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1.
Iron Oxide Particles Alter Bacterial Uptake and the LPS-Induced Inflammatory Response in Macrophages.
Williams, LJ, Tristram, SG, Zosky, GR
International journal of environmental research and public health. 2020;(1)
Abstract
Exposure to geogenic (earth-derived) particulate matter (PM) is linked to severe bacterial infections in Australian Aboriginal communities. Experimental studies have shown that the concentration of iron in geogenic PM is associated with the magnitude of respiratory health effects, however, the mechanism is unclear. We investigated the effect of silica and iron oxide on the inflammatory response and bacterial phagocytosis in macrophages. THP-1 and peripheral blood mononuclear cell-derived macrophages were exposed to iron oxide (haematite or magnetite) or silica PM with or without exposure to lipopolysaccharide. Cytotoxicity and inflammation were assessed by LDH assay and ELISA respectively. The uptake of non-typeable Haemophilus influenzae by macrophages was quantified by flow cytometry. Iron oxide increased IL-8 production while silica also induced significant production of IL-1β. Both iron oxide and silica enhanced LPS-induced production of TNF-α, IL-1β, IL-6 and IL-8 in THP-1 cells with most of these responses replicated in PBMCs. While silica had no effect on NTHi phagocytosis, iron oxide significantly impaired this response. These data suggest that geogenic particles, particularly iron oxide PM, cause inflammatory cytokine production in macrophages and impair bacterial phagocytosis. These responses do not appear to be linked. This provides a possible mechanism for the link between exposure to these particles and severe bacterial infection.
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2.
Plasma 25-Hydroxyvitamin D Levels and VDR Gene Expression in Peripheral Blood Mononuclear Cells of Leukemia Patients and Healthy Subjects in Central Kazakhstan.
Zhumina, AG, Li, K, Konovalova, AA, Li, YA, Ishmuratova, MY, Pogossyan, GP, Danilenko, M
Nutrients. 2020;(5)
Abstract
Low blood levels of the vitamin D metabolite 25-hydroxyvitamin D [25(OH)D] have been associated with an increased risk and poorer outcomes of various cancers, including hematological malignancies. The Central Kazakhstan area has a relatively high incidence rate of leukemia. However, the relationship between vitamin D status and leukemia or other types of cancer in Kazakhstan has not yet been addressed. Therefore, in this first pilot single-center study conducted in Central Kazakhstan, we compared plasma levels of 25(OH)D and the vitamin D receptor (VDR) gene expression levels in peripheral blood mononuclear cells of patients with leukemia and demographically matching healthy volunteers. The levels of 25(OH)D in patients were found to be significantly lower (10.8 ± 7.0 ng/mL; n = 31) than in healthy subjects (21.6 ± 7.8 ng/mL; n = 34; p < 0.0001). A similar difference was observed in both younger (<60 years old) and older (>60 years old) participants, though there was no association between 25(OH)D concentration and age within the patient group. In female patients, 25(OH)D levels were significantly lower than in male patients (p = 0.04). No significant seasonal variations of 25(OH)D were observed in either the patient or the control group. VDR gene expression levels appeared to be similar in leukemia patients and healthy subjects, and no correlation between the cellular VDR expression and plasma 25(OH)D concentrations was observed in either group of participants. We did not observe a significant association of 25(OH)D or VDR levels and overall survival of leukemia patients. This observational study conducted for the first time in Kazakhstan supports previous findings demonstrating reduced blood 25(OH)D levels in cancer (leukemia) patients. Larger studies are required to determine whether low 25(OH)D plasma concentrations represent a risk factor for leukemia development and/or progression.
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3.
Intake of Fermented Dairy Products Induces a Less Pro-Inflammatory Postprandial Peripheral Blood Mononuclear Cell Gene Expression Response than Non-Fermented Dairy Products: A Randomized Controlled Cross-Over Trial.
