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Study objectives: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest i...
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Study objectives: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST).
Methods: Circulating levels of tumor necrosis factor (TNF)-α, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327).
Results: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period.
Conclusions: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.
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The pathophysiology of the vasovagal syncope (WS) is still not completely understood [1]. The Bezold-Jarisch reflex is the habitual model used to explain WS, nevertheless there is a vasodilating response in denervated animals subj...
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The pathophysiology of the vasovagal syncope (WS) is still not completely understood [1]. The Bezold-Jarisch reflex is the habitual model used to explain WS, nevertheless there is a vasodilating response in denervated animals subjected to hemorrhage [2], even in cardiac transplant receptors [3], and in patients with muscarinic blockade by atropine [4], which suggests that other mechanisms are also involved.
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Aim: To study the effects of propyl gallate on the interaction of tumor necrosis factor-α (TNF-α) with its soluble receptor, sTNFR-I. Methods: Interactions between TNF-α and sTNFR-I were analyzed using an IAsys biosensor. sTNFR...
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Aim: To study the effects of propyl gallate on the interaction of tumor necrosis factor-α (TNF-α) with its soluble receptor, sTNFR-I. Methods: Interactions between TNF-α and sTNFR-I were analyzed using an IAsys biosensor. sTNFR-I was immobilized on the carboxymethyl dextran (CMD) surface of the IAsys biosensor cuvettes, and TNF-α preincubated with different concentrations of propyl gallate was added to the cuvettes. The resonant angle shift caused by the binding between TNF-α and sTNFR-I was then recorded. Results: sTNFR-I was immobilized on the CMD surface at a density of 2.76 ng/mm~2. TNF-α then bound the immobilized sTNFR-I specifically, and propyl gallate was able to enhance the binding between TNF-α and sTNFR-I in a dose-dependent manner. Conclusion: The binding between TNF-α and sTNFR-I is one of the targets that propyl gallate can act on in vivo. The IAsys biosensor offers a new clue as to the study on the mechanisms of action of propyl gallate.
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Serum levels of proinflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis factor alpha, (TNF-α), and their inhibitors, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor 1 (sTNFR1), were determined by enzyme-...
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Serum levels of proinflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis factor alpha, (TNF-α), and their inhibitors, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor 1 (sTNFR1), were determined by enzyme-linked immunosorbent assay in 104 patients with Behçet’s disease (65 active, 39 inactive) and 40 healthy controls. The levels of IL-1β and IL-1ra were significantly higher in both active and inactive patients than in control subjects (P<0.01 and P< 0.01, respectively). The concentrations of TNF-α and sTNFR1 were found to be higher in active patients than in controls (P< 0.01 and P< 0.001, respectively). There were no significant differences in the serum levels of these cytokines and their inhibitors between active and inactive patients. Significant increases in mean C-reactive protein level and erythrocyte sedimentation rate were found in patients with active vs inactive disease (P< 0.001 and P< 0.05, respectively). C-reactive protein values correlated with erythrocyte sedimentation rate but not with cytokines or their inhibitors. Our conclusion is that elevated serum TNF-α and sTNFR1 seem to be important inflammatory mediators in Behçet’s disease. The statistically significant increase in these levels may arise from the severity of inflammation in the tissue or organ involved.
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This study investigated the plasma levels of tumor necrosis factor a (INF-alpha) and the expression levels of TNF receptors (TNFRs) in patients with multiple trauma, together with the association between the levels of this cytokin...
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This study investigated the plasma levels of tumor necrosis factor a (INF-alpha) and the expression levels of TNF receptors (TNFRs) in patients with multiple trauma, together with the association between the levels of this cytokine and these cytokine receptors with the severity of traumatic injury. Blood samples were obtained from 60 multiple trauma patients at hospital admission (within 2 h of injury), and 6-8 h and 1-5 days after admission. The plasma levels of TNF-alpha and TNFR1/TNFR2 were detected using enzyme immunoassay. TNFR1 and TNFR2 expression levels on leukocytes, including neutrophils, lymphocytes and monocytes, were determined by flow cytometry. Clinical parameters were determined by injury severity score (ISS). At hospital admission, the plasma TNF-alpha and soluble TNFR levels in the trauma patients were elevated compared with those of healthy controls. Increased expression levels of TNFR1 and TNFR2 were also detected on leukocytes, particularly on lymphocytes and monocytes. The expression levels of the cytokine and the corresponding receptors were correlated with the ISS. TNF-alpha and TNFR expression levels remained significantly elevated for up to the third to fifth day following the traumatic injury. In the trauma patients, increased levels of TNF-alpha and TNFRs were correlated with the severity of traumatic injury in the early post-injury period, supporting the hypothesis that trauma-provoked organ dysfunction may be caused by an overwhelming auto-destructive inflammatory response.
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The host immune responses that mediate Chlamydia-induced chronic disease sequelae are incompletely understood. The role of TNF-alpha, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2), in Chlamydia pneumoniae (CPN)-induced athero...
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The host immune responses that mediate Chlamydia-induced chronic disease sequelae are incompletely understood. The role of TNF-alpha, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2), in Chlamydia pneumoniae (CPN)-induced atherosclerosis was studied using the high-fat diet-fed male C57BL/6J mouse model. Following intranasal CPN infection, TNF-alpha knockout (KO), TNFR1 KO, TNFR2 KO, and TNFR 1/2 double-knockout, displayed comparable serum anti-chlamydial antibody response, splenic antigen-specific cytokine response, and serum cholesterol profiles compared to wild type (WT) animals. However, atherosclerotic pathology in each CPN-infected KO mouse group was reduced significantly compared to WT mice, suggesting that both TNFR1 and TNFR2 promote CPN-induced atherosclerosis. (C) 2018 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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Inflammation including local accumulations of tumor necrosis factor alpha (TNF-alpha) is a part of Alzheimer's disease pathology and may exacerbate age-related neurodegeneration. Most studies on TNF-alpha and TNF neuronal receptor...
