Associations among diabetes medication use, serum magnesium, and insulin resistance in a cohort of older Puerto Rican adults.

BACKGROUND: Hypomagnesemia is commonly observed in individuals with diabetes, but how diabetes medications alter magnesium (Mg) status remains unclear. OBJECTIVES: We aimed to examine the association between diabetes medication and hypomagnesemia and evaluate whether serum Mg mediates the association between diabetes medication and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) in a prospective cohort. METHODS: Adults from the Boston Puerto Rican Health Study were included (n = 1106). Multivariable logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for cross-sectional association between diabetes medication and hypomagnesemia (serum Mg <0.75 mmol/L). Longitudinal mediation analysis was performed to evaluate the direct and indirect (via serum Mg) associations between diabetes medication and 4-y HOMA-IR in 341 participants with baseline hemoglobin A1c (HbA1c) of ≥6.5%. RESULTS: Mean age at baseline was 59.0 ± 7.6 y, with 28.0% male and 45.8% with hypomagnesemia. Use of metformin [OR (95% CI) = 3.72 (2.53, 5.48)], sulfonylureas [OR (95% CI) = 1.68 (1.00, 2.83)], and glitazones [OR (95% CI) = 2.09 (1.10, 3.95)], but not insulin, was associated with higher odds of hypomagnesemia. Use of multiple diabetes medications and longer duration of use were associated with higher odds of hypomagnesemia. Serum Mg partially mediated the association between metformin and HOMA-IR [indirect association: ß (95% CI) = 1.11 (0.15, 2.07)], which weakened the direct association [ß (95% CI) = -5.16 (-9.02, -1.30)] by 22% [total association: ß (95% CI) = -4.05 (-7.59, -0.51)]. Similarly, serum Mg mediated 17% of the association between sulfonylureas and elevated HOMA-IR. However, the mediation by serum Mg was weak for insulin and glitazones. CONCLUSIONS: Diabetes medication, especially metformin, was associated with elevated odds of hypomagnesemia, which may weaken the association between metformin and lowering of HOMA-IR. The causal inference needs to be confirmed in further studies.

Fish and Omega-3 Fatty Acids: Sex and Racial Differences in Cardiovascular Outcomes and Cognitive Function.

Both cardiovascular disease (CVD) and cognitive decline are common features of aging. One in 5 deaths is cardiac for both men and women in the United States, and an estimated 50 million are currently living with dementia worldwide. In this review, we summarize sex and racial differences in the role of fish and its very long chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in preventing CVD events and cognitive decline. In prospective studies, women with higher nonfried and fatty fish intake and women and Black individuals with higher plasma levels of EPA and DHA had a lower risk of CVD. In randomized controlled trials of EPA and DHA supplementation in primary CVD prevention, Black subjects benefited in a secondary outcome. In secondary CVD prevention, both men and women benefited, and Asians benefited as a prespecified subgroup. Fish and omega-3 polyunsaturated fatty acids are associated with prevention of cognitive decline in prospective studies. In randomized controlled trials of EPA and DHA supplementation, women have cognitive benefit. DHA seems more beneficial than EPA, and supplementation is more beneficial when started before cognitive decline. Although studies in women and racial groups are limited, life-long intake of nonfried and fatty fish lowers the risk of CVD and cognitive decline, and randomized controlled trials also show the benefit of EPA and DHA supplementation. These findings should be factored into recommendations for future research and clinical recommendations as dietary modalities could be cost-effective for disease prevention.

Corrigendum: APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts.

[This corrects the article DOI: 10.3389/fnagi.2023.1285333.].

APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts.

