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The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death.We discuss the current insights about impaired ribosome biogenesis and their secondary consequences on protein synthesis, transcriptional and translational responses, proteotoxic stress, and other metabolic pathways associated with cancer and rare diseases. The modulation of different therapeutic chemical entities targeting cancer inDespite the association between inherited mutations affecting ribosome biogenesis and cancer biology, the development of therapeutics targeting the essential cellular machinery has only started to emerge. New chemical entities should be designed to modulate different checkpoints (translating oncoproteins, dysregulation of specific ribosome-assembly machinery, ribosomal stress, and rewiring ribosomal functions). Although safe and effective therapies are lacking, consideration should be given to using existing drugs alone or in combination for long-term safety, with known risks for feasibility in clinical trials and synergistic effects.

Background and aims Low potassium intake, in addition to high sodium, has been associated with higher risk of hypertension and CVD. The Study assessed habitual potassium intake and sodium/potassium ratio of the Italian adult population from 2008 to 2012 to 2018–2019 based on 24-h urine collection, in the framework of the CUORE Project/MINISAL-GIRCSI/MENO SALE PIU’ SALUTE national surveys. Methods and results Data were from cross-sectional surveys of randomly selected age-and-sex stratified samples of resident persons aged 35–74 years in 10 (out of 20) Italian regions. Urinary electrolyte and creatinine measurements were performed in a central laboratory. Analyses considered 942 men and 916 women, examined in 2008–2012, and 967 men and 1010 women, examined in 2018–2019. In 2008–2012, the age-standardized mean of potassium intake (urinary potassium accounts for 70% of potassium intake) was 3147 mg (95% CI 3086–3208) in men and 2784 mg (2727–2841) in women, whereas in 2018–2019, it was 3043 mg (2968–3118) and 2561 mg (2508–2614) respectively. In 2008–2012, age-adjusted prevalence of persons with an adequate potassium intake (i.e. ≥ 3510 mg/day) was 31% (95% CI 28–34%) for men and 18% (16–21%) for women; in 2018–2019, it was 26% (23–29%) and 12% (10–14%) respectively. The sodium/potassium ratio significantly decreased both in men and women. Conclusions The average daily potassium intake of the Italian general adult population remains lower than the WHO and EFSA recommended level. These results suggest the need of a revision to strengthen initiatives for the promotion of an adequate potassium intake at the population level.

The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been linked to the presence of α,β-unsaturated structural systems. The α,β-unsaturated carbonyl, sulfonyl and sulfinyl functional groups are reportedly the major α,β-unsaturated moieties involved in the activation of the NRF2 signaling pathway. The carbonyl, sulfonyl and sulfinyl groups are generally electron-withdrawing groups, and the presence of the α,β-unsaturated structure qualifies them as suitable electrophiles for Michael addition reaction with nucleophilic thiols of cysteine residues within the proximal negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1). The physicochemical property such as good lipophilicity of these moieties is also an advantage because it ensures solubility and membrane permeability required for the activation of the cytosolic NRF2/KEAP1 system. This review provides an overview of the reaction mechanism of α,β-unsaturated moiety-bearing compounds with the NRF2/KEAP1 complex, their pharmacological properties, structural activity-relationship and their effect on antioxidant and anti-inflammatory responses. As the first of its kind, this review article offers collective and comprehensive information on NRF2-activators containing α,β-unsaturated moiety with the aim of broadening their therapeutic prospects in a wide range of oxidative stress-related diseases.