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Inflammation including local accumulations of tumor necrosis factor alpha (TNF-alpha) is a part of Alzheimer's disease pathology and may exacerbate age-related neurodegeneration. Most studies on TNF-alpha and TNF neuronal receptors are conducted by using embryonic neurons. Few studies consider age-related deficits that may occur in neurons. Age-related changes in susceptibility to TNF-alpha through TNF receptor 1 (TNFR1) and receptor 2 (TNFR2) expression could increase susceptibility to beta-amyloid (1-42, Abeta42). Evidence is conflicting about which receptor mediates survival and/or apoptosis. We determined how aging affects receptor expression in cultured adult rat cortical neurons. Old neurons were more susceptible to Abeta42 toxicity than middle-aged neurons, and the addition of TNF-alpha was neuroprotective in middle-aged neurons, but exacerbated the toxicity from Abeta42 in old neurons. These pathologic and protective responses in old and middle-aged neurons, respectively, correlated with higherstarting TNFR1 and TNFR2 mRNA levels in old vs. middle-aged neurons. Middle-aged neurons treated with TNF-alpha plus Abeta42 did not show an increase in either TNFR1 or TNFR2 mRNA, but old neurons showed an up-regulation in TNFR2 mRNA and not TNFR1 mRNA. Despite these mRNA changes, surface immunoreactivity of both TNFR1 and TNFR2 increased with the dose of TNF-alpha in middle-aged neurons. However, middle-aged neurons treated with TNF-alpha plus Abeta42 showed an up-regulation in both TNFR1 and TNFR2 surface expression, whereas old neurons failed to up-regulate surface expression of either receptor. These findings support the hypothesis that age-related changes in TNF-alpha surface receptor expression contribute to the neuronal loss associated with inflammation in Alzheimer's disease.
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Background: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. Methods: Normotensive men (NT, n=60) and treated stage 2 and 3 ...
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Background: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. Methods: Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately. Results: HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-α levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters. Conclusion: These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT.
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Activation of inflammatory processes has been observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor-α (TNF-α) sig...
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Activation of inflammatory processes has been observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor-α (TNF-α) signaling system plays a central role. TNF-α converting enzyme (TACE) does not only cleave pro-TNF-α but also TNF receptors, however, whether the TACE activity and soluble TNF receptors (sTNFRs) were changed in the plasma were not clear. The aim of this study was to determine whether the levels of TACE activity and sTNFRs are sufficiently altered in the plasma of AD patients to be helpful in AD diagnosis. We examined TACE levels in the plasma of 153 patients with AD, 98 patients with amnestic mild cognitive impairment (aMCI), 53 patients with vascular dementia (VaD), and 120 age-matched healthy control subjects, and found TACE activity and sTNFRs were significantly higher in patients with AD and aMCI compared with control subjects (TACE: P< 0.001, P< 0.01; sTNFR1: P< 0.001, P< 0.001; sTNFR2: P< 0.001, P< 0.01, respectively). The TACE activity and sTNFRs levels in VaD patients were significantly higher than the levels observed in AD patients (TACE activity: P< 0.001, sTNFR1: P< 0.01, sTNFR2: P< 0.01). In the plasma of AD patients, the levels of both TACE activity and sTNFRs positively correlated with the levels of Aβ40 and negatively correlated with the ratio of Aβ42/Aβ40. AD patients with at least one copy of the ApoEε4 allele showed higher TACE activity and sTNFR plasma levels compared with patients without the ApoEε4 allele. We then combined the data on plasma TACE activity, sTNFRs, and Aβ with the presence of the APOEε4 allele and found that this biomarker panel exhibited a high sensitivity and specificity for discriminating AD patients from non-demented control subjects and VaD patients.
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Objective: To investigate membrane tumor necrosis factor receptor 1 protein expression level in deeidua and concentration of soluble tumor necrosis factor receptor 1 in serum in women with unexplained early spontaneous abortion, t...
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Objective: To investigate membrane tumor necrosis factor receptor 1 protein expression level in deeidua and concentration of soluble tumor necrosis factor receptor 1 in serum in women with unexplained early spontaneous abortion, threatened abortion, and compare the levels with healthy pregnant women. Methods: Thirty-seven women with unexplained early spontaneous abortion, 27 women with threatened abortion, and 34 healthy pregnant women undergoing artificial abortion of pregnancy at 6 - 10 weeks of gestation were selected. Decidual samples were collected when women were undergoing artificial abortion, and blood samples were collected at the same time. The level of membrane tumor necrosis factor receptor 1 in deeidua was detected by flow cytometer, and the concentration of soluble tumor necrosis factor receptor 1 in sera was measured with an enzyme-linked immunosorbent assay. Results: The percentages of membrane tumor necrosis factor receptor 1 positive decidual cells were 16.42 +- 7.10 Mean +- SD for women with unexplained early spontaneous abortion and 13.14 +-6.30 for healthy pregnant women ( P < 0.05) . Serum concentration of soluble tumor necrosis factor receptor 1 was significantly higher in women with unexplained early spontaneous abortion than in healthy pregnant women and in women with threatened abortion, and no difference was found between healthy pregnant women and women with threatened abortion. Conclusion: Women with unexplained early spontaneous abortion present significantly higher expression of tumor necrosis factor receptor 1 than healthy pregnant women, suggesting that over- expression of tumor necrosis factor receptor 1 may contribute to the development of early spontaneous abortion.
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