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Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00713-1.

Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension. Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension.

DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.

Lal and colleagues1 reported an integrative approach-combining transcriptomics, iPSCs, and epidemiological evidence-to identify and repurpose metformin, a main first-line medication for the treatment of type 2 diabetes, as an effective risk reducer for atrial fibrillation.

The incidence and the burden of cardiovascular disease (CVD), coronary heart disease (CHD), type 2 diabetes mellitus (T2DM), and the metabolic syndrome are greatly increasing in our societies. Together, they account for 31% of all deaths worldwide. This chapter focuses on the role of two revolutionary discoveries that are changing the future of medicine, induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 technology, in the study, and the cure of cardiovascular and metabolic diseases.We summarize the state-of-the-art knowledge about the possibility of editing iPSC genome for therapeutic applications without hampering their pluripotency and differentiation, using CRISPR/Cas technology, in the field of cardiovascular and metabolic diseases.

Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-021-00487-y.

Human-induced pluripotent stem cells (iPSCs) can be derived from adult stem cells by forced expression of defined transcription factors. This paves the way for autologous iPSC-derived therapies, which, however, are not yet considered safe. Moreover, reprogramming of somatic cells into iPSCs is an inefficient process, in the range of 0.1%–1%. The epigenetic mechanisms implicated in iPSCs reprogramming are not well understood. The substitution of canonical histone H2A with macroH2A1 histone variant exon-spliced isoforms (macroH2A1.1 and macroH2A1.2) appears as an emerging regulator of iPSCs identity. In particular, we have previously shown that overexpression of macroH2A1.1 led to a more efficient iPSCs reprogramming, by not fully defined mechanisms. Cleavage under targets and tagmentation (CUT&Tag) is a recent methodology used for robust epigenomic profiling of a limited amount of cells. Here, we performed the first integrative CUT&Tag/RNA-Seq analysis of the histone variant macroH2A1-dependent orchestration of iPSCs reprogramming using human umbilical vein endothelial cells (HUVEC) during their reprogramming into iPSC over-expressing tagged macroH2A1.1 or macroH2A1.2. Our results demonstrate a higher and more widespread genome occupancy and a greater number of differentially expressed genes orchestrated by macroH2A1.1 in HUVEC undergoing reprogramming as compared to macroH2A1.2, which involved pervasive functions related to the three embryonic germ layers and increased overlap with CTCF, FOS, GATA2, and POLR2A transcription factor binding sites. In particular, all predicted macroH2A1.1 activating pathways were related to ectoderm/neural processes. As macroH2A1 isoforms have been previously associated with pathologies of the nervous system, our findings may provide relevant molecular insights for modeling neurodegenerative diseases using iPSCs.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

Objective:Cardiovascular disease remains a leading cause of mortality worldwide. Ceramide scores have been associated with adverse outcomes in patients with established coronary artery disease. The prognostic value of ceramide score has not been assessed in the general population. We tested the hypothesis that ceramide scores are associated with major adverse cardiac events (MACE) in a community-based cohort with average coronary artery disease burden at enrollment.Approach and results:In a prospective community-based cohort, we performed passive follow-up using a record linkage system to ascertain the composite outcome of MACE, defined as acute myocardial infarction, coronary revascularization (bypass grafting or percutaneous intervention), stroke, or death. Ceramides were analyzed as log-transformed continuous variables, ratios or scores, and quartiles with adjustment for confounders. We analyzed 1131 subjects, 52% females, mean age±(SD) 64±9 years. After a median follow-up of 13.3 years (Q1, 12.7; Q3, 14.4), 486 patients experienced a MACE: myocardial infarction (80), coronary artery bypass surgery (34), percutaneous coronary intervention (62), stroke (94), and all-cause death (362). Ceramide ratios were significantly associated with MACE independently of LDL-c (low-density lipoprotein cholesterol) and conventional coronary artery disease risk factors. Those in the highest quartile of ceramide score had nearly 1.5-fold risk of MACE, hazard ratio, 1.47 (95% CI, 1.12–1.92). There was a dose-response association across quartiles of ceramide ratios and MACE.Conclusions:Elevated ceramide score is a robust predictor of cardiovascular disease and MACE in the community. The risk conferred by the ceramide score has a dose-response behavior and is independent of conventional risk factors.

