Engineered Mesoporous Silica-Based Nanoparticles: Characterization of Surface Properties.

Mesoporous silica-based nanomaterials have emerged as multifunctional platforms with applications spanning catalysis, medicine, and nanotechnology. Since their synthesis in the early 1990s, these materials have attracted considerable interest due to their unique properties, including high surface area, tunable pore size, and customizable surface chemistry. This article explores the surface properties of a series of MSU-type mesoporous silica nanoparticles, elucidating the impact of different functionalization strategies on surface characteristics. Through an extensive characterization utilizing various techniques, such as FTIR, Z-potential, and nitrogen adsorption porosimetry, insights into the surface modifications of mesoporous silica nanoparticles are provided, contributing to a deeper understanding of their nanostructure and related interactions, and paving the way to possible unexpected actionability and potential applications.

Impact of COVID-19 Lockdown on Metabolic/Inflammatory Profile in Adolescents: Cellular Studies and Predictive Biomarkers.

CONTEXT: The COVID-19 pandemic and its lockdown restrictions changed people's lifestyles with potential negative impact on health. OBJECTIVE: This longitudinal study aimed to assess the COVID-19 lockdown influence on the adherence to the Mediterranean diet (MD) pattern and its effects on the metabolic inflammatory profile in a cohort of healthy adolescents. METHODS: We analyzed anthropometric measurements, body composition, and MD adherence along with serum metabolic and inflammatory profile in 77 healthy adolescents from southern Italy before and after the COVID-19 pandemic lockdown. Additionally, we evaluated the biological properties of prelockdown and postlockdown serum on human HepG2 and HuH-7 hepatic cells. RESULTS: We did not observe any significant differences in anthropometric and body composition parameters as well as MD adherence score in adolescents between prelockdown and postlockdown COVID-19. Intriguingly, although the metabolic profile of adolescents postlockdown was within the normal range, we evidenced increased levels of fasting glucose, triglycerides, total cholesterol, and low-density lipoprotein (LDL) along with a reduction in high-density lipoprotein (HDL) in postlockdown compared with prelockdown adolescent serum. In addition, elevated levels of tumor necrosis factor (TNF)-α, interleukin-1ß, and ferritin were found in postlockdown adolescents compared with their prelockdown counterparts. Consistent with the biochemical parameters, we observed enhanced lipid accumulation with altered mitochondrial functions and increased reactive oxygen species production in HepG2 and HuH-7 cells treated with pooled serum from postlockdown with respect to prelockdown period. Receiver operator characteristic curve analysis identified total cholesterol, LDL, HDL, TNF-α, and ferritin to be predictive serum markers for metabolic and inflammatory profiling after the lockdown period. CONCLUSION: Our findings highlight that the COVID-19 lockdown, forcing sedentary behavior, had a negative impact on adolescents' metabolic and inflammatory profile which may result in long-term poor health outcomes.

FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity.

Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.

Androgens Modulate Bcl-2 Agonist of Cell Death (BAD) Expression and Function in Breast Cancer Cells.

Androgen receptor (AR) expression in estrogen receptor-positive (ER+) breast cancer (BC) correlates with lower tumor grade and a better clinical outcome. Additionally, in normal mammary epithelium or ER+ BC preclinical models, androgens counteract basal/ER-dependent proliferation. Here, we report an additional mechanism, underlining the protective role exerted by AR. Specifically, the activation of intracellular AR upregulates the Bcl-2-family protein BAD, and TCGA database analyses show that in ER+ BC, BAD expression is associated with better disease-free survival. Ligand-activated AR influences its own and BAD cellular compartmentalization by enhancing levels in the nucleus, as well as in mitochondrial fractions. In both compartments, BAD exerts unconventional functions. In the nucleus, BAD and AR physically interact and, upon androgen stimulation, are recruited at the AP-1 and ARE sites within the cyclin D1 promoter region, contributing to explaining the anti-proliferative effect of androgens in BC cells. Androgens cause an enrichment in BAD and AR content in the mitochondria, correlated with a decrease in mitochondrial function. Thus, we have defined a novel mechanism by which androgens modulate BAD expression, its mitochondria localization, and nuclear content to force its ability to act as a cell cycle inhibitor, strengthening the protective role of androgen signaling in estrogen-responsive BCs.

