Increased Serum Levels Of TNF-α Research Articles

Fried Soybean Oil Causes Systemic Low-Grade Inflammation by Disrupting the Balance of Gut Microbiota in Mice.

Previous reports have mainly investigated the long-term effects (>30 d), such as gut microbiota dysbiosis and systemic low-grade inflammation, in mice fed fried oil. However, short-term intake of deep-fried oil is more likely to occur in daily life, and such studies are lacking. This study aimed to investigate the short-term effects of fried oil intake on systemic low-grade inflammation. Male Kunming mice were fed non-fried soybean oil or low (25%), medium (50%), or high (100%)-fried oil at 4.4 g/kg for 6 d. Serum and fecal samples were collected on day 7. In all groups fed fried oil, the serum levels of tumor necrosis factor (TNF-α) were significantly elevated 2-4-fold. Among the gut microbiota, the abundance of Alloprevotella significantly decreased by up to 76%, while Lactobacilli significantly increased by up to 385%. The fecal valeric acid content was significantly increased and positively correlated with TNF-α levels. Both valeric acid and TNF-α levels were positively correlated with the abundance of Lactobacilli and negatively correlated with that of Alloprevotella. In summary, a short-term ingestion of even low doses of fried oil alters the gut microbiota Alloprevotella and Lactobacilli and increases fecal valeric acid content, which correlates with increased serum TNF-α levels.

Genistein mitigates nitroglycerine-induced migraine: modulation of nitric oxide-mediated vasodilation and oxidative stress.

Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress.

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

PurposeThe receptor-interacting protein kinase (RIPK4) has an oncogenic function in melanoma, regulates NF-κB and Wnt/β-catenin pathways, and is sensitive to the BRAF inhibitors: vemurafenib and dabrafenib which lead to its decreased level. As its role in melanoma remains not fully understood, we examined the effects of its downregulation on the transcriptomic profile of melanoma.MethodsApplying RNA-seq, we revealed global alterations in the transcriptome of WM266.4 cells with RIPK4 silencing. Functional partners of RIPK4 were evaluated using STRING and GeneMANIA databases. Cells with transient knockdown (via siRNA) and stable knockout (via CRISPR/Cas9) of RIPK4 were stimulated with TNF-α. The expression levels of selected proteins were assessed using Western blot, ELISA, and qPCR.ResultsGlobal analysis of gene expression changes indicates a complex role for RIPK4 in regulating adhesion, migration, proliferation, and inflammatory processes in melanoma cells. Our study highlights potential functional partners of RIPK4 such as BIRC3, TNF-α receptors, and MAP2K6. Data from RIPK4 knockout cells suggest a putative role for RIPK4 in modulating TNF-α-induced production of IL-8 and IL-6 through two distinct signaling pathways—BIRC3/NF-κB and p38/MAPK. Furthermore, increased serum TNF-α levels and the correlation of RIPK4 with NF-κB were revealed in melanoma patients.ConclusionThese data reveal a complex role for RIPK4 in regulating the immune signaling network in melanoma cells and suggest that this kinase may represent an alternative target for melanoma-targeted adjuvant therapy.

Impact of TNF-α profile in recurrent pregnancy loss pathogenesis: A patient based study from Assam

