeletal components and by decreasing MMP-2 activity.
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http://dx.doi.org/10.3892/ijo.2011.1030DOI Listing
July 2011

Dual targeting of tumor and endothelial cells by gonadotropin-releasing hormone agonists to reduce melanoma angiogenesis.

Endocrinology 2010 Oct 4;151(10):4643-53. Epub 2010 Aug 4.

Department of Endocrinology, Physiopathology, and Applied Biology, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.

We showed previously that GnRH receptors are expressed in melanoma cells; their activation reduces cell growth and metastatic behavior. Here, we investigated whether GnRH agonists might affect the expression of genes involved in melanoma progression. By genome-wide transcriptomic and real-time PCR analysis, we first observed that GnRH agonists decrease the expression of the pro-angiogenic factor vascular endothelial growth factor (VEGF) (all isoforms) in BLM melanoma cells. Then, we demonstrated that GnRH agonists specifically decrease the expression of the VEGF165 isoform as well as its secretion from BLM cells. These data suggested that activation of GnRH receptors might reduce the pro-angiogenic behavior of melanoma cells. To verify this hypothesis, we treated BLM cells with a GnRH agonist; the conditioned medium from these cells was tested to assess its capability to stimulate human umbilical vein endothelial cell (HUVEC) motility. The migration of HUVECs towards the conditioned medium of GnRH agonist-treated BLM cells was significantly lower than the migration of HUVECs toward the conditioned medium of untreated cells. Thus, GnRH agonists reduce the pro-angiogenic behavior of melanoma cells through a decreased production of bioactive VEGF. We then found that GnRH receptors are also expressed on HUVECs and that GnRH agonists reduce their ability to proliferate and to form capillary-like tubes when stimulated by VEGF. These findings suggest that GnRH agonists exert an anti-angiogenic activity indirectly by decreasing VEGF secretion from tumor cells and directly by counteracting the pro-angiogenic activity of the growth factor. These data might lead to the development of novel targeted approaches for melanoma.
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http://dx.doi.org/10.1210/en.2010-0163DOI Listing
October 2010

Novel insights into GnRH receptor activity: role in the control of human glioblastoma cell proliferation.

Oncol Rep 2009 May;21(5):1277-82

Department of Endocrinology, University of Milano, 20133 Milano, Italy.

Malignant glioblastoma is one of the highest proliferative and invasive tumors within the central nervous system (CNS); the therapeutical options for this disease are still very poor. Receptors for gonadotropin-releasing hormone (GnRH) have been reported to be present in glioblastoma tissues. This study aimed to determine the role of these receptors in the control of glioma growth. In two human glioblastoma cell lines, U87MG and U373, we demonstrated the expression of GnRH receptors, both at mRNA and protein levels. We also found that GnRH receptor is expressed in glioblastoma tissues from tumor patients as shown by Western blotting. In U87MG and U373 cell lines, we found the expression of mRNA for GnRH, indicating the presence of an autocrine GnRH-based system in these cell lines. Treatment of the two cell lines with a GnRH agonist resulted in a significant decrease of cell proliferation. Moreover, the GnRH agonist significantly counteracted the forskolin-induced increase of intracellular cAMP levels in these cells. These findings suggest that the GnRH receptor might represent a molecular target for an endocrine therapeutical approach against gliomas.
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http://dx.doi.org/10.3892/or_00000351DOI Listing
May 2009

Type I gonadotropin-releasing hormone receptor mediates the antiproliferative effects of GnRH-II on prostate cancer cells.

J Clin Endocrinol Metab 2009 May 3;94(5):1761-7. Epub 2009 Feb 3.

Center of Endocrinological Oncology, Department of Endocrinology, Physiopathology and Applied Biology, University of Milano, 20133 Milano, Italy.

Background: GnRH-II has been shown to exert a strong antiproliferative action on tumors of the female reproductive system. The data so far reported on the effects of GnRH-II on prostate cancer growth are controversial. Moreover, it is still unclear through which receptor [type I or type II GnRH-receptor (GnRH-R)] GnRH-II might modulate cancer cell proliferation.

Objective: The objective of this work was to investigate whether GnRH-II might affect the proliferation of prostate cancer cells and to identify the GnRH-R through which the peptide might exert its activity.

Design: We investigated the effects of GnRH-II on prostate cancer cell proliferation. We then transfected PC3 cells with a small interfering RNA targeted to type I GnRH-R. After receptor silencing we evaluated the effects of GnRH-II on cell proliferation and on forskolin-induced intracellular cAMP accumulation. Similar experiments were performed by silencing type II GnRH-R.

