1,720,982 research outputs found
Il controllo dell’appetito e della sazietà nell’uomo : basi biologiche e applicazioni cliniche
No full textMODELLI SPERIMENTALI DI SOVRACCARICO DIETETICO DI FERRO: EFFETTI CENTRALI E PERIFERICI SU METABOLISMO E FUNZIONE RIPRODUTTIVA
Full text linkBackground and Aim. Iron is an essential micronutrient, which is involved as a cofactor in fundamental biochemical activities, and it is necessary for proper brain development in the fetal and early neonatal period. However, cellular iron overload produces toxic build-up in many organs, including brain, and, under aerobic conditions, catalyses the propagation of reactive oxygen species and the generation of highly reactive radicals through Fenton Chemistry. Association between metabolic and reproductive impairment has been proved in patients affected by dysmetabolic iron overload syndrome (DIOS). In particular, iron is the most important factor afflicting the hypothalamic-pituitary axis in a dose-dependent fashion leading to hypogonadotropic hypogonadism (HH). Our previous studies in a mouse model of DIOS showed the association between dietary iron overload, visceral adipose tissue insulin resistance and hypertriglyceridemia.
Aim of this thesis was to assess whether and how iron overload may affect (a) the reproductive axis (mainly at the hypothalamic-pituitary levels) in a mouse model of DIOS; (b) the migratory feature and GnRH secretory pattern in GN-11 and GT1-7 cells, in vitro models of immature/migratory and mature/GnRH-secreting neurons, respectively.
Results. In male mice, dietary-iron overload (IED) led to: a) an increment in testis iron content, b) a reduction in testicular weight and length, c) no changes in hypothalamic iron content c) no changes in mRNA levels of iron-responsive genes, transferrin receptor (TfR) and ferritin H (FtH), in testes and hypothalamus d) an up-regulation of hypothalamic GnRH mRNA levels, e) no changes in hypothalamic Kiss1 and GPR54 gene expression, e) a reduction in pituitary LHβ gene expression. Moreover, the hypothalamic increment of TNFα gene expression along with the phosphorylation/activation of AMPK protein suggested the presence of an inflammatory condition. Increased hypothalamic CHOP mRNA levels also confirmed the endoplasmic reticulum stress feature. IED mice gained less weight than controls showing a reduction in VAT mass and in serum leptin levels, whereas hypothalamic NPY mRNA levels were increased and POMC gene expression was reduced. Western blot analysis showed that the pAkt/Akt ratio was up-regulated in the hypothalamus of IED mice, whereas phosphorylation of ERK1/2 (pERK) protein resulted unchanged in both groups. As far as GN-11 and GT1-7 cells are concerned, a 24-hour treatment with 200 μM Ferric Ammonium Citrate (FAC, source of ferric iron) induced an increment in the intracellular specific iron content of both cell-based models without affecting the cell viability and morphology. Gene expression analysis showed that both cell lines express TfR and FtH, whose mRNA levels were modulated by iron overload. Exposure of GN-11 cells to FAC resulted in the dose (200–1000 μM FAC for 24 hours)- and time (24-72 hours with 200 μM FAC)-dependent inhibition of FBS-induced chemomigration, as assessed by Boyden chamber assay. Pre-treatment with 200 μM deferoxamine (DFO, a specific iron chelator) reverted the above reported iron-driven effect on cell migration. Time-course experiments showed that 200 μM FAC was associated with increased pERK1/2 and pAkt protein levels and with decreased pAMPK ones. Chemomigration assays carried out with the specific inhibitors of ERK1/2, Akt and AMPK highlighted that only Akt pathway seems involved in FAC-mediated inhibition of GN-11 cell migration. In GN-11 cells, iron treatment increased IL-6 gene expression in a dose-dependent mode, whereas NF-kB nuclear translocation and activation was not affected. Up-regulated SOD2 mRNA levels confirmed a condition of activated oxidative stress.
