Microplastics and Nanoplastics in Atheromas and Cardiovascular Events.

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).

Author Correction: Metastatic-niche labelling reveals parenchymal cells with stem features.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metastatic-niche labelling reveals parenchymal cells with stem features.

Direct investigation of the early cellular changes induced by metastatic cells within the surrounding tissue remains a challenge. Here we present a system in which metastatic cancer cells release a cell-penetrating fluorescent protein, which is taken up by neighbouring cells and enables spatial identification of the local metastatic cellular environment. Using this system, tissue cells with low representation in the metastatic niche can be identified and characterized within the bulk tissue. To highlight its potential, we applied this strategy to study the cellular environment of metastatic breast cancer cells in the lung. We report the presence of cancer-associated parenchymal cells, which exhibit stem-cell-like features, expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. In ex vivo assays, lung epithelial cells acquire a cancer-associated parenchymal-cell-like phenotype when co-cultured with cancer cells and support their growth. These results highlight the potential of this method as a platform for new discoveries.

DNA Methylation-derived biological age and long-term mortality risk in subjects with type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. METHODS: Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. RESULTS: Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05-1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43-9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. CONCLUSIONS: These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.

MiR-422a promotes adipogenesis via MeCP2 downregulation in human bone marrow mesenchymal stem cells.

Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous transcriptional regulator. The study of this protein has been mainly focused on the central nervous system because alterations of its expression are associated with neurological disorders such as Rett syndrome. However, young patients with Rett syndrome also suffer from osteoporosis, suggesting a role of MeCP2 in the differentiation of human bone marrow mesenchymal stromal cells (hBMSCs), the precursors of osteoblasts and adipocytes. Here, we report an in vitro downregulation of MeCP2 in hBMSCs undergoing adipogenic differentiation (AD) and in adipocytes of human and rat bone marrow tissue samples. This modulation does not depend on MeCP2 DNA methylation nor on mRNA levels but on differentially expressed miRNAs during AD. MiRNA profiling revealed that miR-422a and miR-483-5p are upregulated in hBMSC-derived adipocytes compared to their precursors. MiR-483-5p, but not miR-422a, is also up-regulated in hBMSC-derived osteoblasts, suggesting a specific role of the latter in the adipogenic process. Experimental modulation of intracellular levels of miR-422a and miR-483-5p affected MeCP2 expression through direct interaction with its 3' UTR elements, and the adipogenic process. Accordingly, the knockdown of MeCP2 in hBMSCs through MeCP2-targeting shRNA lentiviral vectors increased the levels of adipogenesis-related genes. Finally, since adipocytes released a higher amount of miR-422a in culture medium compared to hBMSCs we analyzed the levels of circulating miR-422a in patients with osteoporosis-a condition characterized by increased marrow adiposity-demonstrating that its levels are negatively correlated with T- and Z-scores. Overall, our findings suggest that miR-422a has a role in hBMSC adipogenesis by downregulating MeCP2 and its circulating levels are associated with bone mass loss in primary osteoporosis.

Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (i) reduce cardiovascular and renal events in patients with and without type 2 diabetes (T2D). However, the underlying mechanisms are debated. Low-grade inflammation (LGI) is a key driver of vascular complications, suggested to be attenuated by SGLT-2i in animal models. Based on a specific working hypothesis, here we investigated the net effect of SGLT-2i on LGI in patients with T2D and the possible underlying mechanism. We enrolled patients with T2D treated either with a stable therapy with SGLT-2i or with other glucose-lowering drugs (GLD) (n = 43 per group after matching for a range of pro-inflammatory variables), and tested hs-CRP and interleukin (IL)-6 as primary variables of interest. Patients treated with SGLT-2i had lower circulating levels of IL-6, a prototypical marker of LGI, but also of uric acid and fasting insulin, compared with patients treated with other GLD. Then, to explore whether uric acid and insulin might mediate the effect of SGLT-2i on IL-6, we tested physiologically pertinent doses of these two molecules (i.e. 0.5 mM uric acid and 1 nM insulin) in two in vitro models of LGI, i.e. monocytes (THP-1) treated with LPS and endothelial cells (HUVEC) exposed to hyperglycaemia. Results from in vitro models supported a pro-inflammatory role for uric acid and its combination with insulin in monocytes and for uric acid alone in hyperglycaemia-stimulated endothelial cells. On the contrary, we observed no drug-intrinsic, anti-inflammatory effect for dapagliflozin, empagliflozin, and canagliflozin in the same models. Overall, these results suggest that SGLT-2i possess a tangible activity against LGI, an effect possibly mediated by their ability to lower uric acid and insulin concentrations and that juxtaposes other proposed mechanisms in explaining the observed benefit of this class on cardiovascular and renal endpoints.