Background: Apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD), and the ε4 allele (APOE4) may interact with lifestyle factors that relate to brain structural changes, underlying the increased risk of AD. However, the exact role of APOE4 in mediating interactions between the peripheral circulatory system and the central nervous system, and how it may link to brain and cognitive aging requires further elucidation. In this analysis, we investigated the association between APOE4 carrier status and multimodal biomarkers (diet, blood markers, clinical diagnosis, brain structure, and cognition) in the context of gene-environment interactions. Methods: Participants were older adults from a longitudinal observational study, the Boston Puerto Rican Health Study (BPRHS), who self-identified as of Puerto Rican descent. Demographics, APOE genotype, diet, blood, and clinical data were collected at baseline and at approximately 12th year, with the addition of multimodal brain magnetic resonance imaging (MRI) (T1-weighted and diffusion) and cognitive testing acquired at 12-year. Measures were compared between APOE4 carriers and non-carriers, and associations between multimodal variables were examined using correlation and multivariate network analyses within each group. Results: A total of 156 BPRHS participants (mean age at imaging = 68 years, 77% female, mean follow-up 12.7 years) with complete multimodal data were included in the current analysis. APOE4 carriers (n = 43) showed reduced medial temporal lobe (MTL) white matter (WM) microstructural integrity and lower mini-mental state examination (MMSE) score than non-carriers (n = 113). This pattern was consistent with an independent sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) of n = 283 non-Hispanic White adults without dementia (mean age = 75, 40% female). Within BPRHS, carriers showed distinct connectivity patterns between multimodal biomarkers, characterized by stronger direct network connections between baseline diet/blood markers with 12-year blood/clinical measures, and between blood markers (especially lipids and cytokines) and WM. Cardiovascular burden (i.e., hypertension and diabetes status) was associated with WM integrity for both carriers and non-carriers. Conclusion: APOE4 carrier status affects interactions between dietary factors, multimodal blood biomarkers, and MTL WM integrity across ~12 years of follow-up, which may reflect increased peripheral-central systems crosstalk following blood-brain barrier breakdown in carriers.

Sex, Racial, and Ethnic Disparities in Acute Coronary Syndrome: Novel Risk Factors and Recommendations for Earlier Diagnosis to Improve Outcomes.

In this review, sex, racial, and ethnic differences in acute coronary syndromes on a global scale are summarized. The relationship between disparities in presentation and management of acute coronary syndromes and effect on worse clinical outcomes in acute coronary syndromes are discussed. The effect of demographic, geographic, racial, and ethnic factors on acute coronary syndrome care disparities are reviewed. Differences in risk factors including systemic inflammatory disorders and pregnancy-related factors and the pathophysiology underlying them are discussed. Finally, breast arterial calcification and coronary calcium scoring are discussed as methods to detect subclinical atherosclerosis and start early treatment in an attempt to prevent clinical disease.

Dietary Oxidized Linoleic Acids Modulate Fatty Acids in Mice.

Objective: An elevated concentration of oxidized lipids along with the abnormal accumulation of lipids has been linked to the formation of atheromatous plaque and the development of cardiovascular diseases. This study aims to investigate if consumption of different concentrations of dietary oxidized linoleic acid alters the distribution of long chain fatty acids (LCFAs) within the liver relative to plasma in mice. Methods: C57BL/6 male mice (n = 40) were divided into 4 groups: Standard chow as plain control (P group, n =10), Chow supplemented with linoleic acid 9 mg/mouse/day, linoleic control (C group, n=0), oxidized linoleic acid; 9 mg/mouse/day (A group, n=10) and oxidized linoleic acid 18 mg/mouse/day diet (B group, n=10). Liver and plasma samples were extracted, trans-esterified and subsequently analyzed using gas chromatography mass spectrometry (GC-MS) for LCFAs; palmitic acid, stearic acid, oleic acid, linoleic acid and arachidonic acid. Results: LCFA methyl esters were eluted and identified based on their respective physiochemical characteristics of GCMS assay with inter assay coefficient of variation percentage (CV%, 1.81-5.28%), limits of quantification and limit of detection values (2.021-11.402 mg/mL and 1.016-4.430 mg/mL) respectively. Correlation analysis of liver and plasma lipids of the mice groups yielded coefficients (r=0.96, 0.6, 0.8 and 0.33) with fatty acid percentage total of (16%, 10%, 16% and 58%) for the P, C, A and B groups respectively. Conclusion: The sustained consumption of a diet rich in oxidized linoleic acid disrupted fatty acid metabolism. The intake also resulted in elevated concentration of LCFAs that are precursors of bioactive metabolite molecule.

