Nutriepigenetics and cardiovascular disease

Purpose of review: We present a current perspective of epigenetic alterations that can lead to cardiovascular disease (CVD) and the potential of dietary factors to counteract their actions. In addition, we discuss the challenges and opportunities of dietary treatments as epigenetic modifiers for disease prevention and therapy. Recent findings: Recent epigenome-wide association studies along with candidate gene approaches and functional studies in cell culture and animal models have delineated mechanisms through which nutrients, food compounds and dietary patterns may affect the epigenome. Several risk factors for CVD, including adiposity, inflammation and oxidative stress, have been associated with changes in histone acetylation, lower global DNA methylation levels and shorter telomere length. A surplus of macronutrients such as in a high-fat diet or deficiencies of specific nutrients such as folate and other B-vitamins can affect the activity of DNA methyltransferases and histone-modifying enzymes, affecting foetal growth, glucose/lipid metabolism, oxidative stress, inflammation and atherosclerosis. Bioactive compounds such as polyphenols (resveratrol, curcumin) or epigallocatechin may activate deacetylases Sirtuins (SIRTs), histone deacetylases or acetyltransferases and in turn the response of inflammatory mediators. Adherence to cardioprotective dietary patterns, such as the Mediterranean diet (MedDiet), has been associated with altered methylation and expression of genes related to inflammation and immuno-competence. Summary: The mechanisms through which nutrients and dietary patterns may alter the cardiovascular epigenome remain elusive. The research challenge is to determine which of these nutriepigenetic effects are rev

The Interplay between Housing Environmental Attributes and Design Exposures and Psychoneuroimmunology Profile-An Exploratory Review and Analysis Paper in the Cancer Survivors' Mental Health Morbidity Context

Adult cancer survivors have an increased prevalence of mental health comorbidities and other adverse late-effects interdependent with mental illness outcomes compared with the general population. Coronavirus Disease 2019 (COVID-19) heralds an era of renewed call for actions to identify sustainable modalities to facilitate the constructs of cancer survivorship care and health care delivery through physiological supportive domestic spaces. Building on the concept of therapeutic architecture, psychoneuroimmunology (PNI) indicators—with the central role in low-grade systemic inflammation—are associated with major psychiatric disorders and late effects of post-cancer treatment. Immune disturbances might mediate the effects of environmental determinants on behaviour and mental disorders. Whilst attention is paid to the non-objective measurements for examining the home environmental domains and mental health outcomes, little is gathered about the multidimensional effects on physiological responses. This exploratory review presents a first analysis of how addressing the PNI outcomes serves as a catalyst for therapeutic housing research. We argue the crucial component of housing in supporting the sustainable primary care and public health-based cancer survivorship care model, particularly in the psychopathology context. Ultimately, we illustrate a series of interventions aiming at how housing environmental attributes can trigger PNI profile changes and discuss the potential implications in the non-pharmacological treatment of cancer survivors and patients with mental morbidities

Cannabinoid interventions for improving cachexia outcomes in cancer: a systematic review and meta-analysis

Cancer-associated cachexia (CAC) is a wasting syndrome characterized by involuntary weight loss and anorexia. Clear definition and diagnostic criteria for CAC are lacking, which makes it difficult to estimate its prevalence, to interpret research and to compare studies. There is no standard treatment to manage CAC, but previous studies support the use of cannabinoids for cachexia in other chronic diseases including HIV and multiple sclerosis. However, only a few randomized controlled trials (RCTs) and one meta-analysis of this intervention in cancer populations are available. Non-randomized studies of interventions (NRSIs) are often excluded from reviews due to variable methodology and potential for biases. This review aimed to consider NRSIs alongside RCTs to provide a complete summary of the available evidence that clinical decision makers could use in future investigations. Literature searches were conducted using three databases for relevant RCTs or NRSIs according to Cochrane methodology. Abstract and full texts of retrieved manuscripts were selected and retrieved by two investigators based on the PRISMA-A guidelines, and risk of bias and quality of evidence assessments were performed. Outcome data on weight, appetite, quality of life, performance status, adverse effects, and mortality were combined by narrative synthesis and meta-analysis where possible. Ten studies were included, four of which were RCTs and six NRSIs matching the eligibility criteria. Very low-quality evidence from meta-analysis suggested no significant benefits of cannabinoids for appetite compared with control (standardized mean difference: -0.02; 95% confidence interval: -0.51, 0.46; P = 0.93). Patient-reported observations from NRSIs suggested improvements in appetite. Another meta-analysis of moderate quality evidence showed that cannabinoids were significantly less efficient than active or inactive control on quality of life (standardized mean difference: -0.25; 95% confidence interval: -0.43, -0.07; P = 0.007). The effectiveness of cannabinoids alone to improve outcomes of CAC remains unclear. Low-quality evidence from both RCTs and NRSIs shows no significant benefits of cannabinoids for weight gain, appetite stimulation, and better quality of life, three important outcomes of cachexia. Higher quality research integrating cannabinoids into multi-modal therapies may offer better opportunities for developing CAC-specific treatments. This review also highlights that findings from non-randomized studies of interventions (NRSIs) can provide evidence of the effects of an intervention and advocate for the feasibility of larger RCTs

Comparison of environmental impacts of individual meals - Does it really make a difference to choose plant-based meals instead of meat-based ones?

