Plasma Levels Of Proinflammatory Cytokines Research Articles

Suppression of lncRNA MALAT1 reduces pro-inflammatory cytokines production by regulating miR-150-5p/ZBTB4 axis through JAK/STAT signal pathway in systemic juvenile idiopathic arthritis

Systemic juvenile idiopathic arthritis (sJIA) is a common chronic disease occurring in children. Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of diverse human diseases. This study aimed to explore the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and its mechanism in sJIA. We found that the expression of MALAT1, the plasma level of pro-inflammatory cytokines (IL-6, IL-17, IL-1β, and TNF-α) as well as MMP-8 and MMP-9 production were significantly elevated in sJIA patients. Moreover, we observed that the production of these cytokines in peripheral blood mononuclear cells (PBMCs) from sJIA patients were reduced after MALAT1 knockdown. Furthermore, bioinformatics analysis predicted that MALAT1 might bind to miR-150-5p and ZBTB4 was a downstream target gene of miR-150-5p. Besides, rescue assays revealed that MALAT1 knockdown-mediated suppressive effects on cytokine production could be reversed by ZBTB4 overexpression. In addition, MALAT1 activated the JAK/STAT signaling by upregulating ZBTB4 expression. In summary, our findings demonstrated that MALAT1 promoted pro-inflammatory cytokine and MMP production by targeting the miR-150-5p/ZBTB4 axis through JAK/STAT signaling pathway in sJIA, suggesting that MALAT1 may have a potential diagnostic biomarker for the pathogenesis and therapy of sJIA.

Heparan sulfate consumption as a potential mechanism of intra-cardiac thrombosis in SARS-CoV-2 infection

Cardiac injury occurs in up to 36% of hospitalized patients with COVID-19.1.Lala A. Johnson K.W. Januzzi J.L. et al.Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection.J Am Coll Cardiol. 2020; 76 (533 LP - 546)https://doi.org/10.1016/j.jacc.2020.06.007Crossref Scopus (384) Google Scholar Exact mechanism of cardiac injury in COVID-19 is not well understood, but may relate to direct cardiomyocyte damage, coronary plaque destabilization, cytokine inflammatory response, and intracoronary microthrombi formation. Lindner et al.2.Lindner D. Fitzek A. Bräuninger H. et al.Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases.JAMA Cardiol. 2020; (Published online July 27)https://doi.org/10.1001/jamacardio.2020.3551Crossref PubMed Scopus (423) Google Scholar in an autopsy study identified SARS-CoV-2 RNA in the myocardium in 24 of 39 autopsy cases. However, none of the 39 patients had myocarditis. Plasma pro-inflammatory cytokine levels were increased in 16 patients, suggesting cytokine response as a plausible cause of cardiac injury in COVID-19. Early reports identified ACE2 as a receptor for the SARS-CoV-2. Clausen et al.3.Clausen T.M. Sandoval D.R. Spliid C.B. et al.SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2.Cell. 2020; (Published online September 142020.07.14.201616)https://doi.org/10.1016/j.cell.2020.09.033Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar have recently identified heparan sulfate as a co-receptor for ACE2, whereby SARS-CoV-2 binds to heparan sulfate, a negatively charged polymer, through a positively charged site adjacent to the ACE2 binding domain. Heparan sulfate is ubiquitously expressed in mammalian tissues, and ACE2 is broadly expressed in the arterial, capillary, and venous endothelial cells. Heparan sulfate also interacts with antithrombin, which subsequently undergoes conformation change, resulting in the generation of the active form of antithrombin. The active form of antithrombin inhibits the procoagulant factors Xa and thrombin (IIa) (Fig. 1). Additionally, Gue et al.4.Gue Y.X. Gorog D.A. Reduction in ACE2 may mediate the prothrombotic phenotype in COVID-19.Eur Heart J. 2020; 41: 3198-3199https://doi.org/10.1093/eurheartj/ehaa534Crossref PubMed Scopus (14) Google Scholar suggested that reduction in ACE2 activity may increase vascular permeability resulting in increased expression of tissue factor in subendothelial cells, leucocytes, and platelets with subsequent activation of coagulation and thrombosis. As SARS-CoV-2 binds heparan sulfate and ACE2 for cellular entry, it is possible that the high expression of ACE2 in the heart would facilitate an interaction between SARS-CoV-2 and heparan sulfate, leading to heparan sulfate consumption. A lower level of heparan sulfate would lead to a reduction in antithrombin activation creating a hypercoagulable state. Heparan sulfate also mediates antithrombin's anti-inflammatory activity.5.Liu J. Pedersen L.C. Anticoagulant heparan sulfate: structural specificity and biosynthesis.Appl Microbiol Biotechnol. 2007; 74: 263-272https://doi.org/10.1007/s00253-006-0722-xCrossref PubMed Scopus (108) Google Scholar Loss of antithrombin's anti-inflammatory activity can potentially lead to endothelialitis and subsequent endothelial injury and intra-cardiac thrombus formation. We believe that heparan sulfate consumption during SARS-CoV-2 cellular entry might play a role in the thrombotic events associated with COVID-19 infection.

