ROLE OF BLUEBERRY POLYPHENOLS ON MARKERS OF OXIDATIVE STRESS, INFLAMMATION AND HEPATIC LIPID ACCUMULATION

Ruolo dei polifenoli del mirtillo sui marker di stress ossidativo, infiammazione e accumulo epatico di lipidi Negli ultimi anni la crescente epidemia di obesit\ue0, sindrome metabolica e di malattie cronico-degenerative \ue8 diventata un problema emergente nei paesi occidentali con un grave impatto economico sul sistema sanitario. Di conseguenza vi \ue8 una forte richiesta di strategie preventive facilmente fruibili dalla popolazione. Lo stile di vita e il comportamento alimentare sono senza dubbio fattori coinvolti sia nello sviluppo sia nella progressione delle malattie croniche. Strategie preventive che agiscano sulle abitudini dietetiche potrebbero essere in grado di ridurre il rischio di sviluppare malattie degenerative e le complicanze ad esse associate. Le linee guida per una sana alimentazione raccomandano l\u2019assunzione di frutta e verdura ad alto contenuto di composti bioattivi come ad esempio i frutti di bosco. Oltre alle conosciute propriet\ue0 biologiche di questi composti ed in particolare dei polifenoli, poco \ue8 noto sui meccanismi d\u2019azione e il loro potenziale sinergico o agonistico. Ci\uf2 \ue8 in parte dovuto alla mancanza di studi di intervento e di studi sulle propriet\ue0 dei singoli composti e dei loro metaboliti valutati in modelli e condizioni sperimentali appropriate. L\u2019obiettivo della presente tesi di dottorato \ue8 stato quello di studiare il ruolo dei composti bioattivi del mirtillo nella modulazione di marker di stress ossidativo, infiammazione e accumulo epatico di lipidi attraverso approcci in vitro e in vivo. La prima parte della tesi \ue8 stata focalizzata sullo studio della capacit\ue0 dei polifenoli del mirtillo di modulare alcuni biomarker di stress ossidativo in giovani volontari fumatori. In una sperimentazione precedente era stato dimostrato, che l\u2019assunzione di una porzione di mirtillo era in grado di contrastare il peggioramento della funzione endoteliale e l\u2019aumento della pressione causati dal fumo di una sigaretta. Pertanto, \ue8 stato effettuato uno studio sullo stesso gruppo di soggetti per valutare la variazione dei livelli di alcuni marker di stress ossidativo. I risultati non hanno evidenziato n\ue8 un aumento delle difese antiossidanti, n\ue9 una riduzione dei marker di stress ossidativo. Inoltre, dopo il fumo non \ue8 emerso un aumento significativo del danno al DNA nelle cellule mononucleate separate da sangue periferico, n\ue9 un miglioramento nella protezione del danno al DNA dopo l\u2019assunzione di mirtillo. La seconda parte, svolta nel laboratorio di Medicina interna e malattie metaboliche, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, ha avuto come obiettivo lo studio della capacit\ue0 di frazioni estratte da un liofilizzato di mirtillo selvatico, ricco in antociani e composti fenolici, di ridurre l\u2019accumulo di lipidi in cellule di epatocarcinoma HepG2 supplementate con acidi grassi (OA, acido oleico e PA, acido palmitico). In particolare, sono state testate le frazioni antocianiche e fenoliche, nonch\ue9 i singoli antociani e corrispettivi metaboliti, in dosi raggiungibili attraverso la dieta. I risultati hanno evidenziato che entrambe le frazioni erano in grado di ridurre l\u2019accumulo di lipidi nelle concentrazioni pari a 0.1 \ub5M and 1 \ub5M rispetto al trattamento con i soli acidi grassi. Inoltre, la supplementazione con i singoli composti mostrava effetti differenti e specifici in funzione del tipo di molecola utilizzata, suggerendo un potenziale effetto sinergico esercitato dei composti presenti nelle frazioni. Nessun effetto significativo \ue8 stato ottenuto con i metaboliti. In conclusione, attraverso questa tesi di dottorato, \ue8 stato possibile aggiungere alcuni risultati utili per l\u2019analisi e la comprensione del ruolo dei polifenoli del mirtillo nella modulazione di marker di stress ossidativo e nella prevenzione dell\u2019accumulo epatico di lipidi. Lo studio in vivo non ha permesso di dimostrare una modulazione dei marker di stress ossidativo e di difesa antiossidante a seguito del consumo di una porzione di mirtillo, mentre lo studio in vitro ha mostrato un