Objective To explore the roles of cytokines in the pathogenesis of hemorrhagic fever with renal syndrome（HFRS）. Methods Double-antibody sandwich ELISA was used to determine serum interleukin （IL）-6, urine tumor ne...Objective To explore the roles of cytokines in the pathogenesis of hemorrhagic fever with renal syndrome（HFRS）. Methods Double-antibody sandwich ELISA was used to determine serum interleukin （IL）-6, urine tumor necrosis factor （TNF）, IL-6 and IL-8 levels in 56 patients with HFRS. Results Serum IL-6, urine TNF, IL-6 and IL-8 concentrations in HFRS patients were significantly higher than those in control group, respectively （P<0.001）. The concentrations increased at fever stage, then continued to increase during hypotension stage and peaked at oliguria stage. The concentrations of serum IL-6, urine TNF, IL-6 and IL-8 increased in accord with the severity of the disease and differed greatly among different types of the disease. Serum IL-6 had remarkable relationships with serum specific antibodies. It was positively related to serum β2-microglobulin （β2-MG）, blood ureanitrogen （BUN） and creatinine （Cr）. Significant positive relationships were also found both between urine IL-6 and TNF, and between IL-6 and IL-8 （r=0.5768, P<0.05; r=0.3760, P<0.01）. Conclusion TNF, IL-6 and IL-8 activated during the course of the disease. IL-6 is associated with the immunopathological lesions caused by the hyperfunction of humoral immune response. IL-6, IL-8 and TNF are involved in the renal immune impairment. Determining them might, in certain extent, be used in predicting the prognosis and outcome of patients with HFRS.展开更多
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 i...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.展开更多
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 improv...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.展开更多
PSV23SMTNF and pSPMoIL-3 plasmids were cleaved to release murine interleukin-3 (mIL-3)and murine tumor necrosis factor (mTNF) complementary DNA (cDNA) resectively.The 3'terminal instable sequence of mIL-3 cDNA was...PSV23SMTNF and pSPMoIL-3 plasmids were cleaved to release murine interleukin-3 (mIL-3)and murine tumor necrosis factor (mTNF) complementary DNA (cDNA) resectively.The 3'terminal instable sequence of mIL-3 cDNA was deleted with Nco I digestion. Both cDNAs展开更多
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 tumo...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.展开更多
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 a...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.展开更多
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 co...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.展开更多
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. Twen...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.展开更多
Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has c...Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.展开更多
Objective To evaluate the effect of lamivudine on immunity of chronic hepatitis B by observing the sequential changes of serum TNF-α and HBV-DNA level. Methods 31 CHB patients with elevated serum ALT/AST level and HB...Objective To evaluate the effect of lamivudine on immunity of chronic hepatitis B by observing the sequential changes of serum TNF-α and HBV-DNA level. Methods 31 CHB patients with elevated serum ALT/AST level and HBVDNA level higher than 106 copies/mL were treated with lamivudine (100mg/day) for one year. The sequential serum samples, which were taken at the 0, 3 rd, 6 th, 12 th month after initiation of therapy, were used to detect serum level of TNF-α and quantity of HBV-DNA respectively. Results ① The serum TNF-α levels were higher than normal value before treatment in all patients; ② At In the 3 rd month of treatment, The the serum HBV-DNA level began to decline and became negative in the 54.9% of all patients. At the end of treatment, HBV-DNA was negative in 48.4% of all patients; ③ The decrease of TNF-α level was later than HBVDNA level drop. TNF-α level began to decline after 6 months treatment. At the end of treatment, TNF-α level was lower than that at in 6 th month, TNF-α level returned to normal in the 38.7% of all patients; ④ The TNF-α level decreased significantly after 6 months treatment in the patients with ALT>80IU/L at the beginning of treatment. But in the patients with ALT≤80IU/L, the TNF-α level decreased just after 12 months treatment; ⑤ TNF-α level fell obviously and early in patients whose HBVDNA became negative at in the 3 rd month. Conclusion Lamivudine can suppress the replication of HBVDNA quickly, and decrease TNF-α level in the serum TNF-α level. It suggests that lamivudine can modulate immune response directly or indirectly. The changes of serum TNF-α level may be used to evaluate the clinical efficacy of lamivudine.展开更多