Inflammatory marker changes in a 24-month dietary and physical activity randomised intervention trial in postmenopausal women

Chronic low-grade inflammation plays a role in the pathogenesis of several chronic diseases including cancer. Physical activity (PA) and diet have been supposed to modulate inflammatory markers. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of pro-inflammatory cytokines, a secondary analysis in the DAMA factorial trial. The 234 study participants (healthy postmenopausal women with high breast density, 50–69 years, non smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Interleukins (IL)-1α, -1β, -6, tumor necrosis factor-α and C-reactive protein were measured at baseline and at the end of the intervention. Intention-to-treat-analyses were carried out using Tobit regression. Although all cytokines tended to increase over time, after 24 months women in the PA intervention (arms 2 + 3) showed lower levels of IL-1α (exp(β) = 0.66; p = 0.04) and IL-6 (exp(β) = 0.70; p = 0.01) in comparison with women in the control group (arms 1 + 4). No effects of the dietary intervention emerged. In healthy postmenopausal women with high breast density a moderate-intensity PA appears to slow the age-related increase of pro-inflammatory cytokines.

Enhanced neutrophil apoptosis accompanying myeloperoxidase release during hemodialysis

Biocompatibility of hemodialysis (HD) systems have been considerably improved. However, mortality and morbidity rates of patients have remained high, raising questions regarding the biocompatibility of current systems. In the present study, 70 patients on regular HD (51 males; mean age, 63 years; median duration of HD, 18 months) with high-performance membrane (polysulfone, 77%; polymethylmethacrylate, 23%) at Tohoku University Hospital were examined. Blood samples before and after HD, were subjected to measure apoptosis cells of white blood cells, plasma levels of the following molecules: myeloperoxidase (MPO), pentraxin 3 (PTX3), angiogenin, complements, and 17 cytokines. The main findings were as follows: significant decreases in leukocyte counts by dialysis, significant increases in apoptosis-positive leukocytes by dialysis (neutrophils and monocytes), and significant decrease in plasma angiogenin accompanying increase in plasma MPO and PTX3 levels, with no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products by dialysis. The findings underlined the unsolved issue of bio-incompatibility of HD systems, and suggest the possible pathology of neutrophil apoptosis accompanying MPO release for the development of microinflammation in patients on HD.

Trans fat intake during pregnancy or lactation increases anxiety-like behavior and alters proinflammatory cytokines and glucocorticoid receptor levels in the hippocampus of adult offspring

Changes in dietary habits, including the increased consumption of processed foods, rich in trans fatty acids (TFA), have profound effects on offspring health in later life. Thus, this study aimed to assess the influence of maternal trans fat intake during pregnancy or lactation on anxiety behavior, as well as markers of inflammation, oxidative stress, and expression of glucocorticoid receptors (GR) of adult male offspring. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0 g/kg body weight) during pregnancy or lactation. After weaning, male offspring received only standard diet. On the postnatal day 60, anxiety-like symptoms were assessed, the plasma was collected for the quantification of cytokines levels and the hippocampus removed for biochemical and molecular analysis. Our findings have evidenced that offspring from HVF-supplemented dams during pregnancy or lactation showed significantly greater levels of anxiety behavior. HVF supplementation increased plasma levels of proinflammatory cytokines and these levels were higher in the lactation period. In contrast, HVF supplementation decreased plasma levels of IL-10 in relation to SO/FO in both periods. Biochemical evaluations showed higher reactive species generation, protein carbonyl levels and catalase activity in offspring from HVF-supplemented dams during lactation. In addition, offspring from HVF-supplemented dams showed decreased GR expression in both supplemented periods. Together, these data indicate that consumption of TFA in different periods of development may increase anxiety-like behavior at least in part via alterations in proinflammatory and anti-inflammatory cytokine levels and GR expression in limbic brain regions.

Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series.

Background:Coronavirus disease 2019 (COVID-19) has infected more than 4.4 million people and caused more than 300,000 deaths partly through acute respiratory distress syndrome with propensity to affect African American and Hispanic communities disproportionately. Patients with worse outcomes have exhibited higher blood plasma levels of proinflammatory cytokines. Activation of the vitamin D receptor expressed on immune cells has been shown to directly reduce the secretion of inflammatory cytokines, such as interleukin-6, and indirectly affect C-reactive protein.Areas of Uncertainty:The significance of the vitamin D pathway in patients diagnosed with COVID-19.Therapeutic Innovation:Vitamin D supplementation in patients after diagnosis of COVID-19.Patients and Pharmacological Interventions:We report 4 vitamin D deficient patients diagnosed with COVID-19 in April 2020 who were provided with either cholecalciferol of 1000 IU daily (standard dose) or ergocalciferol 50,000 IU daily for 5 days (high dose) as part of supplementation.Clinical Outcomes:Patients that received a high dose of vitamin D supplementation achieved normalization of vitamin D levels and improved clinical recovery evidenced by shorter lengths of stay, lower oxygen requirements, and a reduction in inflammatory marker status.Conclusions:Vitamin D supplementation may serve as a viable alternative for curtailing acute respiratory distress syndrome in patients in underserved communities where resources to expensive and sought-after medications may be scarce. Randomized clinical trials will serve as an appropriate vessel to validate the efficacy of the therapeutic regimen and dissection of the pathway.

Longitudinal Dynamics of the Neutralizing Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

BackgroundCoronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific neutralizing antibodies (NAbs) in patients with COVID-19.MethodsBlood samples (n = 173) were collected from 30 patients with COVID-19 over a 3-month period after symptom onset and analyzed for SARS-CoV-2–specific NAbs using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines.ResultsSARS-CoV-2–specific NAb titers were low for the first 7–10 days after symptom onset and increased after 2–3 weeks. The median peak time for NAbs was 33 days (interquartile range [IQR], 24–59 days) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR, 19.6–42.4%). NAb titers increased over time in parallel with the rise in immunoglobulin G (IgG) antibody levels, correlating well at week 3 (r = 0.41, P < .05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including stem cell factor (SCF), TNF-related apoptosis-inducing ligand (TRAIL), and macrophage colony-stimulating factor (M-CSF).ConclusionsThese data provide useful information regarding dynamic changes in NAbs in patients with COVID-19 during the acute and convalescent phases.

The spleen mediates chronic sleep restriction-mediated enhancement of LPS-induced neuroinflammation, cognitive deficits, and anxiety-like behavior.

Chronic sleep restriction promotes neuroinflammation and cognitive deficits in neurodegenerative and neurobehavioral diseases. The spleens of mice exposed to chronic and repeated psychological stress serve as a reservoir of inflammatory myeloid cells that are released into the blood and brain following secondary acute stress. Here, we tested whether chronic and repeated short-term sleep restriction (CRSR) would exacerbate lipopolysaccharide (LPS)-induced neuroinflammation, cognitive deficits, and anxiety-like behavior in a spleen-dependent manner. LPS was administered to aged mice 14 days after exposure to CRSR consisting of three cycles of 7 days of sleep restriction with 7-day intervals in between. CRSR increased plasma proinflammatory cytokine levels, blood-brain barrier permeability, hippocampal proinflammatory cytokine levels, and transition of microglia to the M1 phenotype 24 h after LPS treatment. This in turn led to cognitive deficits and anxiety-like behavior. Interestingly, removal of the spleen 14 days prior to CRSR abrogated the enhancement of LPS-induced increases in systemic inflammation, neuroinflammation, cognitive deficits, and anxiety-like behavior. These data indicate that the spleen was essential for CRSR-induced exacerbation of LPS-induced brain damage.