Peptides Targeting HER2-Positive Breast Cancer Cells and Applications in Tumor Imaging and Delivery of Chemotherapeutics.

Breast cancer represents the most common cancer type and one of the major leading causes of death in the female worldwide population. Overexpression of HER2, a transmembrane glycoprotein related to the epidermal growth factor receptor, results in a biologically and clinically aggressive breast cancer subtype. It is also the primary driver for tumor detection and progression and, in addition to being an important prognostic factor in women diagnosed with breast cancer, HER2 is a widely known therapeutic target for drug development. The aim of this review is to provide an updated overview of the main approaches for the diagnosis and treatment of HER2-positive breast cancer proposed in the literature over the past decade. We focused on the different targeting strategies involving antibodies and peptides that have been explored with their relative outcomes and current limitations that need to be improved. The review also encompasses a discussion on targeted peptides acting as probes for molecular imaging. By using different types of HER2-targeting strategies, nanotechnology promises to overcome some of the current clinical challenges by developing novel HER2-guided nanosystems suitable as powerful tools in breast cancer imaging, targeting, and therapy.

Hybrid Polymer-Silica Nanostructured Materials for Environmental Remediation.

Due to the ever-growing global population, it is necessary to develop highly effective processes that minimize the impact of human activities and consumption on the environment. The levels of organic and inorganic contaminants have rapidly increased in recent years, posing a threat to ecosystems. Removing these toxic pollutants from the environment is a challenging task that requires physical, chemical, and biological methods. An effective solution involves the use of novel engineered materials, such as silica-based nanostructured materials, which exhibit a high removal capacity for various pollutants. The starting materials are also thermally and mechanically stable, allowing for easy design and development at the nanoscale through versatile functionalization procedures, enabling their effective use in pollutant capture. However, improvements concerning mechanical properties or applicability for repeated cycles may be required to refine their structural features. This review focuses on hybrid/composite polymer-silica nanostructured materials. The state of the art in nanomaterial synthesis, different techniques of functionalization, and polymer grafting are described. Furthermore, it explores the application of polymer-modified nanostructured materials for the capture of heavy metals, dyes, hydrocarbons and petroleum derivatives, drugs, and other organic compounds. The paper concludes by offering recommendations for future research aimed at advancing the application of polymer-silica nanostructured materials in the efficiency of pollutant uptake.

Serum from Adolescents with High Polyphenol Intake Exhibits Improved Lipid Profile and Prevents Lipid Accumulation in HepG2 Human Liver Cells.

The traditional Mediterranean diet (MD) is characterized by a high phenolic-rich food intake, including in particular vegetables and fruits, but also legumes, whole grain cereals, nuts, and extra virgin olive oil. Evidence for beneficial effects of polyphenols in humans depends on the amount consumed and on their bioavailability. Here, we evaluated the association between the estimated polyphenol intake by fruits and vegetables food source and serum biochemical parameters in healthy adolescents, recruited into the DIMENU research project. Categorizing adolescents into three groups according to their estimated total polyphenol intake, we found that adolescents who declared high consumption of polyphenols had a higher adherence to the MD and had a better serum lipid profile than adolescents consuming low amounts of polyphenols. Moreover, using human HepG2 liver cells treated with oleic acid as an in vitro model for studying lipid accumulation, we showed that intracellular lipid accumulation is alleviated by serum from adolescents consuming a polyphenol-rich diet following MD recommendations. Our data underline the importance of promoting adherence to the typical MD foods as a superior strategy to prevent metabolic and chronic diseases and to ensure a better quality of life among adolescents.

