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Background: Berberine is a natural alkaloid with hypoglycemic properties. However, its therapeutic use is limited by a very low oral bioavailability. Here we developed a new oral formulation of berberine based on Sucrosomial® technology and tested its effect on insulin resistance. Methods: Sucrosomial® berberine was first tested in vitro in the hepatoma cell line Huh7 to assess its effect on proteins involved in glucose homeostasis and insulin resistance. The pharmacokinetics and efficacy on insulin resistance were then studied in C57BL/6 mice fed with standard (SD) and high-fat diet (HFD) for 16 weeks and treated daily during the last 8 weeks with oral gavage of Sucrosomial® berberine or berberine. Results: Sucrosomial® berberine did not affect Huh7 cell viability at concentrations up to 40 µM. Incubation of Huh7 with 20 µM of Sucrosomial® and control berberine induced glucokinase (GK) and the phosphorylation of 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), both known targets for the control of insulin resistance. In vivo, we observed an 8-fold higher plasma concentration after 3 weeks of oral administration of 50 mg/kg/day of Sucrosomial® formulation compared to berberine. HFD, compared to SD, induced insulin resistance in mice as determined by oral glucose tolerance test (OGTT). The treatment with a 6.25 mg/kg/daily dose of Sucrosomial® berberine significantly reduced the area under the curve (AUC) of OGTT (73,103 ± 8645 vs. 58,830 ± 5597 mg/dL × min), while control berberine produced the same effects at 50 mg/Kg/day (51518 ± 1984 mg/dL × min). Under these conditions, the two formulations resulted in similar berberine plasma concentration in mice. Nevertheless, a different tissue distribution of metabolites was observed with a significant accumulation of reduced, demethylated and glucuronide berberine in the brain after the oral administration of the Sucrosomial® form. Glucuronide berberine plasma concentration was higher with Sucrosomial® berberine compared to normal berberine. Finally, we observed similar increases of AMPK phosphorylation in the liver in response to the treatment with Sucrosomial® berberine and berberine. Conclusions: The Sucrosomial® formulation is an innovative and effective technology to improve berberine gastrointestinal (GI) absorption with proven in vitro and in vivo activity on insulin resistance.

Background & aims: Recent studies have verified that the SARS-CoV-2 infection (from December 2019 has affected 123 million people throughout the world and more than 3 million people in Italy), can have medium-term and long-term effects, collectively referred to as “post-Covid syndrome” or “long-Covid” characterized by chronic fatigue, followed by muscle weakness, dyspnea and headache. Chronic fatigue or chronic tiredness is a persistent symptom both in patients who have experienced a severe infection and in those who have experienced a mild form of infection. Studies conducted on both patients discharged from hospital and patients managed at home showed that there was no association between the severity of the Coronavirus disease (Covid-19) and the subsequent chronic fatigue symptom. The aim of this study was to evaluate the ability of a nutritional supplement based on vitamins, minerals, amino acids and plant extracts (Apportal®) intake, to ameliorate the general health status in particular the chronic fatigue symptom in subjects after SARS-CoV-2 negativity. Methods: Participants were advised to take one sachet daily of Apportal® for 28 consecutive days. At the beginning (T0), after 14 days (T1) and after 28 days (T2) of supplementation, general fatigue, mental fatigue and Quality of Life indexes were evaluated through specific questionnaires. The assessment of quality of life and health status were measured through the EuroQoL-5D questionnaire, chronic fatigue using the FACIT-Fatigue questionnaire and mental fatigue using the modified Chalder questionnaire. Results: 201 subjects were enrolled for the study;results showed a significant improvement in all indexes analyzed after 14 and 28 days of supplementation. The main significant improvement was observed after the first 14 days and it was further confirmed at 28 days as well. The RTE (Relative Treatment Effect) trend about quality of life, health status, FACIT-Fatigue and mental fatigue in the three questionnaires was statistically significant (Wald Statistic, p < 0.0001). The data of FACIT-questionnaire showed an improvement of at least 1 unit in 76.62% of subjects after 14 days and in 90.05% of subjects after 28 days. An improvement of 10-unit was found in about one third of subjects after 14 days and in half of the subjects after 28 days. Conclusions: This study shows that Apportal® can reduce chronic fatigue and improve quality of life and health status in subjects after SARS-CoV-2 negativity due to the synergistic effect of its components. © 2021 The Authors

Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon diversity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae, Oscillibacter and Faecalibaculum. None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.