BackgroundLacunae exist in understanding the underlying etiology in majority of recurrent pregnancy loss (RPL) cases. Given the significance of regulated immune-modulation in pregnancy, and the central role of pro-inflammatory TNF-α plays in it; this study targeted to appraise the significance of TNF-α profile in RPL pathogenesis in an ethnically distinct population from Assam, India. MethodsTerm delivery, medically terminated pregnancy (MTP) and RPL cases (based on ASRM criteria) were enrolled with no anatomical and chromosomal abnormalities or pathological infections; and blood and/or placenta/product of conceptus (POC) tissue samples were collected with informed consent. Serum level and tissue level TNF-α expression profile were screened using specific molecular tools, and was correlated with TNF-α −308 G/A genotype; for its association with RPL predisposition. ResultsA significant gestation specific increase in serum TNF-α levels was observed in MTP cases (19.932 ± 4.407 pg/mL) compared to term delivery subjects (p = 0.001), while a comparable levels were observed with RPL cases (22.709 ± 5.833 pg/mL) (p = 0.646). A site specific (POC) increased expression was observed in RPL compared to MTP cases at both at transcript (6.37 ± 3.714 folds) and protein levels. The TNF-α -308 variant genotype was associated with increased predisposition to RPL (OR = 1.721) compared to MTP as well as significantly increased serum TNF-α levels (p = 0.017); especially in subjects with a homozygous TNF-α -308 A/A genotype. ConclusionOur data emphasizes on the importance of site specific TNF-α expression levels in RPL pathogenesis in the studied population, and underlines its importance in screening, clinical stratification, and therapeutics by molecular targeting using TNF-α inhibitors.

Celastrol induces caspase-dependent apoptosis of hepatocellular carcinoma cells by suppression of mammalian target of rapamycin.

To investigate the efficacy of celastrol treatment of hepatocellular carcinoma (HCC) cells in vitro and in vivo and to propose a mechanism of action. A human HepG2 liver cancer cell line and a xenograft tumor model were used to investigate the effects of celastrol on HCC in vitro and in vivo. A CCK-8 kit was used to detect cell viability. Flow cytometry and terminal-deoxynucleoitidyl transferase mediated nick end labeling staining were used to detect apoptosis. Western blotting and immunohistochemistry were used to detect the expression of cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, cleaved-PARP, mammalian target of rapamycin (mTOR), and p-mTOR. Hematoxylin-eosin staining was used to observe the tissue morphology. Celastrol decreased the viability of HepG2 cells and induced apoptosis. Western blot assays indicated that celastrol up-regulated cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, and cleaved-PARP by inhibiting the phosphorylation of mTOR in HepG2 cells. Moreover, celastrol inhibited the tumor growth in a xenograft model. Celastrol also induced caspase-dependent apoptosis (up-regulation of cleaved-caspase- 3, -8, -9, and cleaved-PARP) and inhibited the activation of mTOR in vivo. Celastrol induces caspase-dependent apoptosis in HCC cells by inhibiting the activation of mTOR.

Serum progranulin to TNF-α ratio in patients with gonarthrosis.

Progranulin (PGRN) is a growth factor that has antiinflammatory, immunosuppressive, and chondroprotective effects. It blocks Tumor Necrosis Factor-α (TNF-α) signal pathway by binding its receptor. Recently, it has been claimed that PGRN may be overexpressed in patients with Osteoarthritis (OA). However, these patients tend to be obese and obesity also may be one of the factors that affect PGRN levels. The aim of this study was to compare the PGRN levels of patients with Knee OA (KOA) with that of healthy controls by eliminating the effect of obesity and to evaluate PGRN-to-Tumor Necrosis Factor-α (TNF-α) ratio in KOA, both of which were investigated first in literature by this study. A total of 80 individuals (40 patients with KOA and 40 healthy controls) were included in this study. The patients and controls were divided into two groups according to their Body Mass Indexes (BMI): nonobese (BMI between 18.5 and 24.9) and obese (BMI of 30 or higher). Each of the groups included 20 subjects and had an equal number of men and women. Blood samples were obtained from all participants, and the serum PGRN and TNF-α levels were measured using commercial ELISA kits. There was no difference among groups in terms of age (P = 0.416) and gender distribution. There was no statistical difference among study groups with regard to serum PGRN levels. Serum TNF-α levels were significantly higher in obese controls (P < 0.001) and nonobese patients (P = 0.003) compared to that of nonobese healthy controls. Correspondingly, serum PGRN-to-TNF-α ratio was considerably lower in obese controls (P < 0.001) and nonobese patients (P < 0.001) by comparison with that of nonobese healthy controls. We determined that both obesity and KOA increased serum TNF-α levels and concordantly decreased serum PGRNto- TNF-α ratio. The results of the study suggest that the activation of the PGRN pathway and/or the inhibition of the TNFα pathway may be essential in terms of the reestablishment of the disrupted inflammatory balance in patients with KOA. Level III, Diagnostic study.

