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Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.
Ter Horst, R, van den Munckhof, ICL, Schraa, K, Aguirre-Gamboa, R, Jaeger, M, Smeekens, SP, Brand, T, Lemmers, H, Dijkstra, H, Galesloot, TE, et al
Arteriosclerosis, thrombosis, and vascular biology. 2020;(7):1787-1800
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OBJECTIVE Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.
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Vegetarian-Based Dietary Patterns and their Relation with Inflammatory and Immune Biomarkers: A Systematic Review and Meta-Analysis.
Craddock, JC, Neale, EP, Peoples, GE, Probst, YC
Advances in nutrition (Bethesda, Md.). 2019;(3):433-451
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Dietary patterns with substantial proportions of energy from plant sources have been associated with favorable biomarkers of low-grade inflammation. Less is known of the relation between vegetarian-based dietary patterns and markers of inflammation and immune status. This systematic review and meta-analysis aimed to determine the relation between vegetarian-based dietary patterns and inflammatory and immune markers (C-reactive protein, tumour necrosis factor α, fibrinogen, natural killer cells, leukocytes, lymphocytes, thrombocytes, interleukins, and immunoglobulins). PubMed, Medline, and Cochrane scientific databases were searched to identify relevant studies. Random effects meta-analyses were conducted to assess the weighted mean differences (WMDs) for each outcome variable between vegetarian and non-vegetarian groups. Thirty observational and 10 intervention studies were included in the review. Pooled effects of vegetarian-based dietary patterns were associated with significantly lower concentrations of CRP (WMD: -0.61 mg/L; 95% CI: -0.91, -0.32 mg/L; P = 0.0001), fibrinogen (WMD: -0.22 g/L; 95% CI: -0.41, -0.04 mg/L; P = 0.02), and total leukocyte (WMD: -0.62 × 10(3)/μL; 95% CI -1.13 × 10(3), -0.10 × 10(3)/μL; P = 0.02) compared with those following non-vegetarian dietary patterns in observational studies. Insufficient data were identified for a meta-analysis of intervention studies. This study provides evidence that vegetarian-based dietary patterns are associated with lowered serum C-reactive protein, fibrinogen, and total leukocyte concentrations. Future research should focus on large-scale intervention trials, contrasting differences in inflammation and immune status and function between vegetarian and non-vegetarian-based populations.
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Particulate metal exposures induce plasma metabolome changes in a commuter panel study.
Ladva, CN, Golan, R, Liang, D, Greenwald, R, Walker, DI, Uppal, K, Raysoni, AU, Tran, V, Yu, T, Flanders, WD, et al
PloS one. 2018;(9):e0203468
Abstract
INTRODUCTION Advances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures. METHODS A 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog. RESULTS HRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response. CONCLUSIONS Acute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation.
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A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults.
Paniz, C, Bertinato, JF, Lucena, MR, De Carli, E, Amorim, PMDS, Gomes, GW, Palchetti, CZ, Figueiredo, MS, Pfeiffer, CM, Fazili, Z, et al
The Journal of nutrition. 2017;(9):1677-1685
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Abstract
Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown.Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon γ (IFNG), tumor necrosis factor α (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers.Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells.Results: Serum folate concentrations increased by ∼5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased (>1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both).Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells. This trial was registered at www.ensaiosclinicos.gov.br as RBR-2pr7zp.
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Effects of four antiplatelet/statin combined strategies on immune and inflammatory responses in patients with acute myocardial infarction undergoing pharmacoinvasive strategy: Design and rationale of the B and T Types of Lymphocytes Evaluation in Acute Myocardial Infarction (BATTLE-AMI) study: study protocol for a randomized controlled trial.
Fonseca, FAH, Izar, MC, Maugeri, IML, Berwanger, O, Damiani, LP, Pinto, IM, Szarf, G, França, CN, Bianco, HT, Moreira, FT, et al
Trials. 2017;(1):601
Abstract
BACKGROUND Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. DISCUSSION BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. TRIAL REGISTRATION ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014.
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Vitamin D receptor activation reduces inflammatory cytokines and plasma MicroRNAs in moderate chronic kidney disease - a randomized trial.
