The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.

Iron deficiency (ID) and iron deficiency anemia (IDA) are highly prevalent worldwide. Oral iron salts, especially ferrous sulfate, are commonly used for the treatment of iron deficiency (ID). However, its use is associated with gastrointestinal side effects, thus compromising treatment compliance. Intravenous iron administration is a more costly and logistically complex alternative and is not risk-free, as infusion and hypersensitivity reactions may occur. Sucrosomial^® iron is an oral formulation consisting of ferric pyrophosphate conveyed by a phospholipid and sucrester matrix (sucrosome^®). Intestinal Sucrosomial^® iron absorption is mediated by enterocytes and M cells, through the paracellular and transcellular routes, and occurs mostly as intact particles. These pharmacokinetic properties of Sucrosomial^® iron result in higher iron intestinal absorption and excellent gastrointestinal tolerance compared to oral iron salts. The evidence derived from clinical studies supports the use of Sucrosomial^® iron as a valid first option for the treatment of ID and IDA, especially for subjects who are intolerant or refractory to conventional iron salts. Newer evidence also demonstrates the effectiveness of Sucrosomial^® iron, with a lower cost and fewer side effects, in certain conditions usually treated with IV iron in current clinical practice.

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. 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. 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. 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.

Sucrosomial^® 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^® 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^® 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^® 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^® 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^® Iron did not. We conclude that anemic mice are interesting models to study the absorption of oral iron, and that Sucrosomial^® Iron is to be preferred over Ferrous Sulfate because of similar absorption but without inducing an inflammatory response.

The present study aimed to demonstrate that Sideral^® RM (SRM, Sucrosomial^® 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 (C_max) compared to FP, thus increasing iron bioavailability (AUC_rel = 1.8). This led to increased iron availability in the bone marrow at 5 h after single dose gavage.

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 asLachnospiraceae,OscillibacterandFaecalibaculum. 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.