Rundblad, A, Holven, KB, Øyri, LKL, Hansson, P, Ivan, IH, Gjevestad, GO, Thoresen, M, Ulven, SM
Molecular nutrition & food research. 2020;(21):e2000319
Abstract
SCOPE It is aimed to investigate how intake of high-fat meals composed of different dairy products with a similar fat content affects postprandial peripheral blood mononuclear cell (PBMC) expression of inflammation-related genes, as well as circulating inflammatory markers and metabolites. METHODS AND RESULTS Healthy subjects (n = 47) consume four different high-fat meals composed of either butter, cheese, whipped cream, or sour cream in a randomized controlled cross-over study. Fasting and postprandial PBMC gene expression, plasma metabolites, and circulating inflammatory markers are measured. Using a linear mixed model, it is found that expression of genes related to lymphocyte activation, cytokine signaling, chemokine signaling, and cell adhesion is differentially altered between the four meals. In general, intake of the fermented products cheese and sour cream reduces, while intake of the non-fermented products butter and whipped cream increases, expression of these genes. Plasma amino acid concentrations increase after intake of cheese compared to the other meals, and the amino acid changes correlate with several of the differentially altered genes. CONCLUSION Intake of fermented dairy products, especially cheese, induces a less inflammatory postprandial PBMC gene expression response than non-fermented dairy products. These findings may partly explain inconsistent findings in studies on health effects of dairy products.
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4.
The Effects of Aronia melanocarpa Juice Consumption on the mRNA Expression Profile in Peripheral Blood Mononuclear Cells in Subjects at Cardiovascular Risk.
Stojković, L, Jovanović, I, Zivković, M, Zec, M, Djurić, T, Zivotić, I, Kuveljić, J, Kolaković, A, Kolić, I, Djordjević, A, et al
Nutrients. 2020;(5)
Abstract
Foods and food products that contain polyphenols are proposed to modulate risk of cardiovascular disease. The aim of this three-arm, crossover, randomized, double-blind, placebo-controlled intervention study was to examine the impact of Aronia melanocarpa juice (AMJ), high-polyphenol (AMJ treatment, 1.17 g/100 mL polyphenols) and low-polyphenol (dAMJ treatment, 0.29 g/100 mL polyphenols) dose, on the transcriptome in peripheral blood mononuclear cells (PBMC) of 19 subjects at cardiovascular risk. Transcriptome data were obtained by microarray. Bioinformatic functional annotation analysis was performed on both the whole transcriptome datasets and the differentially expressed genes (DEGs). Expression of selected DEGs was validated by RT-qPCR. Administration of AMJ and dAMJ treatments during the two consecutive four-week treatment periods had additive effects on PBMC transcriptome profiles, with the most pronounced and specific effect noticed for AMJ in the last treatment period (TP3) of the trial. Between the high-dose and low-dose treatments in TP3, there was a multitude of overlapping DEGs and DEG-enriched biological processes and pathways, which primarily included immunomodulation and regulation of cell proliferation/death. Increased expression of TNF, IL1B, IL8, RGS1, OSM, and DUSP2 in TP3 was confirmed by RT-qPCR. The results suggest the immunomodulatory effects of prolonged habitual consumption of polyphenol-rich aronia juice in individuals at cardiovascular risk.
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5.
Associations between dietary patterns and gene expression pattern in peripheral blood mononuclear cells: A cross-sectional study.