Macrophage activation and polarization play a central role in atherosclerotic plaque fate. The M1/M2 activation phenotypes represent two profiles of the macrophage polarization state. During atherosclerosis regression or stabilization, macrophages switch from M1 proinflammatory phenotype to M2 anti-inflammatory reparative one. Here, we investigated whether the natural compound lupeol, a pentacyclic triterpene, induces phenotypical and functional changes in human M1 macrophages and counteracts the proinflammatory signalling triggered by 7-keto-cholesterol (7KC), a major product of oxidative stress-mediated cholesterol oxidation. Flow cytometric and immunochemical analysis showed that the treatment with lupeol of M1 monocyte-derived macrophagesM(IFN-γ/LPS)specifically stimulated these cells to upregulate the expression of the anti-inflammatory cytokines interleukin- (IL-)10 and TGF-β, and of the scavenger receptor CD36, whereas downregulated the proinflammatory cytokine IL-12 and the M1 activation marker HLA-DR. Pretreatment of macrophages with lupeol prevented the release of IL-12, IL-1β, and the upregulation of HLA-DR expression triggered by 7KC and increased the IL-10 production and CD36 expression. This treatment also prevented the impairment of endocytosis triggered by 7KC and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M1-polarized THP-1 macrophages, whereas showed an additive effect in reactive oxygen species (ROS) production. Western blotting analysis of autophagy markers LC3-I/II and p62-SQSTM1 in M1-polarized THP-1 macrophages demonstrated that lupeol activated autophagy as indicated by increased LC3-II levels, and by marked inhibition of p62. These findings indicate that lupeol has a cytoprotective effect on 7KC-proinflammatory signalling by efficiently switching the macrophage polarization toward an anti-inflammatory phenotype, probably through the activation of the autophagy pathway by increasing ROS production, the reduction of cellular lipid accumulation, and an overall reduction of proinflammatory phenotype. Thus, our data demonstrating an anti-inflammatory and immunomodulatory activity of lupeol in human M1 macrophages suggest its usefulness as an adjunctive drug in the therapy of atherosclerosis.

Objectives Antiphospholipid syndrome (APS) is a prothrombotic condition defined by recurrent thrombosis, pregnancy complications and circulating antiphospholipid antibodies (aPL), including anti-β2-glycoprotein I (β2-GPI). In clinical practice it is possible to find patients with APS persistently negative for the aPL tests according to Sydney criteria (‘seronegative APS’, SN-APS). Recently, several autoimmune responses have been described as a consequence of post-translational modifications of their target autoantigens. This study was undertaken to test carbamylated-β2-GPI (Carb-β2-GPI) as a new autoantigen of APS. Methods β2-GPI was carbamylated by potassium cyanate and used to investigate its effect on monocyte-derived dendritic cell (moDC) phenotype and function. Sera from 114 SN-APS patients, 60 APS, 20 patients with RA, 20 non-APS thrombosis and 50 healthy donors were analysed for anti-Carb-β2-GPI by ELISA. Results Carb-β2-GPI is able to activate moDCs, inducing upregulation of CD80, CD86 and CD40, activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and nuclear factor-κB, and IL-12p70 release. Serological results showed that both 37/114 SN-APS (32.46%) and 23/60 APS (38.33%) patients resulted positive for anti-Carb-β2-GPI. Interestingly, SN-APS patients who tested positive for anti-Carb-β2-GPI showed a higher prevalence of thrombocytopenia (P = 0.04, likelihood positive ratio of 3.9). Conclusion Data obtained from both functional tests on moDCs and immunological approaches prompted identification of Carb-β2-GPI as a ‘new’ antigenic target in APS. In particular, anti-Carb-β2-GPI revealed a potential usefulness in identification of a significant proportion of SN-APS patients. Moreover, since patients who tested positive for anti-Carb-β2-GPI reported a high risk of thrombocytopenia, this test may be considered a suitable approach in the clinical evaluation of SN-APS.

ObjectivesTo assess in the Italian general adult population the trends of blood pressure (BP) and prevalence of raised BP (RBP), hypertension and its control in order to evaluate population health and care, and the achievement of an RBP 25% relative reduction as recommended by the WHO at population level.DesignResults comparison of health examination surveys, cross-sectional observational studies based on health examination of randomly selected age and sex stratified samples including residents aged 35–74 years. Data of the 2018/2019 survey were compared with the previous ones collected in 1998/2002 and 2008/2012.SettingHealth examination surveys conducted in Italy within the CUORE Project following standardised methodologies.Participants2985 men and 2955 women examined in 1998/2002, 2218 men and 2204 women examined in 2008/2012 and 1031 men and 1066 women examined in 2018/2019.Primary and secondary outcome measuresAge-standardised mean of BP, prevalence of RBP (systolic BP and/or diastolic BP ≥140/90 mm Hg), hypertension (presenting or being treated for RBP) and its awareness and control, according to sex, age class and educational level.ResultsIn 2018/2019, a significant reduction was observed in systolic BP and diastolic BP in men (1998/2002: 136/86 mm Hg; 2008/2012: 132/84 mm Hg; and 2018/2019: 132/78 mm Hg) and women (132/82 mm Hg, 126/78 mm Hg and 122/73 mm Hg), and in the prevalence of RBP (50%, 40% and 30% in men and 39%, 25% and 16% in women) and of hypertension (54%, 49% and 44% in men and 45%, 35% and 32% in women). Trends were consistent by age and education attainment. In 2018/2019, hypertensive men and women with controlled BP were only 27% and 41%, but a significant favourable trend was observed.ConclusionsData from 2018/2019 underlined that RBP is still commonly observed in the Italian population aged 35–74 years, however, the WHO RBP target at that time may be considered met.