L’essai examine les interpretations par Etienne Gilson et Robert Markus de la civitas terrena (ou civitas diaboli) theorisee par Augustin dans le De civitate Dei. Apres avoir rappele les aspects les plus troublants et ambigus de la notion augustinienne de la civitas terrena, a savoir son champ semantique flexible et sa consistance paradoxale, la maniere dont ces questions sont abordees par Gilson et Markus offre le point de depart pour une reflexion plus vaste sur leurs relectures respectives de la pensee d’Augustin, et son application au present. Bien qu’opposees a maints egards, ces relectures (ecclesiologique pour Gilson et politique pour Markus) se rapprochent dans leur dissolution du couple augustinien (civitas terrena/civitas dei) au sein d’un schema tripartite. En cela, elles sont representatives d’une tendance majoritaire dans la reception moderne et contemporaine de l’œuvre de l’eveque d’Hippone.

EnglishTaking as a starting point a review of the edition of the Alphabetum narrationum by Arnold de Liege, in CCCM 160, Turnhout, 2015, the essay returns to some fundamental questions and offers new information. These include the sources of the Alphabetum and their editorial treatment; the originality that can reasonably be attributed to Arnold and the meaning of the label "Narrator" in his collection; the editorial approach adopted in the CCCM edition; new details about the Parisian exemplar of this work (around 1308) in the light of the results of new surveys; and the historical contextualization of exempla, tested through a case study. The essay is supplemented, in appendix, by a preliminary evaluation of the two Brussels manuscripts identified by the reviewers. francaisEn prenant comme point de depart un compte-rendu de l'edition de l'Alphabetum narrationum d'Arnold de Liege, in CCCM 160, Turnhout, 2015, l'article revient sur quelques questions fondamentales en offrant de nouveaux complements. Il est question notamment des sources de l'Alphabetum et de leur traitement editorial; de l'originalite que l'on peut raisonnablement attribuer a Arnold et du sens de l'etiquette de « Narrator » dans ce recueil; de la demarche editoriale adoptee dans l'edition du CCCM; des precisions concernant l'exemplar parisien de cet ouvrage (vers 1308) a la lumiere des resultats des nouveaux sondages; et de la mise en contexte historique des exempla a partir d'un cas specifique. L'article est complete, en annexe, par une premiere evaluation des deux manuscrits de Bruxelles signales par les recenseurs.

Dante is a ‘civic author’ and a ‘poet of the city’, but what do these labels mean? This chapter envisions the civitas (community) as an emotional and intellectual pivot of Dante’s theological-political thought and literary imagination. The comprehensive analysis of the uses of civitas(and synonyms) in Dante’s lexicon deploys its rich semantic field in the framework of typical late medieval tensions and cleavages. The chapter also focusses on some fundamental problems inherent to this notion—its articulation with, on the one hand, the pluralitas and, on the other hand, the universal monarchy—and dismisses the hypothesis that Dante developed an anti-civitasstance during his life. Finally, the chapter points out the legacy of Dante’s typological approach, namely concerning the new importance attributed to history, gendered personifications, and authorship in a vernacular literary work.

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder caused by genetic mutations on TMPRSS6 gene which encodes Matriptase2 (MT2). An altered MT2 cannot appropriately suppress hepatic BMP6/SMAD signaling in case of low iron, hence hepcidin excess blocks dietary iron absorption, leading to a form of anemia resistant to oral iron supplementation. In this study, using the IRIDA mouse model Mask, we characterized homozygous (msk/msk) compared to asymptomatic heterozygous (msk/wt) mice, assessing the major parameters of iron status in different organs, at different ages in both sexes. The effect of carbonyl iron diet was analyzed as control iron supplementation being used for many studies in mice. It resulted effective in both anemic control and msk/msk mice, as expected, even if there is no information about its mechanism of absorption. Then, we mainly compared two forms of oral iron supplement, largely used for humans: ferrous sulfate and Sucrosomial iron. In anemic control mice, the two oral formulations corrected hemoglobin levels from 11.40 ± 0.60 to 15.38 ± 1.71 g/dl in 2-4 weeks. Interestingly, in msk/msk mice, ferrous sulfate did not increase hemoglobin likely due to ferroportin/hepcidin-dependent absorption, whereas Sucrosomial iron increased it from 11.50 ± 0.60 to 13.53 ± 0.64 g/dl mainly in the first week followed by a minor increase at 4 weeks with a stable level of 13.30 ± 0.80 g/dl, probably because of alternative absorption. Thus, Sucrosomial iron, already used in other conditions of iron deficiency, may represent a promising option for oral iron supplementation in IRIDA patients.