Christensen, JJ, Ulven, SM, Thoresen, M, Westerman, K, Holven, KB, Andersen, LF
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(11):2111-2122
Abstract
BACKGROUND AND AIMS Diet may alter gene expression in immune cells involved in atherosclerotic cardiovascular disease susceptibility. However, we still lack a robust understanding of the association between diet and immune cell-related gene expression in humans. Therefore, we examined associations between dietary patterns (DPs) and gene expression profiles in peripheral blood mononuclear cells (PBMCs) in a population of healthy, Norwegian adults (n = 130 women and 105 men). METHODS AND RESULTS We used factor analysis to define a posteriori DPs from food frequency questionnaire-based dietary assessment data. In addition, we derived interpretable features from microarray-based gene expression data (13 967 transcripts) using two algorithms: CIBERSORT for estimation of cell subtype proportions, and weighted gene co-expression network analysis (WGCNA) for cluster discovery. Finally, we associated DPs with either CIBERSORT-predicted PBMC leukocyte distribution or WGCNA gene clusters using linear regression models. We detected three DPs that broadly reflected Western, Vegetarian, and Low carbohydrate diets. CIBERSORT-predicted percentage of monocytes associated negatively with the Vegetarian DP. For women, the Vegetarian DP associated with a large gene cluster consisting of 600 genes mainly involved in regulation of DNA transcription, whereas for men, the Western DP inversely associated with a smaller cluster of 36 genes mainly involved in regulation of metabolic and inflammatory processes. A subsequent protein-protein interaction network analysis suggested that genes within these clusters might physically interact in biological networks. CONCLUSIONS Although the present findings are exploratory, our analysis pipeline serves as a useful framework for studying the association between diet and gene expression.
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6.
Ubiquinol (Reduced Coenzyme Q10) and Cellular Oxygen Consumption in Patients Undergoing Coronary Artery Bypass Grafting.
Holmberg, MJ, Uber, A, Stankovic, N, Chen, CO, Grossestreuer, AV, Donnino, MW, Andersen, LW, Liu, X
Journal of intensive care medicine. 2020;(8):797-804
Abstract
Ubiquinol is a fundamental component of cellular metabolism. Low ubiquinol levels have been associated with mortality. This was a substudy of a randomized trial in patients undergoing coronary artery bypass grafting. We drew blood before and after surgery. Ubiquinol or placebo was added to peripheral blood mononuclear cells for oxygen consumption (OCR) measurements. In vivo ubiquinol levels were lower postsurgery compared to presurgery (0.16 μmol/L [quartiles: 0.02-0.39], P = .01), although the difference disappeared when adjusting for hemoglobin levels (P = .30). There was no difference in presurgical basal (1.0 mL/min/mg [95% confidence interval [CI]: -0.9 to 2.2], P = .08) and maximal (0.5 mL/min/mg [95% CI: -4.3 to 7.3], P = .56) OCR in cells receiving ubiquinol or placebo. There was a difference in postsurgical basal (1.1 mL/min/mg [95% CI: 0.9-1.6], P < .001) and maximal (4.2 mL/min/mg [95% CI: 0.3-7.0], P = .01) OCR between the groups. We found no association between ubiquinol and OCR levels (all P > .05).
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7.
Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study.
Juncal-Ruiz, M, Riesco-Davila, L, Vazquez-Bourgon, J, Ortiz-Garcia de la Foz, V, Mayoral-Van Son, J, Ayesa-Arriola, R, Setien-Suero, E, Leza, JC, Lopez-Hoyos, M, Crespo-Facorro, B
International journal of molecular sciences. 2020;(17)
Abstract
Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.
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8.
Decrease of Perforin Expressing Lymphocytes after On-Pump Coronary Artery Bypass Grafting Surgery Irrespective of Carbohydrate Preoperative Oral Feeding.