Bisphenol A (BPA) and perfluorooctanoic acid (PFOA) are synthetic compounds widely utilized in industrial activities devoted to the production of daily life plastic, metal products, and packaging from which they are able to migrate to food and water. Due to their persistence in the environment, living organisms are chronically exposed to these pollutants. BPA and PFOA have adverse effects on tissues and organs. The aim of this study was to identify the molecular targets and biochemical mechanisms involved in their toxicity.HepG2 and HaCaT cells were treated with BPA or PFOA, and the trypan blue exclusion test and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay were performed to define the conditions for subsequent investigations. We conducted quantitative PCR and western blot analysis to evaluate the expression of proteins involved in nitric oxide (NO) signaling. Cell-based assays were carried out to evaluate reactive oxygen species (ROS) production, nitrite/nitrate (NOx) accumulation, 3-nitrotyrosine (3-NT) formation, and mitochondrial membrane potential (MMP) determination in treated cells.HepG2 and HaCaT cells incubated for 24 h with subtoxic concentrations of BPA or PFOA (50 and 10 μM, respectively) exhibited altered mRNA and protein expression levels of NO synthase isoforms, manganese superoxide dismutase, and cytochrome c. Treatment with PFOA led to activation of inducible NO synthase (NOS), a marker of nitrosative stress, accompanied by the increased production of ROS, NOx, and 3-NT and alterations of the MMP compared to controls.The results of this study indicate the major involvement of the NO signaling axis in the persistent alteration of cell redox homeostasis and mitochondrial dysfunction induced by BPA and PFOA, highlighting the specific role of PFOA in NOS regulation and induction of nitro-oxidative stress.

Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10−7–10−9 M) for 8–36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2–antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis.

Background/Objectives Obesity is associated with an increased risk of noncommunicable diseases, such as diabetes, coronary heart disease, stroke, cancers, and conditions, including obstructive sleep apnea and osteoarthritis. Obesity is largely preventable, and halting its rise is one of the World Health Organization Global Action Plan for the Prevention of Noncommunicable Diseases targets. This study aimed to assess trends of anthropometric measurements in Italy using the data collected within the CUORE Project health examination surveys (HESs) 1998, 2008, and 2018. Subjects/Methods Within the HESs 1998–2002, 2008–2012, and 2018–2019, anthropometric measurements were collected in random samples of the resident population aged 35–74 years, stratified by age and sex, from 10 Italian Regions in Northern, Central, and Southern Italy (2984 men and 2944 women, 2224 men and 2188 women, 1035 men and 1065 women, respectively). Weight, height, and waist and hip circumferences were measured using standardized methodologies. A standardized questionnaire was used to collect data on education. Indicators were age standardized. Results For both men and women, mean body mass index in 2018 was comparable with those in 1998 and 2008 (in 1998, 2008, and 2018—men: 26.7, 27.5, and 27.0 kg/m2; women: 26.2, 26.6, and 26.3 kg/m2). In 1998, 2008, 2018 prevalence of overweight resulted 49%, 47%, 46% in men and 33%, 32%, 28% in women respectively; prevalence of obesity resulted 17%, 24% 20% in men and 19%, 23%, 23% in women respectively. All indicators of excess weight worsen with increasing age and are more severe in persons with a lower educational level. Conclusions Although the overall trend of excess weight over the past two decades appeared to be substantially stable in the Italian adult population, the continuous strengthening of undertaken initiatives should continue since there remains a high proportion of overweight or obesity and a gap between educational levels.

