Soluble Tumor Necrosis Factor-α Research Articles

Dysfunction of circulating endothelial progenitor cells in major depressive disorder.

Despite mounting evidence demonstrates circulating endothelial progenitor cells (cEPCs) quantitative changes in depression, no study has investigated cEPC functions in major depressive disorder (MDD). We investigated the role of cEPC adhesive and apoptotic functions in MDD. We recruited 68 patients with MDD and 56 healthy controls (HCs). The depression symptoms, anxiety, psychosomatic symptoms, subjective cognitive dysfunction, quality of life, and functional disability were evaluated using the Hamilton Depression Rating Scale and Montgomery-Åsberg Depression Rating Scale, Hamilton Anxiety Rating Scale, Depression and Somatic Symptoms Scale (DSSS), Perceived Deficits Questionnaire-Depression, 12-Item Short Form Health Survey (SF-12), and Sheehan Disability Scale (SDS), respectively. Working memory and executive function were assessed using a 2-back task and Wisconsin Card Sorting Test (WCST). Inflammatory marker (soluble interleukin-6 receptor, C-reactive protein, and tumor necrosis factor-α receptor-1), cEPC adhesive, and apoptotic levels were measured using in vitro assays. The MDD patients showed significantly lower cEPC adhesive levels than the HCs, and this difference in adhesive function remained statistically significant even after adjusting for inflammatory marker levels. The cEPC adhesion levels were in inverse correlations with commission and omission errors in 2-back task, the percent perseverative response and percent perseverative errors in WCST, and the DSSS and SDS scores, but in positive correlations with SF-12 physical and mental component scores. cEPC apoptotic levels did not differ significantly between the groups. The findings indicate that cEPC adhesive function is diminished in MDD and impacts various aspects of cognitive and psychosocial functions associated with the disorder.

Ectodomain Shedding by ADAM17 Increases the Release of Soluble CD40 from Human Endothelial Cells under Pro-Inflammatory Conditions.

Homozygosity for the C allele of the -1T>C single nucleotide polymorphism (SNP) of the CD40 gene (rs1883832) is associated with susceptibility to coronary heart disease (CHD), enhanced CD40 expression, and shedding. The disintegrin metalloprotease ADAM17 can cleave various cell surface proteins. This study investigates an association between ADAM17-mediated CD40 shedding and inflammation in CC genotype human endothelial cells. Human umbilical vein endothelial cells (HUVEC) carrying the CC genotype were stimulated with soluble CD40 ligand (sCD40L) or tumor necrosis factor-α (TNFα). Messenger RNA and protein expression were determined with standard methods. Levels of high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), and sCD40 in plasma samples from patients with CHD were assessed using ELISA. ADAM17 surface abundance was elevated following stimulation with CD40L and TNFα just as its regulator iRhom2. Inhibition of ADAM17 prevented TNFα-induced sCD40 and soluble vascular cell adhesion molecule-1 release into the conditioned medium and reinforced CD40 surface abundance. Secondary to inhibition of ADAM17, stimulation with CD40L or TNFα upregulated monocyte chemoattractant protein-1 mRNA and protein. Levels of sCD40 and the inflammatory biomarkers hs-CRP and IL-6 were positively correlated in the plasma of patients with CHD. We provide a mechanism by which membrane-bound CD40 is shed from the endothelial cell surface by ADAM17, boosting sCD40 formation and limiting downstream CD40 signaling. Soluble CD40 may represent a robust biomarker for CHD, especially in conjunction with homozygosity for the C allele of the -1T>C SNP of the CD40 gene.

L- and T-type Ca2+ channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma.