The genetic basis of variability in drug response is at the core of pharmacogenomics (PGx) studies, aiming at reducing adverse drug reaction (ADR), which have interethnic variability. This study used the Kardiovize Brno 2030 random urban Czech sample population to analyze polymorphisms in a wide spectrum of genes coding for liver enzymes involved in drug metabolism. We aimed at correlating real life drug consumption with pharmacogenomic profile, and at comparing these data with the SUPER-Finland Finnish PGx database. A total of 250 individuals representative of the Kardiovize Brno 2030 cohort were included in an observational study. Blood DNA was extracted and 59 single nucleotide polymorphisms within 13 genes (BCHE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, F2, F5, IFNL3, SLCO1B1, TPMT, UGT1A1, VKORC1), associated to different drug metabolizing rates, were characterized by genotyping using a genome wide commercial array. Widely used drugs such as anti-coagulant warfarin and lipid lowering agent atorvastatin were associated to an alarmingly high percentage of users with intermediate/poor metabolism for them. Significant differences in the frequency of normal/intermediate/poor/ultrarapid/rapid metabolizers were observed for CYPD26 (pCYP2C19 (pUGT1A1 (p

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are effective anti-diabetic drugs improving cardiovascular outcomes in type 2 diabetes mellitus (T2DM) patients. This study investigated cardiovascular, cerebrovascular and cognitive outcomes of SGLT2i therapy in patients with atrial fibrillation (AF) and T2DM. Methods: Observational study using TriNetX, a global health research network of anonymised electronic medical records from real-world patients between January 2018 and December 2019. The network includes healthcare organisations globally but predominately in the United States. AF patients (ICD-10-CM code: I48) with T2DM were divided according to SGLT2i use or not, and balanced using propensity score matching (PSM). Patients were followed-up for 3-years. The primary endpoints were ischaemic stroke/transient ischemic attack (TIA), intracranial haemorrhage (ICH), and incident dementia. Secondary endpoints were incident heart failure and mortality. Results: We identified 89,356 AF patients with T2DM of which 5061 (5.7%) were taking a SGLT2i. After PSM, 5049 patients (mean age 66.7 ± 10.6 years; 28.9% female) were included in each group. At 3-years follow-up, the risk of ischaemic stroke/TIA was higher in patients not receiving SGLT2i (HR 1.12, 95% CI 1.01–1.24) and for ICH (HR 1.57, 95% CI 1.25–1.99) and incident dementia (HR 1.66, 95% CI 1.30–2.12). Incident heart failure (HR 1.50, 95% CI 1.34–1.68) and mortality (HR 1.77, 95% CI 1.58–1.99) risks were increased in AF patients not receiving SGLT2i. Conclusions: In our large ‘real world’ analysis of patients with concomitant AF and T2DM, SGLT2i reduced the risk of cerebrovascular events, incident dementia, heart failure and death.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications.In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches.In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine.Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches.

Staining mice tissues for β-galactosidase activity is a fundamental tool to detect age- or disease-associated cellular senescence. However, reported analyses of positivity for senescence-associated β-galactosidase activity or for other markers of senescence in post-mitotic cells of healthy murine tissues have been fragmentary or inconclusive. Here, we attempted to independently deepen this knowledge using multiple senescence markers within the same cells of wild type mice entering middle age (9 months of age). A histochemistry protocol for the pH-dependent detection of β-galactosidase activity in several tissues was used. At pH 6, routinely utilized to detect senescence-associated β-galactosidase activity, only specific cellular populations in the mouse body (including Purkinje cells and choroid plexus in the central nervous system) were detected as strongly positive for β-galactosidase activity. These post-mitotic cells were also positive for other established markers of senescence (p16, p21 and DPP4), detected by immunofluorescence, confirming a potential senescent phenotype. These data might contribute to understanding the functional relation between the senescence-associated β-galactosidase activity and senescence markers in post-mitotic cells in absence of disease or advanced aging.

