The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice

Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

Analyze interleukin-1β,interleukin-6,and tumor necrosis factor-αlevels in dry eye and the therapeutic effect of cyclosporine A

BACKGROUND Dry eye is a common eye disease.Artificial tears supplements are widely used for the treatment of dry eyes.However,multiple adverse effects have been observed in patients receiving long-term treatment with artificial tears,which may affect the therapeutic effect.AIM To analyze the characteristics of interleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α)levels in patients with dry eye and the therapeutic effect of artificial tears combined with cyclosporine A.METHODS A total of 124 dry eye patients treated at The First People’s Hospital of Xining from April 2020 to April 2022 were selected as the observation group,while 20 healthy individuals served as the control group during the same period.Levels of inflammatory markers,including IL-1β,IL-6,and TNF-α,were analyzed.The observation group was further divided into a study group and a control group,each consisting of 62 patients.The control group received artificial tears,whereas the study group received a combination of artificial tears and cyclosporine A.Inflammatory markers,Schirmer’s test(SIT),tear break-up time(TBUT),corneal fluorescein staining(CFS),National Eye Institute Visual Function Questionnaire-25(NEI-VFQ-25)scores,and adverse events(AEs)were compared between the two groups.RESULTS The observation group exhibited significantly elevated serum levels of IL-1β,IL-6,and TNF-αin comparison to the healthy group.Following treatment,the study group demonstrated substantial reductions in IL-1β,IL-6,and TNF-αlevels relative to the control group.Moreover,after treatment,the study group experienced a marked decrease in CFS scores and significant increases in both SIT and BUT levels when compared to the control group.Additionally,significant improvements were observed in the primary symptom of dry eye and secondary symptoms such as photophobia,foreign body sensation,fatigue,red eye,and burning sensation within the study group.Furthermore,post-treatment NEI-VFQ-25 scores across all dimensions exhibited significant enhancements in the study group compared to the control group(P<0.05).It is noteworthy that significant AEs were reported in both groups throughout the treatment period.CONCLUSION Cyclosporine A combined with artificial tears is effective in treating dry eye,yielding enhanced outcomes by improving SIT and TBUT levels,reducing CFS scores,and ameliorating vision-related quality of life.

Efficacy of Laparoscopic Cholecystectomy in Treating Patients with Gallstones and Its Effect on Interleukin-6 and Tumor Necrosis Factor-α Levels

Objective:To investigate the efficacy of laparoscopic cholecystectomy in the treatment of patients with gallstones and its effect on the levels of interleukin-6(IL-6)and tumor necrosis factor-α(TNF-a).Methods:A total of 82 patients with gallstones admitted from July 2020 to July 2023 were recruited and allocated into control and observation groups using the random number table method,with 41 cases in each group.The patients were treated with laparoscopic cholecystectomy,with the anterior triangle anatomical approach to the gallbladder in the control group and the posterior triangle anatomical approach to the gallbladder in the observation group.The treatment effect and inflammatory factor levels of both groups were observed and compared.Results:When comparing the clinical outcomes of both patient groups,the key parameters evaluated included time to mobilization,duration of surgery,extubation time,and intraoperative bleeding.The observation group exhibited a significant advantage in these parameters compared to the control group(P<0.05).Regarding the levels of inflammatory factors between the two groups before and after treatment,there was no significant difference in values before treatment.However,following treatment,patients in the observation group showed significantly lower levels of IL-6,TNF-α,and C-reactive protein(CRP)compared to the control group(P<0.05).Conclusion:Patients undergoing laparoscopic cholecystectomy for gallstones can benefit from the implementation of the posterior triangular anatomical approach to the gallbladder,which not only enhances therapeutic efficacy but also offers significant advantages in reducing levels of IL-6,TNF-α,and CRP.Therefore,it is recommended for the widespread adoption of this treatment approach in clinical practice.