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma, which is the leading cause of irreversible blindness. Disruption of Ca2+ homeostasis plays an important role in glaucoma. Voltage-gated Ca2+ channel blockers have been shown to improve vision in patients with glaucoma. However, whether and how voltage-gated Ca2+ channels are involved in retinal ganglion cell apoptotic death are largely unknown. In this study, we found that total Ca2+ current densities in retinal ganglion cells were reduced in a rat model of chronic ocular hypertension experimental glaucoma, as determined by whole-cell patch-clamp electrophysiological recordings. Further analysis showed that L-type Ca2+ currents were downregulated while T-type Ca2+ currents were upregulated at the later stage of glaucoma. Western blot assay and immunofluorescence experiments confirmed that expression of the CaV1.2 subunit of L-type Ca2+ channels was reduced and expression of the CaV3.3 subunit of T-type Ca2+ channels was increased in retinas of the chronic ocular hypertension model. Soluble tumor necrosis factor-α, an important inflammatory factor, inhibited the L-type Ca2+ current of isolated retinal ganglion cells from control rats and enhanced the T-type Ca2+ current. These changes were blocked by the tumor necrosis factor-α inhibitor XPro1595, indicating that both types of Ca2+ currents may be mediated by soluble tumor necrosis factor-α. The intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and nuclear factor kappa-B signaling pathway mediate the effects of tumor necrosis factor-α. TUNEL assays revealed that mibefradil, a T-type calcium channel blocker, reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension. These results suggest that T-type Ca2+ channels are involved in disrupted Ca2+ homeostasis and apoptosis of retinal ganglion cells in glaucoma, and application of T-type Ca2+ channel blockers, especially a specific CaV3.3 blocker, may be a potential strategy for the treatment of glaucoma.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n=22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n=17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. Our results indicate the bidirectional inflammation-depression relationship in BD.

069 Role of tumor necrosis factor-α and soluble tumor necrosis factor-α receptor-1 in the formation of oligomenorhea in adolescent girls with obesity

Introduction: In recent years, the role of adipose tissue producing pro-inflammatory cytokines involved in the regulation of immunity and reproduction has been actively studied. In this regard, it is relevant to study the immune mechanisms of the formation of ovarian dysfunction in adolescent girls with obesity.

Toll-Like Receptors/TNF-α Pathway Crosstalk and Impact on Different Sites of Recurrent Myocardial Infarction in Elderly Patients.

Background Recurrent myocardial infarction is associated with increased mortality. Risk and predictive factors of recurrent myocardial infarction in elderly patients after coronary stenting are not well known. This research sought to investigate the effects of proinflammatory cytokines and toll-like receptor on recurrent myocardial infarction after coronary stenting in elderly patients. Methods We measured the levels of toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor-α receptor-1 (sTNFR-1), soluble tumor necrosis factor-α receptor-2 (sTNFR-2), endothelial progenitor cells (EPCs), and vascular endothelial growth factor (VEGF) in elderly patients with recurrent myocardial infarction and assessed the changes of proinflammatory cytokines and toll-like receptors in elderly patients with recurrent myocardial infarction after coronary stenting. Results Levels of TLR2, TLR3, TLR4, TNF-α, sTNFR-1, and sTNFR-2 were remarkably increased (P < 0.001), and EPCs and VEGF were remarkably lowered (P < 0.001) in the elderly patients with recurrent myocardial infarction after coronary stent implantation. Increased expressions of proinflammatory cytokines and toll-like receptors induced recurrent myocardial infarction after coronary stenting. Elevated expressions of proinflammatory cytokines and toll-like receptors may be used to identify elderly patients who have an increased risk of developing recurrent myocardial infarction after coronary stenting. Conclusion The increase levels of proinflammatory cytokines and toll-like receptors were associated with recurrent myocardial infarction after coronary stenting. Increased expressions of proinflammatory cytokines and toll-like receptors may be clinically useful biomarkers for predicting recurrent myocardial infarction in the elderly patients after coronary stent implantation.

Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy

BackgroundCOVID-19 presents a spectrum of signs and symptoms in pregnant women that might resemble preeclampsia. Differentiation between severe COVID-19 and preeclampsia is difficult in some cases.ObjectiveTo study biomarkers of endothelial damage, coagulation, innate immune response, and angiogenesis in preeclampsia and COVID-19 in pregnancy in addition to in vitro alterations in endothelial cells exposed to sera from pregnant women with preeclampsia and COVID-19.Study DesignPlasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) and from women with normotensive pregnancies as controls (n=10) and patients with preeclampsia (n=13). A panel of plasmatic biomarkers was assessed, including vascular cell adhesion molecule-1, soluble tumor necrosis factor-receptor I, heparan sulfate, von Willebrand factor antigen (activity and multimeric pattern), α2-antiplasmin, C5b9, neutrophil extracellular traps, placental growth factor, soluble fms-like tyrosine kinase-1, and angiopoietin 2. In addition, microvascular endothelial cells were exposed to patients’ sera, and changes in the cell expression of intercellular adhesion molecule 1 on cell membranes and von Willebrand factor release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of p38 mitogen-activated protein kinase phosphorylation. Statistical analysis included univariate and multivariate methods.ResultsBiomarker profiles of patients with mild COVID-19 were similar to those of controls. Both preeclampsia and severe COVID-19 showed significant alterations in most circulating biomarkers with distinctive profiles. Whereas severe COVID-19 exhibited higher concentrations of vascular cell adhesion molecule-1, soluble tumor necrosis factor-α receptor I, heparan sulfate, von Willebrand factor antigen, and neutrophil extracellular traps, with a significant reduction of placental growth factor compared with controls, preeclampsia presented a marked increase in vascular cell adhesion molecule-1 and soluble tumor necrosis factor-α receptor I (significantly increased compared with controls and patients with severe COVID-19), with a striking reduction in von Willebrand factor antigen, von Willebrand factor activity, and α2-antiplasmin. As expected, reduced placental growth factor, increased soluble fms-like tyrosine kinase-1 and angiopoietin 2, and a very high soluble fms-like tyrosine kinase-1 to placental growth factor ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and neutrophil extracellular traps was also detected in preeclampsia compared with controls. Principal component analysis demonstrated a clear separation between patients with preeclampsia and the other groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to von Willebrand factor, soluble tumor necrosis factor-receptor I, heparan sulfate, and soluble fms-like tyrosine kinase-1. Von Willebrand factor multimeric analysis revealed the absence of von Willebrand factor high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A), whereas in healthy pregnancies and COVID-19 patients, von Willebrand factor multimeric pattern was normal.Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of intercellular adhesion molecule 1 and von Willebrand factor in endothelial cells in culture compared with controls. However, the effect of preeclampsia was less pronounced than the that of severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19 and preeclampsia sera showed an increase in p38 mitogen-activated protein kinase phosphorylation. Patients with severe COVID-19 and preeclampsia were statistically different from controls, suggesting that both severe COVID-19 and preeclampsia sera can activate inflammatory signaling pathways.ConclusionAlthough similar in in vitro endothelial dysfunction, preeclampsia and severe COVID-19 exhibit distinctive profiles of circulating biomarkers related to endothelial damage, coagulopathy, and angiogenic imbalance that could aid in the differential diagnosis of these entities.

Elevated levels of sIL-2R, TNF-α and hs-CRP are independent risk factors for post percutaneous coronary intervention coronary slow flow in patients with non-ST segment elevation acute coronary syndrome

To evaluate the association between circulating levels of inflammatory cytokines and the occurrence of post-percutaneous coronary intervention (PCI) coronary slow flow (CSF) in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). CSF after PCI commonly occurs and implies poor outcomes, while the determinants of post-PCI CSF in patients with NSTE-ACS remain controversial. In this multicenter case control study, 176 patients diagnosed with NSTE-ACS and with post-PCI CSF occurred composed of CSF group, while 352 matched NSTE-ACS patients composed control group. Corrected thrombolysis in myocardial infarction frame count (cTFC), circulating levels of inflammatory cytokines and PCI related parameters were analyzed using Logistic regression models. Among 528 patients with median age of 67 (59–76) and male proportion of 65.5%, 176 (35.0%) patients had occurrence of post-PCI CSF defined as cTFC ≥ 24. Patients with CSF presented more intense inflammatory activity revealed by higher levels of white blood cell, high-sensitivity C-reactive protein (hs-CRP), interleukin-1ß (IL-1ß), soluble IL-2 receptor (sIL-2R), IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α), while PCI related parameters were comparable. Correlation analysis showed cTFC was positively correlated with those inflammatory cytokines. Logistic regression model indicates that hs-CRP (odds ratio (OR) = 3.038, 95% confidence interval (CI) 1.545–5.975), sIL-2R (OR = 2.103, 95% CI 1.959–4.026) and TNF-α (OR = 3.708, 95% CI 1.426–9.641) were valuable predictors for CSF occurrence. Elevated circulating levels of inflammatory cytokine including hs-CRP, sIL-2R and TNF-α rather than PCI related parameters could predict post-PCI CSF in patients with NSTE-ACS.

