Prevention and smoking control: perspectives and criticalities

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Structural and Biological Features of G-Quadruplex Aptamers as Promising Inhibitors of the STAT3 Signaling Pathway

: In this paper, we investigate the structural and biological features of G-quadruplex (G4) aptamers as promising antiproliferative compounds affecting the STAT3 signalling pathway. Targeting the STAT3 protein through high-affinity ligands to reduce its levels or activity in cancer has noteworthy therapeutic potential. T40214 (STAT) [(G3C)4] is a G4 aptamer that can influence STAT3 biological outcomes in an efficient manner in several cancer cells. To explore the effects of an extra cytidine in second position and/or of single site-specific replacements of loop residues in generating aptamers that can affect the STAT3 biochemical pathway, a series of STAT and STATB [GCG2(CG3)3C] analogues containing a thymidine residue instead of cytidines was prepared. NMR, CD, UV, and PAGE data suggested that all derivatives adopt dimeric G4 structures like that of unmodified T40214 endowed with higher thermal stability, keeping the resistance in biological environments substantially unchanged, as shown by the nuclease stability assay. The antiproliferative activity of these ODNs was tested on both human prostate (DU145) and breast (MDA-MB-231) cancer cells. All derivatives showed similar antiproliferative activities on both cell lines, revealing a marked inhibition of proliferation, particularly at 72 h at 30 µM. Transcriptomic analysis aimed to evaluate STAT's and STATB's influence on the expression of many genes in MDA-MB-231 cells, suggested their potential involvement in STAT3 pathway modulation, and thus their interference in different biological processes. These data provide new tools to affect an interesting biochemical pathway and to develop novel anticancer and anti-inflammatory drugs

Exploring New Potential Anticancer Activities of the G-Quadruplexes Formed by [(GTG2T(G3T)3] and Its Derivatives with an Abasic Site Replacing Single Thymidine

In this paper, we report our investigations on five T30175 analogues, prepared by replacing sequence thymidines with abasic sites (S) one at a time, in comparison to their natural counterpart in order to evaluate their antiproliferative potential and the involvement of the residues not belonging to the central core of stacked guanosines in biological activity. The collected NMR (Nuclear Magnetic Resonance), CD (Circular Dichroism), and PAGE (Polyacrylamide Gel Electrophoresis) data strongly suggest that all of them adopt G-quadruplex (G4) structures strictly similar to that of the parent aptamer with the ability to fold into a dimeric structure composed of two identical G-quadruplexes, each characterized by parallel strands, three all-anti-G-tetrads and four one-thymidine loops (one bulge and three propeller loops). Furthermore, their antiproliferative (MTT assay) and anti-motility (wound healing assay) properties against lung and colorectal cancer cells were tested. Although all of the oligodeoxynucleotides (ODNs) investigated here exhibited anti-proliferative activity, the unmodified T30175 aptamer showed the greatest effect on cell growth, suggesting that both its characteristic folding in dimeric form and its presence in the sequence of all thymidines are crucial elements for antiproliferative activity. This straightforward approach is suitable for understanding the critical requirements of the G-quadruplex structures that affect antiproliferative potential and suggests its application as a starting point to facilitate the reasonable development of G-quadruplexes with improved anticancer properties

Site specific replacements of a single loop nucleoside with a dibenzyl linker may switch the activity of TBA from anticoagulant to antiproliferative

Many antiproliferative G-quadruplexes (G4s) arise from the folding of GT-rich strands. Among these, the Thrombin Binding Aptamer (TBA), as a rare example, adopts a monomolecular well-defined G4 structure. Nevertheless, the potential anticancer properties of TBA are severely hampered by its anticoagulant action and, consequently, no related studies have appeared so far in the literature. We wish to report here that suitable chemical modifications in the TBA sequence can preserve its antiproliferative over anticoagulant activity. Particularly, we replaced one residue of the TT or TGT loops with a dibenzyl linker to develop seven new quadruplex-forming TBA based sequences (TBA-bs), which were studied for their structural (CD, CD melting, 1D NMR) and biological (fibrinogen, PT and MTT assays) properties. The three-dimensional structures of the TBA-bs modified at T13 (TBA-bs13) or T12 (TBA-bs12), the former endowed with selective antiproliferative activity, and the latter acting as potently as TBA in both coagulation and MTT assays, were further studied by 2D NMR restrained molecular mechanics. The comparative structural analyses indicated that neither the stability, nor the topology of the G4s, but the different localization of the two benzene rings of the linker was responsible for the loss of the antithrombin activity for TBA-bs13

