Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation.

Chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2 occupancy at target sites in vivo.

Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression.

The Polycomb system modifies chromatin and plays an essential role in repressing gene expression to control normal mammalian development. However, the components and mechanisms that define how Polycomb protein complexes achieve this remain enigmatic. Here, we use combinatorial genetic perturbation coupled with quantitative genomics to discover the central determinants of Polycomb-mediated gene repression in mouse embryonic stem cells. We demonstrate that canonical Polycomb repressive complex 1 (PRC1), which mediates higher-order chromatin structures, contributes little to gene repression. Instead, we uncover an unexpectedly high degree of synergy between variant PRC1 complexes, which is fundamental to gene repression. We further demonstrate that variant PRC1 complexes are responsible for distinct pools of H2A monoubiquitylation that are associated with repression of Polycomb target genes and silencing during X chromosome inactivation. Together, these discoveries reveal a new variant PRC1-dependent logic for Polycomb-mediated gene repression.

Blackthorn-A Valuable Source of Phenolic Antioxidants with Potential Health Benefits.

Prunus spinosa L. fruit, commonly known as blackthorn, is a rich source of bioactive compounds, including flavonoids, anthocyanins, phenolic acids, vitamins, minerals, and organic acids, which exhibit significant antioxidant and antibacterial properties. Notably, flavonoids such as catechin, epicatechin, and rutin have been reported to have protective effects against diabetes, while other flavonoids, including myricetin, quercetin, and kaempferol, exhibit antihypertensive activity. Solvent extraction methods are widely used for the extraction of phenolic compounds from plant sources, owing to their simplicity, efficacy, and broad applicability. Furthermore, modern extraction techniques, such as microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE), have been employed to extract polyphenols from Prunus spinosa L. fruits. This review aims to provide a comprehensive analysis of the biologically active compounds found in blackthorn fruits, emphasizing their direct physiological effects on the human body. Additionally, the manuscript highlights the potential applications of blackthorn fruits in various industries, including the food, cosmetics, pharmaceutical, and functional product sectors.

Lipidomics biomarkers in women with polycystic ovary syndrome (PCOS) using ultra-high performance liquid chromatography-quadrupole time of flight electrospray in a positive ionization mode mass spectrometry.

Polycystic ovary syndrome (PCOS), characterized by oligo-anovulation and androgen excess is considered a high-risk condition for metabolic disorders. Herein, untargeted metabolomics analysis was applied to women with PCOS, aiming to provide deeper insights into lipidomics biomarkers signature of PCOS, for better diagnosis and management. This was a cross-sectional study in which 15 Caucasian women with PCOS and 15 Caucasian healthy, age-matched women were enrolled. Lipidomics analysis was performed using Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Electrospray Mass Spectrometry. Partial Least Squares Discriminant Analysis retrieved the most important discriminative metabolites. Significantly increased levels of triacylglycerol (18:2/18:2/0-18:0) in addition to cholestane-3beta, 5alpha, 6beta-triol (18:0/0:0) and cholestane-5alpha (18:1/0:0) appeared as valuable variables to differentiate subjects with PCOS from controls. Acyl-carnitine 2-hydroxylauroylcarnitine was significantly elevated in PCOS in opposition to decreased phosphocholines metabolites (18:1/18:4, 18:3/18:2), to suggest a metabolic pattern linked to lipid peroxidation. A high fat intake or reduced fat energy consumption during nighttime due to diminished ability to switch to lipid oxidation during fasting time possibly contribute to hypertriglyceridemia found in PCOS. Furthermore, inflammatory mediators including metabolites of the prostaglandin (PG) E2 pathway and oxo-leukotrienes (LT) were increased in patients with PCOS. Potential lipidomics biomarkers were identified that could stratify between women with PCOS and healthy controls. The results show particular alterations in acylglycerols, PGs and LTs and phosphocholines and carnitine metabolites. The lipidomics profiles of PCOS indicate a higher risk of developing metabolic diseases.