Abstract WP210: Eicosapentaenoic Acid (EPA) Decreases Cytokine Release And Inflammatory Proteins In Brain Vascular Endothelium During Inflammation

Background: Brain vascular endothelial cell (EC) dysfunction is characterized by release of pro-inflammatory mediators that contribute to atherosclerosis and ischemic stroke. Treatment with icosapent ethyl (IPE), the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA), reduced first and total ischemic strokes each by 36%, without increasing hemorrhagic stroke, in statin-treated patients with elevated cardiovascular risk (REDUCE-IT). We tested the effects of EPA on cytokine release and expression of inflammatory proteins from brain microvascular ECs during inflammation. Methods: Human brain microvascular endothelial cells (HBECs) were pretreated with the cytokine IL-6 at 12 ng/ml for 2 h before treatment with EPA (40 μM) for 24 h. Proteomic analysis was performed using LC/MS to capture relative expression levels. Only significant changes in protein expression between treatment groups &gt;1-fold were analyzed. Gene set enrichment analysis was also performed on all significantly regulated proteins to identify groups of proteins (pathways) that were affected. Levels of soluble intercellular adhesion molecule-1 (sICAM-1) and tumor necrosis factor-α (TNF-α) were measured by immunochemistry (ELISA). Results: IL-6 exposure produced increased levels of sICAM-1 and TNF-α by 102% and 147% (p&lt;0.001), respectively, in brain ECs compared with vehicle. EPA treatment reduced release of sICAM-1 by 43% (p&lt;0.001) and TNF-α by 52% (p&lt;0.001) compared to IL-6 alone. EPA also downregulated 43 proteins involved in the “neutrophil degranulation” pathway in brain ECs (p-adjusted = 2.63 х 10 -12 ), including heat shock protein 90-alpha and beta by 1.1-fold each relative to IL-6 alone. Conclusions: In brain vascular ECs, EPA significantly reduced expression of pro-inflammatory mediators and proteins associated with neutrophil degranulation under inflammatory conditions. The ability of EPA to reverse brain EC dysfunction during inflammatory may contribute to reductions in stroke risk.

Pro-inflammatory cytokines and suicidal behavior among patients with bipolar I disorder

ObjectiveSuicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. Methods77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Åsberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. ResultsPatients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p < .05). ConclusionThis study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.

Dietary Strawberries Improve Biomarkers of Antioxidant Status and Endothelial Function in Adults with Cardiometabolic Risks in a Randomized Controlled Crossover Trial.

Strawberries, a popularly consumed berry fruit, are rich in bioactive compounds with antioxidant effects. In this study, we examined the effects of two dietary achievable doses of strawberries on the antioxidant status and biomarkers of endothelial function in adults with features of metabolic syndrome and a confirmed low baseline of fruit and vegetable intake. In a 14-week randomized controlled crossover study, participants were assigned to one of three groups for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or 2.5 servings (high dose: 32 g strawberry powder/day). Blood samples and health data were collected at baseline and at the end of each four-week phase of intervention. Thirty-three participants completed all three phases of the trial. Significant increases were observed in serum antioxidant capacity and superoxide dismutase activity as well as decreases in lipid peroxidation after both low and high dose strawberry phases when compared with the control phase. Significant decreases were also observed in soluble vascular cell adhesion molecule-1 and tumor necrosis factor-α with the high dose strawberry phase. These data confirm that consuming strawberries for four weeks significantly improves antioxidant status, endothelial function, and inflammation in adults with cardiometabolic risks.

Suppression of Transmembrane Tumor Necrosis Factor Alpha Processing by a Specific Antibody Protects Against Colitis-Associated Cancer.

Soluble tumor necrosis factor-α (sTNF-α) plays an important role in colitis-associated cancer (CAC); however, little is known about transmembrane TNF-α (tmTNF-α). Here, we observed an increase in sTNF-α mainly in colitis tissues from an azoxymethane/dextran sodium sulfate (DSS)-induced CAC mouse model whereas tmTNF-α levels were chiefly increased on epithelial cells at the tumor stage. The ratio of intracolonic tmTNF-α/sTNF-α was negatively correlated with the levels of pro-inflammatory mediators (IL-1β, IL-6, and NO) and M1 macrophages but positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and the level of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect of tmTNF-α. This effect of tmTNF-α was confirmed again by the induction of resistance to LPS in colonic epithelial cell lines NCM460 and HCoEpiC through the addition of exogenous tmTNF-α or transfection of the tmTNF-α leading sequence that lacks the extracellular segment but retains the intracellular domain of tmTNF-α. A tmTNF-α antibody was used to block tmTNF-α shedding after the first or second round of inflammation induction by DSS drinking to shift the time window of tmTNF-α expression ahead to the inflammation stage. Antibody treatment significantly alleviated inflammation and suppressed subsequent adenoma formation, accompanied by increased apoptosis. An antitumor effect was also observed when the antibody was administered at the malignant phase of CAC. Our results reveal tmTNF-α as a novel molecular marker for malignant transformation in CAC and provide a new insight into blocking the pathological process by targeting tmTNF-α processing.