The Omega-3 Docosahexaenoyl Ethanolamide Reduces CCL5 Secretion in Triple Negative Breast Cancer Cells Affecting Tumor Progression and Macrophage Recruitment.

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.

From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

LPL, FNDC5 and PPARγ gene polymorphisms related to body composition parameters and lipid metabolic profile in adolescents from Southern Italy.

BACKGROUND: Plasma lipid profile and anthropometric variables are known to be under strong genetic control and the identification of genetic variants associated with bioclinical parameters is of considerable public health importance. In this study, a young cohort of healthy individuals was genotyped for genes related to health and pathological conditions, to analyze the association of single nucleotide polymorphisms (SNPs) with different bioclinical parameters, adherence to the Mediterranean Diet (MD) and physical activity, studying the role of lifestyle and body composition parameters on biochemical metabolic profile. METHODS: Association analysis of single variants in the genes of lipoprotein lipase (LPL), fibronectin type III domain containing protein 5 (FNDC5), and peroxisome proliferator-activated receptor-gamma (PPARγ) and haplotype analyses were performed. RESULTS: Multiple (n = 14) common variants in the three genes demonstrated a significant effect on plasma lipoprotein-lipid levels and/or on biochemical parameters in our sample. Specifically, SNPs were related to lipid metabolism (rs3866471, rs4922115, rs11570892, rs248, rs316, rs1059507, rs1801282) or glycemic profile (rs3208305) or anthropometric parameters (rs3480, rs726344, rs1570569) for a total of 26 significant associations (P < 0.01 and/or P < 0.05) and two haplotypes, for the first time, were strongly associated with lipid and body composition parameters. Interestingly, we identified twenty-four new variants not previously described in the literature and a novel significant association between rs80143795 and body composition. CONCLUSIONS: In this study we confirm the association between these SNPs on lipid metabolism and body parameters also in a young cohort, indicating the important role of these genetic factors as determinants of health.

Impact of Mediterranean Diet Food Choices and Physical Activity on Serum Metabolic Profile in Healthy Adolescents: Findings from the DIMENU Project.

Adolescent nutrition and healthy dietary patterns, particularly the Mediterranean diet (MD), have been associated with improved health status and decreased risk of various chronic and metabolic diseases later in life. The aim of this study was to evaluate the impact of the Mediterranean food choices on lipid and glycemic metabolic profile in the total population and in adolescents grouped according to their physical activity (PA) levels at the time of recruitment (T0) and after six months from the administration of a personalized Mediterranean meal plan (T1). As part of the DIMENU study, 85 adolescents underwent measurements of lipid and glucose metabolic profile at T0 and T1. Using three positive items from KIDMED test related to the consumption of typical Mediterranean food (olive oil, fish, and nuts) and three negative items on dietary habits (going to fast-food, consuming biscuits, and candies), we categorized adolescents into six sets in which biochemical parameters were analyzed. In the total sample, significant reductions in serum total cholesterol, LDL, and glucose concentrations were observed for all the sets over the study period. Notably, active subjects, who had a better serum metabolic profile, showed significant improvements of glycemic control after 6 month follow up, while in sedentary adolescents and in those performing moderate PA significant reduction in glycemia, total cholesterol, and LDL was found in all sets. In conclusion, adopting the typical Mediterranean food choices led to a significant reduction in glucose and lipid profile in healthy adolescents, thus making the MD and PA a winning combination for health status.

FoxO3a Inhibits Tamoxifen-Resistant Breast Cancer Progression by Inducing Integrin α5 Expression.

Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor α-positive (ERα+) breast cancer (BC). Here, the role of the Forkhead box class O (FoxO)3a transcription factor in tumor progression has been evaluated in tamoxifen-resistant BC cells (TamR), expressing lower levels of FoxO3a compared to sensitive ones. FoxO3a re-expression reduces TamR motility (wound-healing and transmigration assays) and invasiveness (matrigel transwell invasion assays) through the mRNA (qRT-PCR) and protein (Western blot) induction of the integrin α5 subunit of the α5ß1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion and signaling. The induction occurs through FoxO3a binding to a specific Forkhead responsive core sequence located on the integrin α5 promoter (cloning, luciferase, and ChIP assays). Moreover, FoxO3a failed to inhibit migration and invasion in integrin α5 silenced (siRNA) cells, demonstrating integrin α5 involvement in both processes. Finally, using large-scale gene expression data sets, a strong positive correlation between FoxO3a and integrin α5 in ERα+, but not in ER-negative (ERα-), BC patients emerged. Altogether, our data show how the oncosuppressor FoxO3a, by increasing the expression of its novel transcriptional target integrin α5, reverts the phenotype of endocrine-resistant BC toward a lower aggressiveness.

Nutrition Education Program and Physical Activity Improve the Adherence to the Mediterranean Diet: Impact on Inflammatory Biomarker Levels in Healthy Adolescents From the DIMENU Longitudinal Study.

Adherence to Mediterranean diet (MD) and physical activity (PA) in adolescence represent powerful indicators of healthy lifestyles in adulthood. The aim of this longitudinal study was to investigate the impact of nutrition education program (NEP) on the adherence to the MD and on the inflammatory status in healthy adolescents, categorized into three groups according to their level of PA (inactivity, moderate intensity, and vigorous intensity). As a part of the DIMENU (Dieta Mediterranea & Nuoto) study, 85 adolescents (aged 14-17 years) participated in the nutrition education sessions provided by a team of nutritionists and endocrinologists at T0. All participants underwent anthropometric measurements, bio-impedentiometric analysis (BIA), and measurements of inflammatory biomarkers such as ferritin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Data were collected at baseline (T0) and 6 months after NEP (T1). To assess the adherence to the MD, we used KIDMED score. In our adolescents, we found an average MD adherence, which was increased at T1 compared with T0 (T0: 6.03 ± 2.33 vs. T1: 6.96 ± 2.03, p = 0.002), with an enhanced percentage of adolescents with optimal (≥8 score) MD adherence over the study period (T0: 24.71% vs. T1: 43.52%, p = 0.001). Interestingly, in linear mixed-effects models, we found that NEP and vigorous-intensity PA levels independently influenced KIDMED score (ß = 0.868, p < 0.0001 and ß = 1.567, p = 0.009, respectively). Using ANOVA, NEP had significant effects on serum ferritin levels (p < 0.001), while either NEP or PA influenced ESR (p = 0.035 and 0.002, respectively). We also observed in linear mixed-effects models that NEP had a negative effect on ferritin and CRP (ß = -14.763, p < 0.001 and ß = -0.714, p = 0.02, respectively). Our results suggest the usefulness to promote healthy lifestyle, including either nutrition education interventions, or PA to improve MD adherence and to impact the inflammatory status in adolescence as a strategy for the prevention of chronic non-communicable diseases over the entire lifespan.

Potential Antioxidant and Anti-Inflammatory Properties of Serum from Healthy Adolescents with Optimal Mediterranean Diet Adherence: Findings from DIMENU Cross-Sectional Study.