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course of MPS, oxidative stress appears to be a major one. Oxidative imbalance, occurring in MPS and resulting in increased levels of reactive oxidative species, causes damage of various biomolecules, leading to worsening of symptoms, especially in the central nervous system (but not restricted to this system). A few therapeutic options are available for some types of MPS, including enzyme replacement therapy and hematopoietic stem cell transplantation, however, none of them are fully effective in reducing all symptoms. A possibility that molecules with antioxidative activities might be useful accompanying drugs, administered together with other therapies, is discussed in light of the potential efficacy of MPS treatment.

Ischemic stroke, characterized by the sudden loss of blood flow in specific area(s) of the brain, is the leading cause of permanent disability and is among the leading causes of death worldwide. The only approved pharmacological treatment for acute ischemic stroke (intravenous thrombolysis with recombinant tissue plasminogen activator) has significant clinical limitations and does not consider the complex set of events taking place after the onset of ischemic stroke (ischemic cascade), which is characterized by significant pro-oxidative events. The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of a great number of antioxidant and/or defense proteins, has been pointed as a potential pharmacological target involved in the mitigation of deleterious oxidative events taking place at the ischemic cascade. This review summarizes studies concerning the protective role of Nrf2 in experimental models of ischemic stroke, emphasizing molecular events resulting from ischemic stroke that are, in parallel, modulated by Nrf2. Considering the acute nature of ischemic stroke, we discuss the challenges in using a putative pharmacological strategy (Nrf2 activator) that relies upon transcription, translation and metabolically active cells in treating ischemic stroke patients.

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis and/or pregnancy morbidity. The incidence is around five new cases/100,000 persons per year and the prevalence is around 40-50 cases/100,000. The prevalence is higher (about 30%) among patients with systemic lupus erythematosus. APS is associated with circulating antiphospholipid antibodies (aPLs), a heterogeneous group of autoantibodies directed against negatively charged molecules and a combination of protein-complexed phospholipids. The predominant protein antigen in this disorder is beta 2-glycoprotein I (β2GPI). Despite the discovery of "new" antigenic targets and development of "new" methodological approaches, the laboratory diagnosis of APS is still an evolving field and studies to identify further antigenic target(s) as potential diagnostic markers and risk predictors are in progress. In particular, recent studies were aimed at analyzing the pathogenic role of post-translational modifications (PTMs) of proteins induced by inflammation and/or oxidative stress as modulators of protein structure and function and possibly as a source of antigenic epitopes. The present review is focused on PTMs of self-proteins responsible for autoimmune reactions in patients with APS. At present, the known PTMs in APS involve β2GPI. In particular, the PTM of β2GPI via thiol-exchange reactions is a highly specific phenomenon that makes the protein more antigenic. Other PTMs, including sialylation and acetylation, may affect β2GPI antigenicity. Moreover, the addition or loss of carbohydrate chains affects β2GPI immunoreactivity since carbohydrates are determining factors for β2GPI conformation. In addition to β2GPI, PTMs of other self proteins such as vimentin and annexins may play a role in the immune response during APS. The study of PTMs is useful to clarify the role of modified proteins in the pathogenesis of APS as well as to design more efficient diagnostic/prognostic tools and more targeted therapeutic approaches.

Wound healing involves a series of cellular events in damaged cells and tissues initiated with hemostasis and finally culminating with the formation of a fibrin clot. However, delay in the normal wound healing process during pathological conditions due to reactive oxygen species, inflammation and immune suppression at the wound site represents a medical challenge. So far, many therapeutic strategies have been developed to improve cellular homeostasis and chronic wounds in order to accelerate wound repair. In this context, the role of Nuclear factor erythroid 2-related factor 2 (Nrf2) during the wound healing process has been a stimulating research topic for therapeutic perspectives. Nrf2 is the main regulator of intracellular redox homeostasis. It increases cytoprotective gene expression and the antioxidant capacity of mammalian cells. It has been reported that some bioactive compounds attenuate cellular stress and thus accelerate cell proliferation, neovascularization and repair of damaged tissues by promoting Nrf2 activation. This review highlights the importance of the Nrf2 signaling pathway in wound healing strategies and the role of bioactive compounds that support wound repair through the modulation of this crucial transcription factor.

