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Anti-inflammatory Therapies for Cardiovascular Disease: Signaling Pathways and Mechanisms.
Martínez-Hervás, S, González-Navarro, H
Revista espanola de cardiologia (English ed.). 2019;(9):767-773
Abstract
Cardiovascular diseases (CVD) are the clinical manifestation of atherosclerosis, a chronic inflammatory disease promoted by several risk factors such as dyslipidemia, type 2 diabetes mellitus, hypertension, and smoking. Acute CVD events are the result of an unresolved inflammatory chronic state that promotes the rupture of unstable plaque lesions. Of note, the existing intensive therapies modify risk factors but do not prevent life-threatening recurrent ischemic events in high-risk patients, who have a residual inflammatory risk displayed by increased C-reactive protein (CRP) levels. Better understanding of the role of innate and adaptive immunity in plaque development and rupture has led to intensive investigation of anti-inflammatory strategies for CVD. Some of them are being tested in specific clinical trials and use lower doses of existing medications originally developed for other inflammatory diseases such as rheumatoid arthritis and psoriasis, which have high CVD risk. Other investigations are retrospective and meta-analyses of existing clinical trials that evaluate the incidence of CVD in these inflammatory diseases. Others are based on preclinical testing such as vaccines. In this article, we summarize the main anti-inflammatory strategies and associated molecular mechanisms that are being evaluated in preclinical or clinical CVD studies.
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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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Effect of ß-glucan on serum levels of IL-12, hs-CRP, and clinical outcomes in multiple-trauma patients: a prospective randomized study.
Fazilaty, Z, Chenari, H, Shariatpanahi, ZV
Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES. 2018;(4):287-293
Abstract
BACKGROUND Trauma is associated with a profound immunological dysfunction. This predisposes patients to infections and adverse outcomes. ß-glucan has been implicated in the initiation of anti-microbial immune response. The present study aimed to evaluate the effects of an enteral diet containing ß-glucan on serum levels of IL-12 and highly-sensitive C-reactive protein (hs-CRP), occurrence of infection, and clinical outcomes in critically ill multiple-trauma patients. METHODS Forty multiple trauma patients requiring enteral nutrition for at least 10 days were randomly assigned to the intervention group (n=20) or the placebo group (n=20). The intervention group received a high-protein enteral diet providing 3 g ß-glucan, and the control group received a similar diet, except for 3 g of maltodextrin as a placebo. Serum levels of IL-12 and hs-CRP were measured on days 0, 10, and 21. RESULTS The ß-glucan group showed significantly higher serum levels of IL-12 on day 21 compared to the control group. Infection frequency and duration of mechanical ventilation were significantly lower in the ß-glucan group. A significant difference was found in the Sequential Organ Failure Assessment (SOFA) score in favor of the ß-glucan group. No difference was found in the serum levels of hs-CRP, length of ICU stay, occurrence of infection, and mortality rates between the two groups. CONCLUSION ß-glucan may increase serum levels of IL-12, shorten the duration of mechanical ventilation, and reduce organ failure in critically ill multiple-trauma patients.
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The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
Miroliaee, AE, Salamzadeh, J, Shokouhi, S, Sahraei, Z
Journal of critical care. 2018;:300-305
Abstract
PURPOSE In regard with the effect of immune-stimulants in the treatment of infectious diseases, the effect of vitamin D administration on the outcome of patients with Ventilator-Associated Pneumonia (VAP) with a high rate of mortality, was studied. MATERIAL AND METHOD In this trial, 46 adult patients suffering from VAP and vitamin D deficiency were enrolled. The first group of patients received single intramuscular injection of vitamin D (300000Unit), while the other group were given the placebo. RESULTS Administration of vitamin D significantly enhanced its levels (P<0.0001) in the treated patients (12.28±8.26) in comparison with placebo group (1.15±1.50). Serum Interleukin-6 levels were significantly reduced in the treated group compared to placebo (P=0.01). Although C-Reactive protein (CRP) levels showed an improving trend in the vitamin D group, no significant difference between groups (P=0.12) was found. Interestingly, the mortality rate of patients that treated with vitamin D (5/24) was significantly lower (p=0.04) than that of the placebo group (11/22). CONCLUSION Our results indicate that vitamin D administration can significantly reduce the IL-6 as prognostic marker in VAP patients, and must be considered as adjunct option in the treatment of VAP patients.
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25-hydroxyvitamin D correlates with inflammatory markers in cord blood of healthy newborns.