Embracing Diversity, Equity, and Inclusion in the Scientific Community-Viewpoints of the Diversity, Equity, and Inclusion Committee of the North American Vascular Biology Organization.

Recent increased visibility on racial issues in the United States elicited public outcry and a collective call for action. The social justice movement has facilitated energetic discussions about race, sexual orientation, and various issues of diversity, equity, and inclusion. This article discusses issues faced by people of color that we as scientists can address, as well as challenges faced by women and internationally trained scientists in the scientific community that need immediate attention. Moreover, we highlight various ways to resolve such issues at both institutional and individual levels. Silence and incremental solutions are no longer acceptable to achieving lasting social justice and ensure prosperous societies that work for all.

Association of Diabetes and Hypertension With Brain Structural Integrity and Cognition in the Boston Puerto Rican Health Study Cohort.

BACKGROUND AND OBJECTIVES: The Boston Puerto Rican Health Study (BPRHS) is a longitudinal study following self-identified Puerto Rican older adults living in the Greater Boston area. Studies have shown higher prevalence of hypertension (HTN) and type 2 diabetes (T2D) within this ethnic group compared to age-matched non-Hispanic White adults. In this study, we investigated the associations of HTN and T2D comorbidity on brain structural integrity and cognitive capacity in community-dwelling Puerto Rican adults and compared these measures with older adult participants (non-Hispanic White and Hispanic) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) databases. METHODS: BPRHS participants who underwent brain MRI and cognitive testing were divided into 4 groups based on their HTN and T2D status: HTN-/T2D-, HTN+/T2D-, HTN-/T2D+, and HTN+/T2D+. We assessed microstructural integrity of white matter (WM) pathways using diffusion MRI, brain macrostructural integrity using hippocampal volumes, and brain age using T1-weighted MRI and cognitive test scores. BPRHS results were then compared with results from non-Hispanic White and Hispanic participants from the ADNI and NACC databases. RESULTS: The prevalence of HTN was almost 2 times (66.7% vs 38.7%) and of T2D was 5 times (31.8% vs 6.6.%) higher in BPRHS than in ADNI non-Hispanic White participants. Diffusion MRI showed clear deterioration patterns in major WM tracts in the HTN+/T2D+ group and, to a lesser extent, in the HTN+/T2D- group compared to the HTN-/T2D- group. HTN+/T2D+ participants also had the smallest hippocampal volume and larger brain aging deviations. Trends toward lower executive function and global cognitive scores were observed in HTN+/T2D+ relative to HTN-/T2D- individuals. MRI measures and the Mini-Mental State Examination (MMSE) scores from the HTN+/T2D+ BPRHS group resembled those of ADNI White participants with progressive mild cognitive impairment (MCI), while the BPRHS HTN-/T2D- participants resembled participants with stable MCI. The BPRHS was not significantly different from the ADNI + NACC Hispanic cohort on imaging or MMSE measures. DISCUSSION: The effects of T2D and HTN comorbidity led to greater brain structural disruptions than HTN alone. The high prevalence of HTN and T2D in the Puerto Rican population may be a key factor contributing to health disparities in cognitive impairment in this group compared to non-Hispanic White adults in the same age range. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT01231958.

Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis.