Mansouri, L, Lundwall, K, Moshfegh, A, Jacobson, SH, Lundahl, J, Spaak, J
BMC nephrology. 2017;(1):161
Abstract
BACKGROUND Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD), partly due to endothelial dysfunction and chronic inflammation. Vitamin D treatment in end stage renal disease is suggested to modulate the immune system and lead to improved outcomes. We and others have demonstrated that treatment with vitamin D or activated vitamin D analogues protects the endothelial function in less severe renal disease as well. Since the endothelial protection might be mediated by vitamin D effects on inflammation, we assessed levels of pro-inflammatory cytokines and micro RNAs (miRs) in patients with moderate CKD, treated with an active vitamin D analogue (paricalcitol). METHODS Thirty-six patients with moderate CKD were randomized to 12 weeks treatment with placebo, 1 μg, or 2 μg paricalcitol daily. Cytokines were measured by Milliplex 26-plex. Total RNA was isolated from plasma and miRs were determined by quantitative reverse transcription PCR analysis. RESULTS Selected pro-inflammatory cytokines decreased significantly following treatment, while no change was observed in the placebo group. The micro RNAs; miR 432-5p, miR 495-3p, and miR 576-5p were significantly downregulated in the active treated groups, compared to the placebo group. CONCLUSION Paricalcitol treatment for 12 weeks in patients with moderate CKD reduces cytokines and micro RNAs involved in atherosclerosis and inflammation. The potentially protective role of vitamin D receptor activation in the inflammatory processes regarding the long-term outcomes in CKD patients warrants further studies. TRIAL REGISTRATION SOLID study; NCT01204528 , April 27, 2010.
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Neopterin as an Effect Modifier of the Cardiovascular Risk Predicted by Total Homocysteine: A Prospective 2-Cohort Study.
Bjørnestad, EØ, Borsholm, RA, Svingen, GFT, Pedersen, ER, Seifert, R, Midttun, Ø, Ueland, PM, Tell, GS, Bønaa, KH, Nygård, O
Journal of the American Heart Association. 2017;(11)
Abstract
BACKGROUND Plasma total homocysteine (tHcy) is related to plasma neopterin, an indicator of interferon-γ-mediated immune activation, and both biomarkers positively predict cardiovascular risk. We examined whether the association between tHcy and subsequent risk of acute myocardial infarction (AMI) was modified by systemic concentrations of neopterin and C-reactive protein among patients with coronary heart disease. METHODS AND RESULTS By Cox modeling, we explored the association between tHcy and risk of AMI in 4164 patients with suspected stable angina pectoris. Subgroup analyses were performed according to median levels of neopterin and C-reactive protein. A replication study was performed among 3749 patients with AMI at baseline. Median follow-up was 7.3 and 8.3 years among patients with stable angina pectoris and AMI, respectively. tHcy and neopterin correlated in both cohorts (rs=0.34 and rs=0.30 among stable angina pectoris and AMI patients, respectively, both P<0.001). tHcy predicted AMI in both cohorts, independent of B-vitamin treatment. However, significant risk associations were confined to patients with plasma neopterin above the median (hazard ratios [95% confidence interval] per 1-SD increment of log-transformed tHcy 1.38 [1.26-1.50] and 1.18 [1.10-1.26] among stable angina pectoris and AMI patients, respectively) (Pint<0.005 in both cohorts). Further, adding information on the interaction between tHcy and neopterin improved model discrimination and reclassification. tHcy and C-reactive protein were weakly related, and no effect modification was found by C-reactive protein. CONCLUSIONS Among patients with coronary heart disease, tHcy predicted risk of AMI only in subjects with concomitantly elevated plasma neopterin. Our results motivate further research on the relationship between homocysteine metabolism, cellular immune activation, and atherothrombosis.
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Liver Injury and Endotoxemia in Male and Female Alcohol-Dependent Individuals Admitted to an Alcohol Treatment Program.
Kirpich, IA, McClain, CJ, Vatsalya, V, Schwandt, M, Phillips, M, Falkner, KC, Zhang, L, Harwell, C, George, DT, Umhau, JC
Alcoholism, clinical and experimental research. 2017;(4):747-757
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BACKGROUND Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. METHODS A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. RESULTS Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. CONCLUSIONS The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program.