On Bose-Einstein condensates in the Thomas-Fermi regime

We study a system of N trapped bosons in the Thomas-Fermi regime with an interacting pair potential of the form (gN) N3 beta-1V( N-beta x), for some beta is an element of(0, 1/3) and gN diverging as N ->infinity. We prove that there is complete Bose-Einstein condensation at the level of the ground state and, furthermore, that, if beta is an element of (0, 1/6), condensation is preserved by the time evolution

Potential biomarkers and novel pharmacological targets in protein aggregation-related neurodegenerative diseases

The aggregation of specific proteins plays a pivotal role in the etiopathogenesis of several neurodegenerative diseases (NDs). β-Amyloid (Aβ) peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated protein tau are the two main neuropathological lesions in Alzheimer's disease. Meanwhile, Parkinson's disease is defined by the presence of intraneuronal inclusions (Lewy bodies), in which α-synuclein (α-syn) has been identified as a major protein component. The current literature provides considerable insights into the mechanisms underlying oligomeric-related neurodegeneration, as well as the relationship between protein aggregation and ND, thus facilitating the development of novel putative biomarkers and/or pharmacological targets. Recently, α-syn, tau and Aβ have been shown to interact each other or with other "pathological proteins" to form toxic heteroaggregates. These latest findings are overcoming the concept that each neurodegenerative disease is related to the misfolding of a single specific protein. In this review, potential opportunities and pharmacological approaches targeting α-syn, tau and Aβ and their oligomeric forms are highlighted with examples from recent studies. Protein aggregation as a biomarker of NDs, in both the brain and peripheral fluids, is deeply explored. Finally, the relationship between biomarker establishment and assessment and their use as diagnostics or therapeutic targets are discussed

TUMOR NECROSIS FACTOR ALPHA TRIGGERS OSTEOGENESIS THROUGH THE INVOVLVEMENT OF Gs-COUPLED RECEPTOR SIGNALS

Tumor Necrosis Factor alpha (TNF-α) plays a role in several chronic immune and inflammatory diseases, where inhibition of TNF has led to significant clinical improvement. Actually, this cytokine is involved in bone healing by affecting mesenchymal stem cell (MSC) behaviour in a dose- and time-dependent manner1,2. Indeed, in the early inflammatory phase after fracture, low doses of TNF-α are required to favour MSC migration, survival and differentiation, thus initiating bone repair. At high dose, in the chronic uncontrolled phase of inflammation, the same cytokine has destructive effects on bone and contribute to bone loss1,2. As other soluble factors released in cell microenvironment, the cytokine modulates expression and functioning of different G protein coupled receptors (GPCRs) and of their regulatory proteins (GPCR regulated kinases, GRKs)3, thus dictating the final biological outcome of these receptor proteins in controlling bone anabolic processes. Herein, we investigated the effects of TNF-α low doses on the expression and functional responsiveness of A2B adenosine receptor (A2B AR), a Gs-coupled puringergic receptor that controls mesenchymal stem cell (MSC) differentiation to osteoblasts4,5. In our hands, TNF-α exerted a pro-differentiating action on MSCs, pushing towards an osteoblast phenotype, and without any effects on cell proliferation. The cytokine increased the A2B AR-mediated pro-osteogenic effects, through the A2B AR desensitization impairment mediated by GRK2 inhibition. These data i) support the anabolic effect of sub-massimal concentration of TNF-α in bone reparative processes and ii) demonstrate that the cytokine regulates GPCR responses by interfering with desensitization machinery and potentiating in turn the anabolic responses evoked by Gs-GPCRs. Overall these results indicated that manipulating MSC local environment by lregulates membrane receptors favouring bone remodelling

Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death

Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors (NHI-1 and NHI-2) were studied in GBM-derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type

New insights into the anticancer activity of carnosol: P53 reactivation in the U87MG human glioblastoma cell line

Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- A nd chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule

Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis

A high cell proliferation rate, invasiveness and resistance to chemotherapy are the main features of glioblastoma (GBM). GBM aggressiveness has been widely associated both with a minor population of cells presenting stem-like properties (cancer stem-like cells, CSCs) and with the ability of tumor cells to acquire a mesenchymal phenotype (epithelial-mesenchymal transition, EMT). Carnosol (CAR), a natural inhibitor of MDM2/p53 complex, has been attracted attention for its anti-cancer effects on several tumor types, including GBM. Herein, the effects of CAR on U87MG-derived CSC viability and stemness features were evaluated. CAR decreased the rate of CSC formation and promoted the CSC apoptotic cell death through p53 functional reactivation. Moreover, CAR was able to control the TNF-α/TGF-β-induced EMT, counteracting the effects of the cytokine on EMT master regulator genes (Slug, Snail, Twist and ZEB1) and modulating the activation of miR-200c, a key player in the EMT process. Finally, CAR was able to increase the temozolomide (TMZ) anti-proliferative effects. These findings demonstrate that CAR affected the different intracellular mechanism of the complex machinery that regulates GBM stemness. For the first time, the diterpene was highlighted as a promising lead for the development of agents able to decrease the stemness features, thus controlling GBM aggressiveness