More than one third of global greenhouse gas emissions (GHG) can be attributed to our food system. Limiting global warming to 1.5° or 2 °C will not be possible without reducing GHG emissions from the food system. Dietary change at the meal level is of great importance as day-to-day consumption patterns drive the global food production system. The aim of this paper was to assess the life cycle environmental impact of a sample of meals from different cuisines (chilli, lasagne, curry and teriyaki meals) and their meat-based, vegetarian, vegan, and whole-food vegan recipe variations. The environmental impacts (global warming, freshwater eutrophication, terrestrial acidification and water depletion potential) of 13 meals, made with 33 different ingredients, were estimated from cradle to plate using Life Cycle Assessment (LCA). Results showed that irrespective of the type of cuisine, the plant-based version of meals (vegan and whole-food vegan) had substantially lower environmental impacts across all impact categories than their vegetarian and meat-based versions. On average, meat-based meals had 14 times higher environmental impact, while vegetarian meals had 3 times higher environmental impact than vegan meals. Substantial reductions in the environmental impacts of meals can be achieved when animal-based ingredients (e.g., beef, cheese, pork, chicken) are replaced with whole or minimally processed plant-based ingredients (i.e., vegetables, legumes) in recipes. Swapping animal-based meals for plant-based versions, and preferably transitioning to plant-based diets, present important opportunities for mitigating climate change and safeguarding environmental sustainability

Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD

BACKGROUND: The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. METHODS: The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. RESULTS: The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. CONCLUSION: Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk

Demonstration of the Presence of the "Deleted" MIR122 Gene in HepG2 Cells

MicroRNA 122 (miR-122) is highly expressed in the liver where it influences diverse biological processes and pathways, including hepatitis C virus replication and metabolism of iron and cholesterol. It is processed from a long non-coding primary transcript (~7.5 kb) and the gene has two evolutionarily-conserved regions containing the pri-mir-122 promoter and pre-mir-122 hairpin region. Several groups reported that the widely-used hepatocytic cell line HepG2 had deficient expression of miR-122, previously ascribed to deletion of the pre-mir-122 stem-loop region. We aimed to characterise this deletion by direct sequencing of 6078 bp containing the pri-mir-122 promoter and pre-mir-122 stem-loop region in HepG2 and Huh-7, a control hepatocytic cell line reported to express miR-122, supported by sequence analysis of cloned genomic DNA. In contrast to previous findings, the entire sequence was present in both cell lines. Ten SNPs were heterozygous in HepG2 indicating that DNA was present in two copies. Three validation isolates of HepG2 were sequenced, showing identical genotype to the original in two, whereas the third was different. Investigation of promoter chromatin status by FAIRE showed that Huh-7 cells had 6.2 ± 0.19- and 2.7 ± 0.01- fold more accessible chromatin at the proximal (HNF4α-binding) and distal DR1 transcription factor sites, compared to HepG2 cells (p=0.03 and 0.001, respectively). This was substantiated by ENCODE genome annotations, which showed a DNAse I hypersensitive site in the pri-mir-122 promoter in Huh-7 that was absent in HepG2 cells. While the origin of the reported deletion is unclear, cell lines should be obtained from a reputable source and used at low passage number to avoid discrepant results. Deficiency of miR-122 expression in HepG2 cells may be related to a relative deficiency of accessible promoter chromatin in HepG2 versus Huh-7 cells

Plant-based dietary changes may improve symptoms in patients with systemic lupus erythematosus

INTRODUCTION: Previous studies have reported that patients affected by systemic lupus erythematosus (SLE) are interested in using diet to treat fatigue, cardiovascular disease and other symptoms. However, to date, there is insufficient information regarding the ways for patients to modify their diet to improve SLE symptoms. We investigated the relationship between the eating patterns of SLE patients and their self-reported disease symptoms and general aspects of health. METHODS: A UK-based, online survey was developed, in which patients with SLE were asked about their attitudes and experiences regarding their SLE symptoms and diet. RESULTS: The majority (>80%) of respondents that undertook new eating patterns with increased vegetable intake and/or decreased intake of processed food, sugar, gluten, dairy and carbohydrates reported benefiting from their dietary change. Symptom severity ratings after these dietary changes were significantly lower than before (21.3% decrease, p<0.0001). The greatest decreases in symptom severity were provided by low/no dairy (27.1% decrease), low/no processed foods (26.6% decrease) and vegan (26% decrease) eating patterns (p<0.0001). Weight loss, fatigue, joint/muscle pain and mood were the most cited symptoms that improved with dietary change. CONCLUSION: SLE patients who changed their eating patterns to incorporate more plant-based foods while limiting processed foods and animal products reported improvements in their disease symptoms. Thus, our findings show promises in using nutrition interventions for the management of SLE symptoms, setting the scene for future clinical trials in this area. Randomised studies are needed to further test whether certain dietary changes are effective for improving specific symptoms of SLE

