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Il rene è coinvolto, in prima battuta, nel mantenimento dell'omeostasi dei fluidi e dell'equilibrio idro-elettrolitico ed acido-base, nonché nell'eliminazione delle scorie tossiche. La funzione renale sembra essere strettamente collegata a quella cardiovascolare e, negli ultimi anni, il termine di ‘sindrome Cardio-Renale’ è stato utilizzato per spiegare le correlazioni cliniche tra patologia renale e cardiaca. Lo scompenso cardiaco congestizio (SCC) rappresenta la prima causa di ospedalizzazione nei Paesi occidentali e i pazienti affetti presentano spesso, in associazione, un quadro di malattia renale cronica (MRC) di grado variabile. Sono stati considerati diversi modelli fisiologici e fisiopatologici per spiegare come una condizione di malattia renale cronica possa influenzare lo stato di insufficienza cardiaca. Sicuramente la via metabolica del guanosin monofosfato ciclico (cGMP) e quello dell'ossido nitrico (NO) giocano un ruolo fondamentale di concerto con l'azione dei peptidi natriuretici atrial natriuretic peptide (ANP) e brain natriuretic peptide (BNP) sotto il controllo del sistema delle fosfodiesterasi sieriche. I pazienti con sovraccarico di circolo necessitano di terapie farmacologiche specifiche. La terapia diuretica, spesso in associazione (vedi tiazidici + diuretici d'ansa), rappresenta ancora quella di prima scelta ma, nei pazienti, refrattari alla terapia diuretica a dosi massimali, l'impiego di metodiche extracorporee, quali l'ultrafiltrazione (nelle sue diverse modalità d'impiego), può essere di grande aiuto per il paziente scompensato dal punto di vista cardiologico. (Cardionephrology)

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Abstract non disponibile (Cardionephrology)

La sindrome cardio-renale (SCR) è una sindrome clinica ben nota, che descrive tanto gli effetti negativi dell'insufficienza renale sull'equilibrio cardio-circolatorio quanto quelli dell'insufficienza cardiaca sulla funzione renale. Molti autori hanno studiato l'utilità di marcatori sierologici ai fini dell'identificazione e del monitoraggio ambulatoriale delle varie forme di questa sindrome. L'analisi dei livelli sierici dei peptidi natriuretici è, al momento, quella maggiormente utilizzata, in quanto essi stessi non sono solo direttamente associati alla gravità delhinsufficienza cardiaca, ma anche capaci di rilevare precocemente la disfunzione renale, certamente prima che sia possible osservare un incremento nei livelli sierici di creatinina. NGAL, cistatina C, NAG, KIM-1 e IL-18 rappresentano interessanti biomarcatori per la diagnosi precoce di danno renale acuto (AKI), e quindi per la diagnosi precoce delle forme renocardiache acute, mentre il loro utilizzo in altre forme di SCR non appare codificato. Al contrario, la valutazione di KIM-1 e IL-18 sembra più utile per cercare una diagnostica differenziale tra forme diverse di insufficienza renale acuta. (Cardionephrology)

Un discreto numero di lavori scientifici ha indagato i possibili nessi esistenti tra fistole arterovenose e scompenso cardiaco, con risultati in parte assolutamente consolidati ed in altra parte contrastanti. Altri temi, come lo scompenso del cuore destro, risultano indagati in maniera marginale. Questa rassegna presenta un rapido excursus della letteratura degli ultimi anni e solleva alcuni interrogativi insoluti in materia di cardionefrologia. (Cardionephrology)

Abstract non disponibile (Cardionephrology)

L'eritropoietina, per molti anni intesa unicamente come principale regolatore della massa eritrocitaria circolante, ha svelato nel corso degli anni sempre nuove pagine di fisiologia, che l'hanno mostrata come elemento centrale di un complesso sistema che mantiene l'equilibrio tra ossigenazione periferica, stabilità vascolare e stress ossidativo. Al crescere delle conoscenze sulla fisiologia autocrina e paracrina dell'EPO, sono cresciute le aspettative verso l'utilizzo clinico-pratico di tali conoscenze. La presente review propone una rapida carrellata sulle diverse potenziali applicazioni dell'EPO nel management clinico della cardiopatia ischemica, con particolare riguardo alle strategie testate per ottenere gli effetti pleiotropici dell'EPO senza indurre indesiderati incrementi dell'ematocrito.

I pazienti affetti da malattia renale cronica possono andare incontro a tutta una serie di patologie che colpiscono il pericardio ma, sicuramente, alcune entità nosologiche sono più frequenti di altre. Gli ultimi decenni hanno assistito, per fortuna nostra e dei nostri pazienti, a un netto miglioramento per quanto concerne i protocolli terapeutici per i pazienti nefropatici e le forme tipiche di pericardite uremica, così frequenti negli anni passati, sono ormai uno sbiadito ricordo. È tuttora frequente osservare pazienti con versamento pericardico (idiopatico, ovvero secondario a malattie sistemiche), soprattutto per quanto concerne i pazienti sottoposti a trattamenti depurativi extracorporei ed i pazienti che iniziano il trattamento dialitico in condizioni di emergenza/urgenza (ad esempio, pazienti affetti da scompenso cardiaco congestizio); il versamento pericardico viene schematicamente classificato in lieve, moderato e severo in base all'interessamento più o meno globale del pericardio. Meno frequenti sono gli episodi di pericardite acuta (anch'essa idiopatica o secondaria), spesso su base virale, neoplasticae/o immunologica (vedi pazienti trapiantati in terapia immunosoppressiva). Le forme di pericardite costrittiva sono più rare a documentarsi in corso di malattia renale cronica e, in genere, rappresentano lo stadio finale di diverse patologie sistemiche: l'esito finale è, in genere, la fibrosi pericardica. (Cardionephrology)

Purpose: Mesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC). Expiremental design: Following a run-in phase I study to assess ARB safety, prrHGOC patients with centrally confirmed MSLN positive expression were randomized to ARB or PB (wP 80mg/m2 with Bev 10mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events., Results: The combination of Bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly was well tolerated. Regarding phase II results, mesothelin positivity was 88% and 57 pts were randomized (28 ARB, 29 PB). 42% pts received prior Bev and 23% were platinum refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB respectively (p=0.03, HR= 2.02 [1.06-3.86]). ORR was 21% with ARB and 65% with PB. The most common treatment-related grade ≥ 3 adverse events were anemia (18%) with ARB, and neutropenia (24%) with PB. Higher baseline levels of circulating IL-6 were associated with worse PFS, and its levels decreased with PB treatment., Conclusion: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care.