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).METHODS:We prospectively stu...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).METHODS:We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid.They included 144 males and 56 females with ages ranging between 34 and 62 years.The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation.The severity of underlying liver disease was evaluated using Pugh's modification of Child's criteria(Child-Pugh scores).Ascitic fluid was sent to the laboratory for cell count,culture,sensitivity testing,and measurement of chemical elements(i.e.,albumin,glucose).Specimens were inoculated into aerobic and anaerobic blood culture bottles.Serum and ascitic fluid were also collected in sterile tubes at study entry(before the initiation of antibiotic treatment) and 48 h later.Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture's instructions.RESULTS:Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP.(plasma TNF-α:135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL,P < 0.001;plasma IL-6:32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL,P < 0.001;ascitic fluid TNF-α:647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL,P < 0.001);ascitic fluid IL-6:132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL,P < 0.001).About 48(40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection.[(plasma TNF-α:176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL)(P < 0.001) and(IL-6:57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL)(P < 0.001);ascitic fluid TNF-α:958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL,(P < 0.001),ascitic fluid IL-6:654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL,(P < 0.001)].Twenty nine patients(60.4%) with SBP and renal impairment died whereas,only four patients(5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage(P < 0.0005).CONCLUSION:It appears that TNF-α production may enhance liver cell injury and lead to renal impairment.This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.展开更多
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 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.展开更多
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 ...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展开更多
AIM:To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha(TNF-α)-induced gene expression in human gastric adenocarcinoma cells.METHODS:Knockdown ex...AIM:To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha(TNF-α)-induced gene expression in human gastric adenocarcinoma cells.METHODS:Knockdown experiments were conducted with claudin 1 small interfering RNA(si RNA),and theeffects on the cell cycle,apoptosis,migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells.The gene expression profiles of cells were analyzed by microarray and bioinformatics.RESULTS:The knockdown of claudin 1 significantly inhibited cell proliferation,migration and invasion,and increased apoptosis.Microarray analysis identified 245genes whose expression levels were altered by the knockdown of claudin 1.Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway,which involved MMP7,TNF-SF10,TGFBR1,and CCL2.Furthermore,TNFand nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1.TNF-αtreatment increased claudin 1 expression and cell migration in MKN28 cells.Microarray analysis indicated that the depletion of claudin1 inhibited 80%of the TNF-α-induced m RNA expression changes.Further,TNF-αdid not enhance cell migration in the claudin 1 si RNA transfected cells.CONCLUSION:These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells.A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer.展开更多
AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VAR...AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs(DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.RESULTS Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events(-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events(+5.85 mg/d L, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events(-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β =-0.58, P = 0.01) and hydroxychloroquine(β =-5.78, P = 0.01) use as predictors of lower post-medicationinitiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure(β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.CONCLUSION No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.展开更多
Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes i...Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes increases expression and activity of matrix metalloproteinase-9,a proteolytic enzyme available in specific gelatinase granules,which contain several enzymes including lysozyme.Present work investigated active lysozyme release after phagocytosis of hemozoin and its dependence on production of tumor necrosis factor alpha. Methods:After phagocytosis of hemozoin,hemozoin-containing trophozoites or control meals(opsonized nonparasitized red blood cells and latex particles),monocyte supematants were monitored for 2 hours,in presence of blocking anti-human tumor necrosis factor alpha antibodies or recombinant human tumor necrosis factor alpha cytokine in selected experiments.Lysozyme release was evaluated by a specific spectrometric assay measuring lysozyme activity after coincubation of cell supematants with suspensions of Mycrococcus Lysodeikticus,while levels of soluble tumor necrosis factor alpha were analyzed by specific enzyme-linked immunodsorbent assay. Results:Levels of lysozyme activity and soluble tumor necrosis factor alpha protein were increased in hemozoin in-or trophozoites-laden monocytes supematants.Phagocytosis per se(control meals) also increased lysozyme release,but levels were significantly lower than those obtained after phagocytosis of hemozoin or trophozoites. Interestingly,all effects on lysozyme release observed after phagocytosis were abrogated by blocking anti-human tumor necrosis factor alpha antibodies,while they were mimicked by recombinant human tumor necrosis factor alpha cytokine.Conclusions:Present work shows that phagocytosis of hemozoin promotes monocyte degranulation and enhances active lysozyme release.The effect requires tumor necrosis factor alpha mediation.展开更多