Negative impact of the first COVID-19 lockdown upon health-related behaviours and psychological wellbeing in people living with severe and complex obesity in the UK

BACKGROUND: Coronavirus disease 2019 (COVID-19) has led to unprecedented changes in the way we live, particularly for people at higher risk of severe illness from COVID-19. People with pre-existing health conditions have been markedly impacted and, in some instances, left unsupported due to reduced provision of routine healthcare services. People living with obesity (PLWO) are identified as at higher risk of severe illness from COVID-19 infection. Currently, there is a paucity of evidence about the impact of the first COVID-19 lockdown on PLWO, including those accessing weight management and bariatric surgery services (WMS). METHODS: 543 adults (16–80 years) with obesity (BMI ≥ 30 kg/m2) were recruited between 14th May and 9th July 2020 through social media advertisements, professional and patient obesity organisations and WMS. Participants completed an online survey regarding the impact of the first COVID-19 lockdown upon, mental health, well-being, health-related behaviours, risk mitigating behaviours, access to WMS and weight stigma. FINDINGS: During the first COVID-19 lockdown, the majority of PLWO reported deterioration of their mental health and health-related behaviours such as diet, physical activity (PA) and sleep. With 55% reporting an unhealthier diet, 61% reduced PA and 80% worsening of their sleep. Higher depression and lower wellbeing scores were found to associate with the greatest adverse impact upon health-related behaviours. PLWO who were attending WMS prior to the first lockdown reported a greater deterioration of their diet, with nearly 50% reporting worsening of their diet and PA worsening compared to PLWO who were not attending WMS. Most participants took two or more risk mitigating actions (73%). PLWO attending WMS reported reduced access (44%) with insufficient information (49%) from their clinical service providers. The majority of participants reported no change in perceived weight stigma. INTERPRETATION: This study shows the detrimental impact of the first COVID-19 lockdown on PLWO in relation to health-related behaviours, mental health and access to WMS. Our findings show that PLWO with poor mental health and those attending WMS were most adversely impacted and highlights the need for greater mental health support and continued provision of support from WMS for PLWO during future lockdowns. FUNDING: This research was funded through National Institute for Health Research University College London Hospitals Biomedical Research Centre funding

Expanding the horizons of microRNA bioinformatics

MicroRNA regulation of key biological and developmental pathways is a rapidly expanding area of research, accompanied by vast amounts of experimental data. This data, however, is not widely available in bioinformatic resources, making it difficult for researchers to find and analyse microRNA-related experimental data and define further research projects. We are addressing this problem by providing two new bioinformatics datasets that contain experimentally verified functional information for mammalian microRNAs involved in cardiovascular-relevant, and other, processes. To date, our resource provides over 3,900 Gene Ontology annotations associated with almost 500 miRNAs from human, mouse and rat and over 2,200 experimentally validated miRNA:target interactions. We illustrate how this resource can be used to create miRNA-focused interaction networks with a biological context using the known biological role of miRNAs and the mRNAs they regulate, enabling discovery of associations between gene products, biological pathways and, ultimately, diseases. This data will be crucial in advancing the field of microRNA bioinformatics and will establish consistent datasets for reproducible functional analysis of microRNAs across all biological research areas

Apelinergic system in the kidney: implications for diabetic kidney disease

The bioactive peptides of the apelinergic system and its receptor APJ have been shown to play a protective role in experimental cardiovascular and diabetic kidney disease (DKD). Mechanisms of this renoprotective effect remain to be elucidated. In this study, we examined the localization of APJ within the normal kidney and its kidney expression in the db/db model of DKD. The effect of hyperglycemia and angiotensin II on APJ was examined in cultured podocytes. In the glomerulus, APJ colocalized with podocyte but not endothelial cell markers. In podocytes stimulated with Pyr1 Apelin-13, a change in the phosphorylation status of the signaling proteins, AKT, ERK, and p70S6K, was observed with an increase 15 min after stimulation. Apelin-13 decreased activity of Caspase-3 in podocytes after high glucose treatment reflecting an antiapoptotic effect of APJ stimulation. In podocytes, APJ mRNA was downregulated in high glucose, when compared to normal glucose conditions and exposure to angiotensin II led to a further significant decrease in APJ mRNA. APJ and preproapelin mRNA levels in kidneys from db/db mice were markedly decreased along with decreased tubular APJ protein by western blotting and immunostaining when compared to db/m controls. In conclusion, the apelinergic system is decreased in kidneys from db/db mice. Within the glomerulus, APJ is mainly localized in podocytes and in this cell type its activation by Apelin-13 abolishes the proapoptotic effect of high glucose, suggesting a potential therapeutic role of apelin and emerging agonists with extended half-life for therapy of DKD