Study of tumor necrosis factor receptor in the inflammatory bowel disease

Ulcerative colitis(UC)and Crohn’s disease(CD)are part of Inflammatory Bowel Diseases(IBD)and have pathophysiological processes such as bowel necrosis and enteric neurons and enteric glial cells.In addition,the main inflammatory mediator is related to the tumor necrosis factor-alpha(TNF-α).TNF-αis a mediator of the intestinal inflammatory processes,thus being one of the main cytokines involved in the pathogenesis of IBD,however,its levels,when measured,are present in the serum of patients with IBD.In addition,TNF-αplays an important role in promoting inflammation,such as the production of interleukins(IL),for instance IL-1βand IL-6.There are two receptors for TNF as following:The tumor necrosis factor 1 receptor(TNFR1);and the tumor necrosis factor 2 receptor(TNFR2).They are involved in the pathogenesis of IBD and their receptors have been detected in IBD and their expression is correlated with disease activity.The soluble TNF form binds to the TNFR1 receptor with,and its activation results in a signaling cascade effects such as apoptosis,cell proliferation and cytokine secretion.In contrast,the transmembrane TNF form can bind both to TNFR1 and TNFR2.Recent studies have suggested that TNF-αis one of the main pro-inflammatory cytokines involved in the pathogenesis of IBD,since TNF levels are present in the serum of both patients with UC and CD.Intravenous and subcutaneous biologics targeting TNF-αhave revolutionized the treatment of IBD,thus becoming the best available agents to induce and maintain IBD remission.The application of antibodies aimed at neutralizing TNF-αin patients with IBD that induce a satisfactory clinical response in up to 60%of patients,and also induced long-term maintenance of disease remission in most patients.It has been suggested that anti-TNF-αagents inactivate the pro-inflammatory cytokine TNF-αby direct neutralization,i.e.,resulting in suppression of inflammation.However,anti-TNF-αantibodies perform more complex functions than a simple blockade.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease:A literature review

Tumor necrosis factor-α(TNF-α)antagonists,the first biologics approved for treating patients with inflammatory bowel disease(IBD),are effective for the induction and maintenance of remission and significantly improving prognosis.However,up to one-third of treated patients show primary nonresponse(PNR)to anti-TNF-αtherapies,and 23%-50%of IBD patients experience loss of response(LOR)to these biologics during subsequent treatment.There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs.This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients.Most predictors remain controversial,and only previous surgical history,disease manifestations,drug concentrations,antidrug antibodies,serum albumin,some biologic markers,and some genetic markers may be potentially predictive.In addition,we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists.Therapeutic drug monitoring plays an important role in treatment selection.Dose escalation,combination therapy,switching to a different anti-TNF drug,or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

Joint Detection of Serum Vitamin D,Body Mass Index,and Tumor Necrosis Factor Alpha for the Diagnosis of Crohn’s Disease

Objective Vitamin D(VD)deficiency was reported to contribute to the progression of Crohn’s disease(CD)and affect the prognosis of CD patients.This study investigated the role of serum VD,body mass index(BMI),and tumor necrosis factor alpha(TNF-α)in the diagnosis of Crohn’s disease.Methods CD patients(n=76)and healthy subjects(n=76)were enrolled between May 2019 and December 2020.The serum 25-hydroxyvitamin D[25(OH)D]levels,BMI,and TNF-αlevels,together with other biochemical parameters,were assessed before treatment.The diagnostic efficacy of the single and joint detection of serum 25(OH)D,BMI,and TNF-αwas determined using receiver operating characteristic(ROC)curves.Results The levels of 25(OH)D,BMI,and nutritional indicators,including hemoglobin,total protein,albumin,and high-density lipoprotein cholesterol,were much lower,and the TNF-αlevels were much higher in the CD patients than in the healthy subjects(P<0.05 for all).The areas under the ROC curve for the single detection of 25(OH)D,BMI,and TNF-αwere 0.887,0.896,and 0.838,respectively,with the optimal cutoff values being 20.64 ng/mL,19.77 kg/m^(2),and 6.85 fmol/mL,respectively.The diagnostic efficacy of the joint detection of 25(OH)D,BMI,and TNF-αwas the highest,with an area under the ROC curve of 0.988(95%CI:0.968–1.000).Conclusion The joint detection of 25(OH)D,TNF-α,and BMI showed high sensitivity,specificity,and accuracy in CD diagnosis;thus,it would be effective for the diagnosis of CD in clinical practice.

Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cordderived mesenchymal stem cells by increasing PD-L1 expression

BACKGROUND The immunosuppressive capacity of mesenchymal stem cells(MSCs)is dependent on the“license”of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1(PD-L1),which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases.In MSCs,interferon-gamma(IFN-γ)is a key inducer of PD-L1 expression,which is synergistically enhanced by tumor necrosis factor-alpha(TNF-α);however,the underlying mechanism is unclear.AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs(hUC-MSCs)induced by IFN-γand TNF-α,alone or in combination.Additionally,we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γalone or in combination with TNF-αinduces PD-L1 expression.Moreover,we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters.Finally,we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γand TNF-αin both an in vitro mixed lymphocyte culture assay,and in vivo in mice with dextran sulfate sodium-induced acute colitis.RESULTS Our results suggest that IFN-γinduction alone upregulates PD-L1 expression in hUC-MSCs while TNF-αalone does not,and that the co-induction of IFN-γand TNF-αpromotes higher expression of PD-L1.IFN-γinduces hUCMSCs to express PD-L1,in which IFN-γactivates the JAK/STAT1 signaling pathway,up-regulates the expression of the interferon regulatory factor 1(IRF1)transcription factor,promotes the binding of IRF1 and the PD-L1 gene promoter,and finally promotes PD-L1 mRNA.Although TNF-αalone did not induce PD-L1 expression in hUCMSCs,the addition of TNF-αsignificantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation.TNF-αupregulated IFN-γreceptor expression through activation of the nuclear factor kappa-B signaling pathway,which significantly enhanced IFN-γsignaling.Finally,co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation,and significantly ameliorate weight loss,mucosal damage,inflammatory cell infiltration,and up-regulation of inflammatory factors in colitis mice.CONCLUSION Overall,our results suggest that IFN-γand TNF-αenhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.

Acute heart failure as an adverse event of tumor necrosis factor inhibitor therapy in inflammatory bowel disease:A review of the literature

Tumor necrosis factor inhibitors(anti-TNFs)are widely used therapies for the treatment of inflammatory bowel diseases(IBD);however,their administration is not risk-free.Heart failure(HF),although rare,is a potential adverse event related to administration of these medications.However,the exact mechanism of development of HF remains obscure.TNFαis found in both healthy and damaged hearts.Its effects are concentration-and receptor-dependent,promoting either cardio-protection or cardiomyocyte apoptosis.Experimental rat models with TNFαreceptor knockout showed increased survival rates,less reactive oxygen species formation,and improved diastolic left ventricle pressure.However,clinical trials employing anti-TNF therapy to treat HF had disappointing results,suggesting abolishment of the cardioprotective properties of TNFα,making cardiomyocytes susceptible to apoptosis and oxidation.Thus,patients with IBD who have risk factors should be screened for HF before initiating anti-TNF therapy.This review aims to discuss adverse events associated with the administration of anti-TNF therapy,with a focus on HF,and propose some approaches to avoid cardiac adverse events in patients with IBD.

