scholarly journals O11.2. ELEVATION OF MACROPHAGE-RELATED TRANSCRIPTS IN THE MIDBRAIN IN SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S27-S28
Author(s):  
Tertia Purves-Tyson ◽  
Helen Cai ◽  
Danny Boerrigter ◽  
Debora Rothmond ◽  
Cynthia Shannon Weickert
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Immune Cells ◽  
Symptomatic Patient ◽  
Dopamine Neurons ◽  
Illness Duration ◽  
Macrophage Marker ◽  
Fresh Frozen ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Abstract Background Neuroinflammation and dopamine dysregulation contribute to psychosis and cognitive deficits in schizophrenia. Approximately 50% of people with schizophrenia have elevated gene expression of proinflammatory cytokines in the postmortem midbrain, the location of the dopamine neurons. Infiltration of macrophages into the cortex was identified in a subset of high inflammatory schizophrenia cases. It is not known whether molecular measures of macrophages and cell adhesion molecules are increased in the midbrain in schizophrenia. We hypothesised that gene expression of macrophage markers CD163 (cluster of differentiation 163; perivascular macrophages), Fn1 (fibronectin 1; expressed by peripheral macrophages, not brain microglia), CD64 (pro-inflammatory macrophage), MRC1 (anti-inflammatory macrophage) and intracellular cell adhesion molecule 1 (ICAM1; enabling recruitment of peripheral macrophages into the brain), will be elevated in the midbrain of schizophrenia cases compared to controls. Methods Gene expression was examined by qRT-PCR in the midbrain from 28 schizophrenia cases (13 high inflammation, 15 low inflammation) and 29 healthy controls (low inflammation). ANCOVA, with age, PMI and RIN as covariates when correlations detected, were used to detect differences between diagnostic or diagnostic/inflammatory groups. For schizophrenia cases, antipsychotic doses were converted to chlorpromazine (CPZ) equivalents. Correlations were used to determine relationships between illness duration, antipsychotics and gene expression. CD163+ cells were identified in fresh frozen midbrain (14µm) from schizophrenia and control cases by immunohistochemistry to qualitatively assess their location relative to dopamine neurons. Results We found abundant macrophages (CD163+ cells) in and around blood vessels and in the schizophrenia midbrain parenchyma in close proximity to dopamine neurons. CD163, Fn1 and ICAM mRNAs were increased 237.6%, 39.67% and 137.7% respectively, in schizophrenia cases compared to control cases [all F(1,50 >5.045, p<0.05]. The pro-inflammatory macrophage marker (CD64 mRNA) was increased by 39% (F1,51=11.10, p=0.002), while the anti-inflammatory macrophage marker (MRC1 mRNA) was unchanged (F(1,52=2.97. p=0.09) in schizophrenia midbrain compared to control. CD163 and Fn1 mRNAs were not correlated in controls (R=0.319, p=0.112, n=24) but were correlated in schizophrenia cases (R=0.455, p=0.019, n=24). CD163 and ICAM mRNAs were positively correlated in controls (R=0.42, p=0.031, n=24) and schizophrenia cases (R=0.84, p<0.0001, n=24), and the correlation was stronger in schizophrenia cases (p=0.014). CD163 and ICAM mRNAs were positively correlated with CPZ (Rho>0.5, p<0.02, n=21) but not illness duration (Rho=0.024, p>0.05, n=28). Fn1 mRNA did not correlate with illness duration or antipsychotics. Discussion Increased ICAM1 may lead to increased transmigration of monocytes into the midbrain parenchyma. The increase in CD64 and the positive relationship between Fn1, expressed by peripheral monocytes/macrophages but not brain microglia, and CD163 expression in schizophrenia cases provides support that there is an increase in pro-inflammatory bone marrow-derived immune cells in the psychotic midbrain. These peripheral immune cells may be a source of increased cytokines identified in the midbrain schizophrenia cases and thus may contribute to dopamine neuron pathophysiology. Although the role of antipsychotics in increased macrophage marker expression in the midbrain is suggested, increased antipsychotics in patients displaying higher expression of inflammatory transcripts may indicate a more symptomatic patient requiring higher treatment doses.

scholarly journals Effects of Millimolar Steady-State Hydrogen Peroxide Exposure on Inflammatory and Redox Gene Expression in Immune Cells from Humans with Metabolic Syndrome