Increased IL-8 levels in HIV-infected individuals who initiated ART with CD4+ T cell counts

The identification of inflammatory markers in HIV+ individuals on ART is fundamental since chronic ART-controlled HIV infection is linked to an increased inflammatory state. In this context, we assessed plasma levels of pro-inflammatory cytokines (IL-1β, IL-8, and IL-12p70) of HIV+ individuals who initiated ART after immunosuppression (CD4+ T cell counts <350 cells/mm3). HIV+ individuals were stratified according to two extreme phenotypes: Slow Progressors (SPs; individuals with at least 8 years of infection before ART initiation) and Rapid Progressors (RPs; individuals who needed to initiate ART within 1–4 years after infection). A control group was composed of HIV-uninfected individuals. We found increased IL-8 levels (median: 5.13 pg/mL; SPs and RPs together) in HIV-infected individuals on ART as compared to controls (median: 3.2 pg/mL; p = 0.04), although no association with the progression profile (slow or rapid progressors) or CD4+ T cell counts at sampling was observed. This result indicates that IL-8 is a general marker of chronic inflammation in HIV+ individuals on ART, independently of CD4+ T cell counts at the beginning of the treatment or of the potential progression profile of the patient. In this sense, IL-8 may be considered a possible target for novel therapies focused on reducing inflammation in chronic HIV infection.

A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration

The vagus nerve plays a role in the cross talk between the brain and gut microbiota, which could be involved in depression. The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the brain and gut microbiota. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the depression-like phenotype and the abnormal composition of gut microbiota in mice after lipopolysaccharide (LPS) administration. LPS caused a depression-like phenotype, inflammation, increase in spleen weight, and downregulation of synaptic proteins in the medial prefrontal cortex (mPFC) in the sham-operated mice. In contrast, LPS did not produce a depression-like phenotype and downregulated synaptic proteins in the mPFC after SDV. The spleen weight and plasma levels of pro-inflammatory cytokines in the SDV + LPS group were lower than those of the sham + LPS group. Interestingly, there were positive correlations between the plasma levels of pro-inflammatory cytokines and spleen weight, suggesting a relationship between inflammatory events and spleen weight. Furthermore, LPS led to significant alterations in gut microbiota diversity in sham-operated mice, but not SDV-operated mice. In an unweighted UniFrac PCoA, the dots representing the sham + LPS group were located far away from the dots representing the other three groups. Our results suggest that LPS produces a depression-like phenotype, increases spleen weight, triggers inflammation, downregulates synaptic proteins in the mPFC, and leads to abnormal composition of gut microbiota via the subdiaphragmatic vagus nerve. It is likely that the vagus nerve plays a crucial role in the brain–gut–microbiota axis.

P0936INJURY OF NEUTROPHILS DURING HAEMODIALYSIS AND ITS INVOLVEMENT FOR DEVELOPMENT OF CHRONIC MICROINFLAMMATION

Abstract Background and Aims Owing to the quality developments of membrane material and dislysis water, it is believed that the biocompatibility of haemodialysis (HD) system has been considerably improved. However, mortality and morbidities of dialysis patients have remained unacceptably high, which raises a question as to the biocompatibility improvement of current HD systems. Method Seventy-one patients on regular HD (male/female: 52/19, mean age: 63 years old, median HD duration: 19 months, HD session 3 times a week for 3 to 4 hours each by using high performance synthetic membrane) at Tohoku University Hospital were examined. Blood samples were obtained from all patients before and after the HD session, to measure followings; number of white blood cell fraction, and apotosis cells, plasma levels of following molecules; myeloperoxidase (MPO), pentraxin 3, angiogenin, lactoferrin, complement (C3a, C5a, C5b-9), and 17 cytokines. Apoptosis (positive for Annexin-V-FITC and negative for propidium iodide) was measured in 100,000 cells by flow cytometer, and plasma molecules were measured by ELISA kit. Results The main findings of this study were as follows (changes in the values after HD as compared to the pre HD); the significant decrease of leukocytes counts (neutrophil and lymphocyte), significant increases of apoptosis positive cells of leukocytes (neutrophiles and monocytes), significant increases of plasma MPO and pentraxin3 levels, significant decrease of angiogenin, and, no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products. There was a significant positive correlation between the change in MPO and apoptosis before and after HD. Conclusion Bio-incompatibility of HD has remained a crucial issue even in the current systems. Among the several pathologies, process of neutrophile apoptosis accompanying MPO degranulation, may plays a central role for developing microinflammation. In this regard, change of plasma MPO could be a clinical marker for the biocompatibility of HD system. And in order to achieve better patients’ outcomes, innovative HD systems which fully improve biocompatibility are needed.