Uncovering the main determinants of diet quality is one of the greatest challenges for Public Health, since it could guide future strategies and interventions against cardiovascular diseases (CVDs). The present cross-sectional analysis of the Kardiovize cohort evaluates the prevalence of dietary risk factors for CVDs and their association with social and behavioural characteristics in a random sample of 1536 adults (aged 25-64 years) from Brno, Czech Republic.A face-to-face health interview guided by structured questionnaires was carried out on socio-demographic characteristics (age, sex, educational level, employment, marital status, income, and household size) and behaviours (smoking status, physical activity, and sleep habits). Twelve dietary risk factors covered by the Global Burden of Diseases comparative risk assessment framework were assessed using a Food Frequency Questionnaire. In general, we observed that the consumption of nearly all healthy foods and nutrients was suboptimal, and that it was also aggravated by high intake of foods and nutrients that constituted dietary risk factors. Moreover, we found several associations of social and behavioural characteristics with specific dietary risk factors. Particularly, being male (β = 0.466; SE = 0.079; p 0.001), increasing household size (β = 0.130; SE = 0.047; p = 0.006), low income (β = 0.192; SE = 0.091; p = 0.035), and decreasing physical activity level (β = 0.172; SE = 0.054; p = 0.002) were associated with increasing number of dietary risk factors.Thus, our study raises an urgent need for Public Health strategies promoting healthy eating in adulthood, which should be based on traditional and novel determinants of dietary risk.

Cardiovascular disease (CVD), which is the leading cause of death worldwide, is strongly affected by diet. Diet can affect CVD directly by modulating the composition of vascular plaques, and indirectly by affecting the rate of aging. This review summarizes research on the relationships of fasting, meal timing, and meal frequency with CVD incidence and progression. Relevant basic research studies, epidemiological studies, and clinical studies are highlighted. In particular, we discuss both intermittent and periodic fasting interventions with the potential to prevent and treat CVD.

Objective: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression Methods: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis Results: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma Conclusions: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC.The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods.TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation.Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Summary: Cellular senescence is a major contributor to age-related diseases in humans; however, it also has a beneficial role in physiological and pathological processes, including wound healing, host immunity, and tumour suppression. Reducing the burden of cell senescence in animal models of cardiometabolic disorders, inflammatory conditions, neurodegenerative diseases, and cancer using pharmaceutical approaches that selectively target senescent cells (ie, senolytics) or that suppress senescence-associated secretory phenotype (ie, senomorphics) holds great promise for the management of chronic age-associated conditions. Although studies have provided evidence that senolytics or senomorphics are effective at decreasing the number of senescent cells in humans, the short-term and long-term side-effects of these therapies are largely unknown. In this Review, we systematically discuss the senolytics and senomorphics that have been investigated in clinical trials or have been used off-label, presenting their various adverse effects. Despite the potential of senotherapeutics to transform anti-ageing medicine, a cautionary approach regarding unwanted dose-dependent side-effects should be adopted.

Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management. In this review, we provide an overview of circulating histones as a powerful liquid biopsy approach and methods for their detection. We highlight current knowledge on circulating histones in hematologic malignancies and solid cancer, with a focus on their role in cancer dissemination, monitoring, and tumorigenesis. Last, we describe recently developed strategies to identify cancer tissue-of-origin in blood plasma based on nucleosome positioning, inferred from nucleosomal DNA fragmentation footprint, which is independent of the genetic landscape.

Background Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. Conclusions Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality. While on a high-fat, high-calorie diet, a monthly cycle of 5 days of a fasting-mimicking diet can prevent obesity and related detrimental effects on cardiometabolic health and lifespan in mice.

Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association of CVH metrics with the circulating lipid profile of a population-based cohort. Serum sphingolipid and phospholipid species were extracted from 461 patients of the randomly selected prospective Kardiovize study based on Brno, Czech Republic. Lipids species were measured by a hyphenated mass spectrometry technique, and were associated with poor CVH scores, as defined by the American Heart Association. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) species were significantly lower in ideal and intermediate scores of health dietary metric, blood pressure, total cholesterol and blood fasting glucose compared to poor scores. Current smokers presented higher levels of PC, PE and LPE individual species compared to non-smokers. Ceramide (Cer) d18:1/14:0 was altered in poor blood pressure, total cholesterol and fasting blood glucose metrics. Poor cardiovascular health metric is associated with a specific phospho- and sphingolipid pattern. Circulatory lipid profiling is a potential biomarker to refine cardiovascular health status in primary prevention strategies.