Pro-Osteogenic and Anti-Inflammatory Synergistic Effect of Orthosilicic Acid, Vitamin K2, Curcumin, Polydatin and Quercetin Combination in Young and Senescent Bone Marrow-Derived Mesenchymal Stromal Cells.

During aging, bone marrow mesenchymal stromal cells (MSCs)-the precursors of osteoblasts-undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)-that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)-would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation into osteoblasts, even when cultured without other pro-differentiating factors; and (ii) CUR, PD and QCT exerted an anti-inflammatory effect on sMSCs, and also synergized with OA and VK2 in promoting the expression of the pivotal osteogenic marker ALP in these cells. Overall, these data suggest a potential role of using a combination of all of these natural compounds as a supplement to prevent or control the progression of age-related osteoporosis.

The Combination of Natural Molecules Naringenin, Hesperetin, Curcumin, Polydatin and Quercetin Synergistically Decreases SEMA3E Expression Levels and DPPIV Activity in In Vitro Models of Insulin Resistance.

Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic ß cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydatin, and quercetin (that mirror the nutraceutical formulation GliceFen®, Mivell, Italy) synergistically decreases expression levels of the pro-inflammatory gene SEMA3E in insulin-resistant HepG2 cells and synergistically decreases DPPIV activity in insulin-resistant Hep3B cells, indicating that the combination of these five phytochemicals is able to inhibit pro-inflammatory and insulin resistance molecular mechanisms and could represent an effective innovative complementary approach to T2DM pharmacological treatment.

A Data-Mining Approach to Identify NF-kB-Responsive microRNAs in Tissues Involved in Inflammatory Processes: Potential Relevance in Age-Related Diseases.

The nuclear factor NF-kB is the master transcription factor in the inflammatory process by modulating the expression of pro-inflammatory genes. However, an additional level of complexity is the ability to promote the transcriptional activation of post-transcriptional modulators of gene expression as non-coding RNA (i.e., miRNAs). While NF-kB's role in inflammation-associated gene expression has been extensively investigated, the interplay between NF-kB and genes coding for miRNAs still deserves investigation. To identify miRNAs with potential NF-kB binding sites in their transcription start site, we predicted miRNA promoters by an in silico analysis using the PROmiRNA software, which allowed us to score the genomic region's propensity to be miRNA cis-regulatory elements. A list of 722 human miRNAs was generated, of which 399 were expressed in at least one tissue involved in the inflammatory processes. The selection of "high-confidence" hairpins in miRbase identified 68 mature miRNAs, most of them previously identified as inflammamiRs. The identification of targeted pathways/diseases highlighted their involvement in the most common age-related diseases. Overall, our results reinforce the hypothesis that persistent activation of NF-kB could unbalance the transcription of specific inflammamiRNAs. The identification of such miRNAs could be of diagnostic/prognostic/therapeutic relevance for the most common inflammatory-related and age-related diseases.

Prognostic value of soluble ST2, high-sensitivity cardiac troponin, and NT-proBNP in type 2 diabetes: a 15-year retrospective study.