Tumor Necrosis Factor-Alpha (TNF)-308G/A and Interleukin 8(IL-8)-251C/T Polymorphisms in Pulmonary Tuberculosis Patients from Congo

Background: Tuberculosis (TB) is one of the world’s deadliest infectious diseases. Tumor necrosis factor-Alpha (TNF-α) and Interleukin 8 (IL-8) are involved in the pathogenesis of pulmonary TB (PTB). However, the contribution of polymorphisms of these cytokines to PTB susceptibility needed more investigation across geographic regions and ethnic groups. Purpose: The aim of this study was to investigate the association of the TNF-α-308 G/A and IL-8-251T/A polymorphisms with PTB risk in the Congolese population. Methods: This case-control study included 150 PTB patients and 160 control subjects. Blood samples were collected from all participants and were used for the TNF-α-308 G/A and IL-8-251T/A genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Odds ratios (OR) were calculated to estimate the potential polymorphism associations. A P level of Results: A significant difference was found between PTB patients and controls regarding the TNF-α-308AA genotype (P = 0.035) distribution. Moreover, this genotype was associated with risk to TB (OR = 7.19, 95% CI = 0.85 - 60.65, P = 0.035). The A allele was significantly more frequent in PTB patients than in controls, and was associated with risk to PTB (OR = 1.68, 95% CI = 1.05 - 2.68, P = 0.014). Regarding the IL-8-251T/A gene, TA and AA genotypes were significantly more frequent in PTB patients compared to controls, and were associated with increased risk to PTB (OR = 2.64, 95% CI = 0.97 - 7.18, P = 0.031 and OR = 3.0, 95% CI = 1.13 - 7.98, P = 0.014, respectively). However, the IL-8-251 A allele was not associated to PTB susceptibility (OR = 0.27, 95% CI = 0.15 - 0.44). Conclusion: TNF-α-308G/A and IL-8-251T/A polymorphisms may be associated to PTB susceptibility in the Congolese population, and the AA genotype of both cytokines could be a risk factor.

Anti-and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis,psoriatic arthritis and ankylosing spondylitis

In addition toβ-cell failure with inadequate insulin secretion,the crucial mechanism leading to establishment of diabetes mellitus(DM)is the resistance of target cells to insulin,i.e.insulin resistance(IR),indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor,downstream to the substrates of insulin action.IR is a common feature of most metabolic disorders,particularly type II DM as well as some cases of type I DM.A variety of human inammatory disorders with increased levels of proinflammatory cytokines,including tumor necrosis factor(TNF)-α,interleukin(IL)-6 and IL-1β,have been reported to be associated with an increased risk of IR.Autoimmunemediated arthritis conditions,including rheumatoid arthritis(RA),psoriatic arthritis(PsA)and ankylosing spondylitis(AS),with the involvement of proinflammatory cytokines as their central pathogenesis,have been demonstrated to be associated with IR,especially during the active disease state.There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders.In this review,we focus on the effects of anti-TNF-α-and non-TNF-α-targeted therapies on IR in patients with RA,PsA and AS.Anti-TNF-αtherapy,IL-1 blockade,IL-6 antagonist,Janus kinase inhibitor and phosphodiesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM：To examine the association of genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 with the development of primary open angle glaucoma（POAG）among people in Central Russia.METHODS：The study sample included 443 individuals,of which 252 patients with POAG and 191 individuals in the control group.Genotyping of（-308）G/A TNFα,（＋250）A/G Ltα,（＋36）A/G TNFR1,（＋1663）A/G TNFR2 was performed using polymerase chain reaction.The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables andχ2with the Yates’s correction for continuity and odds ratios（OR）with95%confidence intervals（CI）.RESULTS：Allele（-308）G TNFα（Р=0.01,OR=1.78,95%CI1.12-2.85）was identified as a risk factor for POAG.Homozygotes（-308）AA TNFαare at a lowest risk for development of the disease（Р=0.01,OR=0.0005）.The following combination of genetic variants of cytokines were associated with a reduced risk of POAG：（＋1663）A TNFR2 and（＋250）G Ltα（OR=0.34）CONCLUSION：Genetic polymorphisms（-308）G/A TNFα,（＋250）A/G Ltα,（＋1663）A/G TNFR2 associated with the development of POAG in the population of Central Russia.

