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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.

Background. In humans, ellagitannins (ETs), polyphenols present in nuts, seeds and some fruits such as pomegranates, can be metabolised by intestinal microbiota to urolithins (UTs), which controversial evidence [1] associates to anti-inflammatory and anti-oxidant properties. According to microbiota composition, humans metabolise ETs in line with one of three different metabolic phenotypes or metabotypes: metabotype A (urolithin A and conjugates), metabotype B (conjugates of urolithin B and isourolithin A, in addition to urolithin A), and metabotype 0 (not producing urolithins) [2]. Macrophages play a pivotal role in inflammatory diseases, including atherosclerosis, and differentiate in either M1 macrophages (with pro-inflammatory properties) or M2 macrophages (with anti-inflammatory properties) in response to the cytokine milieu. We hypothesised that ET metabotypes could differently affect macrophages, and hence may display a different potential for prevention of and protection from inflammatory diseases. Aim. To assess the effect(s) of physiological doses of UTs, mimicking the three different human metabotypes of ETs, on gene expression profile in human M1 and M2 polarised macrophages. Methods. Monocytes were isolated from healthy donors’ buffy coats and then stimulated to induce M1 or M2 phenotypes, in the presence or absence of different UT combinations, reproducing the A, B, and 0 metabotypes. The gene expression profile was analysed with whole human genome microarray technology. Gene expression data were analysed with GeneSpring GX v11.5; Differentially expressed genes were identified by Moderated t-test (Benjamini Hochberg correction p-value < 0.05). Gene enrichment analysis was applied on the significant differentially expressed list of genes. Results. The transcriptome of M1 macrophages was minimally influenced by UT metabotypes. In contrast, in M2 macrophages, metabotype A UTs induced extensive significant changes in gene expression of M2 macrophages, apparently enhancing their anti-inflammatory properties, by downregulating the focal adhesion and transendothelial migration pathways, and also amplifying their anti-senescence mechanisms, by upregulating lysosomal activity and DNA repair pathways. Metabotype B reduced the expression of key genes involved in leukocyte transendothelial migration. Conclusions. These findings indicate that metabotype A UTs cause an extensive remodelling of the transcriptomic platform of M2 macrophages, whereas metabotype B UTs induce relatively minor changes. These changes are compatible with an enhancement in M2 macrophages of anti-inflammatory properties and, only for metabotype A UTs, of anti-senescence mechanisms, including autophagy. These data suggest that the people with metabotype A may receive a much greater benefit from high ET intake towards organ damage/clinical events due to inflammatory diseases, in particular, atherosclerosis. Real time PCR validation will be performed to confirm these results. Acknowledgments. This study was supported by the Italian Ministry of Education, University and Research MIUR – SIR programme (no. RBSI14LHMB). References. [1]. Danesi F, Ferguson LR. Could pomegranate juice help in the control of inflammatory diseases? Nutrients. 2017; 9(9):E958. [2]. Tomás-Barberán FA, García-Villalba R, González-Sarrías A, Selma MV, Espín JC. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. Journal of Agricultural and Food Chemistry. 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).

Le urolitine (Uro) sono molecole prodotte nell‟organismo in seguito ad ingestione di alimenti ricchi in ellagitannini, polifenoli presenti in melagrana, frutti di bosco e noci. In relazione alla diversa capacità individuale di produrre Uro, sono stati individuati diversi fenotipi metabolici, detti metabotipi (1). Le Uro stanno dimostrando numerose attività biologiche protettive. Essendo i macrofagi cellule molto plastiche e ubiquitarie, potrebbero rappresentare un target chiave nell‟attività delle diverse Uro. Lo scopo dello studio consiste nel valutare l‟efficacia protettiva dei differenti metabotipi su macrofagi polarizzati in modo proinfiammatorio M1 e immunoregolatorio M2. I monociti sono stati isolati da buffy coats di donatori sani e stimolati per indurre i fenotipi M1 o M2, in presenza o in assenza di differenti combinazioni di Uro, corrispondenti ai metabotipi A e B, a dosi fisiologiche. Si è analizzata l‟espressione genica con tecnica microarray a genoma intero. Il trascrittoma dei macrofagi M1 viene minimamente influenzato dal metabotipo. Diversamente, nei macrofagi M2, il metabotipo A induce una downregolazione delle vie metaboliche connesse all‟adesione focale, alla crescita tumorale e all‟interazione tra recettori di adesione e matrice extracellulare, mentre aumenta l‟espressione di geni relativi all‟attività lisosomiale. Il metabotipo B riduce l‟espressione di geni chiave coinvolti in diverse vie di trasduzione del segnale (mTOR, epidermal growth factor, sfingolopidi). Tali risultati indicano un potenziale effetto inibente dei metabotipi sui geni coinvolti in processi aterosclerotici –legati quindi all‟infiammazione cronica– e proliferativi, e un effetto positivo sull‟attività autofagica, da parte del metabotipo A, ritenuti fondamentali come meccanismi protettivi dalla senescenza cellulare. Studio finanziato dal MIUR, Programma SIR2014 (RBSI14LHMB). 1 Tomás-Barberán et al. 2014 J Agric Food Chem 62:6535-8.