The effect of phototherapy on serum level of tumor necrosis factor alpha in neonates in Damietta governorate

Background: Jaundice is one of the most common conditions confronting neonatologists daily. Phototherapy is generally regarded as a safe method for treating hyperbilirubinemia, but it may also lead to undesired effects, one of these effects that it can affect the function of the immune system of the newborn. Aim of the work: The aim of the work was to study the effect of phototherapy on the serum level of tumor necrosis factor- alpha [TNF-α] in neonates. Patients and methods: A total of 35 cases of term neonates with Neonatal Jaundice and indirect hyperbilirubinemia high to the level that need phototherapy for 72hrs or more according to the guidelines of the American Academy of Pediatrics were included in this study, and 15 healthy matched newborns were selected as controls. TNF-α was measured before exposure and after 72 hours phototherapy and from control group at the time of examination. Serum levels of TNF alpha were measured using enzyme linked immunosorbent assay kits. Results: The results showed that there was no statistically significant in patient group before phototherapy in comparison to control group as regards TNF-α, patient demographics or laboratory data. On the other side, serum TNF-α levels significantly increased after exposure to phototherapy for 72 hours when compared to values before phototherapy (151.49±61.97 vs 61.36±31.96 respectively), indicating the influence of phototherapy on serum level of TNF-α. Conclusion: The results demonstrated increased serum TNF-α level after 72 hours may affect the immune system in neonates.

Correlation between circulating level of tumor necrosis factor-alpha and insulin resistance in Nigerian women with gestational diabetes mellitus.

Background:Gestational diabetes mellitus (GDM) results from an imbalance between insulin resistance and insulin secretion capacity during pregnancy. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that is proposed to be involved in the pathogenesis of the insulin resistance, but the findings from studies across different ethnic groups are inconsistent or even conflicting.Aim:The aim of this study is to determine the relationship between maternal circulating level of TNF-α and insulin resistance in pregnant Nigerian women with GDM.Methodology:This was a cross-sectional analytical study involving 100 women with GDM and another 100 pregnant women with normal gestation. They were evaluated between 24 and 28 weeks’ gestation. Diagnosis of GDM was based on the WHO diagnostic criteria. Fasting serum insulin and TNF-α levels were measured. Insulin resistance index was calculated as homeostasis model assessment of insulin resistance. Multivariate correlation analysis was used to determine the relationship between the maternal serum level of TNF-α and the insulin resistance.Results:Pregnant women with GDM had greater insulin resistance than observed in the normal controls (3.14 ± 0.19 vs. 2.89 ± 0.20, P < 0.05). There was a positive correlation between serum TNF-α level and insulin resistance among the pregnant women with GDM (r = 0.49, P < 0.05). Multiple linear regression analysis indicated that TNF-α is a predictor of insulin resistance in pregnancies complicated by GDM.Conclusion:It is concluded that among pregnant Nigerian women with GDM in this study, increased serum TNF-α level is associated with greater insulin resistance independent of age and body mass index.

Clinical significance of tumor necrosis factor-α-863 C/A and -1031 T/C promoter polymorphisms in systemic lupus erythematosus patients: Relation to disease activity and damage

