THE ASSOCIATION BETWEEN TUMOR NECROSIS FACTORαGENE POLYMORPHISM AND ASTHMA

Objective.In this study,we investigated the hypothesis that tumor necrosis factor(TNF)α-308gene polymorphism might be of the genetic predisposition to asthma and asthma phenotypes.Methods.TNFα-308gene polymorphism was genotyped in221random unrelated Northern Chinese population(comprising125asthmatics and96healthy controls)and52individuals from12asthmatic families with Han ethnic by using polymerase chain reaction(PCR)-restriction fragment length polymor-phism(RFLP).Methacholine(Mch)broncho-challenge test,bronchial reversibility test and lung function were underwent in all asthmatics.Results.TNFα-3082homozygosity was present at a significantly higher frequency in asthmatics than that in controls(20.8%vs11.4%,P<0.05,OR2.259),the TNF allele2was also higher in asthmatics compared with controls(0.42vs0.33,P<0.01).TNFα-3082homozygosity was an weak independent risk factor for asthma etiology(OR0.226,P<0.05).Moreover,patients carrying TNFα-3082homozy-gosity had less responsive to inhaledβ 2 -agonist in20minutes than patients carrying other two genotypes(24.1%vs29.5%vs38.8%,P<0.05).Linkage analysis didn’t support that TNFαgene was linked to asthma (Likelihood of odds,LOD<1)based on familial data.Conclusion These results suggest that TNFα-3082homozygosity may be of a component contribut-ing to the genetic predisposition to asthma ,and airway responsiveness toβ2 -agonist.

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.

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.

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

Early screening to identify and diagnose primary nasal tuberculosis in patients with tumor necrosis factor inhibitors

In this editorial,we comment on the article by Liu et al.Based on our analysis of a case report,we consider that early screening and recognition of primary nasal tuberculosis are crucial for patients undergoing treatment with tumor necrosis factor inhibitor(TNFi).While TNFi therapy increases the risk of reactivating latent tuberculosis,primary nasal tuberculosis remains rare due to the protective mechanisms of the nasal mucosa.Risk factors for primary nasal tuberculosis include minimally invasive nasal surgery,diabetes,and human immunodefi ciency virus.Patients with early symptoms such as nasal congestion,rhinorrhea,altered olfaction,epistaxis,or ulceration,and unresponsive to conventional antibiotics and antihistamines should undergo early rhinoscopy,possibly followed by repeated tissue biopsies and acid-fast bacilli culture when necessary.When diagnosis is challenging,it is essential to consider local tuberculosis epidemiology and the efficacy of diagnostic antituberculosis treatment.The preferred method for tuberculosis screening is the Interferon Gamma Release Assay,with a general recommendation for screening at 3 and 6 months after initial treatment and then every six months.However,the optimal frequency is not yet consensus-driven and may be increased in economically viable settings.

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.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Uptake of bacterial lipopolysaccharide and expression of tumor necrosis factor α mRNA in isolated rat intrahepatic bile duct epithelial cells *

AIM To study the uptake of bacterial lipopolysaccharides (LPS) and expression of tumor necrosis factor α mRNA (TNF α mRNA) with cultured rat intrahepatic bile duct epithelial cells.

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

Effects on the Tumor Specific Growth Factor and Tumor Necrosis Factorαin Rats'Precancerous Lesion of Primary Hepatocellular Carcinoma by Direct Moxibustion at Ganshu(BL 18)Acupoint

Objective： To investigate the effect of direct moxibustion at Ganshu （BL18） on the serum concentrations of tumor specific growth factor （TSGF） and tumor necrosis factor a （TNF-a） in a rat model with precancerous lesion of primary hepatocellular carcinoma （HCC）, so as to explore the mechanism of moxibustion underlying improvement of HCC. Methods： Sixty male Wistar rats were randomly divided into control group （n=10）, model group （n=20）, prevention group 1 （n=15） and prevention group 2 （n=15）. The normal rats were injected with physiological saline as blank control. At the same time, the rats of other three groups were injected with diethylnitrosamine to establish the HCC model. Direct moxibusUon with grain-sized moxa was applied to bilateral Ganshu acupoint of the rats in the prevention group 1 （1 treatment course, 20 days） and prevention group 2 （2 treatment courses, 40 days）, 5 doses for each acupoint, 0.5 mg/dose, once every other day. At each time point （before model establishment, the end of 1st course prevention, the end of 2rid course prevention and the end of model establishment）, serum levels of TSGF and TNF-eL were detected using enzyme-linked immunosorbent assay. Results： Compared with the control group, there was a remarkably increase of serum TSGF and TNF-eL contents in the model group at the end of the experiment （P〈0.05）. At the end of the 1st course of direct moxibustion, the contents of serum TSGF and TNF- a of rats in the prevention group 1 were significantly increased compared with that of the model group （P〈0.05）. At the end of the 2nd course of direct moxibustion, serum TSGF and TNF-a levels of rats in the model group were higher than the normal group with significantly difference （P〈0.05）, and the levels of TSGF and TNF-a in the prevention group 2 were significantly reduced in comparison with the model group （P〈0.05）. Conclusion： It was possible that direct moxibustion could inhibit precancerous lesion and postpone hepatocarcinogenesis, and the therapeutic effect of two courses were better than one course.