The Effect of Chronic Spice Consumption on Plasma Pro-Inflammatory Cytokine Levels and Monocyte Function in Adults with Overweight/Obesity

Abstract Objectives Obesity-induced, chronic, low-grade inflammation is involved in the pathogenesis of cardiovascular disease (CVD). Numerous spices have anti-inflammatory properties in animal models and humans. However, few studies have examined the anti-inflammatory effect of spices in the context of daily meal consumption, which is typically how spices are consumed. The objective of this study was to investigate the anti-inflammatory effect of chronic spice consumption in adults with overweight/obesity at risk for CVD. Methods Nonsmoking adults (30–75 years old) with overweight/obesity (BMI ≥ 25 and ≤ 35 kg/m2), elevated waist circumference (≥94 cm for men and ≥ 80 cm for women) and at least one other risk factor for CVD were recruited for a 3-period, crossover, randomized controlled-feeding study (n = 63). In random order, participants consumed an Average American Diet (AAD) for 4 weeks containing: 1) 0.6 g of spice blend per 2100 kcal, 2) 3.2 g of spice blend per 2100 kcal, or 3) 6.4 g of spice blend per 2100 kcal with a≥2-week washout period between each test period. The spice blend was comprised of 24 popular spices. Blood was collected at baseline and after each test period. Peripheral blood mononuclear cells were isolated, and the % of monocyte subsets (classical; CD14++CD16−, intermediate; CD14++CD16+, non-classical; CD14+CD16++) were quantified using flow cytometry. Plasma pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6, IL-8, MCP-1) were measured using ELISA. In a subset of participants (n = 6), transendothelial migratory function of each monocyte subset through MCP-1 stimulated human umbilical vein endothelial cells was evaluated. Results Plasma IL-6 was significantly reduced after consuming the AAD containing 3.2 g compared to 0.6 g of spice blend in men and postmenopausal women (P = 0.031). Transendothelial migration of classical monocytes was significantly reduced following consumption of the AAD containing 3.2 g and 6.4 g of the spice blend compared to 0.6 g of spice blend (P = 0.011). Conclusions Consumption of an AAD with spices for 4 weeks attenuated inflammatory outcomes including plasma IL-6 and transendothelial migration of classical monocytes in adults with overweight/obesity. Funding Sources McCormick Science Institute.

Elevated Expression of C-Type Lectin Domain Family 5-Member A (CLEC5A) and Its Relation to Inflammatory Parameters and Disease Course in Adult-Onset Still's Disease.

C-type lectin domain family 5-member A (CLEC5A) associates with adaptor DAP12 (DNAX activation protein 12) to form receptor complexes involved in inflammatory responses. We postulated a potential role of CLEC5A in the pathogenesis of adult-onset Still's disease (AOSD) and aimed to investigate CLEC5A expression and its association with activity parameters and disease course. In 34 AOSD patients and 12 healthy controls (HC), circulating levels of CLEC5A-expressing monocytes or granulocytes were determined by flow cytometry analysis, the mRNA expression of CLEC5A and DAP12 on PBMCs by quantitative PCR, and plasma levels of proinflammatory cytokines by ELISA. AOSD patients had significantly higher percentages and mean fluorescence intensity (MFI) of CLEC5A-expressing monocytes (median 62.1% and 3.20, respectively) or granulocytes (72.6% and 3.22, respectively) compared with HC (in monocytes: 17.0% and 0.65, both p < 0.001; in granulocytes: 67.3%, p < 0.05 and 0.90, p < 0.001; respectively). Patients also had significantly higher levels of CLEC5A mRNA expression on PBMCs compared with HC (median 1.77 vs. 0.68, p < 0.05). The levels of CLEC5A-expressing monocytes or granulocytes were positively associated with activity scores and levels of IL-1β and IL-18 in AOSD patients. The patients with a systemic pattern had significantly higher levels of CLEC5A-expressing granulocytes and IL-18 compared to those with a chronic articular pattern of disease course. After 6 months of therapy, levels of CLEC5A-expressing monocytes and granulocytes significantly declined, paralleling the decrease of AOSD activity. Elevated CLEC5A levels and their positive association with activity parameters suggest that CLEC5A is involved in the pathogenesis and may serve as an activity indicator of AOSD.

