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Background: Hyperlipidemia and related metabolic disorders are the main cause of nonalcoholic fatty liver diseases, atherosclerosis and cardiovascular complications. Loquat (Eriobotrya japonica) leaf infusion is an innovative formula derived from Traditional Chinese medicine, known for its therapeutic properties against a number of ailments including inflammation, diabetes and hyperlipidemia. Aim of the study: This study was designed to identify the active compounds of an aqueous extract of E. japonica leaves (ELE) and to investigate its effect on hyperlipidemia and related metabolic complications in high-fat high-sucrose diet-fed mice as well as to elucidate the possible underlying mechanisms. Materials and Methods: Mice were fed a high-fat high-sucrose diet for 3 months and treated with the ELE at doses of 50 mg/kg and 100 mg/kg. Lipids in plasma, liver, adipose tissue, bile and feces were quantified using enzymatic kits. Liver steatosis and oxidative status were highlighted by measuring AST, ALT, ALP, MDA, SOD and catalase activities as well as monitoring of lipid droplets in histological sections. The identification and quantification of possible active compounds were carried out using the HPLC-DAD method. The underlying mechanisms were predicted by in silico study and confirmed by quantifying the expression of the principal involved proteins including PCSK-9, CYP7A1 and p-AMPK in HepG2 cells. Results: The ELE restored lipid metabolism and improved liver histological structures. It also reduced oxidative stress by lowering MDA levels and activating SOD and catalase enzymes. The ELE prevented hepatic steatosis and corrected transaminases profile. HPLC analysis reveals seven phenolic compounds, with ferulic acid being the major one. The extract and its identified phenolic compounds upregulated the expression of CYP7A1 and p-AMPK while downregulated the expression of PCSK-9 in HepG2 cells. The ELE appears to be nontoxic in mice (LD50>5000 mg/kg) and in HepG2 cells at pharmacologically active doses. Conclusion: the ELE could be considered as a source of active biomolecules to produce phytotherapeutics drugs or dietary supplements to treat hyperlipidemia and related cardio-metabolic diseases.

Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is increasingly recognized that heart and brain health represent a lifetime of exposures to shared risk factors (including obesity, hyperlipidemia, diabetes, and hypertension) that compromise cerebrovascular health. We describe the process and resources for establishing a new research Center for Women’s Cardiovascular and Brain Health at the University of California, Davis as a model for: (1) use of the cy pres principle for funding science to improve health; (2) transdisciplinary collaboration to leapfrog progress in a convergence science approach that acknowledges and addresses social determinants of health; and (3) training the next generation of diverse researchers. This may serve as a blueprint for future Centers in academic health institutions, as the cy pres mechanism for funding research is a unique mechanism to leverage residual legal settlement funds to catalyze the pace of scientific discovery, maximize innovation, and promote health equity in addressing society’s most vexing health problems.

Black beans (BB) are an important source of a range of plant bioactive compounds including polyphenols, particularly anthocyanins. Several studies support that consumption of BB is associated with health benefits, including prevention of type 2 diabetes mellitus (T2DM). However, molecular mechanisms underlying the potential health properties of BB on adipose tissue (AT) are still largely unknown. The purpose of this study was to investigate multi-genomic effects of BB intake and identify regulatory networks potentially mediating T2DM on AT. Male Wistar diabetic rats consumed an anthocyanin-rich black bean extract for 5 weeks. Global gene expression from AT, protein coding and non-coding RNA profiles were determined using RNAseq. Biological function analyses were performed using a variety of bioinformatic tools. The evaluation of global gene expression profiles exhibited significant change following BB consumption with 406 significantly differentially expressed genes, 33 miRNA and 39 lncRNA and 3 snRNA. Functional analyses indicated that these genes play an important role in regulation of PI3K signaling, NIN/NF-kB signaling, insulin secretion, and endoplasmic reticulum (ER) organization. Interestingly, transcription factors such as GATA2, or POU2AF1 demonstrated to modulate their activity by BB extract by direct interaction with polyphenol metabolites, or by interactions with cell signaling proteins, like PKB, AKT or PI3K, that could control transcription factor activity and as a result impact on adipogenesis regulation. Therefore, the constant consumption of an anthocyanin-rich black bean extract may have anti-diabetic protective effects by modulating gene expression, resulting in a promising alternative for T2DM patients.

