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Background. Gli ellagitannini (ET), polifenoli presenti nel melograno, una volta ingeriti vengono metabolizzati dal microbiota intestinale a urolitine (Uro), a cui si ascrivono proprietà antinfiammatorie e antiossidanti nell’aterosclerosi. In relazione ai tipi di Uro prodotte, si distinguono due metabotipi, A (Uro A) e B (Uro A, IsoUro A, Uro B e Uro C). I macrofagi sono cellule chiave nell’infiammazione e nell’aterosclerosi, e, pertanto, eccellenti candidati come bersagli dell’azione delle urolitine. Scopo. Valutare l’effetto di dosi fisiologiche di Uro, che mimano i metabotipi, sul trascrittoma di macrofagi umani. Metodi. I monociti sono stati isolati da buffy coat di donatori sani e stimolati per indurre la polarizzazione M1 o M2, in presenza o in assenza di differenti combinazioni di Uro, corrispondenti ai metabotipi A e B. Le alterazioni a livello di trascrittoma sono state rilevate mediante tecnica microarray a genoma intero. Risultati. Il trascrittoma dei macrofagi M1 è stato solo minimamente influenzato dai metabotipi. Al contrario, le Uro del metabotipo A, modificano profondamente l’impronta trascrittomica degli M2, smorzando i processi di adesione focale e di migrazione transendoteliale e amplificando i meccanismi antisenescenza, mediante l’espressione dei geni implicati nell’attività lisosomiale e delle vie di riparazione del DNA. Nel metabotipo B, le modifiche del trascrittoma degli M2 sono molto contenute, e includono la repressione della via del segnale associata alla diapedesi. Conclusioni. Questi dati suggeriscono che le Uro del metabotipo A sono eccellenti candidate al ruolo di sostanze naturali a effetto netto antiaterogenico, attraverso l’esaltazione del ruolo antinfiammatorio dei macrofagi M2. Un ruolo analogo, ma quantitativamente molto minore, potrebbe essere svolto anche dalle urolitine del metabotipo B. Studio finanziato dal MIUR, Programma SIR2014 (RBSI14LHMB).

Objectives. There is strong evidence in animal models suggesting that pomegranate fruit exerts health benefits relating to their antioxidant and anti-inflammatory properties [1]. Beneficial effects are certainly the consequence of the presence of the pomegranate polyphenols, mostly consisting of ellagitannins (ETs). However, studies in humans often failed to show clear associations between pomegranate intake and health outcomes, possibly due to inter-individual variation in absorption, distribution, metabolism, and excretion (ADME) of ETs. Methods. A literature review was conducted using the PubMed and Scopus databases including all original research articles on the relationship between inter-individual variability and ADME of ETs in humans. Data were summarized in a tabulated summary containing: study design, population, description of the intervention, duration, outcomes relevant to inter-individual variability in bioavailability and metabolism of ETs. Results. From 2004 to date, most of the research studies are mainly related to cardiometabolic risk biomarkers. Intervention studies are carried out using pomegranate juice or phenolic extracts at different doses of ETs. Additionally, the study designs used differ for each trial. Data on the four criteria ADME were not available in all publications. Results showed that urolithins are the predominant metabolites following pomegranate consumption. Anyhow, few works are still focused on the bioconversion of pomegranate ETs to their active metabolites. Conclusions. Urolithins are colonic microbiota metabolites of ETs and are considered responsible for in vivo health effects. The recently discovered existence of human metabolic phenotypes or metabotypes [2] could explain the variability seen in diet intervention studies. An understanding of the ADME of ETs in relation to the inter-individual variability is crucial for the elucidation of the mechanisms responsible for the health benefits of pomegranate and other ET-rich foods. Acknowledgments. This study was supported by the SIR programme (no. RBSI14LHMB) granted by the Italian Ministry of Education, University and Research. References. [1] Danesi & Ferguson. Could pomegranate juice help in the control of inflammatory diseases? Nutrients 2017; 9(9):E958. [2] Tomás-Barberán et al. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J. Agric. Food Chem. 2014; 62(28):6535–8.