Gene expression and epigenetic processes in several brain regions regulate physiological processes such as cognitive functions and social behavior. MacroH2A1.1 is a ubiquitous variant of histone H2A that regulates cell stemness and differentiation in various organs. Whether macroH2A1.1 has a modulatory role in emotional behavior is unknown. Here, we employed macroH2A1.1 knock-out (-/- ) mice to perform a comprehensive battery of behavioral tests, and an assessment of hippocampal synaptic plasticity (long-term potentiation) accompanied by whole hippocampus RNA sequencing. MacroH2A1.1-/- mice exhibit a stunningly enhancement both of sociability and of active stress-coping behavior, reflected by the increased social behavior in social activity tests and higher mobility time in the forced swim test, respectively. They also display an increased hippocampal synaptic plasticity, accompanied by significant neurotransmission transcriptional networks changes. These results suggest that systemic depletion of histone macroH2A1.1 supports an epigenetic control necessary for hippocampal function and social behavior.

Simple Summary MacroH2A1, a histone H2A variant, is present as two alternative splicing isoforms, macroH2A1.1 and macroH2A1.2, which are finely regulated through several mechanisms, including post-translational modifications (PTM). In this article, the authors provide the PTM pattern of macroH2A1.1 and macroH2A1.2 in the same experimental setting through mass spec analysis. They report a different phosphorylation level in their intrinsically disordered linker region, which can be responsible for their different biological role, as computational analysis shows. Abstract Background: Gene expression in eukaryotic cells can be governed by histone variants, which replace replication-coupled histones, conferring unique chromatin properties. MacroH2A1 is a histone H2A variant containing a domain highly similar to H2A and a large non-histone (macro) domain. MacroH2A1, in turn, is present in two alternatively exon-spliced isoforms: macroH2A1.1 and macroH2A1.2, which regulate cell plasticity and proliferation in a remarkably distinct manner. The N-terminal and the C-terminal tails of H2A histones stem from the nucleosome core structure and can be target sites for several post-translational modifications (PTMs). MacroH2A1.1 and macroH2A1.2 isoforms differ only in a few amino acids and their ability to bind NAD-derived metabolites, a property allegedly conferring their different functions in vivo. Some of the modifications on the macroH2A1 variant have been identified, such as phosphorylation (T129, S138) and methylation (K18, K123, K239). However, no study to our knowledge has analyzed extensively, and in parallel, the PTM pattern of macroH2A1.1 and macroH2A1.2 in the same experimental setting, which could facilitate the understanding of their distinct biological functions in health and disease. Methods: We used a mass spectrometry-based approach to identify the sites for phosphorylation, acetylation, and methylation in green fluorescent protein (GFP)-tagged macroH2A1.1 and macroH2A1.2 expressed in human hepatoma cells. The impact of selected PTMs on macroH2A1.1 and macroH2A1.2 structure and function are demonstrated using computational analyses. Results: We identified K7 as a new acetylation site in both macroH2A1 isoforms. Quantitative comparison of histone marks between the two isoforms revealed significant differences in the levels of phosphorylated T129 and S170. Our computational analysis provided evidence that the phosphorylation status in the intrinsically disordered linker region in macroH2A1 isoforms might represent a key regulatory element contributing to their distinct biological responses. Conclusions: Taken together, our results report different PTMs on the two macroH2A1 splicing isoforms as responsible for their distinct features and distribution in the cell.

A recent work by Nishina et al. provides new evidence that DPP4 inhibitors exert antitumor effects against hepatocellular carcinoma (HCC) by orchestrating immune responses.

Objective To investigate the association of pet ownership, and specifically dog ownership, with cardiovascular diseases (CVD) risk factors and cardiovascular health (CVH) in the Kardiovize Brno 2030 study, a randomly selected prospective cohort in Central Europe. Patients and Methods We included 1769 subjects (aged from 25 to 64 years; 44.3% males) with no history of CVD who were recruited from January 1, 2013, to December 19, 2014. We compared sociodemographic characteristics, CVD risk factors, CVH metrics (ie, body mass index, healthy diet, physical activity level, smoking status, blood pressure, fasting glucose, and total cholesterol), and score between pet owners and non-pet owners or dog owners and several other subgroups. Results Approximately 42% of subjects owned any type of pet: 24.3% owned a dog and 17.9% owned another animal. Pet owners, and specifically dog owners, were more likely to report physical activity, diet, and blood glucose at ideal level, and smoking at poor level, which resulted in higher CVH score than non-pet owners (median, 10; interquartile range = 3 vs median, 9; interquartile range = 3; P=0.006). Compared with owners of other pets, dog owners were more likely to report physical activity and diet at ideal level. The comparison of dog owners with non-dog owners yielded similar results. After adjustment for covariates, dog owners exhibited higher CVH scores than non-pet owners (β=0.342; SE=0.122; P=0.005), other pet-owners (β=0.309; SE=0.151; P=0.041), and non-dog owners (β=0.341; SE=0.117; P=0.004). Conclusion Except for smoking, dog owners were more likely to achieve recommended level of behavioral CVH metrics (physical activity and diet) than non-dog owners, which translated into better CVH.