Investigating the impact of early-life adversity on physiological, immune, and gene expression responses to acute stress: A pilot feasibility study.

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults’ exposure to ELA influences neuroendocrine and inflammatory responses to acute stress.Materials and methodsParticipants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years (‘ELA group’), and half who confirmed zero (‘controls’). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test.ResultsIn this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.ConclusionOverall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.

The Effects of Diurnal Intermittent Fasting On Proinflammatory Cytokine, Oxidative Stress and Heat Shock Protein 70 Levels

Aim: In this study, it is aimed to assess the effect of intermittent diurnal fasting (DIF) at the beginning (2nd day of Ramadan fasting) and the end of the Ramadan (28th day of Ramadan fasting) on plasma levels of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8)], heat shock protein 70 (Hsp70) and oxidative stress markers [total oxidant status (TOS) and total antioxidant status (TAS)]. Methods: Fifty healthy male volunteers aged between 25-45 years were included in the study. All subjects followed the same dietary regimen before and during Ramadan and were encouraged to continue their usual lifestyle and activities. All biochemical tests were made both at the beginning (2nd day of fasting) and the end of the Ramadan (28th day of fasting). Plasma levels of cytokines (TNF-α and IL-8) Hsp70 were assessed using enzyme-linked immunoassays (ELISA), and oxidative markers (TAS and TOS) were measured spectrophotometric methods. Results: There was a significant decrease in the levels of TNF- α, compared to the beginning of fasting (p 0.05). Therefore, there was a significant increase in the Hsp70 levels compared to the beginning of fasting (p 0.05). Conclusion: DIF decreased proinflammatory cytokine level and oxidative stress parameter while increasing the levels of Hsp70. Keywords: Diurnal Intermittent Fasting, Ramadan, Proinflammatory Cytokines, Heat Shock Protein 70, Oxidative Stress Special Issue of Health Sciences DOI: 10.7176/JSTR/6-03-41

Memory decline correlates with increased plasma cytokines in amyloid-beta (1-42) rat model of Alzheimer's disease.

Dysregulation of inflammatory markers like cytokines is implicated in the pathophysiology of Alzheimer's disease (AD). Altered level of these cytokines show that pathogenesis of AD is beyond dysfunction of neurons resulting from amyloid beta accumulation but involves neuroinflammatory mechanisms elicited by the neuroimmune cell. In this study, we investigated the effect of amyloid-beta (1-42) (Aβ(1-42)) on memory and how inflammatory markers respond to this model of AD. Male Sprague-Dawley rats were used for this study. The animals were randomly divided into four groups euthanized on day 3, 7, 10 and 14 post-lesion with amyloid-beta (5μg/5μl) while corresponding control groups were stereotaxically injected with a vehicle (5μl of 0.01M phosphate- buffered saline). The Morris water maze (MWM) test to access learning and memory was conducted pre and post-lesion and blood was collected through cardiac puncture on day 3, 7, 10 and 14 post lesion. Multiplex immunoassay was performed to determine the plasma levels of IL-1β, IL-6, IL-10 and TNF-α. Our results showed impaired spatial memory and elevated plasma levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) with a concomitantly lowered level of the anti-inflammatory cytokine (IL-10) in the Aβ(1-42) lesioned rats when compared to the vehicle groups. This study showed a negative correlation between the decline in performance of the spatial memory task and plasma levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and positive correlation with the anti-inflammatory cytokine IL-10. In conclusion, this study most importantly demonstrated an association between progressive decline in spatial memory and increased plasma cytokine level induced by the infusion of Aβ(1-42).

Plasma level of pro-inflammatory cytokines in children with atopic dermatitis.

Plasma level of pro-inflammatory cytokines in children with atopic dermatitis.