Background and aims: The WHO Global Action Plan for the Prevention of non-communicable diseases (NCDs) recommends a 30% relative reduction in mean population salt/sodium intake. The study assessed the trend in the habitual salt intake of the Italian adult population from 2008 to 2012 to 2018–2019 based on 24-h urinary sodium excretion, in the framework of the CUORE Project/MINISAL-GIRCSI/MENO SALE PIU’ SALUTE national surveys. Methods and results: Data were from cross-sectional surveys of randomly selected age and sex–stratified samples of resident persons aged 35–74 years in 10 (out of 20) Italian Regions distributed in North, Centre and South of the Country. Urinary sodium and creatinine measurements were carried out in a central laboratory. The analyses included 942 men and 916 women examined in 2008–2012, and 967 men and 1010 women examined in 2018–2019. The age-standardized mean daily population salt (sodium chloride) intake was 10.8 g (95% CI 10.5–11.1) in men and 8.3 g (8.1–8.5) in women in 2008–2012 and respectively 9.5 g (9.3–9.8) and 7.2 g (7.0–7.4) in 2018–2019. A statistically significant (p

Introduction:Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. C...

Background The WHO Global Action Plan for the Prevention of Non-Communicable Disease (WHO-NCD) recommends to halt the rise of obesity by 2025. Obesity is largely preventable. This preliminary analysis aims to assess mean level of BMI and prevalence of obesity in the Italian general adult population using the data collected within the CUORE Project to investigate if Italy can meet the WHO-NCD target. Methods Within the health examination survey conducted in 2018-2019, mean level of BMI and prevalence of obesity (BMI > =30 kg/m2) and overweight (25 Results In this preliminary analysis, mean level of BMI was 26.8 kg/m2 (95% C.I. 26.5-27.1) in men and 25.9 kg/m2 (25.6-26.3) in women. Prevalence of obesity was 19% (16-22) in men and 22% (19-25) in women; prevalence of overweight was 45% (41-48) in men and 28% (25-31) in women. Obesity resulted significantly higher in persons with lower educational level (primary or middle school) vs those with higher education: 26% (20-31) vs 16% (13-19) in men and 33% (27-38) vs 17% (14-20) in women. Both in men and women prevalence of obesity was significantly higher in the Southern regions. Conclusions Preliminary data show that more than half of Italian adults are overweight/obese. However, in comparison to BMI measured in the CUORE Project 10 years earlier, the prevalence of people at normal weight is increasing, moving in the direction of the WHO-NCDs obesity target. Preventive actions at community level should be more incisive in the population at low socio-economic level. Key messages Mean BMI and prevalence of obesity in the Italian general adult population are still high. If confirmed, in the last ten years an increase of normal weight prevalence in the Italian general adult population seems to be occurred.

Background The WHO Global Action Plan for the Prevention of Non-Communicable Disease (WHO-NCD) recommends a 25% relative reduction in the prevalence of raised blood pressure (RBP) by 2025. Prevalence of RBP and mean blood pressure in the Italian general adult population measured in the 2018 CUORE Project-Health Examination Survey are presented to investigate if Italy can reach this target. Methods Within the health examination survey conducted in 2018-2019, representative random samples of resident population, aged 35-74 years, stratified by age and sex (822 men and 869 women) were examined in 8 Italian Regions from the Northern, Central and Southern Italy. Blood pressure was measured by automated oscillometric device using standardized procedures and methods; mean level of two measurements are here considered. RBP is defined as systolic and/or diastolic blood pressure equal or greater than 140/90 mmHg or being under specific drug treatment. The survey is funded by the Italian Ministry of Health-CCM. Results Preliminary analysis shows that prevalence of RBP is 43% (95% C.I. 40-47) in men and 32% (29-36) in women. Prevalence of persons with raised blood pressure and not receiving pharmacological treatment is 19% (15-22) in men and 9% (5-12) in women. In men and women prevalence of raised blood pressure is significantly higher in the Southern Regions. Mean value of systolic blood pressure is 131 mmHg (130-132) in men and 122 mmHg (121-123) in women. Mean value of diastolic blood pressure is 77 mmHg (76-78) in men and 73 mmHg (72-74) in women. Conclusions Preliminary data underline that RBP is commonly observed in the Italian adult population. However, in comparison to data measured within the CUORE Project 10 years earlier, prevalence of RBP and mean blood pressure are declining, facilitating the meeting of WHO-NCDs target. Key messages Raised blood pressure is commonly observed in the Italian general adult population. If confirmed, in the last ten years prevalence of raised blood pressure and mean blood pressure are declining in the Italian general adult population.