Type 2 diabetes mellitus (T2DM) leads to the development of cardiovascular diseases, cognitive impairment, and dementia. There are sex differences in the presentation of T2DM and its associated complications. We sought to determine the impact of sex and T2DM on the brain metabolome to gain insights into the underlying mechanisms of T2DM-associated cognitive complications. Untargeted metabolomic analysis was performed, using liquid chromatography-mass spectrometry, on whole brain tissue from adult male and female db/db mice (a T2DM model) compared to wild-type (WT) C57Bl6/J mice. Regardless of sex, T2DM increased free fatty acids and decreased acylcarnitines in the brain. Sex impacted the number (103 versus 65 in males and females, respectively), and types of metabolites shifted by T2DM. Many choline-containing phospholipids were decreased by T2DM in males. Female-specific T2DM effects included changes in neuromodulatory metabolites (γ-aminobutyric acid, 2-linoleoyl glycerol, N-methylaspartic acid, and taurine). Further, there were more significantly different metabolites between sexes in the T2DM condition as compared to the WT controls (54 vs. 15 in T2DM and WT, respectively). T2DM alters the murine brain metabolome in both sex-independent and sex-dependent manners. This work extends our understanding of brain metabolic sex differences in T2DM, cognitive implications, and potential sex-specific metabolic therapeutic targets.

Grapefruit is a rich source of flavanones, phytochemicals suggested excreting vasculoprotective effects. We previously showed that flavanones in grapefruit juice (GFJ) reduced postmenopausal women’s pulse-wave velocity (PWV), a measure of arterial stiffness. However, mechanisms of flavanone action in humans are largely unknown. This study aimed to decipher molecular mechanisms of flavanones by multi-omics analysis in PBMCs of volunteers consuming GFJ and flavanone-free control drink for 6 months. Modulated genes and microRNAs (miRNAs) were identified using microarrays. Bioinformatics analyses assessed their functions, interactions and correlations with previously observed changes in PWV. GFJ modified gene and miRNA expressions. Integrated analysis of modulated genes and miRNA-target genes suggests regulation of inflammation, immune response, cell interaction and mobility. Bioinformatics identified putative mediators of the observed nutrigenomic effect (STAT3, NF-κB) and molecular docking demonstrated potential binding of flavanone metabolites to transcription factors and cell-signaling proteins. We also observed 34 significant correlations between changes in gene expression and PWV. Moreover, global gene expression was negatively correlated with gene expression profiles in arterial stiffness and hypertension. This study revealed molecular mechanisms underlying vasculoprotective effects of flavanones, including interactions with transcription factors and gene and miRNA expression changes that inversely correlate with gene expression profiles associated with cardiovascular risk factors.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT01272167].

Introduction Although epidemiological studies associate the consumption of sugary beverages with adverse health effects, human experimental studies have demonstrated substantially different metabolic responses when 100% fruit juices are compared with artificial beverages. Fruit juices do not just provide sugars and associated calories, but they are also rich in bioactive compounds. Flavanones are bioactives specifically and abundantly found in citrus foods, with hesperidin as the major representative in sweet oranges. Flavanone intake has been associated with a lower incidence of mortality from cardiovascular disease (CVD). However, clinical evidence are too scarce to confirm the vasculoprotective effects of 100% orange juice (OJ) presumably mediated by flavanones and thereby do not allow firm conclusions to be drawn about their efficacy.Methods and analysis The HESPER-HEALTH study aims to assess the efficacy of OJ in improving vascular function and the contribution of hesperidin to these effects. This double-blind, randomised, controlled, crossover study will be carried out in 42 volunteers predisposed to CVD, based on age and on overweight. It includes three 6-week periods of consumption of 330 mL/d of OJ versus control drinks with and without hesperidin at a dose in agreement with a daily OJ serving (approx. 200–215 mg). The primary outcome is endothelial function, assessed by flow mediated dilation, with measurements performed at fasting and postprandially in response to a challenge meal. The secondary outcomes include bioavailability and metabolism of flavanones, changes in other markers of vascular function, systemic biomarkers of cardiovascular risk, endothelial dysfunction and inflammation, vitamin C and carotenoids status, anthropometry and body composition, gut microbiota composition, nutrigenomic response and in oxylipin profiling.Ethics and dissemination This ongoing study was approved by the Ethics committee Sud-Est III, Bron, France on 17 November 2020. The trial is registered on ClinicalTrials.gov. The results will be disseminated in peer-reviewed journals.Trial registration number NCT04731987; Pre-results.