During adolescence, health status is influenced by several factors, among which dietary pattern is a crucial element of lifestyle in terms of prevention and treatment of metabolic and chronic diseases. The most studied healthy dietary pattern is the Mediterranean Diet (MD), due to a combination of foods that are rich in antioxidant and anti-inflammatory nutrients. The aim of this study, carried out in healthy adolescents from the DIMENU study, is to assess the adherence to the MD, as well as the dietary nutrient intake and to evaluate the potential antioxidant and anti-inflammatory properties of sera from participants grouped according to the MD score. Using the KIDMED score, as the MD quality index for children and teenagers, we found that the adolescents in this study had an average adherence to the MD (6.71 ± 2.58). Adolescents were clustered into three groups based on their MD adherence. Assessment of quality by 24 h recall revealed higher intakes in polyunsaturated fatty acid (PUFA)/saturated fatty acid (SFA) ratio, dietary fibers, vitamins, and total oxygen radical absorbance capacity (ORAC) in the optimal than in poor MD adherence group. We observed that dietary PUFA/SFA ratio was negatively correlated with serum C-Reactive Protein levels, and total dietary fibers were inversely correlated with Erythrocyte Sedimentation Rate values, while total ORAC was directly correlated with serum glucose concentrations. Interestingly, the reactive oxygen metabolite (ROM) concentrations, determined by the ROM assay, were significantly lower in pooled sera from optimal than poor adherers. Finally, using lipopolysaccharide-stimulated human macrophages, as an in vitro model of acute inflammation, we found a reduced secretion of pro-inflammatory cytokines upon serum treatment from adolescents with optimal respect to medium and poor MD adherence. Our results highlight the anti-inflammatory and antioxidant properties of serum from adolescents with healthy nutrition in terms of adherence to the MD, which may have a positive impact on the prevention of chronic diseases in adulthood.

The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.

Production of Plant-Derived Oleuropein Aglycone by a Combined Membrane Process and Evaluation of Its Breast Anticancer Properties.

Natural products and herbal therapies represent a thriving field of research, but methods for the production of plant-derived compounds with a significative biological activity by synthetic methods are required. Conventional commercial production by chemical synthesis or solvent extraction is not yet sustainable and economical because toxic solvents are used, the process involves many steps, and there is generally a low amount of the product produced, which is often mixed with other or similar by-products. For this reason, alternative, sustainable, greener, and more efficient processes are required. Membrane processes are recognized worldwide as green technologies since they promote waste minimization, material diversity, efficient separation, energy saving, process intensification, and integration. This article describes the production, characterization, and utilization of bioactive compounds derived from renewable waste material (olive leaves) as drug candidates in breast cancer (BC) treatment. In particular, an integrated membrane process [composed by a membrane bioreactor (MBR) and a membrane emulsification (ME) system] was developed to produce a purified non-commercially available phytotherapic compound: the oleuropein aglycone (OLA). This method achieves a 93% conversion of the substrate (oleuropein) and enables the extraction of the compound of interest with 90% efficiency in sustainable conditions. The bioderived compound exercised pro-apoptotic and antiproliferative activities against MDA-MB-231 and Tamoxifen-resistant MCF-7 (MCF-7/TR) cells, suggesting it as a potential agent for the treatment of breast cancer including hormonal resistance therapies.

Bortezomib-Loaded Mesoporous Silica Nanoparticles Selectively Alter Metabolism and Induce Death in Multiple Myeloma Cells.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR-) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR- normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy.

Evidence for Enhanced Exosome Production in Aromatase Inhibitor-Resistant Breast Cancer Cells.

Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence of AI resistance (AIR). Exosomes act as vehicles to engender cancer progression and drug resistance. The goal of this work was to study exosome contribution in AIR mechanisms, using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term Estrogen Deprived) subline, modeling AIR. We found that exosome secretion was significantly increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators in cancer, that are significantly mapped in "small GTPase-mediated signal transduction", "protein transport" and "vesicle-mediated transport" Gene Ontology categories. Expression of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence, for the first time, that AIR breast cancer cells display an increased capability to release exosomes, which may be associated with an enhanced Rab GTPase expression. These data provide the rationale for further studies directed at clarifying exosome's role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic targets for the management of hormone-resistant breast cancers.

Controlled Release of 5-FU from Chi-DHA Nanoparticles Synthetized with Ionic Gelation Technique: Evaluation of Release Profile Kinetics and Cytotoxicity Effect.