Inflammation, cognitive dysfunction, and suicidal ideation among patients with major depression.

Dysregulated proinflammatory cytokines have been shown to be associated with suicidal behavior. Cognitive deficits in working memory and inhibitory control have been demonstrated in depressed patients and people with suicidal ideation (SI). However, the association between proinflammatory cytokines, SI, and cognitive deficits in patients with major depressive disorder (MDD) remains unclear. A total of 77 patients with MDD and age-/sex-matched 60 healthy individuals were recruited. MDD patients were divided into two groups: with SI (n=36) and no SI (n=41). SI was defined by a score of ≥2 in item 3 of the 17-item Hamilton Rating Scale for Depression. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1, and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. Patients with SI had higher levels of CRP than those without SI and controls (P=.007). CRP was positively associated with SI (β=0.21, P=.037), independent of cognitive function and depressive symptoms. Furthermore, SI was associated with cognitive deficits in working memory and inhibitory control after adjusting for confounding factors (P<.05). Our findings suggest that higher levels of serum CRP and deficits in working memory and inhibitory control may be associated with higher SI among patients with MDD.

A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production

Ikarugamycin (IK) is an antibiotic which has been reported to have a variety of functions, such as inhibition of clathrin-mediated endocytosis (CME), anti-tumor effects and regulation of the immune system. Whether IK influences cytokine production is poorly understood. We have investigated the relationship between IK and production of tumor necrosis factor-α (TNF). TNF plays a pivotal role in pathogenesis of many diseases. Although the dynamics of soluble TNF (sTNF) has been widely explored so far, the functions of the membrane form of TNF (mTNF) have not been fully elucidated. We demonstrated that IK increases the amount of mTNF and prolongs the duration of TNF expression. This effect is unrelated to the shedding activity of disintegrin and metalloproteinase domain-containing protein 17 (ADAM 17). Our results revealed that there is a mechanism to terminate inflammation at the cellular level which IK dysregulates. Furthermore, IK can be a tool to study TNF signaling due to its effect of increasing mTNF expression.

Understanding Restrictive Versus Liberal Fluid Therapy for Major Abdominal Surgery Trial Results: Did Liberal Fluids Associate With Increased Endothelial Injury Markers?

The restrictive versus liberal fluid therapy for major abdominal surgery trial was an international, randomized, assessor-blinded trial comparing restrictive with liberal IV fluid regimens that represented traditional care in patients undergoing major abdominal surgery. Cohort of restrictive versus liberal fluid therapy for major abdominal surgery bloods was collected at a single major site (161 patients) prior to, day 1 and day 3 after surgery. Bloods were blindly and randomly batch analyzed for plasma markers of endothelial/glycocalyx injury-angiopoietin-1, angiopoietin-2, soluble tyrosine-protein kinase-2 receptor, soluble intracellular adhesion molecule-1, syndecan, and tumor necrosis factor-α. Data were examined as restrictive versus liberal enrollment groups and high versus low (± 5,000 mL) fluid groups. Differences were examined by linear mixed modeling. There were no significant differences in any biomarkers between the restrictive (n = 75) and liberal (n = 86) groups. When examined as low (n = 81) and high (n = 79) fluid groups, plasma angiopoietin-2 (p = 0.009) and soluble intracellular adhesion molecule-1 (p = 0.01) were elevated in the high fluid group. There were no differences in other biomarkers. Although these results are consistent with previous findings of vascular injury following liberal fluid therapy, they suggest alternative mechanisms underlie the clinical outcomes from restrictive versus liberal fluid therapy for major abdominal surgery study. NCT01424150.