Abstract TP97: Neuronal Loss of Cd200 Signaling is Sufficient to Impact on Ischemic Stroke

Introduction: CD200 is primarily expressed on neurons and endothelial cells. It binds to its receptor CD200R on immune cells to form an endogenous inhibitory signaling that reduces the activation of leukocytes. Once a stroke occurs, ischemic neurons have compromised CD200 signaling that could impact on post-stroke inflammation and outcomes. Research efforts aimed at altering neuronal CD200 signaling have high translational value. In the present study, we hypothesized that neuronal CD200 signaling plays a critical role in the immune response to stroke. Methods: Neuronal CD200 conditional knockout (CKO) mice (8-12 weeks) generated by a cross between CD200 floxed and enolase (Eno2) Cre mouse were subjected to a 60-minute middle cerebral artery occlusion (MCAO). Stroke outcomes (infarct size and behavioral deficits) were evaluated at 3, 14, and 30 days after MCAO. Fluoro-Jade B (FJB) and TUNEL staining were used to detect degenerating and apoptotic neurons. BrdU and neurofilament-L immunostaining were performed to assess neurogenesis and axonal growth respectively at 14 and 30 days after injury. Resident and peripheral immune cell infiltration in the brain was examined by flow cytometry (FC). MultiPlex was used to measure plasma and brain cytokine levels. Results: After MCAO, CD200 CKO mice had larger infarcts (3d), more brain tissue atrophy (14d and 30d) and worse behavioral outcomes compared to CD200 floxed control mice. FJB and TUNEL staining revealed significantly more neuronal death and apoptosis in CD200 CKO vs. floxed mice. Neurogenesis and axonal regeneration were also significantly compromised by CD200 CKO. FC results showed that microglia exhibited an enhanced pro-inflammatory phenotype in CKO mice, and there was significantly more peripheral immune cell infiltration in the ischemic brain. CD200 CKO also induced higher plasma pro-inflammatory cytokine levels (TNFα, IL1β, and IL-6). Conclusion: Neuronal loss of CD200 is detrimental in stroke. Neuronal CD200 signaling potentially provides a promising therapeutic target for treatment of neuroinflammatory diseases including stroke. Our future work will focus on over-expression of CD200 in neurons by lentivirus technique, in the hope of inducing beneficial effects in stroke.

Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice.

Renal inflammation is a final common pathway of chronic kidney disease including diabetic nephropathy, which is the leading cause of end-stage renal disease and is associated with high cardiovascular risk and significant morbidity and mortality. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) is a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced activation of proinflammatory mediators. In this study, we investigated the renoprotective properties of IRAK-4 inhibitor AS2444697 in KK/Ay type 2 diabetic mice. Four-week repeated administration of AS2444697 dose-dependently and significantly improved albuminuria; hyperfiltration, as measured by creatinine clearance; renal injury, including glomerulosclerosis; tubular injury markers, including urinary N-acetyl-β-D-glucosaminidase activity; and glomerular podocyte injury markers, including urinary nephrin excretion. In addition, AS2444697 attenuated plasma levels of proinflammatory cytokines, including IL-6; plasma levels of endothelial dysfunction markers, including intercellular adhesion molecule-1; and plasma levels and renal contents of oxidative stress markers. In contrast, AS2444697 did not significantly affect food intake or blood glucose levels. These results suggest that AS2444697 attenuates the progression of diabetic nephropathy mainly via anti-inflammatory mechanisms through inhibition of IRAK-4 activity under diabetic conditions and may represent a promising therapeutic option for the treatment of type 2 diabetic nephropathy.

Inflammatory Biomarkers, Microbiome, Depression, and Executive Dysfunction in Alcohol Users.

Alcohol-related disorders (ARD) are highly prevalent among Latin American-Caribbean countries. Mental disorders are common comorbidities in individuals with ARD. However, the etiology of the association between ARD and mental disorders remains unclear. We examined the association of inflammatory cytokines, microbiome, and other biomakers with measures of depression, social anxiety, and executive functions. We observed a significant increase in cytokine and chemokine expression levels in saliva and plasma in the alcohol group (AG) samples. Also, the salivary bacterial composition in the AG revealed an abundance of Prevotella. Depression symptomatology was markedly higher in the AG, but social anxiety levels were negligible. AG also exhibited executive dysfunctions, which negatively correlated with increased plasma levels of pro-inflammatory cytokines and increased salivary concentrations of Prevotella bacteria. Our study suggests that chronic alcohol use correlates with executive dysfunction, immune system dysregulation, and dysbiosis of the salivary microbiota. Additional studies are needed to understand the role of the microbiome and inflammation in alcohol use and mental comorbidities.