Objective Atherosclerosis is a major contributor to cardiovascular disease, with a higher burden on men than women during the occupational age. Intake of individual dietary antioxidants is inversely associated with risk of atherosclerosis development. We aimed to understand the relationship between dietary composite antioxidant intake and the carotid intima media thickness (cIMT), which is a proxy of atherosclerosis progression. Approach and results We performed a cross-sectional analysis that included 894 members of the Kardiovize cohort, a random urban sample population. Nutrient intakes were derived by 24-h recall. We constructed a composite dietary antioxidant index (CDAI), based on zinc, selenium, vitamin A, vitamin C, vitamin E and carotenoids. We considered the CDAI as the exposure variable and primary outcomes were the following cardio-metabolic parameters: body mass index (BMI), waist-to-hip ratio (WHR), body fat mass (BFM), systolic and diastolic blood pressure, triglycerides, HDL and LDL cholesterol, and cIMT. Associations and interactions between variables were evaluated using linear regression analyses. In women, a 1 mg increase in dietary intake of zinc or vitamin E decreased the cIMT by 3.36 and 1.48 µm, respectively, after adjusting for covariates. Similarly, the cIMT decreased by 4.72 µm for each one-unit increase in CDAI (p = 0.018). Beyond CDAI, age (β = 3.61; SE=0.89; p = 0.001), systolic blood pressure (β = 1.30; SE=0.59; p = 0.029) and triglycerides (β = 22.94; SE=10.09; p = 0.024) were significant predictors of cIMT in women. By contrast, we found no association between CDAI and cIMT in men. Conclusions CDAI negatively associates with cIMT in women. These findings indicate that combined intake of nutrients with anti-oxidant properties might prevent the initiation and progression of arterial lesions in a sex-specific manner.

OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in both adults and children. Along with obesity and metabolic syndrome, genetic predisposition influences the progression of NAFLD. Here, we investigated the effect of lifespan/healthspan-related single nucleotide polymorphisms (SNPs) on metabolically associated fatty liver disease in children. METHODS We evaluated the impact of 10 SNPs involved in both human liver/metabolic diseases and healthspan (interleukin-6 [IL-6] rs1800795, antisense non coding RNA in the INK4 locus (ANRIL) rs1556516, SH2B3/ATXN2 rs7137828, FURIN rs17514846, TP53 rs1042522, APOC3 rs2542052, KL rs9536314, KL rs9527025, SIRT6 rs107251, FOXO3 rs2802292) on NAFLD-related metabolic and liver features in 177 pediatric patients with biopsy-proven NAFLD, by comparing them to 146 healthy controls. We then applied a multidimensional reduction (MDR) case-control analysis of SNP-SNP interactions, to identify the joint effect of analyzed SNPs in predicting NAFLD and associated features. RESULTS Discrete SNPs were significantly associated with individual metabolic NAFLD features, but none of them significantly associated with NAFLD diagnosis. By testing potential synergies using the MDR approach, the best combination to diagnose NAFLD (P = 0.0011) resulted in the one encompassing IL-6 rs1800795 and ANRIL rs1556516. Consistently, the risk combinations suggested by SNP-SNP analysis strongly associated with a higher level of fasting plasma blood glucose level (P = 0.024). CONCLUSION In conclusion, here we demonstrated a synergic interaction between IL-6 rs1800795 and ANRIL rs1556516 in the diagnosis of NAFLD, and NAFLD-associated hyperglycemia in children. Larger studies are required to confirm our findings and to elucidate mechanisms by which the genetic interaction between these two genes influences healthspan in pediatric NAFLD.