Agricultural food waste and by-products could provide high-value compounds that positively affect human and environmental health, thus representing promising ingredients for cosmeceutical products. This study explores the biological activities of tomato skin (HP) and pomegranate peel (PPE) extracts on oral mucosa to evaluate their possible use in mouthwashes. The biological activities of the extracts and the mouthwash (MW) containing them were evaluated in Human Primary Gingival Epithelial cells (HGECs). The antioxidant and anti-inflammatory activities were analyzed in HGECs injured with lipopolysaccharides. After 24 h of treatment with PPE, HP, and MW, significant antioxidant activity and an increased Superoxide Dismutase 1 expression ( p < 0.01) were observed. Additionally, the extracts significantly reduced the expression of tumor necrosis factor α ( p < 0.05) and Monocyte Chemoattractant Protein 1 ( p < 0.001), suggesting an anti-inflammatory role. Lastly, the antibacterial activity was assessed against Streptococcus mutans and Streptococcus sanguinis by the broth microdilution method and agar cup diffusion test for the extracts and the mouthwash, respectively, demonstrating strong effectiveness against both oral streptococcus species. Results demonstrate the potential of HP and PPE in reducing oxidative stress, inflammation, and bacterial proliferation within oral mucosa, highlighting food waste up-cycling as a resource for human health.

The anti-cancer potential of eugenol (EUG) is well recognized, whereas that of spermidine (SPD) is subject to dispute and requires further research. The anti-tumorigenic potential of wheat germ SPD (150 µM) and clove EUG (100 µM), alone, in combination as SPD+EUG (50 µM + 100 µM) and, as a supplement (SUPPL; 0.6 µM SPD + 50 µM EUG), was investigated on both metastatic SW620 and primary Caco-2 colorectal cancer (CRC) spheroids. Compared to untreated controls, all treatments significantly reduced the vitality and spheroid area, increased the necrotic area, and induced apoptosis on both cell-type spheroids after 96 h, with a reduced migration evident in 2D (two-dimensional) cultures after 48 h. The comparable anti-CRC effects of the SPD+EUG and the SUPPL reflected a wide-range dose efficacy of SPD and EUG. It is of note that SPD+EUG induced a synergistic effect on the increased caspase-3 expression and reduced the migration percentage in SW620. In more physiologically relevant intestinal equivalents (healthy enterocytes [NCM460], fibroblasts [L929], and monocytes [U937]) containing embedded SW620/Caco-2 spheroids, SPD+EUG administration significantly reduced the spheroid CEA marker and proliferation, whilst simultaneously increasing occludin, autophagy LC3-II expression, and monocyte differentiation, compared to the control models. Exogenous SPD, alone and in combination with EUG, displayed an anti-CRC potential on tumor growth and metastasis, and warrants further investigation.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease. Recently approved molecular/gene treatments do not solve the downstream inflammation-linked pathophysiological issues such that supportive therapies are required to improve therapeutic efficacy and patients' quality of life. Over the years, a plethora of bioactive natural compounds have been used for human healthcare. Among them, plumbagin, a plant-derived analog of vitamin K3, has shown interesting potential to counteract chronic inflammation with potential therapeutic significance. In this work we evaluated the effects of plumbagin on DMD by delivering it as an oral supplement within food to dystrophic mutant of the fruit fly Drosophila melanogaster and mdx mice. In both DMD models, plumbagin show no relevant adverse effect. In terms of efficacy plumbagin improved the climbing ability of the dystrophic flies and their muscle morphology also reducing oxidative stress in muscles. In mdx mice, plumbagin enhanced the running performance on the treadmill and the muscle strength along with muscle morphology. The molecular mechanism underpinning these actions was found to be the activation of nuclear factor erythroid 2-related factor 2 pathway, the re-establishment of redox homeostasis and the reduction of inflammation thus generating a more favorable environment for skeletal muscles regeneration after damage. Our data provide evidence that food supplementation with plumbagin modulates the main, evolutionary conserved, mechanistic pathophysiological hallmarks of dystrophy, thus improving muscle function in vivo; the use of plumbagin as a therapeutic in humans should thus be explored further., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular gene regulatory circuits. For synthetic circuits, how non-genetic properties of the growth environment impact circuit behavior remains poorly explored. Here, we first describe an occurrence of mechano-chemical coupling in synthetic Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated gene expression in different cellular systems in vitro. We then construct, both in vitro and in silico, a synNotch-based signal propagation circuit whose outcome can be regulated by cell density. Spatial and temporal patterning outcomes of this circuit can be predicted and controlled via modulation of cell proliferation, initial cell density, and/or spatial distribution of cell density. Our work demonstrates that synthetic patterning circuit outcome can be controlled via cellular growth, providing a means for programming multicellular circuit patterning outcomes., Competing Interests: Competing interests L.M. is an inventor on a synNotch patent for applications in cancer cell therapy licensed to Gilead. The remaining authors declare no competing interests., (© 2024. The Author(s).)