Characterized as a chronic inflammatory disease of the large arteries, atherosclerosis is the primary cause of cardiovascular disease, the leading contributor of morbidity and mortality worldwide. Elevated plasma cholesterol levels and chronic inflammation within the arterial plaque are major mediators of plaque initiation, progression, and instability. In 2003, the protein PCSK9 (proprotein convertase subtilisin/kexin 9) was discovered to play a critical role in cholesterol regulation, thus becoming a key player in the mechanisms behind atherosclerotic plaque development. Emerging evidence suggests that PCSK9 could potentially have effects on atherosclerosis that are independent of cholesterol levels. The objective of this review was to discuss the role on PCSK9 in oxidation, inflammation, and atherosclerosis. This function activates proinflammatory cytokine production and affects oxidative modifications within atherosclerotic lesions, revealing its more significant role in atherosclerosis. Although a variety of evidence demonstrates that PCSK9 plays a role in atherosclerotic inflammation, the direct mechanism of involvement is still unknown, driving a gap in knowledge to such a predominant player in cardiovascular disease. Investigation of proteins structurally related to PCSK9 may interestingly be the link in unveiling the mechanistic role of this protein's involvement in oxidation and inflammation. Importantly, the unique structure of PCSK9 bears structural homology to a one-of-a-kind domain found in the metabolic protein resistin, which is responsible for many of the same inflammatory outcomes as PCSK9. Closing this gap in knowledge of PCSK9`s role in atherosclerotic oxidation and inflammation will provide fundamental information for understanding, preventing, and treating cardiovascular disease.

Serotonin-Affecting Antidepressant Use in Relation to Platelet Reactivity.

Depression is an independent risk factor of cardiovascular disease morbidity. Serotonin is a key neurotransmitter in depressive pathology, contained within platelets, and is a weak activator of platelets. Our study assessed the link between platelet reactivity traits, depression, and antidepressant (AD) use in a large population sample. Our study was conducted in the Framingham Heart Study (n = 3,140), and AD use (n = 563) and aspirin use (n = 681) were noted. Depression was measured using the Center for Epidemiological Studies-Depression (CES-D) survey. Platelet reactivity traits were measured across multiple agonists using five distinct assays. We utilized a linear mixed effects model to test associations between platelet traits and depression, adjusting for age, sex, aspirin use, and AD use. Similarly, we analyzed trait associations with any AD use, serotonin-affecting ADs, and norepinephrine-affecting ADs, respectively. There were strong associations with reduced platelet function and AD use, particularly with serotonin-affecting medications. This included lower Optimul epinephrine maximal aggregation (P = 4.87E-13), higher U46619 half maximal effective concentration (P = 9.09E-11), lower light transmission aggregometry (LTA) adenosine diphosphate (ADP) final aggregation (P = 1.03E-05), and higher LTA ADP disaggregation (P = 2.28E-05). We found similar associations with serotonin-affecting ADs in an aspirin-taking subset of our sample. There were no significant associations between platelet traits and depression. In the largest study yet of AD use and platelet function we show that antidepressants, particularly serotonin-affecting ADs, inhibit platelets. We did not find evidence that depressive symptomatology in the absence of medication is associated with altered platelet function. Our results are consistent with AD use leading to platelet serotonin depletions, decreased stability of platelet aggregates, and overall decreased aggregation to multiple agonists, which may be a mechanism by which ADs increase risk of bleeding and decrease risk of thrombosis.

Association between inflammation, lipopolysaccharide binding protein, and gut microbiota composition in a New Hampshire Bhutanese refugee population with a high burden of type 2 diabetes.