Background: SARS-CoV-2 belongs to a subgroup of coronaviruses rampant in bats for centuries. It has caused the COVID-19 pandemic. Most patients recover, but a minority of severe cases experience acute respiratory distress or an inflammatory storm devastating many organs that can lead to patient death. The spread of SARS-CoV-2 has been facilitated by the increasing intensity of air travel, urban congestion and human contact during the last half century. Until therapies and vaccines are available, tests for virus and exposure, confinement measures and physical distancing have helped curb the pandemic. Vision: The COVID-19 pandemic calls for safeguards and remediation measures through a systemic response. A myriad of self-organizing initiatives by scientists and citizens is developing an advanced collective intelligence response to the coronavirus crisis. Their integration forms Olympiads of Solidarity and Health. Their ability to optimize our response to COVID-19 could serve as a model to trigger a global metamorphosis of our societies with far-reaching consequences for attacking fundamental challenges facing humanity in the 21st century. Mission: For COVID-19 and these other challenges, there is no alternative but action. Meeting in Paris in 2003, we set out to "rethink research to understand life and improve health." We have now formed an international coalition of academia and industry ecosystems taking a systems medicine approach to understanding COVID-19 by thoroughly characterizing viruses, patients and populations during the pandemic, using openly shared tools. All results will be publicly available with no initial claims for intellectual property rights. This World Alliance for Health and Wellbeing will catalyze the creation of medical and health products such as diagnostic tests, drugs and vaccines that become common goods accessible to all, while seeking further alliances with civil society to bridge with socio-ecological and technological approaches that characterise urban systems, for a collective response to future health emergencies. Funding: This work was supported during its preparation phases by the State Key Laboratory of Medical Genomics, Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B17029) to SJC, LH, CA; European Union grants CASyM (FP7-n°305033) to CA, RB, JR, DR, DS, JT, OW; eTRIKS (IMI-1-n°115446) to CA, RB, YG; PREPARE (FP7n°602525) to CA, PO, SV; and initial funds in support of the deep phenotyping clinical study from philanthropic donors, Gilead, Merck and Novartis to JG, JH, LH; the Ricerca Corrente Program by the Italian Ministry of Health to AC, CPr, GS, AU, VV; the National Megaprojects of China for Infectious Diseases (2017ZX10103009-001, 2018ZX10305409-001-005), Double Firstclass projects from the Ministry of Education to the National Research Center for Translational Medicine Shanghai to SJC; Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) to LJ. Conflict of Interest: Rudi Balling reports being a founder/shareholder of ITTM S.A. and Megeno S.A., outside the submitted work, he is co-inventor and holder of two issued patents; James Heath reports personal fees and other from PACT Pharma, outside the submitted work; Hiroaki Kitano reports grants from Minister of Health, Welfare, and Labor of Japanese Government, grants from Okinawa Prefecture Government, outside the submitted work; Doron Lancet reports personal fees from Weizmann Institute of Science and LifeMap Science Inc., outside the submitted work; Catherine Larue reports personal fees from Genfit, outside the submitted work; Peter Openshaw reports personal fees for consultancy work with Janssen, JJ Susanna Palkonen reports grants from Aimmune, Astra Zeneca, Boehringer Ingelheim, Chiesi, DBV Technologies, GSK, Leo Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, outside the submitted work, is employed by the EFA who receives unrestricted grants from corporate entities as above, represents EFA in the following advisory groups of these entities: Astra Zeneca COPD Advisory Committee, GSK Health Advisory Board and Novartis European Patient Advisory Group, receives no personal gain, honoraria, when applicable expenses are payed to her organization, is in a voluntary function the Chair of the Patient Access Partnership PACT who receives unrestricted grants from EFPIA, MedTech Europe, EUCOPE and Medicines for Europe for core operations, and project grants from individual companies, outside the submitted work; Christophe Pison reports personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, outside the submitted work; Mihael Polymeropulos reports other from Vanda Pharmaceuticals, outside the submitted work; Ulrike Protzer reports grants from VIR Biotechnology, grants and non-financial support from Roche, grants from Alios-JJ Peter Sterk reports other from Breathomix BV, outside the submitted work; Giulio Superti-Furga reports being a shareholder of Proxygen GmbH, Haplogen GmbH and Allcyte GmbH, outside the submitted work; Vincenzo Valentini reports personal fees from Merck Serono, Betaglue, outside the submitted work; Sylvie van der Werf reports other from Sanofi Pasteur, outside the submitted work; she is the holder of four issued patents. The other authors have declared no conflict of interest.

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. Methods Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. Results Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. Conclusions In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC.