BACKGROUND: Patients with type 2 diabetes (T2DM) present an increased risk of cardiovascular (CV) disease and excess CV-related mortality. Beyond the established role of brain natriuretic peptide (BNP) and cardiac troponins (cTn), other non-cardiac-specific biomarkers are emerging as predictors of CV outcomes in T2DM. METHODS: Serum levels of soluble suppression of tumorigenesis 2 (sST2), high-sensitivity (hs)-cTnI, and N-terminal (NT)-proBNP were assessed in 568 patients with T2DM and 115 healthy controls (CTR). Their association with all-cause mortality and the development of diabetic complications was tested in T2DM patients over a median follow-up of 16.8 years using Cox models and logistic regressions. RESULTS: sST2 followed an increasing trend from CTR to uncomplicated T2DM patients (T2DM-NC) to patients with at least one complication (T2DM-C), while hs-cTnI was significantly higher in T2DM-C compared to CTR but not to T2DM-NC. A graded association was found between sST2 (HR 2.76 [95% CI 1.20-6.33] for ≥ 32.0 ng/mL and 2.00 [1.02-3.94] for 16.5-32.0 ng/mL compared to < 16.5 ng/mL, C-statistic = 0.729), NT-proBNP (HR 2.04 [1.90-4.55] for ≥ 337 ng/L and 1.48 [1.05-2.10] for 89-337 ng/L compared to < 89 ng/L, C-statistic = 0.741), and 15-year mortality in T2DM, whereas increased mortality was observed in patients with hs-cTnI ≥ 7.8 ng/L (HR 1.63 [1.01-2.62]). A 'cardiac score' based on the combination of sST2, hs-cTnI, and NT-proBNP was significantly associated with all-cause mortality (HR 1.35 [1.19-1.53], C-statistic = 0.739) and development of CV events. CONCLUSIONS: sST2, hs-cTnI, and NT-proBNP are associated with 15-year mortality and onset of CV events in T2DM. The long-term prognostic value of sST2 and its ability to track variables related to insulin resistance and associated metabolic disorders support its implementation into routine clinical practice.

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

The Association between Single Nucleotide Polymorphisms, including miR-499a Genetic Variants, and Dyslipidemia in Subjects Treated with Pharmacological or Phytochemical Lipid-Lowering Agents.

Disorders of lipoprotein metabolism are among the major risk factors for cardiovascular disease (CVD) development. Single nucleotide polymorphisms (SNPs) have been associated with the individual variability in blood lipid profile and response to lipid-lowering treatments. Here, we genotyped 34 selected SNPs located in coding genes related to lipid metabolism, inflammation, coagulation, and a polymorphism in the MIR499 gene-a microRNA previously linked to CVD-to evaluate the association with lipid trait in subjects with moderate dyslipidemia not on lipid-lowering treatment (Treatment-naïve (TN) cohort, n = 125) and in patients treated with statins (STAT cohort, n = 302). We also explored the association between SNPs and the effect of a novel phytochemical lipid-lowering treatment in the TN cohort. We found that 6 SNPs (in the MIR499, TNFA, CETP, SOD2, and VEGFA genes) were associated with lipid traits in the TN cohort, while no association was found with the response to twelve-week phytochemical treatment. In the STAT cohort, nine SNPs (in the MIR499, CETP, CYP2C9, IL6, ABCC2, PON1, IL10, and VEGFA genes) were associated with lipid traits, three of which were in common with the TN cohort. Interestingly, in both cohorts, the presence of the rs3746444 MIR499 SNP was associated with a more favorable blood lipid profile. Our findings could add information to better understand the individual genetic variability in maintaining a low atherogenic lipid profile and the response to different lipid-lowering therapies.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and ß-caryophyllene association on human endothelial and monocytic cells.

A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal ß-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1ß and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1ß, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Prevalence of residual inflammatory risk and associated clinical variables in patients with type 2 diabetes.

Residual inflammatory risk (RIR) is defined as persistent circulating levels of high sensitivity C-reactive protein (hs-CRP) >2 mg/L despite an optimal (<70 mg/dL) control of LDL-cholesterol (LDL-C) and represents an emerging risk factor for the development of cardiovascular events in patients at high risk of atherosclerosis. Sparse data are available regarding the prevalence of RIR in patients with type 2 diabetes (T2D) and the clinical variables associated with hs-CRP elevation. Here, we report data from a well-characterized cohort of patients with T2D (n = 511) stratified for statins use, LDL-C goal attainment and prevalent T2D complications. Statins use and having at-target LDL-C partially affect the number of patients with inflammatory risk when compared with the whole T2D population, with an RIR prevalence of 39.2%. Among the spectra of complications, only patients with nephropathy had a higher prevalence of inflammatory risk. Total cholesterol, non-HDL-cholesterol, triglycerides, body mass index and waist-hip ratio were associated with hs-CRP, with an increased magnitude in at-target patients. Conversely, glucose-related variables were strongly associated with hs-CRP only in at-target patients, overall suggesting glycaemic control, insulin resistance, non-LDL-C lipid variables and especially central obesity as possible contributors to RIR in patients with T2D and LDL-C <70 mg/dL.

HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma.