Introduction: Obesity is associated to an increased risk of hypertension, non-communicable diseases (NCDs), such as diabetes, coronary heart disease, stroke, and cancers, and conditions including obstructive sleep apnoea and osteoarthritis. Obesity is largely preventable and one of the WHO Global Action Plan for the Prevention of NCDs targets is to halt its rise. Hypothesis: Between 2000 and 2016, obesity trends showed a steady increase in all WHO regions and income groups. This preliminary analysis aims to assess mean level of BMI and prevalence of obesity in the Italian general adult population using the data collected within the CUORE Project-health examination survey. Methods: Within the ongoing survey started in 2018, mean of BMI and prevalence of obesity (BMI>=30 kg/m 2 ) and overweight (252 ) were assessed in random samples of resident population, aged 35-74 years, stratified by age and sex (men 822 and women 869), from 8 Italian Regions in Northern, Central and Southern Italy. Weight and height were measured using standardized methodologies. A standardized questionnaire was used to collect data on education and physical inactivity. The survey is funded by the Italian Ministry of Health-CCM. Results: Mean values of BMI resulted 26.8 kg/m 2 (95% C.I. 26.5-27.1) in men and 25.9 kg/m 2 (25.6-26.3) in women. Prevalence of obesity was 19.0% (16.3-21.7) in men and 21.7% (19.0-24.5) in women; prevalence of overweight was 44.5% (41.1-47.9) in men and 28.4% (25.4-31.4) in women. Obesity levels resulted significantly higher in persons with lower education (primary or high school) vs those with higher level of education: 25.6% (20.0-31.1) vs 16.0% (13.0-19.0) in men and 32.5% (27.0-37.9) vs 16.7% (13.6-19.7) in women. Prevalence of physical inactivity during leisure time was 31.9 % (28.7-35.1) in men and 41.4% (38.2-44.7) in women. Both in men and women the prevalence of obesity was significantly higher in the Southern regions, likewise physical inactivity. Conclusions: Preliminary data of the first 8 Regions (out of 10 to be examined in the on-going survey) underline that more than half of Italian adults are in excess of weight. In comparison to data measured within the CUORE Project 10 years earlier, a slight increasing of normal weight men seems to occur moving in the direction of the WHO-NCDs obesity target.

Introduction: The WHO Global Action Plan for the Prevention of Non-Communicable Diseases (NCDs) recommends a 30% relative reduction in mean population intake of salt/sodium. To this end, the Italian Ministry of Health (MoH) has strengthened prevention and health promotion through the “Gaining health: making healthy choices easy” Programme and the National Preventive Plan (NPP) 2014-2019, with the collaboration of the Interdisciplinary Working group for Salt Reduction in Italy (GIRCSI). Hypothesis: Agreements between the MoH and the associations of artisan bakers and food industry companies were signed since 2009 to reduce the salt content in bread and in other food products. Within the NPP, initiatives as local inter-sectors agreements and information activities for the population and training for food sector operators are implemented. In order to estimate the habitual salt intake and its trend in the general adult population, national surveys, funded by the MoH-CCM, are conducted within the CUORE Project. Methods: Baseline salt intake by the use of 24h urine collections was assessed in 2008-2012 from random samples of persons aged 35-79 years, resident in all Italian 20 Regions. A new survey is ongoing (2018-2019) involving random samples of persons aged 35-74 years, resident in 10 Regions. Urinary sodium excretion is assayed by a central lab at Federico II University of Naples, subjected to strict quality controls. Comparisons are made considering, for both periods, the seven regions examined up to now in the ongoing survey and the age range of 35-74 years. Results: Within the 2018-2019 survey, mean level of sodium chloride per day in 673 men and 709 women was 161 mmol (95% confidence interval: 156-166 mmol) and 122 mmol (119-126 mmol) respectively, whereas in the 2008-2012 survey the corresponding mean levels in 642 men and 627 women was 183 mmol (95% confidence interval: 178-189 mmol) and 140 mmol (135-144 mmol), respectively. A sodium chloride intake level within the WHO recommended upper level of 85 mmol (or 5 grams of salt) per day was detected in 9% (6-11%) of men and 24% (20-27%) of women examined in 2018-2019 vs 5% (3-6%) of men and 16% (13-19%) of women examined in 2008-2012. Conclusions: These preliminary data show that the average habitual sodium intake in Italy is still largely higher than recommended but a significant reduction seems to occur. These results fully justify and encourage the ongoing preventive initiatives for reduction of sodium intake and its monitoring in the population.