Remarkable rutin-rich Hypericum capitatum extract exhibits anti-inflammatory effects on turpentine oil-induced inflammation in rats.

BACKGROUND: Natural extracts with beneficial biological activities are nowadays of high interest, in various treatment or prophylaxis. Hypericum capitatum has been known for its curative effects for centuries and its extracts have become of interest due to their distinct activity among other Hypericaceae members. In this study, further light is aimed to be shed on the secondary-metabolites composition of H. capitatum extracts, using chromatographic techniques and Electron paramagnetic resonance profiles in alkaline medium. Considering that no previous works explored the anti-inflammatory activity of H. capitatum, here, an in vivo study is also designed in order to evaluate this property by assessing the impact of one of H. capitatum extracts in ameliorating turpentine oil-induced inflammation on rats and to quantify their blood antioxidants level. METHODS: Chromatographic techniques and Electron paramagnetic resonance spectroscopy were used in order to describe the chemical profile in different parts of the plant. The in vivo study on turpentine-oil induced inflammation in rats included three doses of H. capitatum extract expressed in rutin concentration. Oxidative stress was measured using total oxidative status, total antioxidant capacity, oxidative stress index, 3-nitrotyrosine, nitric oxide, malondialdehyde, superoxide dismutase, catalase and the inflammatory response was evaluated by performing a complete blood cells count and C reactive protein. RESULTS: The extract was remarkably rich in rutin; however, other polyphenolic-like minor components appeared important in explaining the observed biological properties. The tested extract prevents the increase of inflammation-induced white blood cell count, number of neutrophils, and serum nitric oxide, and did so in a dose-dependent manner, similarly to the positive control-diclofenac. In addition, the same extract appeared to be a good alternative to diclofenac to restore total oxidative status, thiobarbituric active reactive species, total proteins and C reactive proteins. Moreover, antioxidant enzymes such as catalase, superoxide dismutase and total serum thiol concentration were significantly increased by the tested extract. CONCLUSIONS: Due to its powerful reservoir rich in rutin, H. capitatum extract depicted its in vivo antioxidant and anti-inflammatory effects indicating it to be a good alternative to conventional drugs for oxidative stress protection.

Plasma leptin, but not resistin, TNF-α and adiponectin, is associated with echocardiographic parameters of cardiac remodeling in patients with coronary artery disease.

The aim of this research was to assess the relationship between plasma adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-α) levels and echocardiographic parameters of ventricular remodeling in patients with coronary artery disease, without acute myocardial infarction. The study population consisted of 49 patients with echocardiographic measurements performed. After adjustment for age, gender, body mass index, systolic and diastolic blood pressure, and glycaemia, adiponectin was statistically significant associated with interventricular septum thickness (ß = -0.304), left ventricular posterior wall thickness (ß = -0.402), left ventricular end diastolic diameter (LVEDD; ß = 0.385) and left ventricular relative wall thickness (ß = -0.448, p < .05 for all). The associations were no longer significant when only patients without diabetes were included in the analysis. Leptin was associated with LVEDD (ß = -0.354) and left ventricular relative wall thickness (ß = 0.385, p < .05 for all). No associations between resistin, TNF-α and echocardiographic left ventricular parameters assessed were found in these patients. In conclusion, in patients with coronary artery disease and without acute myocardial infarction leptin may represent a potential mechanism of adverse cardiac remodeling. Resistin and TNF-α might not be involved in ventricular remodeling in these patients.

CpG islands recruit a histone H3 lysine 36 demethylase.

In higher eukaryotes, up to 70% of genes have high levels of nonmethylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over 20 years ago, but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, except that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36-specific lysine demethylase enzyme KDM2A. Nucleation of KDM2A at these elements results in removal of H3K36 methylation, creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that preferentially recognizes nonmethylated CpG DNA, and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.