Rosendahl, J, Holmlund-Suila, E, Helve, O, Viljakainen, H, Hauta-Alus, H, Valkama, S, Enlund-Cerullo, M, Hytinantti, T, Tervahartiala, T, Sorsa, T, et al
Pediatric research. 2017;(5):731-735
Abstract
BACKGROUND Vitamin D is a potent immunomodulator and may play a role in the development of the fetal innate immune functions. The aim of our study was to evaluate inflammatory markers in cord blood of healthy newborns in relation to vitamin D status at birth. METHODS We studied the concentrations of inflammatory markers, matrix metalloproteinase 8 (MMP-8) and high sensitivity CRP (hs-CRP), and 25-hydroxyvitamin D (25(OH)D) in cord blood of 939 healthy term infants born to mothers of Caucasian origin. We evaluated perinatal factors that affect the concentrations of MMP-8 and hs-CRP, and further explored associations between cord blood 25(OH)D and these inflammatory biomarkers. RESULTS Majority (99%) of the cohort was vitamin D sufficient (>50 nmol/l or 20 ng/ml). We observed a positive correlation between cord blood 25(OH)D and MMP-8 concentrations, and between 25(OH)D and hs-CRP concentrations. After adjustment for potential confounders (parity, antenatal antibiotic treatment, gestational age, mode of delivery, and maternal prepregnancy BMI), the association of 25(OH)D with MMP-8 and hs-CRP remained significant. CONCLUSION Cord blood 25(OH)D correlates with inflammatory markers MMP-8 and hs-CRP. The findings may reflect the diverse immunomodulatory functions of vitamin D in the innate immune response of the newborn.
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Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder.
Chang, HH, Chen, PS, Wang, TY, Lee, SY, Chen, SL, Huang, SY, Hong, JS, Yang, YK, Lu, RB
Journal of affective disorders. 2017;:151-157
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Abstract
BACKGROUND Balance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti-inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. METHODS During the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5mg/day) arms. The fasting plasma levels of high-sensitivity C-reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. RESULTS A cut-off value of initial CRP level of 2322ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LIMITATIONS We recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. CONCLUSIONS BD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients.
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Plasma Ferritin and Hepcidin Are Lower at 4 Months Postpartum among Women with Elevated C-Reactive Protein or α1-Acid Glycoprotein.
Jorgensen, JM, Yang, Z, Lönnerdal, B, Chantry, CJ, Dewey, KG
The Journal of nutrition. 2017;(6):1194-1199
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Background: Ferritin and hepcidin are markers of iron status that typically increase during inflammation or infection. The postpartum period is a physiologically unique life stage in which the relations between these proteins and other markers of inflammation have not been extensively studied.Objective: We aimed to determine whether 2 markers of inflammation [high-sensitivity C-reactive protein (CRP) and α1-acid glycoprotein (AGP)] were associated with ferritin or hepcidin in postpartum women in California.Methods: This is a secondary analysis of a randomized controlled iron-intervention trial. Plasma CRP, AGP, ferritin, and hepcidin were analyzed at 2 and 17 wk postpartum in 114 lactating women. We examined Pearson correlation coefficients between all biomarkers at both time points and differences in mean values of ferritin and hepcidin between those with and without elevated CRP and/or AGP.Results: At 2 and 17 wk postpartum, 58% and 26% of women had CRP >5 mg/L and 78% and 29% had AGP >1 g/L, respectively. Neither CRP nor AGP was significantly correlated with ferritin (r = 0.07 and -0.06; n = 114 at 2 wk; -0.14 and -0.14; n = 95 at 17 wk) or hepcidin (r = 0.18 and -0.03 at 2 wk; -0.05 and -0.14 at 17 wk; P > 0.05 for all). At 2 wk, geometric mean plasma ferritin and hepcidin concentrations did not differ between women with and without elevated CRP or AGP (P > 0.5), but at 17 wk women with elevated CRP or AGP had lower mean (95% CI) ferritin and hepcidin than did women without either elevated CRP or AGP [ferritin: 30.3 ng/mL (23.4, 39.1 ng/mL) compared with 40.2 ng/mL (32.9, 49.2 ng/mL); P < 0.01; hepcidin: 44.3 ng/mL (32.3, 60.9 ng/mL) compared with 67.6 ng/mL (56.1, 81.5 ng/mL); P = 0.02].Conclusion: Lower ferritin and hepcidin among women with elevated CRP or AGP at 17 wk postpartum suggests that these markers of iron status react differently to physiologic immune activation than to pathologic inflammatory states.
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Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives.
Nakken, B, Papp, G, Bosnes, V, Zeher, M, Nagy, G, Szodoray, P
Immunology letters. 2017;:13-18
Abstract
Early diagnosis and immediately started appropriate treatment are mandatory for the prevention of radiographic progression, functional disability and unfavourable disease outcome in rheumatoid arthritis (RA). The current classification criteria for RA include two different types of biomarkers representing inflammatory processes, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) or immune processes including autoantibodies, such as rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA). After the discovery of RF, the recent recognition of various autoantibodies against post-translationally modified proteins opened new avenues to diagnosing RA and predicting the course of the disease. Citrullination and carbamylation of amino acids generate new epitopes that can potentially promote the production of novel autoantibodies. In spite of growing knowledge, the pathogenic role of these autoantibodies is still not fully elucidated in RA. In this paper, we review the currently available and novel promising immune biomarkers, which may help in early diagnosis and estimating prognosis in RA.