AIM To investigate the association of tumor necrosis factor alpha(TNFα)-G308 A polymorphism with different liver pathological changes in treatment-na?ve Egyptian patients infected with hepatitis C virus(HCV) genotype...AIM To investigate the association of tumor necrosis factor alpha(TNFα)-G308 A polymorphism with different liver pathological changes in treatment-na?ve Egyptian patients infected with hepatitis C virus(HCV) genotype 4.METHODS This study included 180 subjects,composed of 120 treatment-na?ve chronic HCV patients with different fibrosis grades(F0-F4) and 60 healthy controls. The TNFα-G308 A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα-G308 A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence.RESULTS Current data showed that the TNFα-G308 A SNP frequency was significantly different between controls and HCV infected patients(P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients(F2-F4,n = 60) than in early fibrosis patients(F0-F1,n = 60)(P = 0.05,0.04 respectively). Moreover,the GA or AA genotypes increased the TNFα serum level greater than the GG genotype(P = 0.002). The results showed a clear association between severe liver pathological conditions(inflammation,steatosis and fibrosis) and(GA + AA) genotypes(P = 0.035,0.03,0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes(GA + AA) were significantly associated with liver inflammation(OR = 3.776,95%CI: 1.399-10.194,P = 0.009),severe steatosis(OR = 4.49,95%CI: 1.441-14.0,P = 0.010) and fibrosis progression(OR = 2.84,95%CI: 1.080-7.472,P = 0.034). Also,the A allele was an independent risk factor for liver inflammation(P = 0.003),steatosis(P = 0.003) and fibrosis(P = 0.014). CONCLUSION TNFα SNP at nucleotide-308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected展开更多
BACKGROUND Inflammatory cytokines play a vital role in the occurrence of osteoarticular injury and inflammation. Whether inflammation-associated factors interleukin-1β(IL- 1β), IL-6, tumor necrosis factor-α(TNF-α)...BACKGROUND Inflammatory cytokines play a vital role in the occurrence of osteoarticular injury and inflammation. Whether inflammation-associated factors interleukin-1β(IL- 1β), IL-6, tumor necrosis factor-α(TNF-α) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of keen articular cartilage injury remains poorly understood. AIM To measure the levels of inflammatory factors [IL-1β, IL-6, TNF-α and VEGF] in patients with knee articular cartilage injury. METHODS Fifty-five patients with knee articular cartilage injury were selected as patient groups, who were divided into three grades [mild (n = 20), moderate (n = 19) and severe (n = 16)] according to disease severity and X-ray examinations. Meanwhile, 30 healthy individuals who underwent physical examination were selected as the control group. The levels of IL-1β, IL-6, TNF-α and VEGF were measured by ELISA and immunohistochemical staining. RESULTS Compared with the control group, patient groups displayed significantly higher levels of IL-1β, IL-6, TNF-α and VEGF, and the extent of increase was directly proportional to the severity of injury (P < 0.05). In addition, the number of cells with positive staining of IL-1β, IL-6, TNF-α and VEGF in the synovial membrane were significantly increased, along with increased disease severity (P < 0.05). After treatment, the scores of visual analogue scale and the Western Ontario and McMaster University of Orthopaedic Index in patient groups were 2.26 ± 1.13 and 15.56 ± 7.12 points, respectively, which were significantly lower than those before treatment (6.98 ± 1.32 and 49.48 ± 8.96). Correlation analysis suggested that IL-1β and TNF-α were positively correlated with VEGF. CONCLUSION IL-1β, IL-6, TNF-α and VEGF levels are increased in patients with knee articular cartilage injury, and are associated with the disease severity, indicating they might play an important role in the occurrence and development of knee articular cartilage injury. Furthermore, therapeutically targeting them might be a novel approach for the treatment of keen articular cartilage injury.展开更多
文摘Objective To explore the roles of cytokines in the pathogenesis of hemorrhagic fever with renal syndrome（HFRS）. Methods Double-antibody sandwich ELISA was used to determine serum interleukin （IL）-6, urine tumor necrosis factor （TNF）, IL-6 and IL-8 levels in 56 patients with HFRS. Results Serum IL-6, urine TNF, IL-6 and IL-8 concentrations in HFRS patients were significantly higher than those in control group, respectively （P<0.001）. The concentrations increased at fever stage, then continued to increase during hypotension stage and peaked at oliguria stage. The concentrations of serum IL-6, urine TNF, IL-6 and IL-8 increased in accord with the severity of the disease and differed greatly among different types of the disease. Serum IL-6 had remarkable relationships with serum specific antibodies. It was positively related to serum β2-microglobulin （β2-MG）, blood ureanitrogen （BUN） and creatinine （Cr）. Significant positive relationships were also found both between urine IL-6 and TNF, and between IL-6 and IL-8 （r=0.5768, P<0.05; r=0.3760, P<0.01）. Conclusion TNF, IL-6 and IL-8 activated during the course of the disease. IL-6 is associated with the immunopathological lesions caused by the hyperfunction of humoral immune response. IL-6, IL-8 and TNF are involved in the renal immune impairment. Determining them might, in certain extent, be used in predicting the prognosis and outcome of patients with HFRS.