Growth differentiation factor 11 (GDF11 or bone morphogenetic protein 11, BMP11) belongs to the transforming growth factor-β superfamily and is closely related to other family member-myostatin (also known as GDF8). GDF11 was firstly identified in 2004 due to its ability to rejuvenate the function of multiple organs in old mice. However, in the past few years, the heralded rejuvenating effects of GDF11 have been seriously questioned by many studies that do not support the idea that restoring levels of GDF11 in aging improves overall organ structure and function. Moreover, with increasing controversies, several other studies described the involvement of GDF11 in fibrotic processes in various organ setups. This review paper focuses on the GDF11 and its pro- or anti-fibrotic actions in major organs and tissues, with the goal to summarize our knowledge on its emerging role in regulating the progression of fibrosis in different pathological conditions, and to guide upcoming research efforts.

Background Although metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can also occur in lean patients. MAFLD is more aggressive in lean patients compared to obese patients, with a higher risk of mortality. Specific biomarkers to diagnose differentially lean or overweight MAFLD are missing. Histones and nucleosomes are released in the bloodstream upon cell death. Here, we propose a new, fast, imaging and epigenetics based approach to investigate the severity of steatosis in lean MAFLD patients. Results A total of 53 non-obese patients with histologically confirmed diagnosis of MAFLD were recruited. Twenty patients displayed steatosis grade 1 (0–33%), 24 patients with steatosis grade 2 (34–66%) and 9 patients with steatosis grade 3 (67–100%). The levels of circulating nucleosomes were assayed using enzyme-linked immunosorbent assay, while individual histones or histone dimers were assayed in serum samples by means of a new advanced flow cytometry ImageStream(X)-adapted method. Circulating nucleosome levels associated poorly with MAFLD in the absence of obesity. We implemented successfully a multi-channel flow methodology on ImageStream(X), to image single histone staining (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2). We report here a significant depletion of the levels of histone variants macroH2A1.1 and macroH2A1.2 in the serum of lean MAFLD patients, either individually or in complex with H2B. Conclusions In summary, we identified a new circulating histone signature able to discriminate the severity of steatosis in individuals with lean MAFLD, using a rapid and non-invasive ImageStream(X)-based imaging technology.

Significance: Since their discovery, induced pluripotent stem cells (iPSCs) had generated considerable interest in the scientific community for their great potential in regenerative medicine, disease modeling, and cell-based therapeutic approach, due to their unique characteristics of self-renewal and pluripotency. Recent Advances: Technological advances in iPSC genome-wide epigenetic profiling led to the elucidation of the epigenetic control of cellular identity during nuclear reprogramming. Moreover, iPSC physiology and metabolism are tightly regulated by oxidation-reduction events that mainly occur during the respiratory chain. In theory, iPSC-derived differentiated cells would be ideal for stem cell transplantation as autologous cells from donors, as the risks of rejection are minimal. Critical Issues: However, iPSCs experience high oxidative stress that, in turn, confers a high risk of increased genomic instability, which is most often linked to DNA repair deficiencies. Genomic instability has to be assessed before iPSCs can be used in therapeutic designs. Future Directions: This review will particularly focus on the links between redox balance and epigenetic modifications-in particular based on the histone variant macroH2A1-that determine DNA damage response in iPSCs and derived differentiated cells, and that might be exploited to decrease the teratogenic potential on iPSC transplantation. Antioxid. Redox Signal. 34, 335-349.

Comparisons among countries can help to identify opportunities for the reduction of inequalities in cardiometabolic health. The present cross-sectional analysis and meta-analysis aim to address to what extent obesity traits, socioeconomic, and behavioral factors determine poor metabolic health across body mass index (BMI) categories in two urban population-based samples from Central Europe. Data from the CoLaus (~6,000 participants; Lausanne, Switzerland) and the Kardiovize Brno 2030 (~2,000 participants; Brno, Czech Republic) cohorts. For each cohort, logistic regression analyses were performed to identify the main determinants of poor metabolic health overall and stratified by body mass index (BMI) categories. The results of each cohort were then combined in a meta-analysis. We first observed that waist circumference and body fat mass were associated with metabolic health, especially in non-obese individuals. Moreover, increasing age, being male, having low-medium educational level, abdominal obesity, and high body fat mass were the main determinants of the metabolically unhealthy profile in both cohorts. Meta-analysis stratified by BMI categories confirmed the previous results with slight differences across BMI categories. In fact, increasing age and being male were the main determinants of poor metabolic health independent of obesity status. In contrast, low educational level and current smoking were associated with poor metabolic health only in non-obese individuals. In line, public health strategies against obesity and related comorbidities should aim to improve social conditions and to promote healthy lifestyles before the progression of metabolic disorders.