The ionic gelation technique allows us to obtain nanoparticles able to function as carriers for hydrophobic anticancer drugs, such as 5-fluoruracil (5-FU). In this study, reticulated chitosan- docosahexaenoic acid (Chi-DHAr) nanoparticles were synthesized by using a chemical reaction between amine groups of chitosan (Chi) and carboxylic acids of docosahexaenoic acid (DHA) and the presence of a link between Chi and DHA was confirmed by FT-IR, while the size and morphology of the obtained Chi-DHAr nanoparticles was evaluated with dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. Drug-loading content (DLC) and drug-loading efficiency (DLE) of 5-FU in Chi-DHAr nanoparticles were 33.74 ± 0.19% and 7.9 ± 0.26%, respectively, while in the non-functionalized nanoparticles (Chir + 5FU), DLC, and DLE were in the ranges of 23.73 ± 0.14%, 5.62%, and 0.23%, respectively. The in vitro release profile, performed in phosphate buffer saline (PBS, pH 7.4) at 37 °C, indicated that the synthetized Chi-DHAr nanoparticles provided a sustained release of 5-FU. Based on the obtained regression coefficient value (R2), the first order kinetic model provided the best fit for both Chir and Chi-DHAr nanoparticles. Finally, cytotoxicity studies of chitosan, 5-FU, Chir, Chir + 5-FU, Chi-DHAr, and Chi-DHAr + 5-FU nanoparticles were conducted. Overall, Chi-DHAr nanoparticles proved to be much more biocompatible than Chir nanoparticles while retaining the ability to release the drug with high efficiency, especially towards specific types of cancerous cells.

Impact of Vigorous-Intensity Physical Activity on Body Composition Parameters, Lipid Profile Markers, and Irisin Levels in Adolescents: A Cross-Sectional Study.

In adolescence, health status is influenced by several factors, including dietary pattern and physical activity (PA) which are crucial elements of lifestyle in terms of prevention and treatment of metabolic and chronic diseases. The current study aimed to explore the impact of the different intensity levels of PA along with the adherence to a Mediterranean diet (MD), on body composition indices and metabolic parameters in a cohort of adolescents, thereby investigating potential predictors of health behavior in youth. This cross-sectional study was carried out among 92 participants (44 girls and 48 boys, aged 14 to 17 years), which were divided into the following three groups according to intensity levels of PA: Group A (physical inactivity), Group B (moderate PA), and Group C (vigorous-intensity PA). The Questionnaire of Adherence to the Mediterranean Diet (KIDMED test) was used to assess both diet composition and adherence to a MD. All subjects underwent anthropometric measurements, bio-impedentiometric analysis for body composition parameters, and biochemical and hormonal measurements. The majority of adolescents (60.87%) had a medium adherence to the MD, and even a better distribution of food rates was found in adolescents performing vigorous-intensity PA. A comparison of anthropometric measurements and body composition parameters among groups showed that body mass index and fat mass (FM) were significantly lower while body cell mass (BCM), free fat mass (FFM), phase angle (PhA), and total body water (TBW) were higher in Group C adolescents as compared with those of Group A. In Group C, insulin resistance (HOMA-IR) was reduced and insulin levels were inversely associated with FFM (r = -0.454 and p = 0.004) and directly correlated with FM (r = 0.331 and p = 0.003). In the same Group C, we observed elevated serum irisin levels and lower lipid profile markers as compared with Group A. Interestingly, irisin negatively correlated with both total cholesterol (r = -0.428 and p = 0.04) and LDL (r = -0.468 and p = 0.02) in Group C. Finally, a receiver operator characteristic curve (ROC) analysis revealed irisin, LDL, HDL, and body composition variables (FFM, BMC, PhA, and TBW) as the most predictive measures for vigorous-intensity PA. Our results highlight the importance of developing healthy lifestyle programs that include improving the intensity of PA among a young population as a superior strategy for ensuring a better quality of life.