effetto dei bioattivi testati nel contrastare l\u2019accumulo di lipidi. Ulteriori studi saranno sviluppati per esplorare il ruolo, le dosi e i target molecolari di azione dei polifenoli del mirtillo introdotti attraverso la dieta. \u2003In the last decades, the epidemic of obesity, metabolic syndrome, chronic and degenerative diseases has becoming an emerging health problem in Western Countries with serious economic penalties on health care management. As a consequence, there is a strong demand for preventive strategies that could be easily applied by the majority of the population. Lifestyle and dietary behavior are both major risk and protective factors in the development and progression of chronic diseases. Preventive approaches acting on dietary habits would be able not only to decrease the risk of developing degenerative diseases but also to reduce the complications associated with aberrant metabolic states or already established disorders. Dietary guidelines generally recommend the consumption of fruits and vegetable rich in bioactive compounds such as berries. Besides the recognized biological properties of bioactives and in particular polyphenols, little is known on their mechanisms of action and potential synergistic or antagonistic effects. This is partially due to the paucity of well-designed dietary intervention studies and to the lack of investigations on the effects of single compounds and their metabolites in appropriate models and conditions. The objective of the PhD thesis was to study the role of blueberry bioactive compounds in the modulation of markers of oxidative stress, inflammation and hepatic lipid accumulation evaluated through an in vivo and an in vitro study approach. The first part of the thesis was focused on the investigation of blueberry polyphenols ability to modulate several biomarkers related to oxidative stress in young smoker volunteers. We previously documented that a single portion of blueberry was able to counteract the impairment of endothelial dysfunction and the increase in blood pressure caused by acute cigarette smoke. On the same volunteers we analyzed, after blueberry intake, the variations in the levels of oxidative stress markers potentially involved in the endothelial dysfunction observed. We did demonstrate neither an increase in antioxidant defense nor a reduction of oxidative stress markers following blueberry consumption. Moreover, we did not document a significant worsening in DNA oxidative damage in peripheral blood mononuclear cells after smoking or an improvement in DNA damage protection after blueberry intake. The second part of the thesis was performed in the laboratory of Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico and focused on the potential ability of different fractions extracted from a wild blueberry powder rich in ACNs and phenolic acids to counteract lipid accumulation in HepG2 human hepatocytes supplemented with fatty acids (OA, oleic acid and PA, palmitic acid). In particular, we tested ACN and phenolic fractions, as well as the single ACNs and their metabolites in doses achievable through dietary intake. We observed that both ACNs and phenolic fraction were able to reduce significantly lipid accumulation at the concentrations of 0.1 \ub5M and 1 \ub5M compared to OA+PA treatment (p<0.05). Moreover, supplementation with single compounds showed different effects depending on the type of molecule considered suggesting a possible synergistic effect when a mix of compounds is present. No significant effect was observed for any of the metabolites. In conclusion, through this PhD thesis, important results were added to the analysis and the comprehension of the molecular mechanisms and of the role of blueberry polyphenols in the modulation of markers of oxidative stress and in the prevention of lipid accumulation. The in vivo investigation failed to demonstrate that the consumption of a single blueberry portion could modulate markers of oxidative stress and antioxidant defence. The in vitro approach supported the potential effect in counteracting lipid accumulation. Further studies are needed to explore the role, the doses and the molecular targets of action of blueberry polyphenols introduced through the diet