The red microalga Galdieria sulphuraria has emerged as a promising biotechnological platform for large-scale cultivation and production of high-value compounds, such as the blue pigment phycocyanin. However, a large amount of freshwater and a substantial supply of nutrients challenge both the environmental and the economic sustainability of algal cultivation. Additionally, the extremophilic nature of Galdieria sulphuraria requires cultivation in an acidic culture medium that directly leads to strongly acidic wastewater, which in turn generally exceeds legal limits for industrial wastewater discharge. This research aims to address these challenges, by investigating cultivation water reuse as a strategy to reduce the impacts of Galdieria sulphuraria management. The results indicated that a 25 % water reuse may be easily implemented and showed to be effective at the pilot scale, providing no significant changes in microalgae growth (biomass productivity ~0.21 g L -1 d -1 ) or in phycocyanin accumulation (~ 10.8 % w/w) after three consecutive cultivation cycles in reused water. Moreover, a single cultivation cycle with water reuse percentages of 71 and 98 %, achieved with membrane filtration and with centrifugation, respectively, was also successful (biomass productivity ~0.24 g L -1 d -1 ). These findings encourage freshwater reuse implementations in the microalgae sector and support further investigations focusing on coupling cultivation and harvesting in continuous, real-scale configurations. Centrifugation and membrane filtration required substantially different specific electrical energy consumption for water reuse and biomass concentration: in real applications, the former technique would roughly span from 1 to 10 kWh m -3 while the latter is expected to fall within the ample range 0.1-100 kWh m -3 , strongly dependent on system size. For this reason, the most suitable separation train should be chosen on a case-by-case basis, considering the prevailing flow rate and the target biomass concentration factor targeted by the separation process., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vincenzo A. Riggio reports financial support was provided by Polytechnic University of Turin. Mariachiara Zanetti reports financial support was provided by Polytechnic University of Turin. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Waste from the agri-food chain represents a valuable reservoir of organic compounds with health-promoting properties. Momast Plus 30 Bio (MP30B) is a derivative obtained from olive-oil wastewater. Its enrichment in hydroxytyrosol (HT) via a patented technique has paved the way for its potential application as a dietary supplement in preventing cardiovascular diseases. MP30B demonstrates no significant alteration in cardiac and vascular parameters in "ex vivo" studies. However, it exhibits a strong ability to remove reactive oxygen species and exerts anti-inflammatory effects, notably reducing the concentration of iNOS and mitigating heart infections in "in vitro" experiments. Furthermore, MP30B slightly decreases the stiffness of the "ex vivo" thoracic aorta, potentially resulting in lowered arterial pressure and enhanced energy transfer to a normal ventricle. Based on these findings, we posit MP30B as a promising extract for cardiovascular disease prevention, and its specific antibacterial properties suggest its utility in preventing cardiac infections.

Neuroinflammation is a critical aspect of various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This study investigates the anti-neuroinflammatory properties of oleocanthal and its oxidation product, oleocanthalic acid, using the BV-2 cell line activated with lipopolysaccharide. Our findings revealed that oleocanthal significantly inhibited the production of pro-inflammatory cytokines and reduced the expression of inflammatory genes, counteracted oxidative stress induced by lipopolysaccharide, and increased cell phagocytic activity. Conversely, oleocanthalic acid was not able to counteract lipopolysaccharide-induced activation. The docking analysis revealed a plausible interaction of oleocanthal, with both CD14 and MD-2 leading to a potential interference with TLR4 signaling. Since our data show that oleocanthal only partially reduces the lipopolysaccharide-induced activation of NF-kB, its action as a TLR4 antagonist alone cannot explain its remarkable effect against neuroinflammation. Proteomic analysis revealed that oleocanthal counteracts the LPS modulation of 31 proteins, including significant targets such as gelsolin, clathrin, ACOD1, and four different isoforms of 14-3-3 protein, indicating new potential molecular targets of the compound. In conclusion, oleocanthal, but not oleocanthalic acid, mitigates neuroinflammation through multiple mechanisms, highlighting a pleiotropic action that is particularly important in the context of neurodegeneration.

Cell communication coordinates developmental processes, maintains homeostasis, and contributes to disease. Therefore, understanding the relationship between cells in a shared environment is crucial. Here we introduce Positive Ultra-bright Fluorescent Fusion For Identifying Neighbours (PUFFFIN), a cell neighbour-labelling system based upon secretion and uptake of positively supercharged fluorescent protein s36GFP. We fused s36GFP to mNeonGreen or to a HaloTag, facilitating ultra-bright, sensitive, colour-of-choice labelling. Secretor cells transfer PUFFFIN to neighbours while retaining nuclear mCherry, making identification, isolation, and investigation of live neighbours straightforward. PUFFFIN can be delivered to cells, tissues, or embryos on a customisable single-plasmid construct composed of interchangeable components with the option to incorporate any transgene. This versatility enables the manipulation of cell properties, while simultaneously labelling surrounding cells, in cell culture or in vivo. We use PUFFFIN to ask whether pluripotent cells adjust the pace of differentiation to synchronise with their neighbours during exit from naïve pluripotency. PUFFFIN offers a simple, sensitive, customisable approach to profile non-cell-autonomous responses to natural or induced changes in cell identity or behaviour., (© 2024. The Author(s).)

Dietary intervention is considered a safe preventive strategy to slow down aging. This study aimed to evaluate the protective effects of a commercially available supplement and six simpler formulations against DNA damage in 3D human keratinocytes. The ingredients used are well known and were combined into various formulations to test their potential anti-aging properties. Firstly, we determined the formulations' safe concentration by evaluating cytotoxicity and cell viability through spectrophotometric assays. We then examined the presence of tumor p53 binding protein 1 and phosphorylated histone H2AX foci, which are markers of genotoxicity. The foci count revealed that a 24-h treatment with the supplement did not induce DNA damage, and significantly reduced DNA damage in cells exposed to neocarzinostatin for 2 h. Three of the simpler formulations showed similar results. Moreover, the antioxidant activity was tested using a recently developed whole cell-based chemiluminescent bioassay; results showed that a 24-h treatment with the supplement and three simpler formulations significantly reduced intracellular H 2 O 2 after pro-oxidant injury, thus suggesting their possible antiaging effect. This study's originality lies in the use of a 3D human keratinocyte cell model and a combination of natural ingredients targeting DNA damage and oxidative stress, providing a robust evaluation of their anti-aging potential.

Background: Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD., Main Body: Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ ("A"), tau ("T"), and neurodegeneration ("N"), by incorporating a novel inflammatory component ("I")., Conclusions: The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients., (© 2024. The Author(s).)