Results: GnRH-II exerted an antiproliferative activity on prostate cancer cells. Transfection of PC3 cells with a type I GnRH-R small interfering RNA resulted in a significant decrease of the expression of this receptor. After type I GnRH-R silencing: 1) the antiproliferative effect of GnRH-II was completely abrogated; and 2) GnRH-II lost its capacity to counteract the forskolin-induced cAMP accumulation. On the contrary, type II GnRH-R silencing did not counteract the antiproliferative effect of GnRH-II.

Conclusions: GnRH-II exerts a specific and significant antiproliferative action on prostate cancer cells. This antitumor effect is mediated by the activation of type I (but not of type II) GnRH-R and by its coupled cAMP intracellular signaling pathway.
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http://dx.doi.org/10.1210/jc.2008-1741DOI Listing
May 2009

Gonadotropin-releasing hormone agonists suppress melanoma cell motility and invasiveness through the inhibition of alpha3 integrin and MMP-2 expression and activity.

Int J Oncol 2008 Aug;33(2):405-13

Center of Endocrinological Oncology, Institute of Endocrinology, University of Milan, I-20133 Milan, Italy.

Cutaneous melanoma represents the leading cause of skin cancer deaths. The prognosis of highly aggressive, metastatic melanoma is still very poor, due to the resistance of the disseminated tumor to existing therapies. The clarification of the molecular mechanisms regulating melanoma growth and progression might help identify novel molecular targets for the development of new therapeutic interventions. We previously showed that gonadotropin-releasing hormone (GnRH) receptors are expressed in melanoma cells; activation of these receptors by means of GnRH agonists significantly reduces cell proliferation. In the current study, we first showed that GnRH agonists significantly reduced the metastatic behavior of melanoma cells in terms of both cell motility (haptotactic assay using laminin as the chemoattractant) and invasiveness (cell invasion assay evaluating the capacity of the cells to invade a reconstituted extracellular matrix barrier). On the basis of this observation, we then investigated the molecular mechanisms underlying the antimetastatic activity of GnRH agonists. We found that, in melanoma cells, a) the activity of the alpha3 integrin subunit is crucial for the migratory behavior of the cells; b) GnRH agonists significantly reduced alpha3 integrin expression (Western blotting and immunofluorescence studies); c) GnRH agonists significantly reduced MMP-2 expression (comparative RT-PCR) and activity (zymographic analysis performed on cell culture media). These data indicate that GnRH agonists, in addition to the previously reported antiproliferative effect, elicit a strong inhibitory activity on the migratory/invasive behavior of melanoma cells expressing GnRH receptors. These compounds reduce the metastatic potential of melanoma cells by interfering with the expression/activity of cell adhesion molecules (alpha3 integrin) and matrix metalloproteinase (MMP-2).
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August 2008

Clusterin isoforms differentially affect growth and motility of prostate cells: possible implications in prostate tumorigenesis.

Cancer Res 2007 Nov;67(21):10325-33

Institute of Endocrinology, University of Milan, Milan, Italy.

Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with "full-length" CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to alpha-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and alpha-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to alpha-actinin.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-0516DOI Listing
November 2007

Gonadotropin-releasing hormone agonists reduce the migratory and the invasive behavior of androgen-independent prostate cancer cells by interfering with the activity of IGF-I.

Int J Oncol 2007 Jan;30(1):261-71

Institute of Endocrinology, Center for Endocrinological Oncology, University of Milano, Milano, Italy.

Androgen-independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior. We have previously shown that GnRH agonists exert a direct and specific inhibitory action on the proliferation of androgen-independent prostate cancer cells (DU 145). These compounds mainly act by interfering with the mitogenic activity of growth factors, such as the insulin-like growth factor-I (IGF-I). The present experiments were performed to clarify whether GnRH agonists might also affect the migratory and the invasive behavior of androgen-independent prostate cancer cells and to define their mechanism of action. First we showed that the GnRH agonist Leuprolide reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane. Experiments were then performed to clarify whether the GnRH agonist might act by interfering with the pro-metastatic activity of IGF-I. We found that, in androgen-independent prostate cancer cells, Leuprolide: a) interferes with the IGF-I system (receptor protein expression and tyrosine-phosphorylation); b) abrogates the IGF-I-induced phosphorylation of Akt (a kinase previously shown by us to mediate the pro-metastatic activity of IGF-I in prostate cancer cells); c) counteracts the migration and the invasive activity of the cells stimulated by IGF-I; d) abolishes the effects of IGF-I on cell morphology, on actin cytoskeleton organization and on alphavbeta3 integrin expression/cellular localization. These data indicate that GnRH agonists, in addition to their well known antiproliferative effect, can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen-independent prostate cancer cells, expressing the GnRH receptor. GnRH agonists act by interfering with the pro-metastatic activity of the growth factor IGF-I.
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January 2007