Conclusions. The present data show that dietary-iron overload impairs the reproductive axis, probably leading to HH, but further experiments are needed to understand the anatomic site mainly involved in iron-driven damage. Iron treatment negatively affects the migration of GN-11 neuronal cells by the activation of Akt signaling pathway. Hence, iron overload may impair the migration of GnRH neurons from the olfactory placode into forebrain and hypothalamus, where these neurons promote the reproductive competence
Somatostatin, Somatostatin Analogs and Somatostatin Receptor Dynamics in The Biology of Cancer Progression
No full textThe pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half-life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co-expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the μ-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation
Adiponectin interactions in bone and cartilage biology and disease
No full textThe adipokine adiponectin promotes insulin sensitivity and fat β-oxidation. In addition to its metabolic effects, adiponectin is an important local and systemic modulator of bone remodeling and cartilage biology, involving direct and indirect mechanisms and a large set of downstream molecular signals. Moreover, data suggest that changes in adiponectin signaling may be associated with bone and cartilage diseases. Adiponectin seems to exert a negative net effect on bone mass and to be an independent predictor of lower bone mass, whereas available data about actions on cartilage are more controversial, showing both pro- and anti-inflammatory actions. Adiponectin-bone cross talk seems to be reciprocal, as osteocalcin, produced by osteoblasts, has been shown to stimulate adiponectin expression and to improve glucose tolerance. Adiponectin-related signaling in bone and cartilage should be considered within the network of hormonal and nutritional signals that may influence skeleton biology, together with body homeostasis and adipose mass changes
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Could Iron Overload Impair the Migratory Ability of Neurons? Evidence from a Cell-Based Model
No full textBackground: Iron is essential for proper brain development in the fetal and early neonatal period. Iron represents a micronutrient for cellular metabolism and aerobic respiration, but cellular iron overload produces toxic build-up in many organs
(including brain) via free radical formation. In thalassaemic patients with pubertal failure, iron overload is the most important factor afflicting the hypothalamic-pituitary axis, leading to hypogonadotrophic hypogonadism and growth failure. Methods: Mouse GN-11 cells (immature GnRH neurons with migratory ability) were used.
Hepcidin, ferritin and transferrin receptor gene expression was evaluated by PCR. GN-11 chemotaxis was assessed by Boyden chamber assay. Activation of
chemomigration-related cell signaling (extracellular signal-regulated kinase (ERK), 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC)) was evaluated by Western blot analysis. Results: GN-11 cells
express hepcidin, ferritin and transferrin receptor genes. 150 μM ferric ammoniumcitrate (FAC) treatment inhibited (-35%, P < 0.05) FBS-induced chemo-migration of GN-11 cells, which was rescued by pre-treatment with 100 μM deferoxamine, a
specific iron chelator. Time-course experiments showed that 150 μM FAC was able to phosphorylate both ERK and AMPK after 10 min treatment. Specific ERK and AMPK inhibitors, U0126 and Compound C, respectively, abolished FAC-mediated signaling. Moreover, U0126 and Compound C (both 10 μM) counteracted FAC-driven phosphorylation of ACC, an AMPK downstream protein. Conclusions: The present data show that iron negatively affects neuron migration via ERK and AMPK. Among the consequences of this event, iron overload may impair migration of GnRH neurons from the olfactory placode into forebrain and hypothalamus, where they
promote reproductive competence
Impact Of Iron Overload On Reproductive Axis Impairment: Pathophysiological Insights From In Vitro And In Vivo Studies
No full textIntroduction: Iron is an essential micronutrient for proper brain development in the fetal/early neonatal period. Conversely, iron overload is the most important factor afflicting the hypothalamus-pituitary axis leading to hypogonadotropic hypogonadism. Methods: Male C57Bl6/J mice, GN-11 cells (immature/migratory GnRH neurons), qPCR/Western blotting analyses, Boyden’s chamber assay (chemomigration), Ferric Ammonium Citrate (FAC, source of ferric iron). Results: Dietary-iron overload (IED) significantly increased mice testis iron content (+49% vs. Control, CTR) and reduced testicular weight and length. Hypothalamic GnRH gene expression was increased in IED mice (+34% vs. CTR, p< 0.01), leaving Kiss1 and GPR54 unchanged. IED promoted reduction of pituitary LHβ mRNA levels. Treatment of GN-11 cells with 200 μM FAC: a) induced a significant increment of intracellular iron content (24 h; +10 fold vs. CTR); b) modulated transferrin receptor and ferritin H mRNA levels (24 h); c) inhibited FBS-induced chemomigration in dose- (200-1000 μM) and time- (24-72 h) dependent; d) modulated pERK1/2, pAkt and pAMPK protein levels (5-180 min; 5 fold, +95% and -50% vs. CTR, respectively; all p<0.05); e) inhibited GN-11 chemomigration via AKT modulation (as assessed by using a specific Akt inhibitor; 90 min). Conclusions: The impairment of the adult reproductive axis by iron overload, leading to hypogonadotropic hypogonadism, may include specific hypothalamic derangements, in addition to the known pituitary and gonadal changes. Moreover, iron overload appears to negatively affect in vitro GnRH neuron migratory ability, thereby possibly impairing GnRH cell migration from foetal olfactory placode into forebrain and hypothalamus, where these neurons subsequently promote the reproductive competence
- …