Cell-cell interactions are central to development, but exploring how a change in any given cell relates to changes in the neighbour of that cell can be technically challenging. Here, we review recent developments in synthetic biology and image analysis that are helping overcome this problem. We highlight the opportunities presented by these advances and discuss opportunities and limitations in applying them to developmental model systems., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Neuroinflammation, which is mainly triggered by microglia, is a key contributor to multiple neurodegenerative diseases. Natural products, and in particular Cannabis sativa L., due to its richness in phytochemical components, represent ideal candidates to counteract neuroinflammation. We previously characterized different C. sativa commercial varieties which showed significantly different chemical profiles. On these bases, the aim of this study was to evaluate essential oils and aqueous distillation residues from the inflorescences of three different hemp varieties for their anti-neuroinflammatory activity in BV-2 microglial cells. Cells were pretreated with aqueous residues or essential oils and then activated with LPS. Unlike essential oils, aqueous residues showed negligible effects in terms of anti-inflammatory activity. Among the essential oils, the one obtained from 'Gorilla Glue' was the most effective in inhibiting pro-inflammatory mediators and in upregulating anti-inflammatory ones through the modulation of the p38 MAPK/NF-κB pathway. Moreover, the sesquiterpenes ( E )-caryophyllene, α-humulene, and caryophyllene oxide were identified as the main contributors to the essential oils' anti-inflammatory activity. To our knowledge, the anti-neuroinflammatory activity of α-humulene has not been previously described. In conclusion, our work shows that C. sativa essential oils characterized by high levels of sesquiterpenes can be promising candidates in the prevention/counteraction of neuroinflammation.

Autoimmune thyroid diseases are on the rise worldwide, and such a rapid increase is mainly driven by environmental factors related to changed lifestyles in "modern" societies. In this context, diet seems to play a crucial role. An unhealthy high-energy diet, rich in animal fat and proteins, salt and refined sugars (the so-called "Western diet") negatively influences the risk of autoimmunity by altering the immune balance and the gut microbiota composition, enhancing oxidative stress and promoting inflammation. In contrast, the Mediterranean diet represents a unique model of healthy eating, characterized by a high intake of food from vegetable sources, a low consumption of saturated fats in favor of unsaturated fats (mainly, olive oil), a moderate consumption of fish (typically, the small oily fishes) and dairy products, as well as a moderate consumption of wine at meals, and a low intake of meat. Thanks to its nutritional components, the Mediterranean Diet positively influences immune system function, gut microbiota composition, and redox homeostasis, exerting anti-oxidants, anti-inflammatory, and immunomodulatory effects. The present review was aimed at exploring the existing knowledge on the correlations between dietary habits and thyroid autoimmunity, to evaluate the role of the Mediterranean diet as a protective model.

Aims: The differentiation of left ventricular (LV) hypertrophic phenotypes is challenging in patients with normal ejection fraction (EF). The myocardial contraction fraction (MCF) is a simple dimensionless index useful for specifically identifying cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) when calculated by cardiac magnetic resonance. The purpose of this study was to evaluate the value of MCF measured by three-dimensional automated, machine-learning-based LV chamber metrics (dynamic heart model [DHM]) for the discrimination of different forms of hypertrophic phenotypes. Methods and Results: We analyzed the DHM LV metrics of patients with CA ( n = 10), hypertrophic cardiomyopathy (HCM, n = 36), isolated hypertension (IH, n = 87), and 54 healthy controls. MCF was calculated by dividing LV stroke volume by LV myocardial volume. Compared with controls (median 61.95%, interquartile range 55.43-67.79%), mean values for MCF were significantly reduced in HCM-48.55% (43.46-54.86% p < 0.001)-and CA-40.92% (36.68-46.84% p < 0.002)-but not in IH-59.35% (53.22-64.93% p < 0.7). MCF showed a weak correlation with EF in the overall cohort (R 2 = 0.136) and the four study subgroups (healthy adults, R 2 = 0.039 IH, R 2 = 0.089; HCM, R 2 = 0.225; CA, R 2 = 0.102). ROC analyses showed that MCF could differentiate between healthy adults and HCM (sensitivity 75.9%, specificity 77.8%, AUC 0.814) and between healthy adults and CA (sensitivity 87.0%, specificity 100%, AUC 0.959). The best cut-off values were 55.3% and 52.8%. Conclusions: The easily derived quantification of MCF by DHM can refine our echocardiographic discrimination capacity in patients with hypertrophic phenotype and normal EF. It should be added to the diagnostic workup of these patients.

Castanea sativa is very common in Italy, and the large amount of waste material generated during chestnut processing has a high environmental impact. Several studies demonstrated that chestnut by-products are a good source of bioactive compounds, mainly endowed with antioxidant properties. This study further investigates the anti-neuroinflammatory effect of chestnut leaf and spiny bur extracts, together with the deepest phytochemical characterisation (by NMR and MS) of active biomolecules contained in leaf extracts, which resulted in being more effective than spiny bur ones. BV-2 microglial cells stimulated with lipopolysaccharide (LPS) were used as a model of neuroinflammation. In BV-2 cells pre-treated with chestnut extracts, LPS signalling is partially blocked via the reduced expression of TLR4 and CD14 as well as the expression of LPS-induced inflammatory markers. Leaf extract fractions revealed the presence of specific flavonoids, such as isorhamnetin glucoside, astragalin, myricitrin, kaempferol 3-rhamnosyl (1-6)(2″-trans-p-coumaroyl)hexoside, tiliroside and unsaturated fatty acids, all of which could be responsible for the observed anti-neuroinflammatory effects. Interestingly, the kaempferol derivative has been identified in chestnut for the first time. In conclusion, the exploitation of chestnut by-products is suitable for the achievement of two goals: satisfaction of consumers' demand for new, natural bio-active compounds and valorisation of by-products.

Neurodegenerative diseases, characterized by progressive loss in selected areas of the nervous system, are becoming increasingly prevalent worldwide due to an aging population. Despite their diverse clinical manifestations, neurodegenerative diseases are multifactorial disorders with standard features and mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress and inflammation. As there are no effective treatments to counteract neurodegenerative diseases, increasing interest has been directed to the potential neuroprotective activities of plant-derived compounds found abundantly in food and in agrifood by-products. Food waste has an extremely negative impact on the environment, and recycling is needed to promote their disposal and overcome this problem. Many studies have been carried out to develop green and effective strategies to extract bioactive compounds from food by-products, such as peel, leaves, seeds, bran, kernel, pomace, and oil cake, and to investigate their biological activity. In this review, we focused on the potential neuroprotective activity of agrifood wastes obtained by common products widely produced and consumed in Italy, such as grapes, coffee, tomatoes, olives, chestnuts, onions, apples, and pomegranates.