基金Research Support Foundation of the State of São Paulo(FAPESP,Brazil),No.2014/25927-2,No.2018/07862-1National Council for Scientific and Technological Development(CNPq,Brazil)Higher Education Personnel Improvement Coordination(CAPES,Brazil).
文摘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.
文摘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.
文摘PSV23SMTNF and pSPMoIL-3 plasmids were cleaved to release murine interleukin-3 (mIL-3)and murine tumor necrosis factor (mTNF) complementary DNA (cDNA) resectively.The 3'terminal instable sequence of mIL-3 cDNA was deleted with Nco I digestion. Both cDNAs
基金This research was funded by Guangzhou Science and Technology Plan Projects(No.202002020066)the Young Scientists to the NSFC Application of Guangdong Provincial People’s Hospital(No.8210120306)the Open Foundation of the State Key Laboratory of Bioactive Seaweed Substance(No.SKL-BMSG2022-03)。
文摘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.
文摘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.
文摘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.
文摘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.
文摘Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.
文摘Objective To evaluate the effect of lamivudine on immunity of chronic hepatitis B by observing the sequential changes of serum TNF-α and HBV-DNA level. Methods 31 CHB patients with elevated serum ALT/AST level and HBVDNA level higher than 106 copies/mL were treated with lamivudine (100mg/day) for one year. The sequential serum samples, which were taken at the 0, 3 rd, 6 th, 12 th month after initiation of therapy, were used to detect serum level of TNF-α and quantity of HBV-DNA respectively. Results ① The serum TNF-α levels were higher than normal value before treatment in all patients; ② At In the 3 rd month of treatment, The the serum HBV-DNA level began to decline and became negative in the 54.9% of all patients. At the end of treatment, HBV-DNA was negative in 48.4% of all patients; ③ The decrease of TNF-α level was later than HBVDNA level drop. TNF-α level began to decline after 6 months treatment. At the end of treatment, TNF-α level was lower than that at in 6 th month, TNF-α level returned to normal in the 38.7% of all patients; ④ The TNF-α level decreased significantly after 6 months treatment in the patients with ALT>80IU/L at the beginning of treatment. But in the patients with ALT≤80IU/L, the TNF-α level decreased just after 12 months treatment; ⑤ TNF-α level fell obviously and early in patients whose HBVDNA became negative at in the 3 rd month. Conclusion Lamivudine can suppress the replication of HBVDNA quickly, and decrease TNF-α level in the serum TNF-α level. It suggests that lamivudine can modulate immune response directly or indirectly. The changes of serum TNF-α level may be used to evaluate the clinical efficacy of lamivudine.