Effect of tumor necrosis factor-alpha in rats with hepatic ischemia-reperfusion injury

BACKGROUND: With the development of hepatic surgery, especially liver transplantation, the pathophysiological processes of hepatic ischemia-reperfusion (I/R) injury have gained special attention. Controlling I/R injury has become one of the most important factors for successful liver transplantation. This study aimed to investigate the effects of tumor necrosis factor-alpha (TNF-alpha) in rats with hepatic I/R injury and promote the recognition of I/R injury in the liver. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into 2 groups. Rats in the sham-operated (SO) group served as controls. Rats in the hepatic ischemia-reperfusion (I/R) group underwent reperfusion after 30 minutes of liver ischemia. Rats were sacrificed at 1, 6 and 12 hours. The expression of TNF-alpha mRNA in the liver was measured by RT-PCR. Histological changes in the liver were assessed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were measured. RESULTS: The expression of TNF-alpha mRNA in the SO group was decreased compared with that in the I/R group (P<0.05). TNF-a mRNA expression progressively increased in the I/R group. The serum levels of ALT and AST in the I/R group were higher than those in the SO group (P<0.01). The histological changes were in accord with hepatic I/R injury. CONCLUSION: ALT and AST in serum are closely related to hepatic I/R injury and inflammatory reaction. TNF-alpha production in the liver triggers hepatic I/R injury through a cascade.

Changes of Tumor Necrosis Factor-α and the Effects of Ulinastatin Injection during Cardiopulmonary Cerebral Resuscitation

Summary: The changes of tumor necrosis factor-α (TNF-α) and brain ultrastructure during cardiopulmonary resuscitation and the effects of ulinastation injection were observed, and the mechanism was investigated. Twenty-four adult healthy Sprague-Dawley rats were randomly divided into control group (8 rats), resuscitation group (8 rats) and ulinastatin (UTI) group (8 rats). Rats in control group underwent tracheotomy without clipping the trachea to induce circulatory and respiratory standstill. Rats in resuscitation and ulinastatin group were subjected to the procedure of establishing the model of cardiopulmonary cerebral resuscitation (CPCR). Rats in ulinastatin group were given with UTI 104 U/kg once after CPCR. In the control group, the plasma was collected immediate, 30 min, 2 h, 4 h, and 6 h after tracheotomy. In resuscitation group and UTI group, plasma was collected immediate after tracheotomy, 30 min, 2 h, 4 h and 6 h after successful resuscitation. The plasma levels of TNF-α were determined by radioimmunoassay (RIA). At the end of the experiment, 2 rats were randomly selected from each group and were decapitated. The cortex of the brain was taken out immediately to observe the ultrastructure changes. In control group, there were no significant differences in the level of TNF-α among different time points (P>0.05). In resuscitation group, the level of TNF-α was increased obviously after resuscitation (P<0.01) and reached its peak 2 h later after resuscitation. An increasing trend of TNF-α showed in UTI group. There were no differences in TNF-α among each sample taken after successful resuscitation and that after tracheotomy. The utrastructure of brains showed the injury in UTI group was ameliorated as compared with that in resuscitation group. In early period of CPCR, TNF-α was expressed rapidly and kept increasing. It indicated that TNF-α might take part in the tissue injury after CPCR. The administration of UTI during CACR could depress TNF-α and ameliorate brain injury. By regulating the expression of damaging mediator, UTI might provide a protective effect on the tissue injury after CPCR.

