Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

ERα/LKB1 complex upregulates E-cadherin expression and stimulates breast cancer growth and progression upon adiponectin exposure.

Adiponectin is the major adipocytes-secreted protein involved in obesity-related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα-positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα-coactivator. Here, we showed that adiponectin-mediated ERα transactivation enhances E-cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E-cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E-cadherin expression in ERα-positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E-cadherin gene promoter by ERα/LKB1-complex. The impact of E-cadherin on ERα-positive breast cancer cell proliferation comes from the evidence that in the presence of E-cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E-cadherin connects cell polarity and growth, we investigated if the adiponectin-enhanced E-cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin-treated MCF-7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF-7 cells revealed an enhanced E-cadherin-mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF-7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin-treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E-cadherin expression, alters cell polarity and stimulates ERα-positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden.

Analysis of circulating extracellular vesicle derived microRNAs in breast cancer patients with obesity: a potential role for Let-7a.

BACKGROUND: The incidence of obesity, a known risk factor for several metabolic and chronic diseases, including numerous malignancies, has risen sharply in the world. Various clinical studies demonstrate that excessive Body Mass Index (BMI) may worsen the incidence, prognosis, and mortality rates of breast cancer. Thus, understanding the link tying up obesity and breast cancer onset and progression is critically important, as it can impact patients' survival and quality of life. Recently, circulating extracellular vesicle (EV) derived miRNAs have attracted much attention for their diagnostic, prognostic and therapeutic potential in oncology research. Although the potential role of EV-derived miRNAs in the early detection of breast cancer has been repeatedly mentioned, screening of miRNAs packaged within serum EVs has not yet been reported in patients with obesity. METHODS: Circulating EVs were isolated from normal weight (NW), and overweight/obese (OW/Ob) breast cancer patients and characterized by Transmission Electron Microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and protein marker expression. Evaluation of EV-associated miRNAs was conducted in a screening (RNA-seq) and a validation (qRT-PCR) cohort. Bioinformatic analysis was performed to uncover significantly enriched biological processes, molecular functions and pathways. ROC and Kaplain-Meier survival analyses were used for clinical significance. RESULTS: Comparison of serum EV-derived miRNAs from NW and OW/Ob patients detected seven differentially expressed miRNAs (let-7a-5p, miR-122-5p, miR-30d-5p, miR-126-3p, miR-27b-3p, miR-4772-3p, and miR-10a-5p) in the screening cohort. GO analysis revealed the enrichment of protein phosphorylation, intracellular signal transduction, signal transduction, and vesicle-mediated transport among the top biological processes. In addition, the target genes were significantly enriched in pathways related to PI3K/Akt, growth hormones, and insulin signalings, which are all involved in obesity-related diseases and/or breast cancer progression. In the validation cohort, qRT-PCR confirmed a significant down-regulation of EV-derived let-7a in the serum of OW/Ob breast cancer patients compared to NW patients. Let-7a levels also exhibited a negative correlation with BMI values. Importantly, decreased let-7a miRNA expression was associated with higher tumor grade and poor survival in patients with breast cancer. CONCLUSION: These results suggest that serum-EV derived miRNAs may reflect a differential profile in relation to a patient's BMI, which, once validated in larger cohorts of patients, could provide insights into novel specific biomarkers and innovative targets to prevent the progression of obesity-mediated breast cancer.

Unraveling the Role of Adiponectin Receptors in Obesity-Related Breast Cancer.

Obesity has a noteworthy role in breast tumor initiation and progression. Among the mechanisms proposed, the most validated is the development of chronic low-grade inflammation, supported by immune cell infiltration along with dysfunction in adipose tissue biology, characterized by an imbalance in adipocytokines secretion and alteration of their receptors within the tumor microenvironment. Many of these receptors belong to the seven-transmembrane receptor family, which are involved in physiological features, such as immune responses and metabolism, as well as in the development and progression of several malignancies, including breast cancer. These receptors are classified as canonical (G protein-coupled receptors, GPCRs) and atypical receptors, which fail to interact and activate G proteins. Among the atypical receptors, adiponectin receptors (AdipoRs) mediate the effect of adiponectin, the most abundant adipocytes-derived hormone, on breast cancer cell proliferation, whose serum levels are reduced in obesity. The adiponectin/AdipoRs axis is becoming increasingly important regarding its role in breast tumorigenesis and as a therapeutic target for breast cancer treatment. The objectives of this review are as follows: to point out the structural and functional differences between GPCRs and AdipoRs, and to focus on the effect of AdipoRs activation in the development and progression of obesity-dependent breast cancer.

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.

Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.

miRNAs in the Box: Potential Diagnostic Role for Extracellular Vesicle-Packaged miRNA-27a and miRNA-128 in Breast Cancer.