Dietary anthocyanins may slow cognitive decline, improve cognitive performance and exert neuroprotective effects against neurodegenerative disorders. However, the underlying mechanisms of their action are not fully understood. This study investigated the effects of 12-week anthocyanin-rich bilberry extract supplementation (0.02%) on global gene expression in the hippocampus of ApoE-/- mice to help the understanding of molecular mechanisms underlying anthocyanin neuroprotective effects. Gene expression analysis identified 1698 differently expressed genes, with 611 downregulated and 1087 upregulated genes. Bioinformatics revealed that these genes regulate different biological processes, including neurogenesis, inflammation, metabolism, cell to cell adhesion, cytoskeleton organization, and Alzheimer's and Parkinson's disease pathology. The bioinformatic analysis also proposed potential miRNAs and transcription factors that could be involved in the mediation of these nutrigenomic effects. Results from molecular docking also suggested that anthocyanins could bind to top transcription factors with, as potential consequence, an impact on their gene expression regulation. Taken together, integrated analysis revealed a multi-target mode of action of anthocyanin-rich bilberry extract in the hippocampus underlying their neuroprotective properties.

Cerebral blood vessels are lined with endothelial cells and form the blood-brain barrier. Their dysfunction constitutes a crucial event in the physiopathology of neurodegenerative disorders and cognitive impairment. Epicatechin can improve cognitive functions and lower the risk for Alzheimer’s disease or stroke. However, molecular mechanisms of epicatechin on brain vascular endothelium are still unexplored. The objective of this study was to investigate the biological effects of gut microbiome-derived metabolites of epicatechin, 5-(4′-Hydroxyphenyl)-γ-valerolactone-3′-sulfate and 5-(4′-Hydroxyphenyl)-γ-valerolactone-3′-O-glucuronide, in TNF-α-stimulated human brain microvascular endothelial cells at low (nM) concentrations by evaluating their multi-omic modification (expression of mRNA, microRNA, long non-coding RNAs, and proteins). We observed that metabolites are biologically active and can simultaneously modulate the expression of protein-coding and non-coding genes as well as proteins. Integrative bioinformatics analysis of obtained data revealed complex networks of genomics modifications by acting at different levels of regulation. Metabolites modulate cellular pathways including cell adhesion, cytoskeleton organization, focal adhesion, signaling pathways, pathways regulating endothelial permeability, and interaction with immune cells. This study demonstrates multimodal mechanisms of action by which epicatechin metabolites could preserve brain vascular endothelial cell integrity, presenting mechanisms of action underlying epicatechin neuroprotective properties.

In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation.Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found.Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans.

BackgroundPolyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee or wine. Epidemiological, clinical and animal studies support a role of polyphenols in the prevention of various diseases, such as cardiovascular diseases, cancers or neurodegenerative diseases. Recent findings suggest that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. However, the impact of polyphenol on the expression of microRNA, small non-coding RNAs, has not yet been studied. The aim of this study was to investigate the impact of dietary supplementation with polyphenols at nutritional doses on miRNA expression in the livers of apolipoprotein E-deficient mice (apoE⁻/⁻) jointly with mRNA expression profiling.Methodology/principal findingsUsing microarrays, we measured the global miRNA expression in the livers of wild-type (C57B6/J) mice or apoE⁻/⁻ mice fed diets supplemented with one of nine different polyphenols or a control diet. This analysis revealed that knock-out of the apoE gene induced significant modulation in the expression of miRNA. Moreover, changes in miRNA expression were observed after polyphenol supplementation, and five miRNAs (mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1*, mmu-miR-467b* and mmu-miR-374*) were identified as being commonly modulated by these polyphenols. We also observed that these polyphenols counteracted the modulation of miRNA expression induced by apoE mutation. Pathway analyses on these five miRNA-target genes revealed common pathways, some of which were also identified from a pathway analysis on mRNA profiles.ConclusionThis in vivo study demonstrated for the first time that polyphenols at nutritional doses modulate the expression of miRNA in the liver. Even if structurally different, all polyphenols induced a similar miRNA expression profile. Common pathways were identified from both miRNA-target and mRNA analysis, revealing cellular functions that could be regulated by polyphenols at both the miRNA and mRNA level.