The Change of Interleukin-6 and Tumor Necrosis Factor in Patients with Obstructive Sleep Apnea Syndrome

The levels of lipopolysaccharide (LPS) induced interleukin 6 (IL 6) and tumor necrosis factor α (TNF α) expression in culture of peripheral blood mononuclear cells (PBMC) and the plasma levels of IL 6 and TNF α in the patients with obstructive sleep apnea syndrome (OSAS) were measured and the relationship between OSAS and IL 6 or TNF α expression studied. Both IL 6 and TNF α were detected by using ELISA in 22 patients with OSAS and 16 normal controls. The levels of LPS induced IL 6 (787.82±151.97 pg/ml) and TNF α (4165.45±1501.43 pg/ml) expression in the supernatant of the culture of PBMC and plasma level of IL 6 (50.67±4.70 pg/ml) and TNF α (299.09±43.57 pg/ml) in the patients with OSAS were significantly higher than those in the normal controls (in the supernatant of the culture of PBMC: 562.69±197.54 pg/ml and 1596.25±403.08 pg/ml respectively; in the plasma: 12.69±2.75 pg/ml and 101.88±21.27 pg/ml respectively). There were significantly positive correlation between the levels of IL 6 and TNF α and the percentage of time of apnea and hyponea, as well as the percentage of time spending at SaO 2 below 90 % in the total sleep time. It was concluded that LPS induced IL 6 and TNF α levels as well as plasma IL 6 and TNF α levels in the patients with OSAS were up regulated, which may be associated with the pathogenesis of OSAS.

Anti Cervix Cancer Activity of Co-immobilized Tumor Necrosis Factor-α and Interferon-γ

Tumor necrosis factor α （TNF-α） and interferon-γ （IFN-γ） are cytokines with strong antitumor activities. They were reacted with a photoactive arylazide-4-azidobenzoic acid, resulting in photoactive TNF-α and IFN-γ. The infrared （IR） spectra of these products showed the characteristic absorption of an azido group at 2127 cm^-1. By photo-immobilization, this modified TNF-α and IFN-γ were immobilized on polystyrene membranes for cell culture to prepare biomaterials. The micro-morphology of photoactive cytokines was observed with a scanning electron microscope （SEM）. The inhibitory effect on growth of Hela cells and inducing apoptosis activity of these two cytokines were analyzed by growth curve, transmission electron microscope （TEM） and fluorescence active cell sorter （FACS）. The results showed that co-immobilization of IFN-γ and TNF-α had significant inhibitory effect on growth of Hela cells, inhibitory rate up to 82%, and IFN-γ had obviously synergistic action.

Quercetin exerts anti-inflammatory effects via inhibiting tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in normal human gastric epithelial cells

BACKGROUND Gastric injury is the most common digestive system disease worldwide and involves inflammation,which can lead to gastric ulcer or gastric cancer(GC).Matrix metallopeptidase-9[MMP-9(gelatinase-B)]plays an important role in inflammation and GC progression.Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities.However,the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear.AIM To assess whether tumor necrosis factor-α(TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells.METHODS The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the antiinflammatory effects of quercetin.The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line.Cell migration was measured using Transwell assay.The expression of proto-oncogene tyrosine-protein kinase Src(cSrc),phospho(p)-c-Src,extracellular-signal-regulated kinase 2(ERK2),p-ERK1/2,c-Fos,p-c-Fos,nuclear factor kappa B(NF-κB/p65),and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity.p65 expression was detected by immunofluorescence.MMP-9 m RNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction(q RT–PCR)and gelatin zymography,respectively.RESULTS q RT-PCR and gelatin zymography showed that TNF-αinduced MMP-9 m RNA and protein expression in a dose-and time-dependent manner.These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-αantagonist(TNFR inhibitor)in a dose-and timedependent manner.Quercetin and TNF-αantagonists decreased the TNF-α-induced phosphorylation of c-Src,ERK1/2,c-Fos,and p65 in a dose-and time-dependent manner.Quercetin,TNF-αantagonist,PP1,U0126,and tanshinone IIA(TSIIA)reduced TNF-α-induced c-Fos phosphorylation and AP-1–Luciferase(Luc)activity in a dose-and time-dependent manner.Pretreatment with quercetin,TNF-αantagonist,PP1,U0126,or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65–Luc activity in a dose-and timedependent manner.TNF-αsignificantly increased GES-1 cell migration,and these results were reduced by pretreatment with quercetin or a TNF-αantagonist.CONCLUSION Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src–ERK1/2 and c-Fos or NF-κB pathways.