A serving of blueberry (V. corymbosum) acutely improves peripheral arterial dysfunction in young smokers and non-smokers : two randomized, controlled, crossover pilot studies

Several studies have documented the important role of polyphenol-rich foods in the modulation of vascular remodelling and function. This study aimed to evaluate the capacity of a single portion of blueberry (V. corymbosum) to acutely improve peripheral arterial dysfunction in a group of young volunteers. Twenty-four healthy males (12 non-smokers and 12 smokers) were recruited for two different randomized, controlled, crossover pilot acute studies. In the first study, non-smokers were exposed to a control treatment (C; 300 mL of water with sugar) and a blueberry treatment (BB; 300 g of blueberry). In the second study, smokers underwent 3 different protocols: (1) - smoking treatment (S); (2) - control treatment (CS; 300 mL of water with sugar + smoking); (3) - blueberry treatment (BS; 300 g of blueberry + smoking). Each treatment (1 day long) was separated by a one week washout period. Blood pressure, peripheral arterial function (reactive hyperemia index, RHI, a marker of endothelial function) and arterial stiffness (digital augmentation index, dAix and dAix normalized by considering a heart rate of 75 bpm, dAix@75) were measured before and after each treatment. In the first study, the consumption of blueberry and control treatment acutely increased peripheral arterial function in the group of non-smokers. The improvement in RHI was higher and significantly different after blueberry treatment compared to the control treatment (54.8 \ub1 8.4% BB vs. 28.2 \ub1 8.3% C; p = 0.01). No effects were observed for markers of arterial stiffness, blood pressure and heart rate. Acute cigarette smoke significantly increased blood pressure and heart rate, while no significant effect was registered in peripheral arterial function and stiffness. The intake of blueberry and control treatment before a cigarette did not counteract the increase in blood pressure and heart rate, while it significantly improved peripheral arterial function. In particular, a significant increase was observed following BS (35.2 \ub1 7.5% RHI; p = 0.02) and CS treatments (34.6 \ub1 11.9% RHI; p = 0.02) when compared to only smoking treatment. No difference between BS and CS was detected. In conclusion, the intake of blueberry and control treatments acutely improved peripheral arterial dysfunction both in smoker and in non-smoker subjects. Further studies should be performed to confirm the results obtained and reveal the potential mechanisms of blueberry in the improvement of endothelial function

Early detection of poor glycemic control in patients with diabetes mellitus in sub-Saharan Africa: a cohort study in Mozambique

Introduction: WHO estimates 422 million cases of diabetes mellitus worldwide. Mozambique has the second-highest mortality related to DM in the African region. Objectives of the present study are to provide data about a DM care service in Mozambique and to evaluate early outcomes of treatment. Methods: The new patients diagnosed with DM in a two-years period in a health centre in Maputo (Mozambique) were included in a retrospective cohort study. Fasting blood glucose (FBG), waist circumference (WC) and BMI were collected at baseline and after three months. Results: 188 patients were enrolled. Median BMI, WC and FBG at baseline were respectively 28 kg/m2(Inter Quartile Range [IQR]23.4-31.8), 98cm (IQR 87-105) and 209mg/dL (IQR 143-295). A non-pharmacological intervention was prescribed for six patients, while 182 patients received metformin 500 mg b.i.d. FBG was significantly reduced at control (226[±103.7]mg/dL vs 186[±93.2]mg/dL, p&lt;0.000); however, glycemic control was reached in 74 patients (39.4%); not controlled patients changed regimen. Elderly patients had a higher glycemic control (adjusted Odds Ratio 2.50, 95% CI 1.11-5.06, p=0.002). Conclusion: Strategies for early detection of scarce glycemic control are feasible in Mozambique and could lead to prompt regimen switch; an invasive therapeutic approach could be preferable in selected cases to achieve control

ORB5: a global electromagnetic gyrokinetic code using the PIC approach in toroidal geometry

This paper presents the current state of the global gyrokinetic code ORB5 as an update of the previous reference [Jolliet et al., Comp. Phys. Commun. 177 409 (2007)]. The ORB5 code solves the electromagnetic Vlasov-Maxwell system of equations using a PIC scheme and also includes collisions and strong flows. The code assumes multiple gyrokinetic ion species at all wavelengths for the polarization density and drift-kinetic electrons. Variants of the physical model can be selected for electrons such as assuming an adiabatic response or a ``hybrid'' model in which passing electrons are assumed adiabatic and trapped electrons are drift-kinetic. A Fourier filter as well as various control variates and noise reduction techniques enable simulations with good signal-to-noise ratios at a limited numerical cost. They are completed with different momentum and zonal flow-conserving heat sources allowing for temperature-gradient and flux-driven simulations. The code, which runs on both CPUs and GPUs, is well benchmarked against other similar codes and analytical predictions, and shows good scalability up to thousands of nodes