Introduction: South Asian refugees experience a high risk of obesity and diabetes yet are often underrepresented in studies on chronic diseases and their risk factors. The gut microbiota and gut permeability, as assessed through circulating lipopolysaccharide binding protein (LBP), may underlie the link between chronic inflammation and type 2 diabetes (T2D). The composition of the gut microbiota varies according to multiple factors including demographics, migration, and dietary patterns, particularly fiber intake. However, there is no evidence on the composition of the gut microbiota and its relationship with metabolic health in refugee populations, including those migrating to the United States from Bhutan. The objective of this study was to examine glycemic status in relation to LBP, systemic inflammation fiber intake, and gut microbiota composition in Bhutanese refugee adults residing in New Hampshire (n = 50). Methods: This cross-sectional study included a convenience sample of Bhutanese refugee adults (N = 50) in NH. Established bioinformatics pipelines for metagenomic analysis were used to determine relative genus abundance, species richness, and alpha diversity measures from shallow shotgun sequences. The relationships between inflammatory markers, gut microbiota composition, dietary fiber, and glycemic status were analyzed. Results: We identified a substantial chronic disease burden in this study population, and observed a correlation between glycemic status, LBP, and inflammation, and a correlation between glycemic status and gut microbiome alpha diversity. Further, we identified a significant correlation between proinflammatory taxa and inflammatory cytokines. SCFA-producing taxa were found to be inversely correlated with age. Conclusion: To date, this is the most comprehensive examination of metabolic health and the gut microbiome in a Bhutanese refugee population in NH. The findings highlight areas for future investigations of inflammation and glycemic impairment, in addition to informing potential interventions targeting this vulnerable population.

The impact of altered mechanobiology on aortic valve pathophysiology.

Calcific aortic valve disease (CAVD) is the most prevalent valvulopathy worldwide. Until recently, CAVD was viewed as a passive, degenerative process and an inevitable consequence of aging. Recent improvements in disease modeling, imaging, and analysis have greatly enhanced our understanding of CAVD. The aortic valve and its constituent cells are subjected to extreme changes in mechanical forces, so it follows that any changes in the underlying mechanobiology of the valve and its cells would have dire effects on function. Further, the mechanobiology of the aortic valve is intimately intertwined with numerous molecular pathways, with signal transduction between these aspects afforded by the dynamic plasma membrane. Changes to the plasma membrane itself, its regulation of the extracellular matrix, or the relay of signals into or out of the cell would negatively impact cell and tissue function. PURPOSE OF REVIEW: This review seeks to detail past and current published reports related to the mechanobiology of the aortic valve with a special emphasis on the implications of altered mechanobiology in the context of calcific aortic valve disease. RECENT FINDINGS: Investigations characterizing membrane composition and dynamics have provided new insights into the earliest stages of calcific aortic valve disease. Recent studies have suggested that the activation or suppression of key pathways contribute to disease progression but may also offer therapeutic targets. SUMMARY: This review highlights the critical involvement of mechanobiology and membrane dynamics in normal aortic valve physiology as well as valve pathology.

Corrigendum to "Dietary Lipids in Health and Disease".

[This corrects the article DOI: 10.1155/2019/5729498.].

Eicosanoids: Atherosclerosis and cardiometabolic health.

Cardiovascular diseases (CVD) have been the leading causes of death in the U.S. for nearly a century. Numerous studies have linked eicosanoids to cardiometabolic disease. Objectives and Methods: This review summaries recent advances and innovative research in eicosanoids and CVD. Numerous review articles and their original human or animal studies were assessed in the relevant and recent studies. OUTCOME: We identified and discussed recent trends in eicosanoids known for their roles in CVD. Their subsequent relationships were assessed for any possible implications associated with consumption of different dietary lipids, essentially omega fatty acids. Eicosanoids have been heavily sought after over recent decades for their direct role in mediating the enhancement and resolution of acute immune responses. Given the short half-life of these oxidized lipid metabolites, studies on atherosclerosis have had to rely on the metabolites that are actively involved in eicosanoid production, signaling or redox reactions as markers for atherosclerosis-related molecular behaviors. CONCLUSION: Further investigations expending current knowledge, should be applied to narrow the specific class and species of eicosanoids responsible for inciting inflammation especially in the context of recent clinical studies assessing the role of dietary lipid in cardiovascular diseases.

Polyphenolic Compounds and Gut Microbiome in Cardiovascular Diseases.