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

Background and aims Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms. Methods CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 μM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR. Results Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response. Conclusions In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs.

Individuals with type 2 diabetes show shorter leukocyte telomere length (LTL) compared to people without diabetes. Reduced LTL is associated with increased carotid intima-media thickness (IMT) in healthy subjects. The aim of the study is to assess whether LTL also correlates with IMT in patients with diabetes. In a cohort of 104 subjects with type 2 diabetes and atherogenic dyslipidemia, we assessed anthropometric, hemodynamic and metabolic parameters. Common carotid IMT was expressed as the maximum IMT. LTL was assessed by a specific real-time PCR reaction. At univariate analysis, IMT values were positively correlated with age (p

Macrophages, a heterogeneous and ubiquitous cell population representing up to 15% of the cellular content of different types of tissue, are the principal cell mediators in response to pathogens, inflammation process, tissue homeostasis and repair and play a pivotal role in atherosclerosis and insulin resistance because of their capacity to be the major source of inflammatory cytokines, which can function through paracrine and endocrine mechanisms. Recently, differently activated macrophage populations have been described, depending on a large variety of microenvironmental signals, and it is now recognized that their activation plays a crucial role in the development and progression of atherosclerosis. There is good evidence of the ability of conjugated linoleic acids and polyphenolic compounds to modulate inflammation in experimental models involving macrophages. This observation leaves room to the intriguing hypothesis that macrophage polarization could represent one of the unifying mechanisms through which specific food components can exert anti-inflammatory effects in humans, contributing to the prevention of chronic diseases strongly linked to inflammation, such as atherosclerosis. Future studies should be addressed to substantiate this hypothesis, investigating whether or not physiological concentrations of food-derived metabolites can perturb macrophage activation in vitro. On the in vivo side, the evaluation of macrophage populations in tissues, however complex, should be included among the analyses performed in observational and intervention studies, in order to understand if macrophage activation is involved in the anti-inflammatory activity of a specific dietary regimen.

The number of Endothelial Progenitor Cells (EPCs) is considered a novel marker of cardiovascular (CV) disease. It is not clear which are the main determinants of EPC number in apparently healthy subjects in the absence of overt clinical CV or metabolic abnormalities. We evaluated the main clinical determinants of EPC levels in a population of healthy subjects with normal glucose tolerance.EPC number was determined in 122 healthy subjects (73M/49F;36.6 ± 8yrs). Blood samples were collected to test biochemical variables. OGTT was performed and insulin resistance/compensatory hyperinsulinemia was defined according to fasting plasma insulin (FPI) levels. EPCs were identified as cells co-expressing CD133/CD34/KDR antigens by flow-cytometry. CD133(+)/KDR(+) count inversely correlated with BMI (rho=-0.18;p 0.05), waist circumference (-0.2;0.05), diastolic (-0.23;0.01) and systolic blood pressure (-0.21;0.05), uric acid (-0.24;0.005), PAI-1 (-0.197;0.05) and FPI (-0.2;0.05) and directly correlated with HDL cholesterol (0.182;0.05). CD34(+)/CD133(+)/KDR(+) count inversely correlated with uric acid (-0.28;0.005) and FPI (-0.2;0.05). EPC number was lower in males (p 0.05) and gender was the only independent predictor of EPC count (p 0.05). By dividing the population in four subgroups based on gender and insulin resistance, CD133(+)/KDR(+) levels were lower in insulin resistant compared to insulin sensitive males (p 0.05) with no differences in females.The male gender is an independent predictor of low EPC levels in healthy subjects. This might contribute to explaining the higher CV risk in males compared to pre-menopausal age-matched females. In this study a reduced EPC number seems to be associated with insulin resistance in male subjects.