Circulating extracellular vesicle (EV)-derived microRNAs (miRNAs) are now considered the next generation of cancer "theranostic" tools, with strong clinical relevance. Although their potential in breast cancer diagnosis has been widely reported, further studies are still required to address this challenging issue. The present study examined the expression profiles of EV-packaged miRNAs to identify novel miRNA signatures in breast cancer and verified their diagnostic accuracy. Circulating EVs were isolated from healthy controls and breast cancer patients and characterized following the MISEV 2018 guidelines. RNA-sequencing and real-time PCR showed that miRNA-27a and miRNA-128 were significantly down-regulated in patient-derived EVs compared to controls in screening and validation cohorts. Bioinformatics analyses of miRNA-target genes indicated several enriched biological processes/pathways related to breast cancer. Receiver operating characteristic (ROC) curves highlighted the ability of these EV-miRNAs to distinguish breast cancer patients from non-cancer controls. According to other reports, the levels of EV-miRNA-27a and EV-miRNA-128 are not associated with their circulating ones. Finally, evidence from the studies included in our systematic review underscores how the expression of these miRNAs in biofluids is still underinvestigated. Our findings unraveled the role of serum EV-derived miRNA-27a and miRNA-128 in breast cancer, encouraging further investigation of these two miRNAs within EVs towards improved breast cancer detection.

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.

Proteomic Profiling of Extracellular Vesicles Released by Leptin-Treated Breast Cancer Cells: A Potential Role in Cancer Metabolism.

Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese patients.

The weight of obesity in breast cancer progression and metastasis: Clinical and molecular perspectives.

The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.

Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma Growth.

Although in past decades the adipokine leptin and its own receptor have been considered as significant cancer biomarkers, their potential involvement in human testicular seminoma growth and progression remains unexplored. Here, we showed that the expression of leptin and its receptor was significantly higher in human testicular seminoma compared with normal adult testis. Human seminoma cell line TCam-2 also expressed leptin along with the long and short isoforms of leptin receptor, and in response to leptin treatment showed enhanced activation of its downstream effectors. In line with these results, leptin stimulation significantly increased the proliferation and migration of TCam-2 cells. Treatment of TCam-2 cells with the peptide Leu-Asp-Phe-Ile (LDFI), a full leptin-receptor antagonist, completely reversed the leptin-mediated effects on cell growth and motility as well as reduced the expression of several leptin-induced target genes. More importantly, the in vivo xenograft experiments showed that LDFI treatment markedly decreased seminoma tumor growth. Interestingly, LDFI-treated tumors showed reduced levels of the proliferation marker Ki-67 as well as decreased expression of leptin-regulated genes. Taken together, these data identify, for the first time, leptin as a key factor able to affect testicular seminoma behavior, highlighting leptin receptor as a potential target for novel potential treatments in this type of cancer.

Alternative Splicing of ALS Genes: Misregulation and Potential Therapies.

Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Parkinson's, Alzheimer's, and Huntington's disease affect a rapidly increasing population worldwide. Although common pathogenic mechanisms have been identified (e.g., protein aggregation or dysfunction, immune response alteration and axonal degeneration), the molecular events underlying timing, dosage, expression, and location of RNA molecules are still not fully elucidated. In particular, the alternative splicing (AS) mechanism is a crucial player in RNA processing and represents a fundamental determinant for brain development, as well as for the physiological functions of neuronal circuits. Although in recent years our knowledge of AS events has increased substantially, deciphering the molecular interconnections between splicing and ALS remains a complex task and still requires considerable efforts. In the present review, we will summarize the current scientific evidence outlining the involvement of AS in the pathogenic processes of ALS. We will also focus on recent insights concerning the tuning of splicing mechanisms by epigenomic and epi-transcriptomic regulation, providing an overview of the available genomic technologies to investigate AS drivers on a genome-wide scale, even at a single-cell level resolution. In the future, gene therapy strategies and RNA-based technologies may be utilized to intercept or modulate the splicing mechanism and produce beneficial effects against ALS.

Adherence to the Mediterranean diet pattern among university staff: a cross-sectional web-based epidemiological study in Southern Italy.

In this cross-sectional web-survey, carried out in 340 employees (24-67 years) among university staff of Southern Italy, we assessed the adherence to the Mediterranean Diet (MD). Using an online questionnaire based on validated 14-point MD Adherence Screener (MEDAS), the mean of the score was 7.34 (±1.9) for total population independently of sex. In population divided by the cut-off age of 45 years, MD adherence resulted significantly lower in younger respect to older group (p = .003). In multiple regression analyses we observed the direct association between MEDAS score and older age group also after adjustments. Importantly, in all sample the percentage of adherers to recommendations for fruits, nuts and fish resulted outside dietary guidelines. The present findings underscore the need to develop healthy education programmes aimed to improve the consumption of several components of the MD, particularly among young adults, in order to prevent the early onset of chronic non-transmittable diseases.