BACKGROUND: Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed. METHODS: A sphere formation assay, cell proliferation, RT-PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α. RESULTS: Propagation of four renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage-independent floating spheres led to the expansion of cells bearing the CXCR4 (CD184) surface marker. Inhibition of the CXCR4 pathway reduced sphere expansion. The enhanced self-renewal activity of the CXCR4-positive spheres was preceded by the upregulation of HIF2α. Knockdown of HIF2α abrogated CXCR4 expression and sphere formation. Finally, RCC-derived spheres showed an undifferentiated phenotype in vivo and formed subcutaneous tumours that highly expressed HIF2α and CXCR4. Inhibition of HIF2α abolished tumour growth in animal models. CONCLUSIONS: These results suggest that the generation of RCC-derived CSCs involves the activation of HIF2α and may provide a foundation for the development of new strategies to prevent the induction of CSCs in RCC.

Atrial High-Rate Episodes in Elderly Patients: The Anticoagulation Therapy Dilemma.

Atrial fibrillation (AF) has been associated with higher morbidity and mortality rates, especially in older patients. Subclinical atrial fibrillation (SCAF) is defined as the presence of atrial high-rate episodes (AHREs) > 190 bpm for 10 consecutive beats > 6 min and <24 h, as detected by cardiac implanted electronic devices (CIEDs). The selection of eligible patients for anticoagulation therapy among elderly individuals with AHREs detected through CIEDs remains a contentious issue. The meta-analysis of ARTESiA and NOAH-AFNET 6 clinical trials revealed that taking Edoxaban or Apixaban as oral anticoagulation therapy can reduce the risk of stroke by approximately 32% while increasing the risk of major bleeding by approximately 62%. However, it is still unclear which are, among patients with SCAF, those who can take the highest net clinical benefit from anticoagulant therapy. The present review summarizes the current evidence on this intriguing issue and suggests strategies to try to better stratify the risk of stroke and systemic embolism in patients with AHREs. We propose incorporating some parameters including chronic kidney disease (CKD), obesity, enlarged left atrial volume, the efficacy in blood pressure management, and frailty into the traditional CHA2DS2-VASc score. Future trials will be needed to verify the clinical usefulness of the proposed prognostic score mainly in the view of a personalized therapeutic approach in patients with SCAF.

Low circulating levels of miR-17 and miR-126-3p are associated with increased mortality risk in geriatric hospitalized patients affected by cardiovascular multimorbidity.

MultiMorbidity (MM), defined as the co-occurrence of two or more chronic conditions, is associated with poorer health outcomes, such as recurrent hospital readmission and mortality. As a group of conditions, cardiovascular disease (CVD) exemplifies several challenges of MM, and the identification of prognostic minimally invasive biomarkers to stratify mortality risk in patients affected by cardiovascular MM is a huge challenge. Circulating miRNAs associated to inflammaging and endothelial dysfunction, such as miR-17, miR-21-5p, and miR-126-3p, are expected to have prognostic relevance. We analyzed a composite profile of circulating biomarkers, including miR-17, miR-21-5p, and miR-126-3p, and routine laboratory biomarkers in a sample of 246 hospitalized geriatric patients selected for cardiovascular MM from the Report-AGE INRCA database and BioGER INRCA biobank, to evaluate the association with all-cause mortality during 31 days and 12 and 24 months follow-up. Circulating levels of miR-17, miR-126-3p, and some blood parameters, including neutrophil to lymphocyte ratio (NLR) and eGFR, were significantly associated with mortality in these patients. Overall, our results suggest that in a cohort of geriatric hospitalized patients affected by cardiovascular MM, lower circulating miR-17 and miR-126-3p levels could contribute to identify patients at higher risk of short- and medium-term mortality.

Is it time to revise the fighting strategy toward type 2 diabetes? Sex and pollution as new risk factors.