Immunomodulatory effect of a wild blueberry anthocyanin-rich extract in human Caco-2 intestinal cells

Intestinal inflammation is a natural process crucial for the maintenance of gut functioning. However, abnormal or prolonged inflammatory responses may lead to the onset of chronic degenerative diseases, typically treated by means of pharmacological interventions. Dietary strategies for the prevention of inflammation are a safer alternative to pharmacotherapy. Anthocyanins and other polyphenols have been documented to display anti-inflammatory activity. In the present study, three bioactive fractions (anthocyanin, phenolic, and water-soluble fractions) were extracted from a wild blueberry powder. The Caco-2 intestinal model was used to test the immunomodulatory effect of the above fractions. Only the anthocyanin-rich fraction reduced the activation of NF-\u3baB, induced by IL-1\u3b2 in intestinal epithelial Caco-2 cells. Specifically, concentrations of 50 and 100 \u3bcg mL(-1) decreased NF-\u3baB activation by 68.9 and 85.2%, respectively (p 64 0.05). These preliminary results provide further support for the role of food bioactives as potential dietary anti-inflammatory agents

Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft

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Risk factors for ischaemic heart disease in a Cretan rural population: a twelve year follow-up study

<p>Abstract</p> <p>Background</p> <p>Crete has been of great epidemiological interest ever since the publication of the Seven Countries Study. In 1988 a well-defined area of rural Crete was studied, with only scarce signs of coronary heart disease (CHD) despite the unfavorable risk profile. The same population was re-examined twelve years later aiming to describe the trends of CHD risk factors over time and discuss some key points on the natural course of coronary heart disease in a rural population of Crete.</p> <p>Methods and Results</p> <p>We re-examined 200 subjects (80.7% of those still living in the area, 62.4 ± 17.0 years old). The prevalence of risk factors for CHD was high with 65.9% of men and 65.1% of women being hypertensive, 14.3% of men and 16.5% of women being diabetic, 44% of men being active smokers and more than 40% of both sexes having hyperlipidaemia. Accordingly, 77.5% of the population had a calculated Framingham Risk Score (FRS) ≥ 15%, significantly higher compared to baseline (p < 0.001). The overall occurrence rate for CHD events was calculated at 7.1 per 1000 person-years (95% confidence interval: 6.8–7.3).</p> <p>Conclusion</p> <p>The study confirms the unfavorable risk factor profile of a well defined rural population in Crete. Its actual effect on the observed incidence of coronary events in Cretans remains yet to be defined.</p

Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs

Background: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. Sources of material: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. Abstract of findings: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. Conclusion: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk

Numerical tools for burning plasmas

The software stack under development within a European coordinated effort on tools for burning plasma modelling is presented. The project is organised as a Task (TSVV Task 10) under the new E-TASC initiative (Litaudon et al 2022 Plasma Phys. Control. Fusion 64 034005). This is a continued effort within the EUROfusion inheriting from the earlier European coordination projects as well as research projects based at various European laboratories. The ongoing work of the TSVV Tasks is supported by the Advanced Computing Hubs. Major projects requiring the high performance computing (HPC) resources are global gyrokinetic codes and global hybrid particle-magnetohydrodynamics (MHD) codes. Also applications using the integrated modelling tools, such as the Energetic-Particle Workflow, based on the ITER Integrated Modelling & Analysis Suite (IMAS), or the code package for modelling radio-frequency heating and fast-ion generation may require intensive computation and a substantial memory footprint. The continual development of these codes both on the physics side and on the HPC side allows us to tackle frontier problems, such as the interaction of turbulence with MHD-type modes in the presence of fast particles. One of the important mandated outcomes of the E-TASC project is the IMAS-enabling of EUROfusion codes and release of the software stack to the EUROfusion community