Chemometric discrimination of different tomato cultivars based on their volatile fingerprint in relation to lycopene and total phenolics content.

INTRODUCTION: The characteristic flavour of tomato is given by a complex mixture of sugars, acids, amino acids, minerals and volatile metabolites. Of these, volatile compounds are considered to greatly influence the flavour of tomato fruits. The volatile aroma compounds and phytochemical content of tomatoes are dependent on genotype, environmental conditions and cultural practices, and can thus be used for cultivar discrimination. OBJECTIVE: To assess the possibility of using the volatile profile of tomato to fingerprint and discriminate different tomato cultivars based on an 'in-tube extraction' technique coupled to gas chromatography, combined with mass spectrometry (ITEX/GC-MS) and a chemometric approach. RESULTS: Using the ITEX/GC-MS technique, 61 volatiles were analysed and separated from tomato cultivars, with 58 being identified. The main volatiles identified in all tomato cultivars were: hexanal, trans-2-hexenal, 1-hexanol, 3-pentanone, 3-methylbutanol, 2-methylbutanol, 3-methylbutanal and 6-methyl-5-hepten-2-one. The lycopene content and total phenolic compound content of the tomato cultivars varied between 36.78 and 73.18 mg/kg fresh weight (fw) and from 119.4 to 253.7 mg of gallic acid equivalents (GAE) per kilogram fresh weight, respectively. Volatile fingerprint and phytochemical composition led to a good differentiation between tomato cultivars, with the first two principal components explaining 89% of the variance in the data. CONCLUSION: The tomato cultivars studied were easily discriminated based on their characteristic volatile profile that was obtained using the reliable ITEX/GC-MS technique. Principal component analysis revealed, in addition to volatile compounds, the important role played by the total phenolic content in tomato cultivar discrimination, which is highly correlated with phenotypic and biochemical differences between tomato cultivars.

Recent advances and insights into the bioactive properties and applications of Rosa canina L. and its by-products.

Rosa canina L., commonly known as rosehip, is of notable scientific interest for its applications in nutrition, cosmetics, and pharmaceuticals. This review article highlights its health-promoting properties, including antioxidant, anti-inflammatory, hepatoprotective, and anticarcinogenic effects, attributed to its rich content of phenolic acids, carotenoids, tocopherols, and vitamins. With growing interest in sustainable practices, rosehip by-products are increasingly valorized. For instance, cold-pressed rosehip seed oil is a valuable source of polyunsaturated fatty acids, while incorporating rosehip pomace into snacks enhances their nutritional profile, positioning them as potential functional foods and dietary supplements. This article aims to provide a comprehensive overview of advancements in utilizing rosehip and its by-products, emphasizing their role in enriching food and pharmaceutical products with nutritional and functional bioactivities.

Enhancing phenolic and lipid compound production in oat bran via acid pretreatment and solid-state fermentation with Aspergillus niger.

Oat (Avena sativa) processing generates a large amount of by-products, especially oat bran. These by-products are excellent sources of bioactive compounds such as polyphenols and essential fatty acids. Therefore, enhancing the extraction of these bioactive substances and incorporating them into the human diet is critical. This study investigates the effect of acid pretreatment on the solid-state fermentation of oat bran with Aspergillus niger, with an emphasis on the bioaccessibility of phenolic acids and lipid profile. The results showed a considerable increase in reducing sugars following acid pretreatment. On the sixth day, there was a notable increase in the total phenolic content, reaching 58.114 ± 0.09 mg GAE/g DW, and the vanillic acid level significantly rose to 77.419 ± 0.27 µg/g DW. The lipid profile study revealed changes ranging from 4.66 % in the control to 7.33 % on the sixth day of SSF. Aside from biochemical alterations, antioxidant activity measurement using the DPPH technique demonstrated the maximum scavenging activity on day 4 (83.33 %). This study highlights acid pretreatment's role in enhancing bioactive compound accessibility in solid-state fermentation and its importance for functional food development.