We previously showed, in healthy, middle-aged, moderately overweight men, that orange juice decreases diastolic blood pressure and significantly improves postprandial microvascular endothelial reactivity and that hesperidin could be causally linked to the observed beneficial effect of orange juice. The objective was to determine the effect of chronic consumption of orange juice on the gene expression profile of leukocytes in healthy volunteers and to assess to what extent hesperidin is involved in the effect of orange juice.Volunteers were included in a randomized, controlled, crossover study. Throughout three 4-week periods, volunteers consumed daily: 500 ml orange juice, 500 ml control drink plus hesperidin or 500 ml control drink and placebo. Blood samplings were performed on 10 overnight-fasted subjects after the 4-week treatment period. Global gene expression profiles were determined using human whole genome cDNA microarrays. Both orange juice and hesperidin consumption significantly affected leukocyte gene expression. Orange juice consumption induced changes in expression of, 3,422 genes, while hesperidin intake modulated the expression of 1,819 genes. Between the orange juice and hesperidin consumption groups, 1,582 regulated genes were in common. Many of these genes are implicated in chemotaxis, adhesion, infiltration and lipid transport, which is suggestive of lower recruitment and infiltration of circulating cells to vascular wall and lower lipid accumulation.This study shows that regular consumption of orange juice for 4 weeks alters leukocyte gene expression to an anti-inflammatory and anti-atherogenic profile, and hesperidin displays a relevant role in the genomic effect of this beverage.ClinicalTrials.gov NCT 00983086.

Practical aspects of Lagenaria vulgaris shell conversion to activated carbon were examined along with its use in ranitidine adsorption. Kinetics and isotherms of adsorption onto Lagenaria vulgaris carbon (LVC) were correlated to several theoretical adsorption models. The best fit was found in the case of Langmuir and pseudo-second-order model indicating monolayer adsorption. The influence of pH under kinetic study showed slightly hindered adsorption below pH 4. The optimal adsorbent dosage was set to 1 g/L. LVC was characterized by several complementary techniques, including wet chemical techniques such as Boehm’s titrations and determination of pHPZC and pH of LVC, which revealed neutral nature of the adsorbent. N2 sorptometry determined specific surface area of 665 m2/g and significant ratio of micropores in the sample with maximum wall’s diameter of 2.2 nm. Fourier transform infrared spectroscopy (FTIR) confirmed the role of lignin and cellulose in the formation of the final LVC structure. Porous structure of the material was proved by using scanning electron microscopy. Preparation of LVC material drew attention as an easy and low-cost process for production of a highly efficient adsorbent which exhibited fast kinetics of ranitidine removal in the first minutes of contacting and large adsorption capacity (315.5 mg/g) at equilibrium.

The possibility of using low-nutrient R2A medium for determining the total count of aerobic mesophilic bacteria was investigated. Sampling of water from particular points of water treatment and distribution at Kruševac drinking water treatment plant was conducted. The samples were inoculated simultaneously on Plate Count Agar (PCA) and R2A media, and incubated at 37 °C and at room temperature. The bacterial count was determined after 48, 72, 120 and 168 h. The statistical analysis of the results showed significantly higher bacterial count on R2A medium compared to PCA. Moreover, a significantly higher bacterial count developed at room temperature compared to the temperature of 37 C. R2A medium recorded 3.6% of unsafe samples in the distribution system after the 7-day incubation at room temperature. On the basis of the ob¬tained results, an optimum method for determining the total count of aerobic mesophilic bacteria for all investigated waters has been defined. The process of incubation is predictable and it can be described by a mathematical model in the form of a polynomial of the second or the third power.

A two-step optimized laboratory synthetic method of zinc dialkyldithiocarbamates is presented. In the course of the first phase, a sodium salt of dialkyldithiocarbamic acid has been synthesized from the dialkylamines, carbon disulfide and sodium hydroxide. The synthesis of zinc dialkyldithiocarbamates was achieved by the precipitation from sodium dialkyldithiocarbamic acid by zinc sulfate under the optimized conditions. The synthesized products have been characterized by FTIR, 1H and 13C NMR, AAS spectroscopic methods, as well as by elemental analysis and melting points. Kinetic studies of the motor oil oxidation inhibited by synthesized compounds have been tested using a standard method.