Diabetes mellitus, a metabolic condition affecting around 537 million individuals worldwide, poses significant challenges, particularly among the elderly population. The etiopathogenesis of type 2 diabetes (T2D) depends on a combination of the effects driven by advancing age, genetic background, and lifestyle habits, e.g. overnutrition. These factors influence the development of T2D differently in men and women, with an obvious sexual dimorphism possibly underlying the diverse clinical features of the disease in different sexes. More recently, environmental pollution, estimated to cause 9 million deaths every year, is emerging as a novel risk factor for the development of T2D. Indeed, exposure to atmospheric pollutants such as PM2.5, O3, NO2, and Persistent Organic Pollutants (POP)s, along with their combination and bioaccumulation, is associated with the development of T2D and obesity, with a 15 % excess risk in case of exposure to very high levels of PM2.5. Similar data are available for plasticizer molecules, e.g. bisphenol A and phthalates, emerging endocrine-disrupting chemicals. Even though causality is still debated at this stage, preclinical evidence sustains the ability of multiple pollutants to affect pancreatic function, promote insulin resistance, and alter lipid metabolism, possibly contributing to T2D onset and progression. In addition, preclinical findings suggest a possible role also for plastic itself in the development of T2D. Indeed, pioneeristic studies evidenced that micro- or nanoplastics (MNP)s, particles in the micro- or nano- range, promote cellular damage, senescence, inflammation, and metabolic disturbances, leading to insulin resistance and impaired glucose metabolism in animal and/or in vitro models. Here we synthesize recent knowledge relative to the association between air-related or plastic-derived pollutants and the incidence of T2D, discussing also the possible mechanistic links suggested by the available literature. We then anticipate the need for future studies in the field of candidate therapeutic strategies limiting pollution-induced damage in preclinical models, such as SGLT-2 inhibitors. We finally postulate that future guidelines for T2D prevention should consider pollution and sex an additional risk factors to limit the diabetes pandemic.

Sex/gender-related differences in inflammaging.

Geroscience puts mechanisms of aging as a driver of the most common age-related diseases and dysfunctions. Under this perspective, addressing the basic mechanisms of aging will produce a better understanding than addressing each disease pathophysiology individually. Worldwide, despite greater functional impairment, life expectancy is higher in women than in men. Gender differences in the prevalence of multimorbidity lead mandatory to the understanding of the mechanisms underlying gender-related differences in multimorbidity patterns and disability-free life expectancy. Extensive literature suggested that inflammaging is at the crossroad of aging and age-related diseases. In this review, we highlight the main evidence on sex/gender differences in the mechanisms that foster inflammaging, i.e. the age-dependent triggering of innate immunity, modifications of adaptive immunity, and accrual of senescent cells, underpinning some biomarkers of inflammaging that show sex-related differences. In the framework of the "gender medicine perspective", we will also discuss how sex/gender differences in inflammaging can affect sex differences in COVID-19 severe outcomes.

Zingiber officinale Roscoe Rhizome Extract Exerts Senomorphic and Anti-Inflammatory Activities on Human Endothelial Cells.

Aging is related to a low-grade and sterile inflammation called inflammaging, recognized as the main risk factor for age-related disease (ARD) development. Inflammaging is fostered by the repeated activation of immune cells, as well as by the accumulation of senescent cells. Recently, a number of natural compounds have gained attention to be tested as anti-aging therapies, based on their anti-inflammatory activity and/or ability to reduce the pro-inflammatory secretome of senescent cells (senomorphyc activity). Here, we investigated the anti-inflammatory and senomorphic properties of an Asian-native Zingiber officinale Roscoe extract (ZOE), commonly consumed as a food spice and herbal medicine. We employed two models of primary endothelial cells (HUVECs), such as the replicative-senescence and LPS-induced response, to investigate the anti-inflammatory/senomorphic effect of ZOE, and one cellular model of neuroinflammation, i.e., immortalized murine microglial cells (BV2). First, we found that the ZOE treatment induced the inhibition of NF-kB activation in BV2 cells. Among the constituents of ZOE, we showed that the terpenoid-enriched fraction (ZTE) was the component able to counteract the phosphorylation of NF-kB(p65), while 6-gingerol (GIN) and 6-shogaol (SHO) did not produce any significant effect. Further, we observed that the treatment with 10 µg/mL of ZOE exerted anti-inflammatory activity on LPS-stimulated young (y)HUVEC and senomorphyc activity on replicative senescent (s)HUVEC, significantly reducing the expression levels of IL-1ß, TNF -α, IL-8, MCP-1, and ICAM-1. Moreover, the ZTE treatment was able to significantly reduce the IL-8 levels secreted in the medium of both LPS-stimulated yHUVEC and sHUVEC. Overall, our data suggest a potential protective role of ZOE on neuroinflammation and endothelial inflammation/activation, thus suggesting its potential relevance in delaying/postponing ARD development and progression, characterized by endothelial dysfunction.