Effects of erythropoietin on the expression of tumor necrosis factor-alpha and Bax after facial nerve axotomy in rats

This study sought to evaluate the effect of high-dose erythropoietin （EPO; 5 000 IU/kg） on the expression of tumor necrosis factor-alpha （TNF-α） and Bax in the facial nucleus after facial nerve transection in rats. A total of 42 Wistar rats of both genders were used in this study, and 40 rats were randomly divided into 2 groups： EPO group and model group. The EPO group was treated with EPO once a day for 5 days at a dose of 5 000 IU/kg body weight. The model group was treated with saline of the same amount. At day 3 after EPO （or saline） treatment, the right facial nerves of the 40 rats were transected at the level of the stylomastoid foramen, with the left sides untreated. The remaining 2 rats that did not undergo axotomy served as the control group. The surviving motor neurons in operated rats were counted in coronal paraffin sections of the facial nucleus. The expression of TNF-a and Bax in the facial nucleus was detected by immunohistochemical staining at days 3, 7, 14, 21, and 28 after axotomy. At days 14, 21, and 28 after facial nerve axotomy, a significantly greater proportion of facial motor neurons survived in the EPO group than in the model group. After axotomy, the expression of TNF-a and Bax increased in motor neurons in both the EPO and the model groups. TNF-o expression reached its peak level at day 14 after axotomy, while Bax expression reached its peak level at day 21. TNF-α expression was much lower in the EPO group than in the model group at all time points. No significant difference in Bax expression was found between the EPO and the model groups. These results indicate that high-dose EPO treatment attenuates the increase in TNF-α expression in the facial nucleus and reduces the loss of motor neurons after facial nerve transection in rats. However, high-dose EPO treatment has little effect on Bax expression.

Experimental Study on Inhibitory Effect of Niacinamide on Tumor Necrosis Factor-alpha-induced Matrix Degradation of Annulus Fibrous Tissue in vitro

The inhibitory effect of niacinamide on tumor necrosis factor-α （TNF-α） induced annulus fibrous （AF） degradation was assessed, and the mechanism of the inhibition was investigated. Chiba＇s intervertebral disc （IVD） culture model was established. Forty-eight IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups （12 IVDs in each group）, and various concentrations of niacinamide and TNF-α were added to the medium for intervention： negative control group, niacinamide control group （0.5 mg/mL niacinamide）, degeneration group （10 ng/mL TNF-α）, and treatment group （0.5 mg/mL niacinamide and 10 ng/mL TNF-α）. After one week＇s culture, AFs were collected for glycosaminoglycan （GS） content measurement, safranin O-fast green staining, and immunohistochemical staining for type Ⅰ , Ⅱ collagen and cysteine containing aspartate specific prote- ase-3 （Caspase-3）. It was found that the GS content in treatment group was increased by about 48% as compared with degeneration group （t=16.93, P〈0.001）, and close to that in niacinamide control group （t=0.71, P=0.667）. Safranine O-fast green staining exhibited higher staining density and better histological structure of AF in the treatment group as compared with the degeneration group. Immunohistochemical staining for both TypeⅠ and Ⅱ collagen demonstrated that lamellar structure and continuity of collagen in treatment group were better reserved than in degeneration group. Positive staining rate of Caspase-3 in AFs of negative control group, niacinamide control group, degeneration group and treatment group was 3.4%, 4.3%, 17.9% and 10.3% respectively. The positive rate in treatment group was significantly lower than in degeneration group （P〈0.01）. It was concluded that niacinamide could effectively alleviate TNF-α induced destruction and synthesis inhibition of matrix ingredients in AFs. The inhibition may be related with reduction of expression of Caspase-3. Thus, niacinamide is of potential for IVD degeneration clinical treatment.