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1920 ◽  
Author(s):  
Carla Busquets-Cortés ◽  
Xavier Capó ◽  
Emma Argelich ◽  
Miguel Ferrer ◽  
David Mateos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Hydrogen Peroxide ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
High Concentration ◽  
Anti Inflammatory ◽  
Related Proteins

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) can exert opposed effects depending on the dosage: low levels can be involved in signalling and adaptive processes, while higher levels can exert deleterious effects in cells and tissues. Our aim was to emulate a chronic ex vivo oxidative stress situation through a 2 h exposure of immune cells to sustained H2O2 produced by glucose oxidase (GOX), at high or low production rate, in order to determine dissimilar responses of peripheral blood mononuclear cells (PBMCs) and neutrophils on ROS and cytokine production, and mitochondrial dynamics-related proteins, pro/anti-inflammatory and anti-oxidant gene expression. Immune cells were obtained from subjects with metabolic syndrome. H2O2 at low concentrations can trigger a transient anti-inflammatory adiponectin secretion and reduced gene expression of toll-like receptors (TLRs) in PBMCs but may act as a stimulator of proinflammatory genes (IL6, IL8) and mitochondrial dynamics-related proteins (Mtf2, NRF2, Tfam). H2O2 at a high concentration enhances the expression of pro-inflammatory genes (TLR2 and IL1β) and diminishes the expression of mitochondrial dynamics-related proteins (Mtf1, Tfam) and antioxidant enzymes (Cu/Zn SOD) in PBMCs. The GOX treatments produce dissimilar changes in immune cells: Neutrophils were more resistant to H2O2 effects and exhibited a more constant response in terms of gene expression than PBMCs. We observe emerging roles of H2O2 in mitochondrial dynamics and redox and inflammation processes in immune cells.

scholarly journals Clinical significance and biological role of L1 cell adhesion molecule in gastric cancer

2019 ◽  
Vol 121 (12) ◽  
pp. 1058-1068 ◽  
Author(s):  
Takashi Ichikawa ◽  
Yoshinaga Okugawa ◽  
Yuji Toiyama ◽  
Koji Tanaka ◽  
Chengzeng Yin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Tumour Progression ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Fresh Frozen ◽  
L1 Cell Adhesion Molecule ◽  
L1cam Expression

Abstract Background L1 cell adhesion molecule (L1CAM) is highly expressed in malignant tumours and might play a pivotal role in tumour progression. Methods We analysed by immunohistochemistry L1CAM protein expression in formalin-fixed, paraffin-embedded specimens from 309 GC patients. We performed propensity score matching (PSM) analysis to clarify the prognostic impact of L1CAM in GC patients. We evaluated L1CAM gene expression in fresh frozen specimens from another group of 131 GC patients to establish its clinical relevance. The effects of changes in L1CAM were investigated in vitro and in vivo. Results L1CAM was mainly expressed in tumour cells of GC tissues. Elevated L1CAM expression was an independent prognostic factor for overall and disease-free survival, and an independent risk factor for distant metastasis in GC patients. PSM analysis showed that high L1CAM expression was significantly associated with poor prognosis. L1CAM gene expression using fresh frozen specimens successfully validated all of these findings in an independent cohort. Inhibition of L1CAM suppressed cell proliferation, cycle progress, invasion, migration and anoikis resistance in GC cells. Furthermore, L1CAM inhibition suppressed the growth of peritoneal metastasis. Conclusion L1CAM may serve as a feasible biomarker for identification of patients who have a high risk of recurrence of GC.

scholarly journals AB0171 THE IMMUNOMODULATORY AND ANTI-INFLAMMATORY EFFECTS OF BOSENTAN IN SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1385.2-1386
Author(s):  
M. G. Tinti ◽  
T. Mazza ◽  
L. D’agruma ◽  
A. De Cata
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Systemic Sclerosis ◽  
Differentially Expressed Genes ◽  
Immune Cells ◽  
Differentially Expressed ◽  
Immunomodulatory Activity ◽  
Z Score ◽  
Anti Inflammatory ◽  
Antigen Presenting