Epigenetic Modifications of the α-Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects

Epigenetic regulation may contribute to the beneficial effects of physical activity against age-related neurodegeneration. For example, epigenetic alterations of the gene encoding for α-synuclein (SNCA) have been widely explored in both brain and peripheral tissues of Parkinson’s disease samples. However, no data are currently available about the effects of physical exercise on SNCA epigenetic regulation in ageing healthy subjects. The present paper explored whether, in healthy individuals, age and physical activity are related to blood intron1-SNCA (SNCAI1) methylation, as well as further parameters linked to such epigenetic modification (total, oligomeric α-synuclein and DNA methyltransferase concentrations in the blood). Here, the SNCAI1 methylation status increased with ageing, and consistent with this result, low α-synuclein levels were found in the blood. The direct relationship between SNCAI1 methylation and α-synuclein levels was observed in samples characterized by blood α-synuclein concentrations of 76.3 ng/mg protein or lower (confidence interval (CI) = 95%). In this selected population, higher physical activity reduced the total and oligomeric α-synuclein levels. Taken together, our data shed light on ageing- and physical exercise-induced changes on the SNCA methylation status and protein levels of α-synuclein

G PROTEIN-COUPLED RECEPTOR DESENSITISATION REGULATES STEM CELL DIFFERENTIATION

G-protein coupled receptors (GPCRs) play a key role in many complex biological processes, including regulation of stem cell pluripotency and differentiation. Signal transduction pathways that are activated during stem cell renewal and differentiation are shared, cross-activated or synergistic with GPCR stimulation [1]. Regulation of GPCR responses involved the activation of desensitization machinery, which started with phosphorylation of agonist-activated receptor by second messenger-dependent and/or GPCR kinases (GRKs)[1]. Besides controlling receptor responsiveness, GRKs can also act as agonist-regulated scaffolds assembling macromolecular signalosomes in the receptor environment, thereby contributing to signal propagation from cytosol to nucleus, and controlling gene transcription machinery [2]. Recent evidence suggests that the desensitization machinery fulfils a vital role in regulating cellular responses to GPCRs, and that changes in expression/functioning of these regulatory proteins may be crucial in the control of cell differentiation program [3]. These data are consistent with the notion that GPCR responsiveness may be differentially regulated during cell differentiation. In our hands, two different cellular models (oligodendrocyte precursor cells, OPCs, and mesenchymal stem cells, MSCs) were used to investigate the role of the GPCR desensitisation machinery in stem cell differentiation. During OPC differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impairs remyelination under demyelinating conditions [4]. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of p53 protein. In maturing OPCs, the inhibition of Mdm2-p53 interactions increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. In MSCs, the A2B adenosine receptor (A2BAR) has been recently emerged as the major AR involved in osteoblastogenesis [5]. Proinflammatory cytokines, such as Tumour Necrosis Factor- (TNF-, have been demonstrated to regulate MSC differentiation and bone remodelling. Herein, we show that TNF- diminished GRK2 levels in MSCs, thus blocking A2BAR desensitization. As a result, TNF- enhanced the A2BAR-mediated responses and favoured MSC differentiation to osteoblasts in response to receptor agonists. The findings get new insights for discovering of the signals at the basis of cell differentiation

Thyroglobulin measurement in the washout of fine needle aspirates for the diagnosis of suspicious cervical lymph nodes

Ultrasound-guided fine-needle aspiration cytology (FNAC) for suspicious cervical lymph nodes (CLN) is the gold standard technique for the identification of metastases from differentiated thyroid carcinomas. Thyroglobulin protein (Tgp) assay in the washout of needles employed for FNA biopsies (FNAB) has been reported to refine and support FNAC performances, especially in cases of inadequate sampling or cystic lymph nodes. In the present work, we evaluated the usefulness of routine measurement of Tgp in the FNAB washout of suspicious cervical lymph nodes (CLN), and its ability to increase the FNAC accuracy in the diagnosis of metastatic CLN. A case study of 45 CLN with histological diagnosis from 36 patients was analyzed. Histology showed metastases from papillary thyroid carcinomas (PTC) in 31 CLN, from anaplastic thyroid cancer (ATC) in 3 CLN, from medullary thyroid cancer (MTC) in 4 CLN, and metastases from extrathyroidal malignancies in 5 CLN. Two CLN analyzed were found to be non-neoplastic. The overall accuracy of FNAC was 82.9%, and that of Tgp was 91.1%, not statistically different. However, Tgp determination was found essential in 4 cases of metastatic CLN from DTC with inadequate cytology, and in 1 case in which the FNAC provided a false negative result. We demonstrated that FNAC and Tgp assay show similar diagnostic accuracies, and that Tgp measurement may represent the only available information in case of inadequate lymph node sampling or cystic lymph nodes