Although it is clearly established that the abuse of alcohol is seriously harmful to health, much epidemiological and clinical evidence seem to underline the protective role of moderate quantities of alcohol and in particular of wine on health. This narrative review aims to re-evaluate the relationship between the type and dose of alcoholic drink and reduced or increased risk of various diseases, in the light of the most current scientific evidence. In particular, in vitro studies on the modulation of biochemical pathways and gene expression of wine bioactive components were evaluated. Twenty-four studies were selected after PubMed, Scopus and Google Scholar searches for the evaluation of moderate alcohol/wine consumption and health effects: eight studies concerned cardiovascular diseases, three concerned type 2 diabetes, four concerned neurodegenerative diseases, five concerned cancer and four were related to longevity. A brief discussion on viticultural and enological practices potentially affecting the content of bioactive components in wine is included. The analysis clearly indicates that wine differs from other alcoholic beverages and its moderate consumption not only does not increase the risk of chronic degenerative diseases but is also associated with health benefits particularly when included in a Mediterranean diet model. Obviously, every effort must be made to promote behavioral education to prevent abuse, especially among young people.

Although the lineage-determining ability of transcription factors is often modulated according to cellular context, the mechanisms by which such switching occurs are not well known. Using a transcriptional programming model, we found that Atoh1 is repurposed from a neuronal to an inner ear hair cell (HC) determinant by the combined activities of Gfi1 and Pou4f3. In this process, Atoh1 maintains its regulation of neuronal genes but gains ability to regulate HC genes. Pou4f3 enables Atoh1 access to genomic locations controlling the expression of sensory (including HC) genes, but Atoh1 + Pou4f3 are not sufficient for HC differentiation. Gfi1 is key to the Atoh1-induced lineage switch, but surprisingly does not alter Atoh1's binding profile. Gfi1 acts in two divergent ways. It represses the induction by Atoh1 of genes that antagonise HC differentiation, a function in keeping with its well-known repressor role in haematopoiesis. Remarkably, we find that Gfi1 also acts as a co-activator: it binds directly to Atoh1 at existing target genes to enhance its activity. These findings highlight the diversity of mechanisms by which one TF can redirect the activity of another to enable combinatorial control of cell identity., Competing Interests: Author AC is currently employed by Novartis AG, and previously by AgenTus Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Costa, Powell, Malaguti, Soufi, Lowell and Jarman.)

The aim of this study is to advance means for microalgae dewatering with the simultaneous reuse of water as new cultivation medium, specifically through ceramic membrane filtration. Three algae, namely, Spirulina platensis, Scenedesmus obliquus, and Chlorella sorokiniana were tested by filtering suspensions with four ceramic membranes having nominal pore sizes of 0.8 μm, 0.14 μm, 300 kDa, 15 kDa. The observed flux values and organic matter removal rates were related to the membrane pore size and cake layer properties, with some differences in productivity between algae types, likely due to cell size and shape. Interestingly, similar near steady-state fluxes (70-120 L m -2 h -1 ) were measured using membranes with nominal pore size above 15 kDa, suggesting the dominance of cake layer filtration independently of the initial flux. Virtually complete algae cells rejections and high nutrient passage (>75%) were observed in all combinations. When the permeate streams were used as media for new growth cycles of the various algae, no or little growth was observed with Spirulina p., while Chlorella s. (permeate from 300 kDa membrane) and especially Scenedesmus o. (permeate from 0.14 μm membrane) showed the fastest growth rates, almost comparable to those observed with ideal fresh media., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Endothelial damage is recognized as the initial step that precedes several cardiovascular diseases (CVD), such as atherosclerosis, hypertension, and coronary artery disease. It has been demonstrated that the best treatment for CVD is prevention, and, in the frame of a healthy lifestyle, the consumption of vegetables, rich in bioactive molecules, appears effective at reducing the risk of CVD. In this context, the large amount of agri-food industry waste, considered a global problem due to its environmental and economic impact, represents an unexplored source of bioactive compounds. This review provides a summary regarding the possible exploitation of waste or by-products derived by the processing of three traditional Italian crops-apple, pear, and sugar beet-as a source of bioactive molecules to protect endothelial function. Particular attention has been given to the bioactive chemical profile of these pomaces and their efficacy in various pathological conditions related to endothelial dysfunction. The waste matrices of apple, pear, and sugar beet crops can represent promising starting material for producing "upcycled" products with functional applications, such as the prevention of endothelial dysfunction linked to cardiovascular diseases.