Cetylated fatty acids (CFAs) are a group of fats that contain a single ester group within a hydrocarbon chain, which are reported to have beneficial biological effects. A novel mixture of CFAs produced by combining fatty acids derived from refined olive oil with cetyl esters (Lipocet®) is proposed for use as a food ingredient and was therefore subjected to a nonclinical safety assessment. The safety of Lipocet® was evaluated in a bacterial reverse mutation test and an in vitro mammalian cell micronucleus test, followed by a 90-day oral (gavage) toxicity study. In the 90-day study, Sprague-Dawley rats were administered with the vehicle (corn oil) or Lipocet® at 1,500, 3,000, or 4,500 mg/kg body weight/day for 90 days. A comparator reference control group received noncetylated fatty acids derived from olive oil at 4,500 mg/kg body weight/day to identify any effects that may be expected following consumption of high doses of fat. Lipocet® was nongenotoxic in vitro. In the 90-day study, changes observed in hematological and clinical biochemistry parameters were minor in nature and/or showed poor dose dependency. Histopathology findings in the gastrointestinal tract and lungs were noted but were not associated with a clear dose response and were likely incidental. Moreover, Lipocet® was just as well tolerated as the reference control. Therefore, 4,500 mg/kg body weight/day (the highest dose tested) was considered the no-observed-adverse-effect-level. These results support the safety of Lipocet® for use as a food ingredient.

Appropriate nutraceutical combinations may represent a valid approach to prevent vascular calcification associated with chronic kidney disease (CKD). In the present study, we tested the effect of a new nutraceutical combination named RenaTris&reg, containing MK-7, magnesium carbonate, and Sucrosomial&reg, Iron, on vascular calcification in uremic rats. Rats were randomly divided into three groups, i.e. control (high-phosphate diet), uremic (high-phosphate diet containing 0.5% adenine), and supplemented uremic diet (0.5% adenine, MK-7, magnesium carbonate, and Sucrosomial&reg, Iron). After six weeks, sera and vascular calcification were examined. The uremic diet increased creatinine and phosphate levels and induced extensive vascular calcification. The uremic condition also induced a mild hypercholesterolemic condition (+52% of total cholesterol, p &lt, 0.05). The supplemented uremic diet did not reduce creatinine, phosphate levels, or vascular calcification, however, we observed a significant hypocholesterolemic effect (&minus, 18.9% in supplemental uremic vs. uremic diet, 0.05). Similar to simvastatin, incubation of cultured human hepatoma cells (Huh7) with MK-7 significantly reduced cholesterol biosynthesis (&minus, 38%) and induced 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and low-density lipoprotein receptor (LDLR) at both mRNA and protein levels. The effect of MK-7 on LDLR was counteracted by the co-incubation with squalene. Unlike simvastatin, MK-7 reduced PCSK9 in Huh7. These results indicated that the new nutraceutical combination significantly impacts cholesterol metabolism and its supplementation may help to control mild hypercholesterolemic conditions in CKD patients.

This volume aims to foster the dialogue between two usually distinct scholarly traditions: on the one hand, the studies revolving around cultural and political activity, as well as the didactic, theological, religious and pastoral initiatives undertaken by the Dominican Order in the urban context; on the other hand, the scholarship on the history of Florence between the thirteenth and fourteenth centuries, seen as a case study representative of the evolutions of late medieval communal institutions in the Italian peninsula. The essays focus on the reciprocal interactions and influences between religious and political cultures, along with those between mendicant and lay contexts.

The present study aimed to demonstrate that Sideral&reg, RM (SRM, Sucrosomial&reg, Raw Material Iron) is transported across the excised intestine via a biological mechanism, and to investigate the effect that this transport route may produce on oral iron absorption, which is expected to reduce the gastrointestinal (GI) side effects caused by the bioavailability of non-absorbed iron. Excised rat intestine was exposed to fluorescein isothiocyanate (FITC)-labeled SRM in Ussing chambers followed by confocal laser scanning microscopy to look for the presence of fluorescein-tagged vesicles of the FITC-labeled SRM. To identify FITC-labeled SRM internalizing cells, an immunofluorescence analysis for macrophages and M cells was performed using specific antibodies. Microscopy analysis revealed the presence of fluorescein positive particulate structures in tissues treated with FITC-labeled SRM. These structures do not disintegrate during transit, and concentrate in macrophage cells. Iron bioavailability was assessed by determining the time-course of Fe3+ plasma levels. As references, iron contents in liver, spleen, and bone marrow were determined in healthy rats treated by gavage with SRM or ferric pyrophosphate salt (FP). SRM significantly increased both area under the curve (AUC) and clearance maxima (Cmax) compared to FP, thus increasing iron bioavailability (AUCrel = 1.8). This led to increased iron availability in the bone marrow at 5 h after single dose gavage.