Uveal melanoma (UM) is the most common primary intraocular tumour in adults. The most accurate prognostic factor of UM is classification by gene expression profiling. Currently, the role of epigenetics is much less defined compared to genetic mechanisms. We recently showed a strong prognostic role of the expression levels of histone variant macroH2A1 in UM patients. Here, we assessed the mechanistic effects of macroH2A1 on UM progression. UM cell lines were stably knocked down (KD) for macroH2A1, and proliferation and colony formation capacity were evaluated. Mitochondrial function was assayed through qPCR and HPLC analyses. Correlation between mitochondrial gene expression and cancer aggressiveness was studied using a bioinformatics approach. MacroH2A1 loss significantly attenuated UM cells proliferation and aggressiveness. Furthermore, genes involved in oxidative phosphorylation displayed a decreased expression in KD cells. Consistently, macroH2A1 loss resulted also in a significant decrease of mitochondrial transcription factor A (TFAM) expression, suggesting impaired mitochondrial replication. Bioinformatics analyses uncovered that the expression of genes involved in mitochondrial metabolism correlates with macroH2A1 and with cancer aggressiveness in UM patients. Altogether, our results suggest that macroH2A1 controls UM cells progression and it may represent a molecular target to develop new pharmacological strategies for UM treatment.

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance. ispartof: THERANOSTICS vol:10 issue:2 pages:910-924 ispartof: location:Australia status: published

Maternal nutrition during pregnancy, and other perinatal periods, programs offspring physiology and metabolism, as well as the risk of suffering metabolic diseases during adulthood. During pregnancy, there is a double interaction of nutritional intake and genetic background due to the maternal feeding and genes, and fetal genetic information and in utero nutrient availability. The main molecular mechanism implicated in developmental programming appears to be epigenetics, which regulate gene expression patterns during embryo and postnatal stages in a cellular- and tissue-specific manner, affecting metabolic and physiologic-related key genes. Epigenetic profiles are nutritionally modulated, and also the expression patterns of genes related to nutrient metabolism can be epigenetic driven. Therefore, there appears a novel scientific perspective involving nutriepigenetic and nutriepigenomic regulation, which has to be integrated into the traditional nutrigenetic and nutrigenomic lines of sight. Interestingly, maternal programming may predispose the transcriptomic patterns during different lifetime periods and appear to be also transmissible across successive generations. Although human studies of developmental programming are recent and mainly observational, there is evidence of epigenetically driven programming due to different macro- and micronutrient distribution as well as by total caloric intake. However, although omics-based human approaches have importantly increased the knowledge for future nutrition-based epigenetic regulation, ethical and practical considerations lead to animal approaches as the most useful mechanistic research tool. There is still needed a deeper understanding of the nutritionally driven epigenetic reactions in utero that may lead to apply an effective personalized maternal nutrition during pregnancy.

Existing data have described benefits and drawbacks of alcohol consumption on cardiovascular diseases (CVD), but no research has evaluated its association with the cardiovascular health (CVH) score proposed by the American Heart Association. Here, we conducted a cross-sectional analysis on the Kardiovize cohort (Brno, Czech Republic), to investigate the relationship between alcohol consumption and CVH. We included 1773 subjects (aged 25&ndash, 64 years, 44.2% men) with no history of CVD. We compared CVD risk factors, CVH metrics (i.e., BMI, healthy diet, physical activity level, smoking status, blood pressure, fasting glucose, and total cholesterol) and CVH score between and within several drinking categories. We found that the relationship between drinking habits and CVH was related to the amount of alcohol consumed, drinking patterns, and beverage choices. Heavy drinkers were more likely to smoke tobacco, and to report diastolic blood pressure, fasting glucose, triglycerides, and low-density lipoprotein (LDL)-cholesterol at higher level than non-drinkers. Among drinkers, however, people who exclusively drank wine exhibited better CVH than those who exclusively drank beer. Although our findings supported the hypothesis that drinking alcohol was related to the CVH in general, further prospective research is needed to understand whether the assessment of CVH should incorporate information on alcohol consumption.