Optimization of culture conditions for high-level expression of soluble and active tumor necrosis factor-α in E. coli

Anti-TNF inhibitors exert their therapeutic effect by inhibition of the excessive amounts of TNF-α within the body. Recombinant TNF-α should be produced in a soluble refolded form to investigate the effectiveness and efficiency of anti-TNF-α compounds. In this research, the designed cassette was subcloned in the pET28a expression vector and expressed in E. coli BL21 (DE3). The identity of the protein was confirmed through SDS-PAGE and Western blotting. After optimizing expression conditions, protein purification was performed using native Ni-NTA affinity chromatography. The biological activity of the soluble recombinant TNF-α was investigated using MTT assay. Also, the affinity of an anti-TNF-α agent, Altebrel, was investigated against the expressed protein through ELISA. Optimization of TNF-α expression conditions represented that the highest expression could be achieved at 37 °C using 0.5 mM IPTG 6 h post-induction. The recombinant protein represented an inhibitory effect on the L929 murine fibroblast cell line and was successfully detected by Altebrel in ELISA. Binding kinetics were also studied using Cimzia as an anti-TNF-α molecule and 7.2 E−13M was calculated as the equilibrium dissociation constant value (KD). The significant expression level of the recombinant protein in the soluble form, its high purity, and assessment of its biological activity showed that the expressed protein could be used in tests of ELISA and MTT to assess the activity of anti-TNF-α agents.

Increased Proinflammatory Cytokines, Executive Dysfunction, and Reduced Gray Matter Volumes In First-Episode Bipolar Disorder and Major Depressive Disorder

BackgroundsThe association between systemic inflammation, executive dysfunction, and gray matter (GM) volume difference in first-episode affective disorders, including bipolar and major depressive disorders, is unclear. MethodsTwenty-two patients with first-episode bipolar disorder, 22 age- and sex-matched patients with first-episode major depressive disorder, and 22 matched controls were enrolled in our study; all patients underwent comprehensive assessments, including clinical assessment, executive function examination (Wisconsin card sorting test [WCST]), proinflammatory cytokine receptors (soluble interleukin-6 receptor and tumor necrosis factor-α receptor 1 [TNFR1]), and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze the GM volume difference between bipolar and major depressive disorders. ResultsPatients with bipolar disorder were more likely to exhibit higher levels of TNFR1 (P = .038), more number of deficits in WCST (P < .05), and smaller GM volume in the middle frontal cortex (uncorrected voxel level P < .001) compared with those with major depressive disorder and healthy controls. Positive associations were observed between the middle frontal cortex volume, executive function, and the TNFR1 level. DiscussionGM volume reduction in the middle frontal cortex, a greater level of systemic inflammation, and executive dysfunction were observed in first-episode affective disorders, especially bipolar disorder. A positive correlation between middle frontal cortex volume, executive function, and the TNFR1 level may indicate a divergent effect of brain and systemic inflammation functioning in the early phase (first episode) of affective disorder.

Association of soluble interleukin-2 receptor α and tumour necrosis factor receptor 1 with heart failure: The Multi-Ethnic Study of Atherosclerosis.

AimsSoluble tumour necrosis factor‐α receptor 1 (sTNF‐αR1) and interleukin‐2 receptor α (sIL‐2Rα) predict incident heart failure (HF) in the elderly population. However, the association of these biomarkers with HF in a multi‐ethnic asymptomatic population is unclear. We aimed to investigate the association of sTNF‐αR1 and sIL‐2Rα with incident HF in a multi‐ethnic population of middle age and older participants.Methods and resultsThe multi‐ethnic study of atherosclerosis is a prospective population‐based study of 6814 participants aged 45–84 years who were free of clinical cardiovascular disease at enrolment. We included 2869 participants with available sTNF‐αR1 or sIL‐2Rα level measurement at baseline multi‐ethnic study of atherosclerosis exam (2000–2002). We used Cox proportional‐hazards model to investigate the association between sTNF‐αR1 and sIL‐2Rα with incident HF after adjusting for traditional cardiovascular risk factors and coronary artery calcium score measured by cardiac computed tomography. Among the included participants, the mean (standard deviation) age was 61.6 (10.2) years and 46.7% were men. The median (interquartile range) sTNF‐αR1 and sIL‐2Rα were 1293 (1107–1547) and 901 (727–1154) pg/mL. During a median follow‐up of 14.2 (interquartile range: 11.7–14.8) years, 130 participants developed HF. In multivariable analysis, the hazard ratio (95% confidence interval, P value) of incident HF for each standard deviation increment of log‐transformed sTNF‐αR1 and sIL‐2Rα was 1.43 (1.21–1.7, P ≤ 0.001) and 1.26 (1.04–1.53, P = 0.02), respectively. Excluding participants with interim coronary heart disease, we found a statistically significant association between sTNF‐αR1 and HF with hazard ratio of 1.39 (95% confidence interval: 1.11 to 1.74, P = 0.005) and sIL‐2Rα and HF showing a hazard ratio of 1.39 (95% confidence interval: 1.09 to 1.76, P = 0.007).ConclusionssTNF‐αR1 and sIL‐2Rα are associated with a higher risk of incident HF in a multi‐ethnic cohort without a previous history of cardiovascular disease.