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).

TUMOR NECROSIS FACTOR-ALPHA POLYMORPHISM AND SECRETION IN MYASTHENIA GRAVIS

Objective To analyze the relationship between tumor necrosis factor-alpha (TNFα) gene promoter -308 polymorphism and myasthenia gravis (MG) in Chinese and analyze secretion of TNFα in peripheral blood mononuclear cells (PBMC) in MG patients. Methods A biallelic polymorphism at position -308 in the promoter of TNFα gene was screened by PCR amplification and NcoI recognition site. One hundred and twenty-three MG cases and 115 healthy controls were included in this study. MG patients were classified to different groups according to clinical type, age at onset, and sex respectively. PBMC were isolated from 20 patients and 20 healthy controls, and then cultured in the presence or absence of phytohemag- glutinin (PHA) and acetycholine receptors (AchR). The supernatants were harvested after incubation and stored until TNFα was assayed by enzyme-linked immunosorbent assay. Results The frequency of TNFα-308 allele 2 (A) was found significantly increase in MG patients and showed a trend especially in late onset (≥ 40 years) and male patients (P < 0.05). The allele A had no relationship with thymic pathogenesis in MG patients. But frequency of allele A was significantly higher in general type than in ocular type (P < 0.05). MG patients had a higher inducible level of TNFα by PHA and AchR, and could be down regulated after treatment. Conclusion Polymorphism in TNFα gene promoter -308 is associated with onset of MG. The microsatellite allele TNFα2 confer risk for the development of MG in Chinese patients. MG patients have a higher inducible level of TNFα.

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.

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.

Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells

AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-&#x003b1;)-induced gene expression in human gastric adenocarcinoma cells.

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.

Relationship between tumor necrosis factor-α and liver fibrosis

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Influence of granulocyte-macrophage colonystimulating factor and tumor necrosis factor on anti-hepatoma activities of human dendritic cells

INTRODUCTIONDendritic cells (DCs) play a key regulatory role inantitumor immunity,especially in its immuneaccessory role via MHC-Ⅰ molecules.We haverecently reported that DCs were able to enhance thekilling activity of Lymphokine and PHA activatedkiller (LPAK) cells in vitro.In the presentstudy,we evaluated the effects of GM-CSF andTNF upon antitumor activities of freshly

Hepatitis B virus X protein up-regulates tumor necrosis factor-α expression in cultured mesangial cells via ERKs and NF-κB pathways

Objective:To investigate the effects of hepatitis B virus(HBV)X protein(HBx)on the expression of tumor necrosis factor-α(TNF-α)in glomerular mesangial cells(GMCs)and the underlying intracellular signal pathways.Methods:The plasmid pCI-neo-X that carries the X gene of hepatitis B virus was transfected into cultured GMCs.HBx expression in the transfected GMCs was assessed by Western-blot.TNF-αprotein and mRNA were assessed by ELISA and semi-quantitative RT-PCR,respectively.Three kinase inhibitors-U0126,an inhibitor of extracellular signal-regulated kinases(ERKs);lactacvstin,an inhibitor of nuclear factor-κB(NF-κB);and SB203580,a selective inhibitor of p38 MAP kinase(p38 MAPK)were used to determine which intracellular signal pathways may underlie the action of HBx on TNF-αexpression in transfected GMCs.Results:A significant increase in HBx expression in pCI-neo-X transfected GMCs was detected at 36 h and 48 h,which was not affected by any of those kinase inhibitors mentioned above.A similar increase in the expression of both TNF-αprotein and mRNA was also observed at 36 h and 48 h,which was significantly decreased in the presence of U0126 or lactacytin,but not SB203580.Conclusions:HBx upregulates TNF-αexpression in cultured GMCs,possibly through ERKs and NF-κB pathway,but not p38 MAPK pathway.