Aim of the workTo assess the clinical significance of serum levels of tumor necrosis factor alpha (TNF-α) and its -863 C/A and 1031 T/C promoter polymorphism in systemic lupus erythematosus (SLE) patients and find any association to disease activity and damage. Patients and methodsForty-two female SLE patients and 30 age and gender matched healthy control were included. Systemic Lupus Erythematosus Disease Activity Index and the Systemic Lupus International Collaboration Clinics-damage index were assessed. Serum TNF-α levels were measured and genotyped for TNF-α-863 C/A and 1031 T/C promoters. ResultsThe SLE patients had a mean age of 28.5±7.6years and disease duration 3.3±2.9years. The mean serum TNF-α level in the SLE patients (8.2±9.8pg/ml) was significantly higher than in the control (3.5±2.6pg/ml) (p=0.005). The TNF-α-863AA genotype was significantly frequent (52.4%) in the SLE patients compared to control (23.3%) (p=0.012). Those patients had a significantly increased proteinuria and a tendency to a higher serum TNF-α level. Patients with TNF-α-1031 CC genotype had a significantly increased serum TNF-α levels (p=0.002) and frequency of mucocutaneous manifestations (p=0.03) as well as a higher frequency of lupus nephritis (LN) compared to those with TT genotype (p=0.04). Only serum TNF-α level would predict the disease activity. ConclusionTNF-α-863 promoter gene polymorphism may be considered as a genetic marker for SLE susceptibility and its AA genotype was associated with LN and with high serum TNF-α production. The TNF-α-1031 AA genotype was related to an increased serum TNF-α level as well as to mucocutaneous manifestations and LN.

The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

ObjectiveThe aim of this study was used meta-analysis to investigate changes of serum tumor necrosis factor-alpha (TNF-α) in patients with type 1 diabetes mellitus (T1DM).MethodsRelevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and Chinese-Cqvip databases (published from January 1, 1999 to September 30, 2016). Eligible reports were included for pooled analysis of serum TNF-α level and subgroup analysis was performed in relation with age, disease duration and ethnicity.ResultsA total of 23 articles (1631 T1DM cases, 1429 healthy controls) were included for this meta-analysis. Compared with the controls, the patients had significantly increased serum TNF-α level (P < 0.001). Similar results were also found among all subgroup analysis of different age, disease duration and ethnicity (with the exception of Asian) (all P < 0.05). Regression analysis indicated that age (P = 0.680), disease duration (P = 0.957), and ethnicity (P = 0.526) of patients were not significant impact factors for the high heterogeneity. The results were stable according to the sensitivity analysis and no publication bias existed in this meta-analysis.ConclusionsSerum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups.

Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure

Background. Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.Results. As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.Conclusion. Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.

Association Between Tumor Necrosis Factor-α and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: a Meta-Analysis.

Tumor necrosis factor-α (TNF-α) is a cell signaling protein involved in systemic inflammation, and is also an important cytokine in the acute phase reaction. Several studies suggested a possible association between TNF-α and diabetic peripheral neuropathy (DPN) in type 2 diabetic patients, but no accurate conclusion was available. A systematic review and meta-analysis of observational studies was performed to comprehensively assess the association between serum TNF-α levels and DPN in type 2 diabetic patients. We searched Pubmed, Web of Science, Embase, and China Biology Medicine (CMB) databases for eligible studies. Study-specific data were combined using meta-analysis. Fourteen studies were finally included into the meta-analysis, which involved a total of 2650 participants. Meta-analysis showed that there were obviously increased serum TNF-α levels in DPN patients compared with type 2 diabetic patients without DPN (standard mean difference [SMD] = 1.203, 95% CI 0.795-1.611, P < 0.001). There were also obviously increased levels of serum TNF-α in diabetic patients with DPN when compared with healthy controls (SMD = 2.364, 95% CI 1.333-3.394, P < 0.001). In addition, there were increased serum TNF-α levels in painful DPN patients compared with painless DPN patients (SMD = 0.964, 95% CI 0.237-1.690, P = 0.009). High level of serum TNF-α was significantly associated with increased risk of DPN in patients with type 2 diabetes (odds ratio [OR] = 2.594, 95% CI 1.182-5.500, P = 0.017). Increased serum levels of TNF-α was not associated with increased risk of painful DPN in patients with type 2 diabetes (OR = 2.486, 95% CI 0.672-9.193, P = 0.172). Sensitivity analysis showed that there was no obvious change in the pooled estimates when omitting single study by turns. Type 2 diabetic patients with peripheral neuropathy have obviously increased serum TNF-α levels than type 2 diabetic patients without peripheral neuropathy and healthy controls, and high level of serum TNF-α may be associated with increased risk of peripheral neuropathy independently. Further prospective cohort studies are needed to assess the association between TNF-α and DPN.