Biomarkers of Inflammation in Heart Failure Patients with Reduced and Preserved Ejection Fractions: Multi-Ethnic Study of Atherosclerosis

Background: Limited evidence exists examining the relationship between biomarkers of inflammation and heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) subtypes. Purpose: Examine the relationships between biomarkers of inflammation and incident heart failure subtypes in a diverse, population-based sample. Methods: Study sample included 6,814 adult (45-84 years of age) participants in the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease at baseline. The upper quartile of log-transformed C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor-α receptor-1 (sTNFR1) was considered elevated. Heart failure participants with an ejection fraction (EF) <50% were considered HFrEF and those with a borderline EF (41-49%) or EF ≥50% were considered HFpEF. Results: During an average of 11.2 years of follow-up, there were 178 incident heart failure diagnoses; 57 with HFpEF, 86 with HFrEF, and 35 with unknown EF. Following adjustment for age, gender, race/ethnicity, blood pressure, waist circumference, smoking, LDL-C, triglycerides, HDL-C, atrial fibrillation, medications, and level of physical activity, logistic regression revealed significantly increased odds of HFrEF in those with elevated CRP (Odds Ratio [OR] 1.96; 95% Confidence Interval [CI] 1.18-3.13, p<0.01), sTNFR1 (OR 1.95; 95% CI 1.01-3.76, p=0.05) and IL-6 (OR 2.20; 95% CI 1.27-3.81, p<0.01). Comparatively, significantly increased odds of HFpEF were observed only in those with elevated IL-6 (OR 2.21; 95% CI 1.12-4.35, p<0.05). Conclusion: In a diverse sample of U.S. adults, elevated CRP, sTNFR1, and IL-6 levels were associated with increased odds of HFrEF and elevated IL-6 was significantly associated with HFpEF.

Clinical efficacy of aspirin combined with clopidogrel in treating cerebral infarction and its effect on serum hs-CRP, sICAM-1 and TNF-α.

Clinical efficacy of aspirin combined with clopidogrel in treating cerebral infarction and its influence on serum high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and tumor necrosis factor-α (TNF-α) were explored. Ninety patients with acute cerebral infarction treated in Yidu Central Hospital of Weifang were analyzed, and those treated with aspirin alone were group A (n=40) and those treated with aspirin and clopidogrel were group B (n=50) according to the different treatment plans. The NIHSS score, total effective rate and incidence rate of adverse reactions after treatment and admission were compared between the two groups. The expression level of hs-CRP was detected by enzyme-linked immunosorbent assay, and the expression levels of sICAM-1 and TNF-α were analyzed by radioimmunoassay before treatment and three weeks after surgery, respectively, and they were analyzed and compared. After treatment, the total effective rate of patients in group B was significantly higher than that of group A (P<0.05). The general clinical baseline information, NIHSS score, and the expression levels of hs-CRP, sICAM-1, and TNF-α of patients in group B were significantly improved after treatment compared with those before treatment (P<0.05), and the NIHSS score and the expression levels of serum hs-CRP, sICAM-1, and TNF-α of those in group B were significantly lower than those in group A (P<0.05). Combination therapy of aspirin and clopidogrel can improve cerebral infarction effectively, and inhibit the expression levels of hs-CRP, sICAM-1 and TNF-α more effectively than aspirin alone.