Natural and Synthetic PPARγ Ligands in Tumor Microenvironment: A New Potential Strategy against Breast Cancer.

Multiple lines of evidence indicate that activation of the peroxisome proliferator-activated receptor γ (PPARγ) by natural or synthetic ligands exerts tumor suppressive effects in different types of cancer, including breast carcinoma. Over the past decades a new picture of breast cancer as a complex disease consisting of neoplastic epithelial cells and surrounding stroma named the tumor microenvironment (TME) has emerged. Indeed, TME is now recognized as a pivotal element for breast cancer development and progression. Novel strategies targeting both epithelial and stromal components are under development or undergoing clinical trials. In this context, the aim of the present review is to summarize PPARγ activity in breast TME focusing on the role of this receptor on both epithelial/stromal cells and extracellular matrix components of the breast cancer microenvironment. The information provided from the in vitro and in vivo research indicates PPARγ ligands as potential agents with regards to the battle against breast cancer.

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.

AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells.

BACKGROUND: Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. METHODS: Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT-PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA. RESULTS: Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E2-induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter. CONCLUSIONS: Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.

Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERα signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERα-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERα-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERα-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERα-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERα-negative breast cancer, also opportunely combined with antiestrogen therapy. -Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Andò, S. Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.

The Emerging Role of Adiponectin in Female Malignancies.

Obesity, characterized by excess body weight, is now accepted as a hazardous health condition and an oncogenic factor. In different epidemiological studies obesity has been described as a risk factor in several malignancies. Some biological mechanisms that orchestrate obesity-cancer interaction have been discovered, although others are still not completely understood. The unbalanced secretion of biomolecules, called "adipokines", released by adipocytes strongly influences obesity-related cancer development. Among these adipokines, adiponectin exerts a critical role. Physiologically adiponectin governs glucose levels and lipid metabolism and is fundamental in the reproductive system. Low adiponectin circulating levels have been found in obese patients, in which its protective effects were lost. In this review, we summarize the epidemiological, in vivo and in vitro data in order to highlight how adiponectin may affect obesity-associated female cancers.

A Systems Biology Approach for Personalized Medicine in Refractory Epilepsy.

Epilepsy refers to a common chronic neurological disorder that affects all age groups. Unfortunately, antiepileptic drugs are ineffective in about one-third of patients. The complex interindividual variability influences the response to drug treatment rendering the therapeutic failure one of the most relevant problems in clinical practice also for increased hospitalizations and healthcare costs. Recent advances in the genetics and neurobiology of epilepsies are laying the groundwork for a new personalized medicine, focused on the reversal or avoidance of the pathophysiological effects of specific gene mutations. This could lead to a significant improvement in the efficacy and safety of treatments for epilepsy, targeting the biological mechanisms responsible for epilepsy in each individual. In this review article, we focus on the mechanism of the epilepsy pharmacoresistance and highlight the use of a systems biology approach for personalized medicine in refractory epilepsy.

Glucocorticoid Receptor as a Potential Target to Decrease Aromatase Expression and Inhibit Leydig Tumor Growth.

Leydig cell tumors are the most frequent interstitial neoplasms of the testis with increased incidence in recent years. They are hormonally active and are considered one of the steroid-secreting tumors. Although usually benign, the malignant phenotype responds poorly to conventional chemotherapy or radiation, highlighting the need to identify new therapeutic targets for treatment. Here, we identified a novel glucocorticoid-mediated mechanism that controls cell growth in Leydig cell tumors. We found that a synthetic glucocorticoid receptor agonist, dexamethasone, reduces cell proliferation in rat Leydig tumor cells by decreasing the expression and the enzymatic activity of the estrogen-producing enzyme aromatase. This inhibitory effect relies on the ability of activated glucocorticoid receptor to regulate the aromatase gene transcriptional activity through the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors to a newly identified putative glucocorticoid responsive element within the aromatase promoter II. Our in vivo studies reveal a reduction of tumor growth, after dexamethasone treatment, in animal xenografts. Tumors from dexamethasone-treated mice exhibit a decrease in the expression of the proliferation marker Ki-67 and the aromatase enzyme. Our data demonstrate that activated glucocorticoid receptor, decreasing aromatase expression, induces Leydig tumor regression both in vitro and in vivo, suggesting that glucocorticoid receptor might be a potential target for the therapy of Leydig cell tumors.