Iron deficiency (ID) is usually treated with oral iron salts, but up to 50% of patients complain of gastrointestinal side effects, leading to reduced compliance with treatment. Intravenous (IV) iron formulations are increasingly safe, but there is still a risk of infusion, hypersensitivity reactions and the need for venous access and infusion monitoring. Sucrosomial® Iron (SI) is an innovative oral iron formulation in which ferric pyrophosphate is protected by a phospholipid bilayer plus a sucrester matrix (sucrosome), which is absorbed through para-cellular and trans-cellular routes (M cells). This confers SI’s unique structural, physicochemical and pharmacokinetic characteristics, together with its high iron bioavailability and excellent gastrointestinal tolerance. The analysis of the available evidence supports oral SI iron as a valid option for ID treatment, which is more efficacious and tolerable than oral iron salts. SI has also demonstrated a similar effectiveness, with lower risks, in patients usually receiving IV iron (e.g., chronic kidney disease, cancer, bariatric surgery). Thus, oral SI emerges as a valuable first option for treating ID, especially for subjects with intolerance to iron salts or those for whom iron salts are inefficacious. Moreover, SI should also be considered as an alternative to IV iron for initial and/or maintenance treatment in different patient populations.

This paper presents a comparative evaluation of different oral ferric iron formulations for ability to retain Fe3+ in simulated gastric fluid (SGF), be internalized by cells lining intestinal epithelium, and cross it to reach the bloodstream. In all formulations iron was ferric pyrophosphate, the excipients were different types and fractions of lecithin plus sucrose esters of fatty acids matrix (Sideral® RM; PRT1; PRT2) or lecithin without sucrester (SUN). Dissolution kinetics of formulations in SGF was studied by USP method. The ability of the formulations to promote iron intestinal absorption was evaluated by the Caco-2 cell model, measuring cellular ferritin content, and by the excised rat intestine model, yielding apparent permeability parameters (Papp). All formulations limited iron release in SGF to ≤10%. Sideral® RM was by far the most absorbed by Caco-2, as ferritin content was in the order: Sideral® RM≫PRT2>PRT1>SUN>control. The Fe3+ crossing the intestinal barrier was in part reduced to Fe2+ by epithelial enzymes, in part it was carried by formulation rearrangement into nano-structures able to protect it from reduction and apt for internalization by epithelium cells. Papp parameters were in the order: Sideral® RM≫PRT1>PRT2>SUN=control. Relevance of transepithelial Fe2+carrier, DMT-1, to Fe3+ transport was ruled out using a DMT-1 inhibitor. In conclusion, Sideral® RM retains iron in SGF, and is the most suitable for Fe3+ internalization by Caco-2 cells, Fe3+ protection from enzymatic reduction and promotion of Fe3+ absorption across intestinal epithelium, non-mediated by DMT-1.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2GFP, in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene. Tph2GFP mES cells selectively express GFP upon in vitro differentiation toward the serotonergic fate, they synthesize serotonin, possess excitable membranes, and show the typical morphological, morphometrical, and molecular features of in vivo serotonergic neurons. Thanks to the vital reporter GFP, we highlighted by time-lapse video microscopy several dynamic processes such as cell migration and axonal outgrowth in living cultures. Finally, we demonstrated that predifferentiated Tph...

L’exil de Dante se presente, par dela le fait historique, comme une donnee textuelle, systematiquement rappelee dans les œuvres posterieures a son bannissement et elevee par Dante a element macrostructural de l’architecture de la Comedie. Les references a son destin d’exile, qui ponctuent le poeme par le biais des revelations prophetiques, s’imbriquent a la mission prophetico-apostolique que Dante revendique pour lui-meme. L’autobiographie politique devient ainsi fonctionnelle a la construction de l’auctor du poeme comme nouveau prophete et scriba Dei. Cette autobiographie n’est pourtant pas exclusive. Dans la Comedie, elle coexiste avec le recit autobiographique axe sur le parcours du peche a la redemption et evoque par Beatrice au moment des retrouvailles edeniques avec son adepte. Comment alors l’exil politique, signe de l’election divine, s’articule-t-il a l’exil anagogique, signe du peche individuel et exemplum du peche de l’humanite peregrinans ? Il revient a Gennaro Sasso (Le autobiografie di Dante, Aragno 2008) d’avoir pose la question a une tradition critique qui normalement l’elude. Apres avoir montre les limites des demarches habituelles, cet article prend la « dissonance » autobiographique relevee par Sasso comme point de depart pour montrer la longue duree de cette tension dans la production de Dante, pour saisir la technique de composition textuelle qui lui a permis de la controler, et aussi pour reflechir a la polysemie de l’exil dans la culture medievale.