Trend in potassium intake and Na/K ratio in the Italian adult population between the 2008 and 2018 CUORE project surveys

Abstract 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

Iodine Intake Estimated by 24 h Urine Collection in the Italian Adult Population: 2008–2012 Survey

Monitoring the population iodine status is essential for iodine deficiency eradication. This study assessed the average dietary iodine intake and the iodine status of a random sample of the Italian general adult population. The study population included 2378 adults aged 35–79 years (1229 men and 1149 women) from all 20 Italian regions, participating in the Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008–2012 (OEC/HES), and were examined for iodine intake in the framework of the MINISAL-GIRCSI Programme. Dietary iodine intake was assessed by the measurement of 24 h urinary iodine excretion. The median daily iodine intake of the whole population was lower (96 μg/d, interquartile range 51–165) than the daily adequate iodine intake according to both EFSA and WHO recommendation (150 μg/d), with a significantly lower value among women (85 μg/d) compared with men (111 μg/d). Iodine intake diminished with age and increased with BMI (body mass index) in male but not in female participants, without achieving the adequate intake in any sex, age, or BMI category. In this random sample of Italian general adult population examined in 2008–2012, iodine intake still remained lower than the recommended val- ues despite the implementation of a strategy of iodoprophylaxis based on salt iodization in 2005. These data represent a valuable reference for future monitoring of iodine status in our country

Trend of salt intake measured by 24-h urine collection in the Italian adult population between the 2008 and 2018 CUORE project surveys.

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<0.0001) salt intake reduction was thus observed over 10 years for both genders, and all age, body mass index (BMI) and educational classes. Conclusions: The average daily salt intake of the Italian general adult population remains higher than the WHO recommended level, but a significant reduction of 12% in men and 13% in women has occurred in the past ten years. These results encourage the initiatives undertaken by the Italian Ministry of Health aimed at the reduction of salt intake at the population level

Public health genomics research in Italy: an overview of ongoing projects

Public health genomics (PHG) aims to integrate advances in genomic sciences into healthcare for the benefit of the general population. As in many countries, there are various research initiatives in this field in Italy, but a clear picture of the national research portfolio has never been sketched. Thus, we aimed to provide an overview of current PHG research projects at the national or international level by consultation with Italian institutional and academic experts. We included 68 PHG projects: the majority were international projects in which Italian researchers participated (n = 43), mainly funded by the European Commission, while the remainder were national initiatives (N = 25), mainly funded by central government. Funding varied considerably, from € 50,000 to € 80,803,177. Three main research themes were identified: governance (N = 20); precision medicine (PM; N = 46); and precision public health (N = 2). We found that research activities are preferentially aimed at the clinical application of PM, while other efforts deal with the governance of the complex translation of genomic innovation into clinical and public health practice. To align such activities with national and international priorities, the development of an updated research agenda for PHG is needed

Iodine Intake from Food and Iodized Salt as Related to Dietary Salt Consumption in the Italian Adult General Population

Since the Italian iodoprophylaxis strategy is based on the use of iodized salt, we assessed the relationship between dietary salt consumption and iodine intake in the Italian adult population. We estimated the relative contribution given by the use of iodized salt and by the iodine introduced by foods to the total iodine intake. The study population included 2219 adults aged 25–79 years (1138 men and 1081 women) from all Italian regions, participating to the Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008–2012 (OEC/HES), and examined for sodium and iodine intake in the framework of the MINISAL-GIRCSI Programme. Dietary sodium and total iodine intake were assessed by the measurement of 24 h urinary excretion, while the EPIC questionnaire was used to evaluate the iodine intake from food. Sodium and iodine intake were significantly and directly associated, upon accounting for age, sex, and BMI (Spearman rho = 0.298; p < 0.001). The iodine intake increased gradually across quintiles of salt consumption in both men and women (p < 0.001). The European Food Safety Authority (EFSA) adequacy level for iodine intake was met by men, but not women, only in the highest quintile of salt consumption. We estimated that approximately 57% of the iodine intake is derived from food and 43% from salt. Iodized salt contributed 24% of the total salt intake, including both discretionary and non-discretionary salt consumption. In conclusion, in this random sample of the Italian general adult population examined in 2008–2012, the total iodine intake secured by iodized salt and the iodine provision by food was insufficient to meet the EFSA adequate iodine intake