Introduction: Hypertension is a major risk factor for coronary heart disease, chronic kidney disease, ischaemic and haemorrhagic stroke. The WHO Global Action Plan for the Prevention of non-communicable diseases (NCDs) target by 2025 for hypertension is a 25% relative reduction in the prevalence of raised blood pressure. Hypothesis: Prevalence of raised blood pressure in adults has declined in high-income countries over the past few decades; the CUORE project surveys have shown this trend also in Italy from the 1980s to the 2010s. This preliminary analysis aims to assess mean level of blood pressure and prevalence of raised blood pressure in the Italian general adult population using the data collected within the CUORE Project-health examination survey. Methods: Within the ongoing survey, started in 2018, mean of blood pressure and prevalence of raised blood pressure are assessed in random samples of resident population, aged 35-74 years, stratified by age and sex (men 822 and women 869), from 8 Italian Regions from the Northern, Central and Southern Italy. Blood pressure is measured three times consecutively by automated oscillometric device using standardized procedures and methods. Mean level of first two measurements are here considered. Raised blood pressure is defined as systolic and/or diastolic blood pressure equal or greater than 140/90 mmHg or under specific drug treatment. The survey is funded by the Italian Ministry of Health-CCM. Results: Preliminary analysis shows a mean value of systolic blood pressure of 131 mmHg (95% C.I.130-132) in men and 122 mmHg (121-123) in women. Mean value of diastolic blood pressure is 77 mmHg (76-78) in men and 73 mmHg (72-74) in women. Prevalence of raised blood pressure is 43.3% (39.9-46.7) in men and 32.4% (29.2-35.5) in women. In men prevalence of persons with raised blood pressure and untreated is 18.5% (14.6-22.3) and 8.6% (5.4-11.7) in women. In men and women prevalence of raised blood pressure is significantly higher in the Southern regions. Conclusions: Preliminary data of first 8 Regions (out of 10 which should be examined) underline that raised blood pressure is widely present in the Italian adult population. In comparison to data measured within the CUORE Project 10 years earlier, a decrease of mean level of blood pressure and prevalence of raised blood pressure seems to occur facilitating the meeting of WHO-NCDs target.

Background Obesity is a risk factor for the majority of non-communicable diseases-NCDs. In the Italian country profile, the NCD Risk Factor Collaboration estimated the 2010 obesity prevalence at 19.0% (95% confidence interval - C.I. 15.7-22.7) in women aged 18 years and over and 18.5% (95% C.I. 15.1-22.0) in men, with a very low probability (2-9%) of halting the increase of obesity by 2025 (WHO global obesity target). This preliminary analysis aims to assess 20 years trend of BMI and obesity in the Italian general adult population using the data collected within the CUORE Project. Methods Mean of BMI and prevalence of obesity (BMI > =30 kg/m2) in random samples of resident population in 6 Italian Regions, aged 35-74 years, stratified by age and sex, were assessed in an on-going survey started in 2018 (men 612; women 649), and compared to those assessed in the same Regions in 1998-2002 (men 1933, women 1926) and in 2008-2012 (men 1306; women 1318). Weight and height were measured using standardized methodologies. Surveys were partly funded by the Italian Ministry of Health-CCM and approved by the National Institute of Health ethical committee. Results In men, mean values of BMI resulted 26.6 kg/m2 (95% C.I. 26.4-26.8) in 1998 survey, 27.5 (27.2-27.7) in 2008 and 26.5 (26.1-26.8) in 2018; prevalence of obesity was 16.8% (95% C.I. 15.1-18.4) in 1998, 23.5% (21.2-25.8) in 2008 and 17.3% (14.4-20.4) in 2018. In women mean values of BMI were 26.1 kg/m2 (95% C.I.: 25.9-26.4) in 1998, 26.4 (26.1-26.7) in 2008 and 25.5 (25.1-25.9) in 2018; prevalence of obesity was 20.7% (95% C.I.: 18.9-22.5), 21.9% (19.7-24.2) and 19.0% (15.9-22.0) respectively. Conclusions Preliminary data of first 6 Regions (out of 10 to be examined in the on-going survey) suggest that mean BMI and prevalence of obesity in Italian adult population are still very high; if confirmed, in the last ten years a reduction seems to be occurred increasing the probability of meeting the WHO obesity target by 2025. Key messages Mean BMI and prevalence of obesity in Italian adult population are still high. If confirmed, in the last ten years a reduction of mean BMI and prevalence of obesity in Italian adult population seems to be occurred.