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction.

Objective:The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used.Methods:Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.Results:Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group.Conclusion:5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors. (Anatol J Cardiol 2017; 17: 269-75)

Neuroprotective potential of sesamol and its loaded solid lipid nanoparticles in ICV-STZ-induced cognitive deficits: Behavioral and biochemical evidence

Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental paradigm of Alzheimer׳s disease. Sesamol is a potent inhibitor of cytokine production as well as an antioxidant. The present study was designed to evaluate the effectiveness of sesamol in ICV-STZ-induced cognitive deficits in rats by incorporating it into solid lipid nanoparticles (SLNs). ICV-STZ administration produced significant cognitive deficits as assessed by both Morris water maze and elevated plus maze task which is accompanied by significantly enhanced nitrodative stress, altered acetylcholinesterase in rat brain along with significantly increased serum TNF-α levels. Chronic treatment with sesamol and sesamol loaded SLNs dose dependently restored cognitive deficits in ICV-STZ rats along with mitigation of nitrodative stress and cytokine release. Effectiveness of SLNs to deliver sesamol to the brain was shown by a significantly better alleviation of the oxidative stress parameters. Our findings demonstrate that loading of sesamol in SLNs is an effective strategy to mitigate ICV-STZ-induced neuronal dysfunction and memory deficits.

Effect of hemofiltration combined with hemoperfusion on serum TNF-α in severe acute pancreatitis patients with lung injury and on RhoA serine 188 phosphorylation in endothelial cells

Objective To study the effect of hemofiltration plus hemoperfusion(HF+HP) on removal of serum TNF-α in severe acute pancreatitis(SAP) patients with lung injury and on RhoA serine 188 phosphorylation(p-RhoA) in endothelial cells.MethodsTotally 35 SAP patients,including 28 with acute lung injury(ALI)/ acute respiratory distress syndrome(ARDS),and 20 healthy subjects were involved in this study.All the SAP patients were treated in ICU,and the 9 combined with ARDS underwent continuous veno-venous hemofiltration(CVVH) and HP therapy(HF+HP group).The serum TNF-α in SAP patients with different degrees of lung injury and the serum TNF-α in SAP patients with ARDS was determined by ELISA at different time points during HF+HP.For in vitro study the human umbilical vein endothelial cells(HUVECs) were treated with sera from SAP patients with ARDS during HF+HP,and those treated with recombinant TNF-α were taken as a positive control.The changes of p-RhoA and total RhoA were observed by Western blotting analysis.Subcellular distribution of p-RhoA protein was observed by immunofluorescence staining.ResultsWe found that,compared with SAP patients without ALI/ARDS,those with ALI/ARDS,especially those with ARDS(about 7 folds that of the normal control) had a significantly increased serum TNF-α level(P 0.05).The serum TNF-α level began to decrease in the 9 SAP patients with ARDS 6 h after HF+HP treatment,with the decrease reached maximal 20 h after treatment,closing to the level of the normal control group.Meanwhile,the arterial blood PaO2,HCO3-and PaO2/FiO2 ratio were significantly elevated after HF+HP treatment in SAP patients with ARDS(P 0.05).Western blotting analysis showed that p-RhoA level was significantly increased in HUVECs treated with the serum of HF+HP-treated SAP patients with ARDS(P 0.05),and the total RhoA protein expressions were not significantly different among different groups(P 0.05).Immunofluorescence indicated that p-RhoA was largely distributed in the cytoplasm of HUVECs,and the changes were consistent with the data from Western blotting analysis.ConclusionSAP patients with ALI/ARDS have high circulation TNF-α.Treatment with HF+HP can effectively remove the excessive TNF-α in the blood of SAP patients with ALI/ARDS and inhibit activation of RhoA,subsequently decreasing the high permeability of endothelial cells.