Background:Plasma endothelin-1 (ET-1) levels are increased in patients with systemic sclerosis (SSc), playing a central role in the development of fibrosis, vasoconstriction and inflammation1. While the beneficial effect of Bosentan, the endothelin receptor antagonists, have been demonstrated on vasoconstriction and fibrosis, its potential anti-inflammatory and immunomodulatory activity needs to be further investigated.Objectives:To assess whether Bosentan can modulate the gene expression profile of immune cells in sample of patients with limited and diffuse SSc and active digital ulcers.Methods:We enrolled 34 patients affected by SSc. Twenty-four patients were affected by limited SSc and 12 by diffuse SSc. Blood samples were collected from patients before and after 24 weeks of treatment with Bosentan, in the absence of immunosuppressive therapies. All patients received Bosentan 125 mg twice a day for 24 weeks. Gene expression profiles were assessed by GeneChip® Human Transcriptome Array 2.0 microarray technology. Significantly (p-value<0.05) and differentially (|FC|>1.5) expressed genes pre/post treatment were obtained by paired t-statistics, as implemented in Partek Genomics Suite ver. 6.6. These genes were subjected to functional enrichment analysis by Ingenuity Pathway Analysis. The effect of Bosentan on patients was studied on the “diffuse” and “limited” sub-cohorts, individually, as well as on the whole cohort.Results:Contrary to the limited cohort where differentially expressed genes resulted to be all non-coding genes which are almost all over-expressed before treatment, the diffuse cohort was characterized by 19 differentially expressed genes that enrich biological functions and pathways related to the immune system and its organic response (in particular T-cells). Comparing the limited to the diffuse cohort, pre- and post- treatment, a distinct genetic fingerprint emerges, that characterizes the response to Bosentan by the latter cohort as increased apoptosis of lymphocytes (z-score=3.28) and a decreased quantity of antigen presenting cells (from z-score=1.06 (pre) to -0.75 (post)).Conclusion:The presence of an inflammatory microenvironment, as occur in SSc, influence the relative expression of ET-1 receptors on immune cells, which in turn further contribute to the amplification of cellular responses to inflammation. The observed difference response to therapy between the two cohorts of patients was attributed to influence of ET-1 levels on the relative expression of ET-1 receptors on immune cells surface. Interestingly Bosentan, beside the already-known effect on promoting antigen presenting cells apoptosis, seem to exert its immunomodulatory activity also by deregulating functions that mainly involves the T cells and by promoting their apoptosis, which in turn reflect also its anti-inflammatory proprieties.References:[1]Tinazzi E, Puccetti A, Patuzzo G, et al. Endothelin receptors expressed by immune cells are involved in modulation of inflammation and in fibrosis: relevance to the pathogenesis of systemic sclerosis. J Immunol Res. 2015;2015:147616.Disclosure of Interests:None declared

scholarly journals Toxoplasmosis and abortion: pro- and anti-inflammatory cytokines gene expression of the host immune cells

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Mona Said El-Sherbini ◽  
Amany A. Abd El-Aal ◽  
Walid Sayed El-Sherbiny ◽  
Samar Sayed Attia ◽  
Inas Z. Abdel Aziz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Anti Inflammatory

scholarly journals Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function

Immunity ◽  
2014 ◽  
Vol 40 (5) ◽  
pp. 706-719 ◽  
Author(s):  
Dror S. Shouval ◽  
Amlan Biswas ◽  
Jeremy A. Goettel ◽  
Katelyn McCann ◽  
Evan Conaway ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Immune Cells ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Receptor Signaling ◽  
Macrophage Function ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Relative Expression of Mouse Udp-glucuronosyl Transferase 2b1 Gene in the Livers, Kidneys, and Hearts: The Influence of Nonsteroidal Anti-inflammatory Drug Treatment

2019 ◽  
Vol 20 (11) ◽  
pp. 918-923 ◽  
Author(s):  
Yazun Jarrar ◽  
Qais Jarrar ◽  
Mohammad Abu-Shalhoob ◽  
Abdulqader abed ◽  
Esra'a Sha'ban
Keyword(s):  
Gene Expression ◽  
Strongly Correlated ◽  
Chain Reaction ◽  
Inflammatory Drug ◽  
Relative Expression ◽  
Elimination Half ◽  
Endogenous Compounds ◽  
Polymerase Chain ◽  
Anti Inflammatory ◽  
Glucuronosyl Transferase