Neural stem cells (NSCs) have become promising tools for basic research and regenerative medicine. Intracerebral transplantation studies have suggested that these cells may be able to adopt neuronal phenotypes typical of their engraftment site and to establish appropriate connections in the recipient circuitries. Here, we examined the in vivo neurogenic competence of well-characterized NSC lines subjected to in vitro priming and subsequent implantation into the adult intact mouse brain. Upon implantation into the hippocampus and, less frequently, in the striatum and in the cerebral cortex, numerous green fluorescent protein (GFP)-tagged cells acquired differentiated features indistinguishable from resident neurons. Upon closer examination, however, we found that this outcome resulted from fusion of donor cells with local neuronal elements generating long-term persistent GFP+ neuronal hybrids. This fusogenic behavior of NSCs was unexpected and also observed in coculture with E18 hippocampal immature neural cells, but not with microglia or astrocytes. Similar findings were consistently obtained with different NSC lines, mouse recipients, and donor cell-labeling methods. The frequent and cell type-specific fusion of donor NSCs with host neurons highlights a previously underestimated biological property of the nervous tissue that might prove profitable for basic and therapeutically oriented studies. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2

Though, since the second half of the 20th c., scholars have underlined the important differences which separate Orosius’ theological and historiographical approach from that of Augustine, Orosius indeed “benefited very greatly from the general assumption that his Historiae was an indispensable complement to the City of God” (Hillgarth). This article aims to investigate the history of this “general assumption”. In fact, this point seems to be absolutely secondary, if not unknown, in the most ancient sources. Only later, some anonymous works, such as the Dialogus quaestionum LXV (attested from the 8th-9th c.) and a biographical note on Orosius (attested from the 11th c.), started to underline the personal relationship linking these auctoritates, as well as to praise the Augustinian patronage of the Historiae. The topos of their nearness and mutual agreement appears to be definitively established, both in texts and images, during the 12th c. and then transmitted to the modern erudition. The conclusions point...

Introduction: iron homeostasis is maintained by regulating the iron levels in plasma which is maintained by four coordinated processes: duodenal iron absorption, macrophage iron recycling, hepatic iron storage and erythropoiesis. Iron in the Fe2+ form is transported across the apical duodenal membrane by DMT1 and subsequently transferred to the blood via the iron exporter, Ferroportin the only know cell membrane iron exporter. Due to the presence of two check points at cellular levels, iron absorption and release are mainly regulated, because of this iron containing oral formulations are poorly absorbed and bioavailable. To overcome cellular barriers and increasing the bioavailability of supplemented iron forms, there is a need for new carriers that work protecting the iron as well as enhancing its intestinal absorption and release into the blood stream. Moreover thus reducing dosage and side effects. Sucrosomial® Iron (SI) represents an innovative oral iron-containing carrier in which ferric pyrophosphate is protected by a phospholipid bilayer membrane plus a sucrester matrix. To date, in vitro studies have shown that SI is mostly absorbed as vesicle-like structure, bypassing the conventional iron absorption pathway. Due to its behaviour at the gastrointestinal tract, SI is well tolerated and highly bioavailable compared to conventional iron salts. To deeply understand involvement of endocytosis in SI absorption and release, in vitro experiments using endocytosis and ferroportin inhibitors were carried out Aim: to study Sucrosomial® Iron uptake and release in different in vitro systems. Materials and Methods: CACO-2 and THP1 cells were used to investigate the role of FPN in Sucorsomial Iron release from cells. For release study, CACO-2 cells were exposed for 18h to quercetin (150mmol/L) in order to downregulate FPN expression. CACO-2 quercetin pre-treated cells were co-cultured with TPH1 cells, and SI or FAC were added. However, prior to measure cell Ferritin content, the incubation medium was discarded and cells were washed to remove quercetin. Iron uptake-release analysis was performed using co-culture transwell system between CACO-2 cells and TPH1. To investigate the cellular fate of cellular iron in quercetin treated CACO-2 and TPH1 cells we measured cell ferritin content. To inhibit endocytosis absorption pathway, CACO-2, THP1 and HepG2 cells were pre-treated with PitStop2 and Dyngo 4a inhibitors and then treated with SI, or Ferrous Sulfate (FS) or ferric ammonium citrate (FAC). Cellular Ferritin content was measured. Results: in order to understand the effect of quercetin on iron storage, we used CACO2 and TPH1 cells pre-treated with quercetin and then treated with SI, FAC or nothing (control). Quercetin-SI treated CACO-2 cells showed no differences in Ferritin expression compared to control cells (3,94 ngFTL/mg proteins Vs 4,56 ngFTL/mg proteins) while in quercetin-FAC treated cells ferritin expression was decreased compare to control cells (16,3 ngFTL/mg proteins Vs 27,55 ngFTL/mg proteins). In a similar manner, quercetin-SI treated TPH1 cells didn't show increase in Ferritin expression compared to control cells (20 ngFTL/mg proteins Vs 15,15 ngFTL/mg proteins), only in quercetin-FAC treated cells we observed a Ferritin expression increase compared to control untreated cells (16 ngFTL/mg proteins Vs 24 ngFTL/mg proteins). Results from experiments using endocytosis inhibitors showed that SI absorption in CACO-2 cells is inhibited using Dyngo4a (from 4ngFTL/mg proteins to 0,36 ngFTL/ mg proteisn) while PitStop3 seems to reduce SI absorption in THP1 (from 396 ngFL/mg protein to 199,91 ngFTL/mg proteins) and HepG2 cells (from 26,86 ngFL/mg proteins to 3,93 ngFTL/mg proteins), since ferritin expression significantly decrease only in SI treated cells. Conclusions: endocytosis pathway seems to be involved in SI cellular uptake but this process is regulated in different manner probably due to different cell types. Release experiments showed that cells treated with quercetin could reduce for a negative feedback DMT1 expression as well, affecting iron uptake from cells treated with FAC but not with SI and consequently, if SI is able to bypass commonly iron uptake mechanism, FPN inhibition did not show iron release perturbation from cells treated with SI. Disclosures Brilli: Pharmanutra s.p.a.: Consultancy. Martinelli:Janssen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Tarantino:Pharmanutra s.p.a.: Employment.