Targeting the sympathetic nervous system with the selective imidazoline receptor agonist moxonidine for the management of hypertension: an international position statement.

Hypertension is often linked with metabolic risk factors that share common pathophysiological pathways. Despite wide-spread availability of multiple drug classes, optimal blood pressure (BP) control remains challenging. Increased central sympathetic outflow is frequently neglected as a critical regulator of both circulatory and metabolic pathways and often remains unopposed therapeutically. Selective imidazoline receptor agonists (SIRAs) effectively reduce BP with a favorable side effect profile compared with older centrally acting antihypertensive drugs. Hard outcome data in hypertension, such as prevention of stroke, heart and kidney diseases, are not available with SIRAs. However, in direct comparisons, SIRAs were as effective as angiotensin-converting enzyme inhibitors, ß-blockers, calcium channel blockers, and diuretics in lowering BP. Other beneficial effects on metabolic parameters in hypertensive patients with concomitant overweight and obesity have been documented with SIRAs. Here we review the existing evidence on the safety and efficacy of moxonidine, a widely available SIRA, compared with common antihypertensive agents and provide a consensus position statement based on inputs from 12 experts from Europe and Australia on SIRAs in hypertension management.

Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Current strategies for the management of valuable compounds from hops waste for a circular economy.

World beer production generates large volumes of waste discharged with every brew. Recently, new methods of reducing and reusing hops waste: hot trub (HT), and brewer-spent hops (BSH) are being exploited to improve the circular economy processes. This review outlines the current achievements in the management of hops waste. Following an in-depth review of various scientific publications, current strategies are discussed as a sustainable alternative to food waste exploitation and an inexpensive source of valuable compounds. Moreover, key aspects concerning the nutritional value of hops waste and the potential to enhance the functional properties of food and beverages are highlighted. Due to their nutritional composition, hops residues may be used as prospective sources of added-value co-products or additives for food enrichment, especially for products rich in fat, or as a new source of vegetable protein.

Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

Coordination of genomic structure and transcription by the main bacterial nucleoid-associated protein HU.

The histone-like protein HU is a highly abundant DNA architectural protein that is involved in compacting the DNA of the bacterial nucleoid and in regulating the main DNA transactions, including gene transcription. However, the coordination of the genomic structure and function by HU is poorly understood. Here, we address this question by comparing transcript patterns and spatial distributions of RNA polymerase in Escherichia coli wild-type and hupA/B mutant cells. We demonstrate that, in mutant cells, upregulated genes are preferentially clustered in a large chromosomal domain comprising the ribosomal RNA operons organized on both sides of OriC. Furthermore, we show that, in parallel to this transcription asymmetry, mutant cells are also impaired in forming the transcription foci-spatially confined aggregations of RNA polymerase molecules transcribing strong ribosomal RNA operons. Our data thus implicate HU in coordinating the global genomic structure and function by regulating the spatial distribution of RNA polymerase in the nucleoid.

Integrated Technology for Cereal Bran Valorization: Perspectives for a Sustainable Industrial Approach.

Current research focuses on improving the bioaccessibility of functional components bound to cereal bran cell walls. The main bioactive components in cereal bran that have major biological activities include phenolic acids, biopeptides, dietary fiber, and novel carbohydrates. Because of the bound form in which these bioactive compounds exist in the bran matrix, their bioaccessibility is limited. This paper aims to comprehensively analyze the functionality of an integrated technology comprising pretreatment techniques applied to bran substrate followed by fermentation bioprocesses to improve the bioaccessibility and bioavailability of the functional components. The integrated technology of specific physical, chemical, and biological pretreatments coupled with fermentation strategies applied to cereal bran previously-pretreated substrate provide a theoretical basis for the high-value utilization of cereal bran and the development of related functional foods and drugs.

Protective Effects of Wine Polyphenols on Oxidative Stress and Hepatotoxicity Induced by Acrylamide in Rats.