The onset of Cardiovascular Disease (CVD) is known to be associated with multiple risk factors related to exogenous exposures on predisposed genetic makeup. Diet and lifestyle have a cascade effect on microbiota biodiversity, thus impacting inflammation and heart health. Atherosclerosis is a type of CVD where chronic inflammation contributes to plaque buildup in the arteries resulting in narrowed blood vessels, which obstruct blood flow. Polyphenolic compounds, including flavonoids, most commonly consumed in the form of plants, have been identified to have various mechanisms of action to reduce the inflammatory response in the body. Flavonoids provide a variety of nutraceutical functions including antioxidant, antimicrobial, anti-inflammatory, antiangiogenic, antitumor, and improved pharmacokinetic properties. Therefore, the medicinal use of polyphenolic compounds as an intervention for the inflammatory response, especially relating to the gut microbiome, may significantly reduce the risk of atherosclerotic plaque development and disease onset. This review addresses the role of polyphenolic compounds and gut microbiome in cardiovascular disease. Research studies conducted in cells and animals were reviewed. These studies clearly illustrate that dietary polyphenolic compounds influence resident gut microbiota thus they are associated with the prevention of atherosclerosis progression. Further research in this field is warranted to identify potential gut microbiome mediated therapeutic approaches for CVD.

p-Cymene Modulate Oxidative Stress and Inflammation in Murine Macrophages: Potential Implication in Atherosclerosis.

BACKGROUND: p-Cymene (p-CYM) is a common chemical used in air fresheners. OBJECTIVE: The study was designed to investigate the molecular effect of p-CYM on macrophages. MATERIALS AND METHODS: Macrophages (RAW 264.7) were treated with p-CYM (50 uM/L, 150 uM/L and 250 uM/L) for 6 hours, and 24 hours). Gene involved in inflammation, such as the Tumor Necrosis Factor-alpha (TNF-α), and the Monocyte Chemoattractant Protein-1 (MCP-1) and other genes known for their antioxidant activity such as the Paraoxonase 1 (PON-1) were analyzed. RESULTS: Cells treated with p-CYM have shown 30% up-regulation of MCP-1 after 24 hour of exposure; and also a differential up-regulation of TNF-α. However, treatment with p-CYM has resulted in a considerable (37%) dose-dependent downregulation of PON-1 after 24 hours of exposure. PON-1 is known for its antioxidant properties protecting High-Density Lipoproteins (HDL) from oxidation. CONCLUSION: Our findings demonstrate that exposure to p-CYM over time promotes oxidative stress by downregulating antioxidants genes as shown in PON-1 and also stimulates inflammation, a key process during the initiation and progression of atherosclerosis.

Berberine Encapsulated PLGA-PEG Nanoparticles Modulate PCSK-9 in HepG2 Cells.

BACKGROUND: The developments of new parenteral approaches to target PCSK-9 for the treatment of LDL-Cholesterol has yielded impressive results; and have shown significant decreases in the risk of mortality associated with hypercholesterolemia. However improved and convenient alternate approaches that exploit the beneficial drug target properties of PCSK-9 also need to be explored and developed. One such approach is the oral administration of Berberine using nanotechnology. METHODS: Nanoprecipitation encapsulation and physiochemical characterization of Berberine Chloride in PLGA-PEG-PLGA block copolymer has been developed and characterized in Hep-G2 cells using Berberine Chloride encapsulated nanoparticle (Bc-NP). Evaluation of PCSK-9, SREBP- 1, LDL-r, HNF-1alpha mRNAs and PCSK-9 protein expression was performed using quantitative real-time PCR (qPCR) and median fluorescence intensity (MFI) of flow cytometric studies respectively. Pearson's correlation analysis of PCSK-9 mRNA and protein levels in Berberine chloride delivery was performed. RESULTS: The PCSK-9 mRNA and protein expression shows a relationship to the release of Berberine from the encapsulating PLGA-PEG-PLGA polymer in a time dependent manner. CONCLUSION: PCSK-9 modulation by oral administration of Berberine using nanotechnology approach can improve its pharmacokinetic profile. Further studies are needed to maximize its delivery efficiency.