Iron deficiency (ID) is usually treated with oral iron salts, but up to 50% of patients complain of gastrointestinal side effects, leading to reduced compliance with treatment. Intravenous (IV) iron formulations are increasingly safe, but there is still a risk of infusion, hypersensitivity reactions and the need for venous access and infusion monitoring. Sucrosomial® Iron (SI) is an innovative oral iron formulation in which ferric pyrophosphate is protected by a phospholipid bilayer plus a sucrester matrix (sucrosome), which is absorbed through para-cellular and trans-cellular routes (M cells). This confers SI’s unique structural, physicochemical and pharmacokinetic characteristics, together with its high iron bioavailability and excellent gastrointestinal tolerance. The analysis of the available evidence supports oral SI iron as a valid option for ID treatment, which is more efficacious and tolerable than oral iron salts. SI has also demonstrated a similar effectiveness, with lower risks, in patients usually receiving IV iron (e.g., chronic kidney disease, cancer, bariatric surgery). Thus, oral SI emerges as a valuable first option for treating ID, especially for subjects with intolerance to iron salts or those for whom iron salts are inefficacious. Moreover, SI should also be considered as an alternative to IV iron for initial and/or maintenance treatment in different patient populations.

Sucrosomial&reg, Iron is a recently developed formulation to treat iron deficiency based on ferric pyrophosphate covered by a matrix of phospholipids plus sucrose esters of fatty acids. Previous data indicated that Sucrosomial&reg, Iron is efficiently absorbed by iron-deficient subjects, even at low dosage, and without side effects. Its structural properties may suggest that it is absorbed by an intestinal pathway which is different to the one used by ionic iron. Although, studies in vitro showed that Sucrosomial&reg, Iron is readily absorbed, no animal models have been established to study this important aspect. To this aim, we induced iron deficient anemia in mice by feeding them with a low-iron diet, and then we treated them with either Sucrosomial&reg, Iron or sulfate iron by gavage for up to two weeks. Both iron formulations corrected anemia and restored iron stores in a two-week period, but with different kinetics. Ferrous Sulfate was more efficient during the first week and Sucrosomial&reg, Iron in the second week. Of note, when given at the same concentrations, Ferrous Sulfate induced the expression of hepcidin and four different inflammatory markers (Socs3, Saa1, IL6 and CRP), while Sucrosomial&reg, Iron did not. We conclude that anemic mice are interesting models to study the absorption of oral iron, and that Sucrosomial&reg, Iron is to be preferred over Ferrous Sulfate because of similar absorption but without inducing an inflammatory response.