Background: Mouse Udp-glucuronosyl Transferase (UGT) 2b1 is equivalent to the human UGT2B7 enzyme, which is a phase II drug-metabolising enzyme and plays a major role in the metabolism of xenobiotic and endogenous compounds. This study aimed to find the relative expression of the mouse ugt2b1 gene in the liver, kidney, and heart organs and the influence of Nonsteroidal Anti-inflammatory Drug (NSAID) administration. Methods: Thirty-five Blab/c mice were divided into 5 groups and treated with different commonly-used NSAIDs; diclofenac, ibuprofen, meloxicam, and mefenamic acid for 14 days. The livers, kidneys, and hearts were isolated, while the expression of ugt2b1 gene was analysed with a quantitative real-time polymerase chain reaction technique. Results: It was found that the ugt2b1 gene is highly expressed in the liver, and then in the heart and the kidneys. NSAIDs significantly upregulated (ANOVA, p < 0.05) the expression of ugt2b1 in the heart, while they downregulated its expression (ANOVA, p < 0.05) in the liver and kidneys. The level of NSAIDs’ effect on ugt2b1 gene expression was strongly correlated (Spearman’s Rho correlation, p < 0.05) with NSAID’s lipophilicity in the liver and its elimination half-life in the heart. Conclusion: This study concluded that the mouse ugt2b1 gene was mainly expressed in the liver, as 14-day administration of different NSAIDs caused alterations in the expression of this gene, which may influence the metabolism of xenobiotic and endogenous compounds.

Anti-Inflammatory Effects of Novel Standardized Platelet Rich Plasma Releasates on Knee Osteoarthritic Chondrocytes and Cartilage in vitro

2019 ◽  
Vol 20 (11) ◽  
pp. 920-933 ◽  
Author(s):  
Lucía Gato-Calvo ◽  
Tamara Hermida-Gómez ◽  
Cristina R. Romero ◽  
Elena F. Burguera ◽  
Francisco J. Blanco
Keyword(s):  
Gene Expression ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Cartilage Explants ◽  
Ex Vivo Model ◽  
Chondrocyte Viability ◽  
Platelet Concentration ◽  
The Absolute ◽  
Anti Inflammatory

Background: Platelet Rich Plasma (PRP) has recently emerged as a potential treatment for osteoarthritis (OA), but composition heterogeneity hampers comparison among studies, with the result that definite conclusions on its efficacy have not been reached. Objective: 1) To develop a novel methodology to prepare a series of standardized PRP releasates (PRP-Rs) with known absolute platelet concentrations, and 2) To evaluate the influence of this standardization parameter on the anti-inflammatory properties of these PRP-Rs in an in vitro and an ex vivo model of OA. Methods: A series of PRPs was prepared using the absolute platelet concentration as the standardization parameter. Doses of platelets ranged from 0% (platelet poor plasma, PPP) to 1.5·105 platelets/µl. PRPs were then activated with CaCl2 to obtain releasates (PRP-R). Chondrocytes were stimulated with 10% of each PRP-R in serum-free culture medium for 72 h to assess proliferation and viability. Cells were co-stimulated with interleukin (IL)-1β (5 ng/ml) and 10% of each PRP-R for 48 h to determine the effects on gene expression, secretion and intra-cellular content of common markers associated with inflammation, catabolism and oxidative stress in OA. OA cartilage explants were co-stimulated with IL-1β (5 ng/ml) and 10% of either PRP-R with 0.75·105 platelets/µl or PRP-R with 1.5·105 platelets/µl for 21 days to assess matrix inflammatory degradation. Results: Chondrocyte viability was not affected, and proliferation was dose-dependently increased. The gene expression of all pro-inflammatory mediators was significantly and dose-independently reduced, except for that of IL-1β and IL-8. Immunoblotting corroborated this effect for inducible NO synthase (NOS2). Secreted matrix metalloproteinase-13 (MMP-13) was reduced to almost basal levels by the PRP-R from PPP. Increasing platelet dosage led to progressive loss to this anti-catabolic ability. Safranin O and toluidine blue stains supported the beneficial effect of low platelet dosage on cartilage matrix preservation. Conclusion: We have developed a methodology to prepare PRP releasates using the absolute platelet concentration as the standardization parameter. Using this approach, the composition of the resulting PRP derived product is independent of the donor initial basal platelet count, thereby allowing the evaluation of its effects objectively and reproducibly. In our OA models, PRP-Rs showed antiinflammatory, anti-oxidant and anti-catabolic properties. Platelet enrichment could favor chondrocyte proliferation but is not necessary for the above effects and could even be counter-productive.

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