Sokolic, J, Knezevic, D, Kuharic, J, Medved, I, Sustic, A, Zupan, Z, Laskarin, G, Tadin, T, Sotošek Tokmadžić, V
The heart surgery forum. 2019;(3):E218-E224
Abstract
BACKGROUND Coronary artery bypass grafting (CABG) surgery continues to be the gold standard for treating the patients with coronary artery disease. CABG surgery can be performed on or off cardiopulmonary bypass, termed as on-pump or off-pump CABG, respectively. It has been shown that CABG surgery, preferably on-pump CABG surgery, leads to the changes of cell immunity during perioperative and early postoperative period. The mechanisms of regulation of the immune response in patients during and early after surgical revascularization are not fully understood. The aim of this study was to investigate the influence of carbohydrate preoperative oral feeding on frequency and perforin expression in peripheral blood lymphocytes in patients after on- or off-pump CABG surgery in early postoperative period. PATIENTS AND METHODS In this prospective clinical study, 80 patients scheduled for CABG surgery were included in the study. The patients were randomly allocated into four groups (20 in each group): patients in Group 1 underwent on-pump CABG and did not receive carbohydrate preoperative oral feeding; patients in Group 2 underwent on-pump CABG and were preoperatively fed; patients in Group 3 underwent off-pump CABG and did not receive carbohydrate preoperative oral feeding; while patients in Group 4 underwent off-pump CABG and received carbohydrate preoperative oral feeding. Blood samples were collected immediately before (T1), 24 (T2) and 72 (T3) hours after the surgery. Peripheral blood mononuclear cells were isolated by gradient centrifugation and simultaneously labelled by antigens using fluorochrome-conjugated monoclonal antibodies. Frequency of T lymphocytes, NK and NKT cells, their subsets as well as their perforin expression were detected, and analyzed by flow cytometry. RESULTS There was significant decrease in frequency of CD3+ and CD3+CD4+ cells, as well as perforin expressing CD3+CD8+ cells in patients who underwent on-pump CABG in comparison to patients who underwent off-pump CABG 24 hours after the surgery. Carbohydrate preoperative oral feeding did not effect changes in lymphocytes subpopulations and perforin expression at any time point. CONCLUSION Decreases of CD3+ cells on account of CD3+CD4+ subsets, and perforin expressing cells on account of CD3+CD8+ perforin+ cells were found in patients who had undergone on-pump CABG, but not in patients who had undergone off-pump CABG surgery, irrespectively of carbohydrate preoperative oral feeding.
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9.
Association of Folate Metabolites and Mitochondrial Function in Peripheral Blood Cells in Alzheimer's Disease: A Matched Case-Control Study.
Lv, X, Zhou, D, Ge, B, Chen, H, Du, Y, Liu, S, Ji, Y, Sun, C, Wang, G, Gao, Y, et al
Journal of Alzheimer's disease : JAD. 2019;(4):1133-1142
Abstract
BACKGROUND The nutrition state plays an important role in the progress of aging. Folate may play a role in protecting mitochondrial (mt) DNA by reducing oxidative stress. OBJECTIVE The primary aim of this study was to examine the association of mitochondrial oxidative damage with risk of Alzheimer's disease (AD), and to explore the possible role of folate metabolites in this association in a matched case-control study. METHODS Serum folate metabolites and mitochondrial function in peripheral blood cells were determined in 82 AD cases and 82 healthy controls, individually matched by age, gender, and education. RESULTS AD patients had lower serum levels of folate and higher homocysteine (Hcy) concentration. AD patients had a reduced mtDNA copy number, higher mtDNA deletions, and increased 8-OHdG content in mtDNA indicative of reduced mitochondrial function. The highest level of mtDNA copy number would decrease the risk of AD (OR = 0.157, 95% CI: 0.058-0.422) compared to the lowest level, independently of serum folate, and Hcy levels. Serum folate levels correlated with low 8-OHdG content in mtDNA both in AD patients and controls, independently of serum Hcy level. Moreover, serum Hcy levels correlated with low copy number in mtDNA both in AD patients and controls, independently of serum folate levels. CONCLUSION In conclusion, mitochondrial function in peripheral blood cells could be associated with risk of AD independent of multiple covariates. AD patients with a folate deficiency or hyperhomocysteinemia had low mitochondrial function in peripheral blood cells. However, further randomized controlled trials are need to determine a causal effect.
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10.
Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?
In 't Veld, AE, Grievink, HW, Saghari, M, Stuurman, FE, de Kam, ML, de Vries, APJ, de Winter, BCM, Burggraaf, J, Cohen, AF, Moerland, M
International journal of molecular sciences. 2019;(19)
Abstract
Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.