Importins, also called karyopherins, belong to a large family of proteins involved in cytoplasm-to-nucleus transport. Transport machinery generally involves a complex formed by two different importin subtypes (alpha and beta). Both alpha and beta importins are expressed in the brain, and their expression and localization is regulated by physiological neuronal activity. Little is known about regulation of importin expression in brain pathological conditions. Here we studied the expression of importin beta1 (imp beta 1) in the rat hippocampus after acute and chronic seizures induced by the glutamate agonist kainic acid (KA). The overall content of imp beta 1 mRNA and protein did not change after acute KA seizures. However, acute KA seizures rapidly induced the translocation of imp beta 1 protein from the cytoplasm to the nucleus in pyramidal CA1 neurons. KA-induced imp beta 1 translocation was prevented by the NMDA (N-methyl-D-aspartic acid) receptor blocker MK-801. After chronic seizures, the overall levels of imp beta 1 mRNA and protein did not change in the whole hippocampus. Immunohistochemistry revealed a massive loss of imp beta 1-positive neurons in pyramidal layers (that degenerated after KA), whereas an increased number of imp beta 1-positive cells was detected in the stratum radiatum of rats with chronic seizures compared with control animals. Double-labeling experiments identified these cells as glial cells expressing the chondroitin sulfate proteoglycan NG2 (neuron/glial antigen 2), a glial subtype recently shown to regulate hippocampal neuron excitability. These data show a differential regulation of imp beta 1 expression after acute and chronic seizure activity in the rat hippocampus.

Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain. Synopsis: Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntington's disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function. Polymeric nanoparticles (NPs) loaded with cholesterol, modified with glycopeptides g7 (g7-NPs-Chol) to cross the BBB after systemic injection, have been used to deliver cholesterol to the brain of HD mice. These NPs, applied for the first time to a brain disorder, are made of PLGA, which is approved by FDA in various drug delivery systems in humans. Systemic administration of g7-NPs-Chol (i) rescued synaptic communication in striatal medium-sized spiny neurons, (ii) prevented cognitive decline, and (iii) restored the levels of proteins that compose the synaptic machinery in HD mice. g7-NPs or cholesterol itself did not induce inflammatory response in the periphery, where almost all g7-NPs are localized. Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntington's disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function.

Introduction: Proteins such as Ferritin (Ft), Hemoglobin (Hb) and Transferrin Receptor (TfR1) are involved in tissue iron distribution while systemiciron metabolism is regulated by Hepcidin. Interleukin-6 (IL-6) release is induced in response to an inflammatory status and enhances Hepcidin expression, as consequence, dietary iron absorption and macrophage iron recycling are inhibited. Anemia of Chronic Disease (ACD) is a form of anemia associated with many different chronic disorders. It is characterized by high hepcidin and CRP or IL-6 expression and low serum iron transferrin concentration while ferritin can be normal or elevated. Oral iron delivery is especially attractive thanks to the ease of administration, but commonly used iron salts are poorly absorbed and ineffective to increase Hb concentration in particular in patients with ACD. We have developed an oral Iron formulation named Sucrosomial® Iron, preparation of ferric pyrophosphate, covered by a phospholipids plus sucrester matrix, with high bioavailability and tolerability, which promotes ferric iron absorption thanks to gastro-resistant and matrix composition properties and showed Hb concentration improvement not inferior to intravenous iron. Objective: to showpre-clinical and clinical evidences of absorption, effectiveness and tolerability of Sucrosomial Iron using in vivo and in vitro models and in patients with ACD too. Methods: To study the effects of oral supplementation on Iron metabolism and inflammatory status, Hb, Ft, TfR1, Socs3 and Hepcidin expression were analyzed. We have supplemented wild-type (wt) and iron deficient (ID) mice, maintained in iron-free diet for 8 weeks, with 1mg/kg/die of Sucrosomial® Iron or Iron Sulfate or Placebo by oral gavage, for 2 weeks. The role of Sucrosomial® Iron on the inflammatory response, was studied in LPS induced HepG2 hepatoma cells. Cells were treated with Sucrosomial® Iron and the levels of hepcidin were assessed 6, 18 and 24 hours after treatment. To show the efficacy and compliance of Sucrosomial® Iron a multi-centric randomized study on 300 patients with ACD were performed. Patients were supplemented with iron sulfate (65 mg o.i.d.), microencapsulated iron, micronized iron, Sucrosomial® Iron, heminic-chelated bisglycinated and iron chelated bisglycinated iron (30 mg t.i.d.). Median Hb value at the beginning was 8.2 g/dl. In group of patients with high CRP value median Hb value was 7.8 g/dl. Results: In mice treated with Sucrosomial® Iron, Hb level mean increase was 4,9 g/dl while TSAT value is not significantly higher than animals treated with Sulfate Iron. Furthermore mice treated with Sucrosomial® Iron showed a preferential accumulation of iron in spleen. Hepcidin and Socs3 mRNA expression was not induced during Sucrosomial® Iron treatment while was up-regulated in mice treated with Iron Sulfate (Figure 1). In vitro experiments on HepG2 LPS-induced cells displayed that treatment with Sucrosomial Iron® is able to reduce hepcidin concentration at different time points (Figure 2). Data from the clinical study showed that Sucrosomial® Iron is well tolerate and effective ACD patients. Only patients treated with Sucrosomial® Iron showed constant increase in Hb concentration over time. In all groups Hb level achieves a plateau phase after three months and ferritin level starts to increase. At three months higher levels of Hb are present in Sucrosomial® Iron (13.2 g/dl), heminic chelated bisglycinated iron (11.7 g/dl), chelated bisglycinated iron (11.3 g/dl) treated patients. In patients with high CRP level (>30 ng/ml) only those receiving Sucrosomial® Iron showed Hb increase from the tenth week and this continue up to the sixth month (Hb 12.5 g/dl) and seems to be correlated to a significantly decrease of CRP (5 mg/L) (Figure 3). Side effects are higher in ferrous sulfate (15/50) and sunactive treated groups (6/60). Conclusions: In summary, results showed that Sucrosomial® Iron treatment could regulate iron homeostasis through an increase in Hb concentration and better tolerability during inflammatory status. These evidences may suggest that this new oral iron formulation behaves differently than other oral iron salts, perhaps due to different absorption pathways. Besides we have observed a decrease in CRP and Hepcidin concentration, these results should be further investigate. Disclosures Brilli: Pharmanutra S.p.A.: Consultancy. Pera: Pharmanutra S.p.A.: Employment. Tarantino: Pharmanutra S.p.A.: Employment.