Cell-cell interactions govern differentiation and cell competition in pluripotent cells during early development, but the investigation of such processes is hindered by a lack of efficient analysis tools. Here, we introduce SyNPL: clonal pluripotent stem cell lines that employ optimised Synthetic Notch (SynNotch) technology to report cell-cell interactions between engineered 'sender' and 'receiver' cells in cultured pluripotent cells and chimaeric mouse embryos. A modular design makes it straightforward to adapt the system for programming differentiation decisions non-cell-autonomously in receiver cells in response to direct contact with sender cells. We demonstrate the utility of this system by enforcing neuronal differentiation at the boundary between two cell populations. In summary, we provide a new adaptation of SynNotch technology that could be used to identify cell interactions and to profile changes in gene or protein expression that result from direct cell-cell contact with defined cell populations in culture and in early embryos, and that can be customised to generate synthetic patterning of cell fate decisions., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Despite controversial evidences, intra-aortic balloon pump (IABP) is still the most widely used temporary mechanical support device in cardiogenic shock (CS), as a bridge to recovery or to more invasive mechanical supports/heart transplantation., Methods: We analyzed retrospectively data of all patients receiving IABP for CS from 2009 to 2018 in a referral centre for advanced heart failure and heart transplantation; we included CS following acute coronary syndrome (ACS) and other CS etiologies different from ACS. We excluded patients in which IABP was implanted as a support following cardiac surgery, non-cardiac surgery in patients with severe chronic heart failure, or in elective high risk or complicated Cath Lab procedures.We focused on in-hospital outcomes (including death, recovery, heart transplantation, LVAD) and IABP complications., Results: 403 patients received IABP, 303 (75.2%) following ACS and 100 (24.8%) in non-ACS CS. Non-ACS patients were younger (59 ± 18.3 vs 73.1 ± 12.6 years, p < 0.001), had lower median left ventricular ejection fraction (LVEF) (25% [18-35] vs 38% [25-45], p < 0.001). In patients with non-ACS etiologies IABP was more frequently a bridge to heart transplantation [20% (n = 20) vs 0.3% (n = 1), P < 0.001] or LVAD [4% (n = 4) vs 0.6% (n = 2), P  = 0.055], while ACS patients were more frequently discharged without transplantation/LVAD [65.7% (n = 199) vs 33% (n = 33), P < 0.001]. Non-ACS patients showed higher in-hospital mortality [46% (n = 46) vs 33.9% (n = 103), P = 0.042]. Post-transplant/LVAD outcome in non-ACS subgroup was favorable (21 out of 24 patients were discharged). Serious IABP-related adverse events occurred in 21 patients (5.2%). Ischemic/hemorrhagic complications, infections and thrombocytopenia were more frequent with longer IABP stay., Conclusions: Despite therapy including percutaneous circulatory support, mortality in CS is still high. In our experience, in the clinical setting of refractory CS an IABP support represents a relatively safe circulatory support, associated with a low rate of serious complications in complex clinical scenarios., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells' differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

During early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type" (Waddington in Nature 183: 1654-1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772-774, 1988; Lander in Cell 144: 955-969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors ( 5 , 6 , and 12 ), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.

Background: There is a growing awareness that nutritional habits may influence risk of several inflammatory and immune-mediated disorders, including autoimmune diseases, through various mechanisms. The aim of the present study was to investigate dietary habits and their relationship with redox homeostasis in the setting of thyroid autoimmunity. Materials and Methods: Two hundred subjects (173 females and 27 males; median age, 37 years) were enrolled. None were under any pharmacological treatment. Exclusion criteria were any infectious/inflammatory/autoimmune comorbidity, kidney failure, diabetes, and cancer. In each subject, serum thyrotropin (TSH), free thyroxine, antithyroid antibodies, and circulating oxidative stress markers were measured. A questionnaire on dietary habits, evaluating the intake frequencies of food groups and adherence to the Mediterranean diet, was submitted to each participant. Results: Among the 200 recruited subjects, 81 (71 females and 10 males) were diagnosed with euthyroid Hashimoto's thyroiditis (HT); the remaining 119 (102 females and 17 males) served as controls. In questionnaires, HT subjects reported higher intake frequencies of animal foods (meat, p  = 0.0001; fish, p  = 0.0001; dairy products, p  = 0.004) compared with controls, who reported higher intake frequencies of plant foods (legumes, p  = 0.001; fruits and vegetables, p  = 0.030; nuts, p  = 0.0005). The number of subjects who preferentially consumed poultry instead of red/processed meat was lower in HT subjects than in controls ( p  = 0.0141). In logistic regression analysis, meat consumption was associated with increased odds ratio of developing thyroid autoimmunity, while the Mediterranean diet traits were protective. In HT subjects, serum advanced glycation end products (markers of oxidative stress) were significantly higher ( p  = 0.0001) than in controls, while the activity of glutathione peroxidase and thioredoxin reductase, as well as total plasma antioxidant activity, were lower ( p  = 0.020, p  = 0.023, and p  = 0.002, respectively), indicating a condition of oxidative stress. Stepwise regression models demonstrated a significant dependence of oxidative stress parameters on consumption of animal foods, mainly meat. Conclusions : The present study suggests a protective effect of low intake of animal foods toward thyroid autoimmunity and a positive influence of such nutritional patterns on redox balance and potentially on oxidative stress-related disorders.

(1) Background: It is recommended that an athlete, in order to ensure correct nutrition and performance, should consume between 1.2 and 2.0 g/kg/day of protein, while the daily recommended protein intake for a non-athlete is 0.8and 0.9 mg/kg/day. It is unclear if athletes living in Mediterranean countries are able to meet protein requirements without supplementation, since Mediterranean diet de-emphasizes meat and meat products. (2) Methods: 166 athletes (125 males) enrolled between 2017 and 2019 were required to keep a dietary journal for three consecutive days (2 workdays and 1 weekend day). Athletes had to be >18 years old, train in a particular sport activity more than 3 h a week and compete at least at an amateur level. Journal data were collected and then translated into macro-nutrient content (grams of protein, carbohydrates, and lipids) by a nutritionist. (3) Results: The protein intake reported by this specific population vary slightly from the Academy of Nutrition and Dietetics (AND), Dietitians of Canada (DC), and the American College of Sports Medicine (ACSM) joint statement recommendation level. Average protein levels without protein supplementation fell within the protein guidelines. Counterintuitively, the intake among those who supplemented their diet with protein was higher compared with those who did not, even when excluding the contribution of supplements. Although the majority of subjects participating in the study were able to meet protein intake recommended for athletes without protein supplementation, 27% of athletes were below the guideline range. (4) Conclusions: these data suggest that athletes' nutrition should be more often evaluated by a nutritionist and that they will benefit from increasing their nutritional knowledge in order to make better food choices, resorting to protein supplementation only when effectively needed.