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.

Naringenin, together with its glycosidic forms, is a flavanone abundant in grapefruit and orange. It has been detected in human plasma, following citrus juice intake, at sub-µmolar concentrations, and its main phase II conjugated metabolites (naringenin-7-O-glucuronide and narigenin-4'-O-glucuronide) have been identified in urine. Recent evidence suggests a potential active anti-inflammatory role of flavonoids on macrophages, cells actively involved in atherogenesis. The aim of this study was to evaluate the effects of naringenin and its phase II metabolites on the expression of specific genes in differently activated macrophages at concentrations coherent with dietary exposure. Results suggest that phase II metabolites, as well as the aglyconic form of naringenin, were able to perturb macrophage gene expression in directions that are not always consistent with anti-inflammatory effects. Moreover, the effects of metabolites were not always consistent with each other and with those of their aglycone, underlining the paramount importance of testing physiological forms of phytochemicals within in vitro experimental models. In vivo studies are needed to further explore these observations and investigate their practical consequences.

Dietary polyphenolic compounds are poorly absorbed in the small intestine. The absorbed fraction follows the common metabolic pathway of drugs, undergoing phase II enzymatic detoxification with the conjugation of glucuronic acid, sulfate, and methyl groups. However, the unabsorbed fraction can reach the colon, becoming available for the wide array of enzymes produced by the local commensal microbiota. Gut bacteria can hydrolyze glycosides, glucuronides, sulfates, amides, esters, and lactones and are able to break down the polyphenolic skeleton and perform reactions of reduction, decarboxylation, demethylation, and dehydroxylation. These complex modifications generate several low-molecular-weight metabolites that can be efficiently absorbed in situ, subsequently undergoing further phase II metabolism, locally and/or at the liver level, before entering the systemic blood circulation and finally being excreted in urine in substantial quantities that exceed the excretion of phenolic metabolites formed in the upper gastrointestinal tract. This brief work focuses on the phenolic composition and colonic microbial transformation of 2 of the most polyphenol-rich dietary sources, namely, green tea and coffee, and a new interesting and innovative ingredient, hazelnut skin, recently evaluated as one of the richest edible sources of polyphenolic compounds.

Background and aims Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. Methods and results LTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD ( t = 2.70; p = 0.009), age ( r = −0.238; p = 0.032), waist circumference ( r = −0.256; p = 0.02), triglycerides ( r = −0.218; p = 0.049), PAI-1 ( r = −0.288; p = 0.009) and directly correlated with HDL-cholesterol ( r = 0.316; p = 0.004) and EPC number ( r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD ( p = 0.013), EPC count ( p = 0.003), and HDL-cholesterol ( p = 0.017) were independently associated with LTL ( r = 0.62). Conclusion LTL is independently associated to CV risk factors also in healthy young adults.

Due to their recently discovered plasticity, macrophages could be an important target in the treatment and prevention of atherosclerosis, and it is of interest that quercetin has been shown to modulate inflammation in humans through mechanisms involving macrophages. The aim of this work was to investigate the effect of quercetin-3-O-glucuronide (Q3GA), a major circulating human metabolite of quercetin, on gene expression in differently polarized human macrophages. Classical (M1) and alternative (M2a) macrophages were exposed to Q3GA (500 nM). Gene expression was monitored after incubation periods of 6, 12 and 24 h. M1 and M2a macrophages maintained their respective traits. Q3GA did not affect M1 macrophages in the promotion of a defense response, which remains the principal characteristic of this type of activation, but it was able to reduce the transcription of genes involved in inflammation, such as pro-inflammatory interleukins and enzymes involved in oxidative stress responses. Exposure of M2a to Q3GA elicited an improvement in anti-inflammatory features resulting from further down-regulation of pro-inflammatory genes. Thus, Q3GA is a potential anti-atherogenic metabolite, enhancing the anti-inflammatory properties of M2a macrophages and modulating immune response effects in the presence of pro-inflammatory stimuli.