Al di là del dato storico, l'esilio di Dante costituisce un dato testuale, evocato sistematicamente nelle opere posteriori al bando e trasformato in elemento macrotestuale dell'architettura della Commedia. I riferimenti al proprio destino di esule, disseminati nel poema attraverso le rivelazioni profetiche, vengono strettamente legati alla missione profetico-apostolica che Dante rivendica per se stesso. L'autobiografia politica contribuisce così a forgiare dell 'auctor del poema l'immagine di un nuovo profeta e scriba Dei. Tuttavia, questa non è l'unica autobiografia che il poeta offre di sé. Nella Commedia, essa coesiste con il racconto autobiografico del percorso che dal peccato conduce alla redenzione, evocato da Beatrice al momento dell'incontro con Dante nell'Eden. Come si articolano, quindi, l'esilio politico, segno dell'elezione divina, e l'esilio anagogico, segno del peccato individuale e exemplum del peccato dell'umanità peregrinami Gennaro Sasso (Le autobiografie di Dante , Aragno 2008) ha avuto il merito di porre questo interrogativo a una tradizione di studi che di solito lo elude. Dopo aver mostrato i limiti degli approcci consueti, questo contributo prende come punto di partenza la «dissonanza » autobiografica messa in luce da Sasso per illustrare la presenza duratura di tale tensione nella produzione di Dante, per cogliere la tecnica compositiva che gli ha permesso di tenerla sotto controllo nel testo e, inoltre, per riflettere alla polisemia dell'esilio nella cultura medievale., L'exil de Dante se présente, par delà le fait historique, comme une donnée textuelle, systématiquement rappelée dans les œuvres postérieures à son bannissement et élevée par Dante à élément macrostructural de l'architecture de la Comédie. Les références à son destin d'exilé, qui ponctuent le poème par le biais des révélations prophétiques, s'imbriquent à la mission prophético-apostolique que Dante revendique pour lui-même. L'autobiographie politique devient ainsi fonctionnelle à la construction de l'auctor du poème comme nouveau prophète et scriba Dei. Cette autobiographie n'est pourtant pas exclusive. Dans la Comédie , elle coexiste avec le récit autobiographique axé sur le parcours du péché à la rédemption et évoqué par Béatrice au moment des retrouvailles édéniques avec son adepte. Comment alors l'exil politique, signe de l'élection divine, s'articule-t-il à l'exil anagogique, signe du péché individuel et exemplum du péché de l'humanité peregrinare ? Il revient à Gennaro Sasso {Le autobiografie di Dante , Aragno 2008) d'avoir posé la question à une tradition critique qui normalement l'élude. Après avoir montré les limites des démarches habituelles, cet article prend la «dissonance » autobiographique relevée par Sasso comme point de départ pour montrer la longue durée de cette tension dans la production de Dante, pour saisir la technique de composition textuelle qui lui a permis de la contrôler, et aussi pour réfléchir à la polysémie de l'exil dans la culture médiévale., Brilli Elisa. De exiliis Dantis : raisons textuelles et culturelles de l'harmonie entre exil politique et exil anagogique chez Dante. In: Arzanà 16-17, 2013. Écritures de l’exil dans l’Italie médiévale, sous la direction de Anna Fontes Baratto et Marina Gagliano. pp. 215-230.