Castanea sativa cultivation has been present in Mediterranean regions since ancient times. In order to promote a circular economy, it is of great importance to valorize chestnut groves' by-products. In this study, leaves and spiny burs from twenty-four Castanea trees were analyzed by 1 H NMR metabolomics to provide an overview of their phytochemical profile. The Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) performed on these data allowed us to distinguish 'Marrone' from 'Castagna', since the latter were generally more enriched with secondary metabolites, in particular, flavonoids (astragalin, isorhamnetin glucoside, and myricitrin) were dominant. Knowing that microglia are involved in mediating the oxidative and inflammatory response of the central nervous system, the potential anti-inflammatory effects of extracts derived from leaves and spiny burs were evaluated in a neuroinflammatory cell model: BV-2 microglia cells. The tested extracts showed cytoprotective activity (at 0.1 and 0.5 mg/mL) after inflammation induction by 5 µg/mL lipopolysaccharide (LPS). In addition, the transcriptional levels of IL-1β, TNF-α, and NF-kB expression induced by LPS were significantly decreased by cell incubation with spiny burs and leaves extracts. Taken together, the obtained results are promising and represent an important step to encourage recycling and valorization of chestnut byproducts, usually considered "waste".

It's a frightening time due to COVID-19, but the great elderly/centenarians, apparently with more frailty, seem to have a better response to the pandemic. "The South Italy" lifestyle seems an "effective strategy" promoting the well-being embedded in a holistic solution: healthy diet, less exposure to PM10 pollution, protected environment, and moderate physical activity. The European FP7 Project RISTOMED results, since 2010, have shown that dietary intervention improved a heathy status in the elderly people. Based on the RISTOMED results, in addition to sociocultural and environmental factors, the authors suggest an integrated approach for resilience to COVID-19. Such an approach during the next months could make the difference for the success of any government progress policy to fight COVID-19, finalizing long-term well-being and successful aging., (Copyright © 2020 Angelini, Pinto, Hrelia, Malaguti, Buccolini, Donini and Hrelia.)

Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Patrizia Hrelia et al.)

Sweet cherries ( Prunus avium L.) are highly appreciated fruits for their taste, color, nutritional value, and beneficial health effects. In this work, seven new cultivars of sweet cherry were investigated for their main quality traits and nutraceutical value. The phytochemical profile of three classes of phenolic compounds and the antioxidant activity of the new cultivars were investigated through high-performance liquid chromatography with diode array detection (HPLC-DAD) and spectrophotometric assays, respectively, and compared with those of commonly commercialized cultivars. Cyanidine-3- O -rutinoside was the main anthocyanin in all genotypes, and its levels in some new cultivars were about three-fold higher than in commercial ones. The ORAC-assayed antioxidant capacity was positively correlated with the total anthocyanin index. The nutraceutical value of the new cultivars was investigated in terms of antioxidant/neuroprotective capacity in neuron-like SH-SY5Y cells. Results demonstrated that the new cultivars were more effective in counteracting oxidative stress and were also able to upregulate brain-derived neurotrophic factor (BDNF), a pro-survival neurotrophin, suggesting their potential pleiotropic role in counteracting neurodegenerations.

The intrinsic mechanisms that link extracellular signalling to the onset of neural differentiation are not well understood. In pluripotent mouse cells, BMP blocks entry into the neural lineage via transcriptional upregulation of inhibitor of differentiation (Id) factors. We have previously identified the major binding partner of Id proteins in pluripotent cells as the basic helix-loop-helix (bHLH) transcription factor (TF) E2A. Id1 can prevent E2A from forming heterodimers with bHLH TFs or from forming homodimers. Here, we show that overexpression of a forced E2A homodimer is sufficient to drive robust neural commitment in pluripotent cells, even under non-permissive conditions. Conversely, we find that E2A null cells display a defect in their neural differentiation capacity. E2A acts as an upstream activator of neural lineage genes, including Sox1 and Foxd4 , and as a repressor of Nodal signalling. Our results suggest a crucial role for E2A in establishing neural lineage commitment in pluripotent cells., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Iron is a fundamental element in human history, from the dawn of civilization to contemporary days. The ancients used the metal to shape tools, to forge weapons, and even as a dietary supplement. This last indication has been handed down until today, when martial therapy is considered fundamental to correct deficiency states of anemia. The improvement of the martial status is mainly targeted with dietary supplements that often couple diverse co-factors, but other methods are available, such as parenteral preparations, dietary interventions, or real-world approaches. The oral absorption of this metal occurs in the duodenum and is highly dependent upon its oxidation state, with many absorption influencers possibly interfering with the intestinal uptake. Bone marrow and spleen represent the initial and ultimate step of iron metabolism, respectively, and the most part of body iron circulates bound to specific proteins and mainly serves to synthesize hemoglobin for new red blood cells. Whatever the martial status is, today's knowledge about iron biochemistry allows us to embrace exceedingly personalized interventions, which however owe their success to the mythical and historical events that always accompanied this metal., Competing Interests: The authors declare no conflict of interest.

Altered martial indices before orthopedic surgery are associated with higher rates of complications and greatly affect the patient's functional ability. Oral supplements can optimize the preoperative martial status, with clinical efficacy and the patient's tolerability being highly dependent on the pharmaceutical formula. Patients undergoing elective hip/knee arthroplasty were randomized to be supplemented with a 30-day oral therapy of sucrosomial ferric pyrophosphate plus L-ascorbic acid. The tolerability was 2.7% among treated patients. Adjustments for confounding factors, such as iron absorption influencers, showed a relevant response limited to older patients (≥ 65 years old), whose uncharacterized Hb loss was averted upon treatment with iron formula. Older patients with no support lost -2.8 ± 5.1%, while the intervention group gained +0.7 ± 4.6% of circulating hemoglobin from baseline ( p = 0.019). Gastrointestinal diseases, medications, and possible dietary factors could affect the efficacy of iron supplements. Future opportunities may consider to couple ferric pyrophosphate with other nutrients, to pay attention in avoiding absorption disruptors, or to implement interventions to obtain an earlier martial status optimization at the population level.