β-Thalassemia is an inherited single gene disorder related to reduced synthesis of the β-globin chain of hemoglobin. Patients with β-thalassemia present variable clinical severity ranging from asymptomatic trait to severe transfusion-dependent anemia and multiple organs complications. Moreover, multiple immune abnormalities are a major concern in β-thalassemia patients. Aberrant neutrophil effector function plays a pivotal role in infection susceptibility in these patients. In severe and persistent inflammation, immature neutrophils are released from the bone marrow and are functionally different compared with mature ones. Despite some abnormalities reported for thalassemia patient's immune system, few data exist on the characterization of human neutrophils in β-thalassemia. The aim of this study was to investigate the phenotype and function of circulating neutrophil subsets in patients with β-thalassemia major and with β-thalassemia intermedia divided in transfusion-dependent and non-transfusion-dependent. By the use of immunochemical and cytofluorimetric analyses, we observed that patients' CD16+ neutrophils exhibit abnormalities in their phenotype and functions and the abnormalities vary according to the clinical form of the disease and to the neutrophil subset (CD16bright and CD16dim). Abnormalities include altered surface expression of the innate immune receptor CD45, Toll-like receptor 4, and CD32, reduced ability to produce an oxidative burst, and elevated levels of membrane lipid peroxidation, especially in patients with a more severe form of the disease. Overall, our results indicating the occurrence of an immuno-senescent phenotype on circulating neutrophils from thalassemia patients suggest the usefulness of neutrophil feature assessment as a tool for better clinical management of β-thalassemia.

Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R injury (IRI) occurs due to the tissue injury following the reestablishment of blood supply to ischemic tissues, leading to enhanced aseptic inflammation and stimulation of oxidative stress via reactive oxygen and nitrogen species (ROS/RNS). Since ROS causes membrane lipids’ peroxidation, triggers loss of membrane integrity, denaturation of proteins, DNA damage, and cell death, oxidative stress plays a critical part in I/R pathogenesis. Therefore, ROS regulation could be a promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates the expression of several factors involved in the cellular defense against oxidative stress and inflammation, including heme oxygenase-1 (HO-1). Numerous studies have shown the potential role of the Nrf2/HO-1 pathway in IRI; thus, we will review the molecular aspects of Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling pathway in I/R, and we will also highlight the recent insights into targeting this pathway as a promising therapeutic strategy for preventing IRI.

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

We have previously demonstrated that human heat shock protein 90 (HSP90), an intracellular self protein, is the target of cellular and humoral autoimmune responses in patients with carotid atherosclerosis. In this study, we evaluated in vitro whether oxidative stress, a feature of atherosclerotic plaque, alters HSP90 expression in endothelial cells, thus inducing surface localization of this molecule and whether the antioxidant compound 7,8-dihydroxy-4-methylcoumarin (7,8-DHMC) is able to prevent oxidative stress-induced alterations of HSP90 localization. By the use of flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and semiquantitative reverse-transcription polymerase chain reaction, we demonstrated that exposure of human umbilical vein endothelial cells (HUVEC) to the prooxidant compound H2O2 upregulated HSP90 surface expression and reduced its secretion without altering HSP90 gene expression and intracytoplasmic protein levels. Pretreatment of HUVEC with 7,8-DHMC prevented H2O2-induced alterations of HSP90 cellular distribution and secretion. Our results suggest that the strong oxidative conditions of atherosclerotic plaques promote the upregulation of HSP90 surface expression on endothelial cells, thus rendering the protein a possible target of autoimmune reactions. The antioxidant 7,8-DHMC, by preventing oxidative-stress-triggered HSP90 surface upregulation, may be useful to counteract possible autoreactive reactions to HSP90.