In recent years, it has been increasingly suggested that the consumption of natural polyphenols, in moderate amounts, is beneficial for health. The aim of this study was to investigate the efficacy of a red wine (the administered dose of 7 mL/kg/day being equivalent to ~16.5 mg/kg/day total polyphenols) compared to a white wine (the administered dose of 7 mL/kg/day being equivalent to ~1.7 mg/kg/day total polyphenols), on the prevention of acrylamide-induced subacute hepatic injury and oxidative stress in Wistar rats. Hepatic damage due to acrylamide intoxication (the administered dose being 250 µg/kg body weight, for 28 days, by intragastric gavage) was assessed by employing biochemical parameters (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and by histopathological studies. Markers of oxidative damage were measured in terms of plasma malondialdehyde (MDA), hepatic Thiobarbituric Acid Reactive Substances (TBARS) and glutathione (GSH) levels, and liver antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) activities. Regarding hepatic enzyme activities, treatment with red wine significantly decreased the AST values (p < 0.05), while for the ALT values only a normalization tendency was observed. Treatment with red wine and white wine, respectively, significantly prevented the increase in MDA and TBARS levels (p < 0.05), as well as the depletion of GSH (p < 0.05). Red wine treatment normalized the activities of the antioxidant enzymes CAT and SOD in rats intoxicated with acrylamide, while supplementing the diet with white wine did not produce significant differences in the antioxidant enzyme activities. Histopathological findings revealed a moderate protective effect of red wine after four weeks of daily consumption. Our findings provide evidence that red wine, having a higher phenolic content than white wine, has a significant protective effect on oxidative stress and liver injury induced by acrylamide in rats, through its antioxidative activity.

Anthocyanins from Agro-Industrial Food Waste: Geographical Approach and Methods of Recovery-A Review.

Drastic growth in the amount of global food waste produced is observed every year, not only due to incessant population growth but also economic growth, lifestyle, and diet changes. As a result of their increasing health awareness, people are focusing more on healthy diets rich in fruits and vegetables. Thus, following worldwide fruit and vegetable consumption and their processing in various industries (juice, jams, wines, preserves), significant quantities of agro-industrial waste are produced (pomace, peels, seeds) that still contain high concentrations of bioactive compounds. Among bioactive compounds, anthocyanins have an important place, with their multiple beneficial effects on health; therefore, their extraction and recovery from food waste have become a topic of interest in recent years. Accordingly, this review aims to summarize the primary sources of anthocyanins from food waste and the novel eco-friendly extraction methods, such as pulsed electric field extraction, enzyme-assisted extraction, supercritical fluid extraction, pressurized liquid extraction, microwave-assisted extraction, and ultrasonic-assisted extraction. The advantages and disadvantages of these techniques will also be covered to encourage future studies and opportunities focusing on improving these extraction techniques.

Case Report: Acute Splenic Artery Thrombosis in a COVID 19, Postpartum Patient.

The incidence of thromboembolic disease is reported to be high in SARS-CoV2 disease. Pregnancy, an already physiologically hypercoagulable state, associated to COVID 19, generates even more concern regarding the potentially increased risk of thrombotic events. The exact incidence of such complications is yet unknown, but there is data suggesting that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Since the outbreak of the COVID 19 pandemics, the most common described thrombotic events associated with SARS-COV2 infection have been venous thromboembolism and disseminated intravascular coagulation, while arterial thrombotic events are less commonly described. Splenic infarction is a rare disorder that can be secondary to a hypercoagulable state. There are only few cases of splenic infraction described, but none with splenic artery thrombosis, in a post-partum patient, on therapeutic anticoagulation regimen. We present the case of a 31-year-old Caucasian, 26 weeks pregnant woman, with no prior medical history, admitted to the hospital with a severe form of COVID 19 pneumonia and who, during the course of the disease, developed a massive splenic infarction with splenic artery thrombosis.