A switch from E- to N-cadherin regulates the transition from pluripotency to neural identity, but the mechanism by which cadherins regulate differentiation was previously unknown. Here, we show that the acquisition of N-cadherin stabilises neural identity by dampening anti-neural signals. We use quantitative image analysis to show that N-cadherin promotes neural differentiation independently of its effects on cell cohesiveness. We reveal that cadherin switching diminishes the level of nuclear β-catenin, and that N-cadherin also dampens FGF activity and consequently stabilises neural fate. Finally, we compare the timing of cadherin switching and differentiation in vivo and in vitro , and find that this process becomes dysregulated during in vitro differentiation. We propose that N-cadherin helps to propagate a stable neural identity throughout the emerging neuroepithelium, and that dysregulation of this process contributes to asynchronous differentiation in culture., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Over the past few years, the contribution of oxysterols to the onset and development of some of the major neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) has been scientifically asserted, being mainly related to altered brain cholesterol homeostasis. To counteract oxysterol induced inflammation at neuronal level, one possible intervention approach is the administration of some nutrients and/or plant secondary metabolites. On the other hand, the pleiotropic beneficial effects of physical activity seem to play an important role on prevention and counteraction of neurodegenerative diseases, through the modulation of oxysterol homeostasis and the prevention of demyelination. The present review provides a picture of the promising role of nutraceuticals and physical activity on oxysterol-mediated neurodegeneration, pointing out also the different in vitro and in vivo aspects that need to be further investigated for a better understanding of the association of these three counterparts and their overall effect on people at increased risk for neurodegenerative diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Controlling responsiveness to prevailing signals is critical for robust transitions between cell states during development. For example, fibroblast growth factor (FGF) drives naive pluripotent cells into extraembryonic lineages before implantation but sustains pluripotency in primed cells of the post-implantation epiblast. Nanog supports pluripotency in naive cells, while Nodal supports pluripotency in primed cells, but the handover from Nanog to Nodal does not proceed seamlessly, opening up the risk of aberrant differentiation if FGF is activated before Nodal. Here, we report that Id1 acts as a sensor to detect delays in Nodal activation after the downregulation of Nanog. Id1 then suppresses FGF activity to delay differentiation. Accordingly, Id1 is not required for naive or primed pluripotency but rather stabilizes epiblast identity during the transition between these states. These findings help explain how development proceeds robustly in the face of imprecise signals and highlight the importance of mechanisms that stabilize cell identity during developmental transitions., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroinflammation is one of the main contributors to the onset and progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Microglial and astrocyte activation is a brain defense mechanism to counteract harmful pathogens and damaged tissues, while their prolonged activation induces neuroinflammation that can trigger or exacerbate neurodegeneration. Unfortunately, to date there are no pharmacological therapies able to slow down or stop the progression of neurodegeneration. For this reason, research is turning to the identification of natural compounds with protective action against these diseases. Considering the important role of neuroinflammation in the onset and development of neurodegenerative pathologies, natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Marine organisms represent a huge source of natural compounds, and among them, algae are appreciated sources of important bioactive components such as antioxidants, proteins, vitamins, minerals, soluble dietary fibers, polyunsaturated fatty acids, polysaccharides, sterols, carotenoids, tocopherols, terpenes, phycobilins, phycocolloids, and phycocyanins. Recently, numerous anti-inflammatory compounds have been isolated from marine algae with potential protective efficacy against neuroinflammation. This review highlights the key inflammatory processes involved in neurodegeneration and the potential of specific compounds from marine algae to counteract neuroinflammation in the CNS.

Preclinical and clinical studies suggest that many food molecules could interact with drug transporters and metabolizing enzymes through different mechanisms, which are predictive of what would be observed clinically. Given the recent incorporation of dietary modifications or supplements in traditional medicine, an increase in potential food-drug interactions has also appeared. The objective of this article is to review data regarding the influence of food on drug efficacy. Data from Google Scholar, PubMed, and Scopus databases was reviewed for publications on pharmaceutical, pharmacokinetic, and pharmacodynamic mechanisms. The following online resources were used to integrate functional and bioinformatic results: FooDB, Phenol-Explorer, Dr. Duke's Phytochemical and Ethnobotanical Databases, DrugBank, UniProt, and IUPHAR/BPS Guide to Pharmacology. A wide range of food compounds were shown to interact with proteins involved in drug pharmacokinetic/pharmacodynamic profiles, starting from drug oral bioavailability to enteric/hepatic transport and metabolism, blood transport, and systemic transport/metabolism. Knowledge of any food components that may interfere with drug efficacy is essential, and would provide a link for obtaining a holistic view for cancer, cardiovascular, musculoskeletal, or neurological therapies. However, preclinical interaction may be irrelevant to clinical interaction, and health professionals should be aware of the limitations if they intend to optimize the therapeutic effects of drugs., Competing Interests: The authors declare no conflict of interest.

Background: The interest towards botanicals and plant extracts has strongly risen due to their numerous biological effects and ability to counteract chronic diseases development. Among these effects, chemoprevention which represents the possibility to counteract the cancerogenetic process is one of the most studied. The extracts of mushroom Meripilus giganteus (MG) (Phylum of Basidiomycota) showed to exert antimicrobic, antioxidant and antiproliferative effects. Therefore, since its effect in leukemic cell lines has not been previously evaluated, we studied its potential chemopreventive effect in Jurkat and HL-60 cell lines., Methods: MG ethanolic extract was characterized for its antioxidant activity and scavenging effect against different radical species. Moreover, its phenolic profile was evaluated by HPLC-MS-MS analyses. Flow cytometry (FCM) analyses of Jurkat and HL-60 cells treated with MG extract (0-750 μg/mL) for 24-72 h- allowed to evaluate its cytotoxicity, pro-apoptotic and anti-proliferative effect. To better characterize MG pro-apoptotic mechanism ROS intracellular level and the gene expression level of FAS, BAX and BCL2 were also evaluated. Moreover, to assess MG extract selectivity towards cancer cells, its cytotoxicity was also evaluated in human peripheral blood lymphocytes (PBL)., Results: MG extract induced apoptosis in Jurkat and HL-60 cells in a dose- and time- dependent manner by increasing BAX/BCL2 ratio, reducing ROS intracellular level and inducing FAS gene expression level. In fact, reduced ROS level is known to be related to the activation of apoptosis in leukemic cells by the involvement of death receptors. MG extract also induced cell-cycle arrest in HL-60 cells. Moreover, IC 50 at 24 h treatment resulted 2 times higher in PBL than in leukemic cell lines., Conclusions: Our data suggest that MG extract might be considered a promising and partially selective chemopreventive agent since it is able to modulate different mechanisms in transformed cells at concentrations lower than in non-transformed ones.