An inverse correlation between TNF alpha serum levels and heart rate variability in patients with heart failure

BackgroundRecent evidence indicates that chronic heart failure (CHF) is accompanied by both activation of the immune system and autonomic imbalance. There is a growing body of evidence that increased levels of proinflammatory cytokines and other inflammatory markers have important roles as mediators of disease progression and markers of mortality in patients with CHF. ObjectiveThe aim of this study was to investigate connection between autonomic imbalance [obtained by analysis of heart rate variability (HRV)] and activation of the immune system [as measured by serum levels of tumor necrosis factor (TNF)-α] in patients with chronic heart failure. Materials and methodsThis cross-sectional study included 21 patients with CHF and 8 age- and gender-matched healthy control subjects. We assessed HRV by 24-hour electrocardiographic Holter monitoring and measured serum levels of TNF-α using an enzyme-linked immunosorbent assay. Clinical assessment and echocardiography were also performed. ResultsThere was an inverse correlation between serum level of TNF-α and a time-domain parameter of HRV – SDNN (r=−0.542, p<0.05). A similar result was found for HRV triangular index, a geometric measure of HRV (r=−0.556; p<0.05). The correlation was stronger for subjects with a diabetes mellitus, females, and TNFA2 allele carriers (an “A” at position −308A). The pNN50, indirect marker of cardiac vagal activity, was not significantly associated with serum concentration of TNF-α. ConclusionsIn conclusion, the results of the present study indicate that increased serum TNF-α level is significantly associated with reduced HRV indices, suggesting that activation of the immune system in patients with CHF is closely related to autonomic imbalance.

Dietary supplementation with proline confers a positive effect in both porcine circovirus-infected pregnant and non-pregnant mice

Porcine circovirus type 2 (PCV2) is associated with various diseases that impose a significant economic burden on the swine industry. We hypothesised that nutritional supplementation with proline to enhance the immune response might be a useful prophylactic measure against PCV2 infection. To test this hypothesis, in the present study, we measured clinical data, including blood parameters, serum cytokine profile, PCV2 virus load in organs and serum, and microscopic lesions in the lung, liver and spleen, in both PCV2-infected pregnant and non-pregnant mice. Dietary supplementation with proline had no effect (P>0·05) on abortion rates in PCV2-infected pregnant mice, although a numerically lower abortion rate (22·2 v. 44·4%) was observed compared with the control. Dietary supplementation with proline significantly increased serum C-reactive protein levels (P= 0·03) in PCV2-infected pregnant mice, and increased serum TNF-α levels (P= 0·01), leucocytes (P< 0·05), lymphocytes (P< 0·05) and neutrophilic granulocytes (P< 0·05) in PCV2-infected non-pregnant mice. Meanwhile, dietary proline significantly (P< 0·05) decreased the PCV2 virus load in the lung. Furthermore, mice in the dietary proline group showed a significant (P< 0·01) decrease in microscopic lesion scores in the lung, liver and spleen compared with those in the alanine group. Collectively, dietary proline supplementation confers a functional role in PCV2-infected mice.

Circulating Annexin A5 Levels after Atrial Switch for Transposition of the Great Arteries: Relationship with Ventricular Deformation and Geometry

BackgroundInflammatory cytokines, cardiomyocyte apoptosis, and altered collagen turnover may contribute to unfavourable ventricular remodeling. This unfavourable ventricular remodelling is well documented in patients after atrial switch operation for complete transposition of the great arteries. We therefore tested if levels of circulating markers of inflammation, apoptosis, collagen synthesis, and extracellular matrix degradation are altered in patients after atrial switch operation for transposition of the great arteries.Methods and ResultsCirculating tumour necrosis factor (TNF)-α, annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in 27 patients aged 25.2±3.1 years and 20 controls. Ventricular myocardial deformation and left ventricular eccentricity index (EI) were determined by speckle tracking and two-dimensional echocardiography, respectively. Compared with controls, patients had significantly higher circulating AnxA5 (p<0.001) and TNF-α (p = 0.018) levels, but similar PICP, PIIINP, MMP-1 and TIMP-1 levels. For the whole cohort, plasma AnxA5 correlated with serum TNF-α (p = 0.002), systemic ventricular global longitudinal strain (GLS) and systolic and early diastolic strain rate (all p<0.001), and subpulmonary ventricular GLS and early diastolic strain rate (both p<0.001). In patients, plasma AnxA5 level correlated positively with subpulmonary ventricular EI (p = 0.027). Multiple linear regression analysis identified systemic ventricular GLS (β = −0.50, p<0.001) and serum TNF-α (β = 0.29, p = 0.022) as significant correlates of plasma AnxA5.ConclusionsElevated plasma AnxA5 level in patients after atrial switch operation is associated with impaired systemic myocardial deformation, increased subpulmonary ventricular eccentricity, and increased serum TNF-α level.