Introduzione. La plasticità dell’apparato gastrointestinale negli ultimi anni è stato oggetto di numerosi studi. L’evidenza ha mostrato che macrofagi residenti nella mucosa intestinale di soggetti affetti da malattie infiammatorie croniche intestinali (MICI) presentano alterazioni morfo-funzionali rispetto a soggetti sani (Isidro & Appleyard 2016 Am J Physiol Gastrointest Liver Physiol 311:G59-73). A seguito del consumo di alimenti ricchi in ellagitannini e acido ellagico, come melagrana, frutti rossi e noci, vengono prodotte urolitine (Uro) a livello intestinale. Nell’uomo sono stati individuati 3 metabotipi (Met): Met A produce Uro A, Met B produce anche isoUro A e Uro B, Met 0 non produce Uro (Tomás-Barberán et al 2017 Mol Nutr Food Res 61:1500901). Lo scopo dello studio è valutare l’effetto dei Met su macrofagi polarizzati in modo proinfiammatorio M1 similmente a macrofagi intestinali di soggetti affetti da MICI. Metodi. Il fenotipo macrofagico M1, ottenuto da monociti di donatori sani stimolati con LPS+IFNγ, è stato trattato con 3 combinazioni di Uro corrispondenti ai Met. Si è analizzata l’espressione genica con tecnica microarray rispetto a macrofagi a riposo (MR) non stimolati. Risultati. Il Met 0 non influenza il trascrittoma dei macrofagi M1 rispetto a MR. Diversamente i met A e B inducono una repressione dei pathway NF-κB, cronicamente attivo in fenomeni flogistici, e TREM1, che agisce da amplificatore della risposta infiammatoria, oltre a una marcata repressione delle vie dell’inflammasoma responsabili del rilascio di citochine come IL18. Il Met B inibisce inoltre l’espressione di numerose caspasi. Conclusioni. Tali risultati indicano un effetto inibente dei Met A e B su pathway coinvolti nella risoluzione dell’infiammazione, mostrando una tipica ‘response to injury’ ed evocando una risposta riparativa promettente e desiderabile in processi infiammatori cronici come quelli alla base delle MICI. Studio finanziato dal MIUR, Programma SIR2014 (RBSI14LHMB).

Background Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent episodes of intestinal inflammation and is thought to be related to an autoimmune reaction to genetic and environmental factors. Although evidence indicates that a polyphenolic-rich diet plays an important role in modulating aspects of chronic inflammation, few studies have focused on the effect of ellagitannin (ET)-rich food consumption on long-term remission maintenance in IBD patients with a high risk of clinical relapse. Therefore, we hypothesize that supplementation with a pomegranate juice, a naturally rich source of ETs, could significantly modulate the markers of mucosal and systemic inflammation relative to a control group receiving a placebo. Methods/design This double-blind, randomized controlled trial includes patients with IBD involving the colorectum who have been in stable therapy for at least the three previous months and have a high risk of clinical relapse. Participants are randomly allocated to one of two groups: active supplementation (125 mL of cv. Wonderful pomegranate juice) or placebo (125 mL) taken twice daily for 12 weeks. The primary outcome is changes in the fecal neutrophil-derived protein calprotectin, a surrogate marker of mucosal improvement, between the two groups from baseline to 12 weeks later. The secondary outcomes include transcriptomic changes in peripheral blood mononuclear cells and intestinal biopsies and changes in circulating inflammatory markers and trimethylamine-N-oxide levels. Pomegranate ET-derived metabolites are identified and quantified in plasma and urine samples. Discussion The results will provide information on the possible reduction of fecal calprotectin levels following the consumption of pomegranate juice. The findings will also show the in vivo metabolism of pomegranate ETs. Finally, the effect of 12-week pomegranate juice consumption on local and systemic inflammatory markers will be elucidated, which will likely provide additional insights into the maintenance of remission in IBD patients. Trial registration ClinicalTrials.gov, NCT03000101. Registered on 21 December 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3321-8) contains supplementary material, which is available to authorized users.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m²) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (-30 ± 20 mg/dL; p = 0.012), LDL cholesterol (-31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (-14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention., info:eu-repo/semantics/published