Establishment of lipopolysaccharide inducing mouse acute liver iniurv and lethal model

Objective To establish mouse acute liver injury model and lethal model induced by lipopolysaccharide (LPS) injection alone.Methods Mice were injected intraperitoneally ( i.p.) with different concentrations of LPS (0,10,30,50,80 mg/kg).The physiological statuses of mice were observed.The liver tissue of mice was stained by Hematoxylin and Eosin (HE) to examine the injury of the liver.The levels of tumor necrosis factor (TNF)-α in mouse serum were detected by enzyme linked immunosorbent assay (ELISA).The expression and nuclear translocation of nuclear factor (NF)-κB p65 in mouse liver tissue were measured by immunohistochemistry staining.Results No death and liver injury were found in control group mice.No increased NF-κB p65 protein expression and nuclear translocation in liver tissue and increased serum TNF-α levels were detected in control group mice.No deaths of mice were found in group with intraperitoneal injection of LPS at a concentration of 30 mg/kg.As compared with the control group,liver injury,increased NF-κB p65 protein expression and nuclear translocation in liver tissue and increased serum TNF-α levels were detected in this group ( P ＜ 0.01 ).Mice with intraperitoneal injection of LPS at a concentration of LPS 50mg/kg survived no more than 120 h.As compared with the control group,liver injury,significantly increased NF-κB p65 protein expression and nuclear translocation in liver tissue and significantly increased serum TNF-α levels were detected in this group (P ＜0.01 ).Conclusion Our research successfully establishes mice liver injury model and lethal model induced by LPS intraperitoneal injection alone,which provides stable research platform for further medical treatment. Key words: Acute liver injury; Model, animal; Lipopolysaccharide

Modulation of nitrergic pathway by sesamol prevents cognitive deficits and associated biochemical alterations in intracerebroventricular streptozotocin-administered rats

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus. Increasing evidence indicates that factors such as oxidative-nitrergic stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer's disease pathogenesis. Intracerebroventricular (i.c.v.) streptozotocin induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer's disease. In the present study, i.c.v. streptozotocin produced significant cognitive deficits as measured in Morris water maze and elevated plus maze task coupled with increased serum TNF-α levels and marked rise in brain acetylcholinesterase and oxidative-nitrergic stress in female Wistar rats. Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol), a potent anti-oxidant and anti-inflammatory molecule markedly improved cognitive impairment, reduced acetylcholinesterase activity, TNF-α levels and attenuated oxidative-nitrergic stress in brain of i.c.v.-streptozotocin treated rats. Administration of L-arginine (125 mg/kg i.p), a nitric oxide donor, alone to i.c.v.-streptozotocin treated rats accentuated behavioral and biochemical deficits and also abolished the protective effect of sesamol (8 mg/kg). L-NAME (10 mg/kgi.p.), a non-specific NOS inhibitor significantly restored all the behavioral and biochemical indices in i.c.v.-streptozotocin rats. Moreover, combination of L-NAME with sub-effective dose of sesamol (4 mg/kg) potentiated its protective effect. Our findings demonstrate the effectiveness of sesamol in preventing intracerebroventricular streptozotocin-induced cognitive deficits by modulating nitrergic signaling and oxido-inflammatory cascade.