Background Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown. Methods Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34+/CD133+/KDR+/106 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed. Results Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p Conclusions V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013

BackgroundMacrophages are a heterogeneous cell population which in response to the cytokine milieu polarize in either classically activated macrophages (M1) or alternatively activated macrophages (M2). This plasticity makes macrophages essential in regulating inflammation, immune response and tissue remodeling and a novel therapeutic target in inflammatory diseases such as atherosclerosis. The aim of the study was to describe the transcriptomic profiles of differently polarized human macrophages to generate new hypotheses on the biological function of the different macrophage subtypes.Methods and resultsPolarization of circulating monocytes/macrophages of blood donors was induced in vitro by IFN-γ and LPS (M1), by IL-4 (M2a), and by IL-10 (M2c). Unstimulated cells (RM) served as time controls. Gene expression profile of M1, M2a, M2c and RM was assessed at 6, 12 and 24h after polarization with Whole Human Genome Agilent Microarray technique. When compared to RM, M1 significantly upregulated pathways involved in immunity and inflammation, whereas M2a did the opposite. Conversely, decreased and increased expression of mitochondrial metabolism, consistent with insulin resistant and insulin sensitive patterns, was seen in M1 and M2a, respectively. The time sequence in the expression of some pathways appeared to have some specific bearing on M1 function. Finally, canonical and non-canonical Wnt genes and gene groups, promoting inflammation and tissue remodeling, were upregulated in M2a compared to RM.ConclusionOur data in in vitro polarized human macrophages: 1. confirm and extend known inflammatory and anti-inflammatory gene expression patterns; 2. demonstrate changes in mitochondrial metabolism associated to insulin resistance and insulin sensitivity in M1 and M2a, respectively; 3. highlight the potential relevance of gene expression timing in M1 function; 4. unveil enhanced expression of Wnt pathways in M2a suggesting a potential dual (pro-inflammatory and anti-inflammatory) role of M2a in inflammatory diseases.

Insulin resistance is considered to be a pathogenetic mechanism in several and diverse diseases (e.g. type 2 diabetes, atherosclerosis) often antedating them in apparently healthy subjects. The aim of this study is to investigate with a microarray based approach whether IR per se is characterized by a specific pattern of gene expression. For this purpose we analyzed the transcriptomic profile of peripheral blood mononuclear cells in two groups (10 subjects each) of healthy individuals, with extreme insulin resistance or sensitivity, matched for BMI, age and gender, selected within the MultiKnowledge Study cohort (n = 148). Data were analyzed with an ad-hoc rank-based classification method. 321 genes composed the gene set distinguishing the insulin resistant and sensitive groups, within which the "Adrenergic signaling in cardiomyocytes" KEGG pathway was significantly represented, suggesting a pattern of increased intracellular cAMP and Ca2+, and apoptosis in the IR group. The same pathway allowed to discriminate between insulin resistance and insulin sensitive subjects with BMI >25, supporting his role as a biomarker of IR. Moreover, ASCM pathway harbored biomarkers able to distinguish healthy and diseased subjects (from publicly available data sets) in IR-related diseases involving excitable cells: type 2 diabetes, chronic heart failure, and Alzheimer's disease. The altered gene expression profile of the ASCM pathway is an early molecular signature of IR and could provide a common molecular pathogenetic platform for IR-related disorders, possibly representing an important aid in the efforts aiming at preventing, early detecting and optimally treating IR-related diseases.