文摘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).METHODS:We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid.They included 144 males and 56 females with ages ranging between 34 and 62 years.The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation.The severity of underlying liver disease was evaluated using Pugh's modification of Child's criteria(Child-Pugh scores).Ascitic fluid was sent to the laboratory for cell count,culture,sensitivity testing,and measurement of chemical elements(i.e.,albumin,glucose).Specimens were inoculated into aerobic and anaerobic blood culture bottles.Serum and ascitic fluid were also collected in sterile tubes at study entry(before the initiation of antibiotic treatment) and 48 h later.Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture's instructions.RESULTS:Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP.(plasma TNF-α:135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL,P < 0.001;plasma IL-6:32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL,P < 0.001;ascitic fluid TNF-α:647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL,P < 0.001);ascitic fluid IL-6:132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL,P < 0.001).About 48(40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection.[(plasma TNF-α:176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL)(P < 0.001) and(IL-6:57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL)(P < 0.001);ascitic fluid TNF-α:958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL,(P < 0.001),ascitic fluid IL-6:654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL,(P < 0.001)].Twenty nine patients(60.4%) with SBP and renal impairment died whereas,only four patients(5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage(P < 0.0005).CONCLUSION:It appears that TNF-α production may enhance liver cell injury and lead to renal impairment.This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.
文摘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.
基金Natural Science Foundation of the Higher Education Office of Guangdong Province,No.19952901
文摘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
基金Supported by Grants-in-Aid for Young Scientists(B)No.22791295,No.23791557 and No.24791440Grant-in-Aid for Scientific Research(C)from the Japan Society for the Promotion of Science,No.22591464 and No.24591957
文摘AIM:To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha(TNF-α)-induced gene expression in human gastric adenocarcinoma cells.METHODS:Knockdown experiments were conducted with claudin 1 small interfering RNA(si RNA),and theeffects on the cell cycle,apoptosis,migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells.The gene expression profiles of cells were analyzed by microarray and bioinformatics.RESULTS:The knockdown of claudin 1 significantly inhibited cell proliferation,migration and invasion,and increased apoptosis.Microarray analysis identified 245genes whose expression levels were altered by the knockdown of claudin 1.Pathway analysis showed that the top-ranked molecular and cellular function was the cellular movement related pathway,which involved MMP7,TNF-SF10,TGFBR1,and CCL2.Furthermore,TNFand nuclear frctor-κB were the top-ranked upstream regulators related to claudin 1.TNF-αtreatment increased claudin 1 expression and cell migration in MKN28 cells.Microarray analysis indicated that the depletion of claudin1 inhibited 80%of the TNF-α-induced m RNA expression changes.Further,TNF-αdid not enhance cell migration in the claudin 1 si RNA transfected cells.CONCLUSION:These results suggest that claudin 1 is an important messenger that regulates TNF-α-induced gene expression and migration in gastric cancer cells.A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer.
基金Supported by VA HSR&D MERIT Award IIR,No.14-048-3 for Dr Caplansupported by a VA GME Enhancement Award
文摘AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs(DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.RESULTS Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events(-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events(+5.85 mg/d L, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events(-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β =-0.58, P = 0.01) and hydroxychloroquine(β =-5.78, P = 0.01) use as predictors of lower post-medicationinitiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure(β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.CONCLUSION No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.
基金supported in the context of the Italian Malaria Network by grants from Compagnia di San Paolo-IMIthe University of Torino Intramural FundsRegione Piemonte,Ricerca Sanitaria Finalizzata 2007 to PA
文摘Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes increases expression and activity of matrix metalloproteinase-9,a proteolytic enzyme available in specific gelatinase granules,which contain several enzymes including lysozyme.Present work investigated active lysozyme release after phagocytosis of hemozoin and its dependence on production of tumor necrosis factor alpha. Methods:After phagocytosis of hemozoin,hemozoin-containing trophozoites or control meals(opsonized nonparasitized red blood cells and latex particles),monocyte supematants were monitored for 2 hours,in presence of blocking anti-human tumor necrosis factor alpha antibodies or recombinant human tumor necrosis factor alpha cytokine in selected experiments.Lysozyme release was evaluated by a specific spectrometric assay measuring lysozyme activity after coincubation of cell supematants with suspensions of Mycrococcus Lysodeikticus,while levels of soluble tumor necrosis factor alpha were analyzed by specific enzyme-linked immunodsorbent assay. Results:Levels of lysozyme activity and soluble tumor necrosis factor alpha protein were increased in hemozoin in-or trophozoites-laden monocytes supematants.Phagocytosis per se(control meals) also increased lysozyme release,but levels were significantly lower than those obtained after phagocytosis of hemozoin or trophozoites. Interestingly,all effects on lysozyme release observed after phagocytosis were abrogated by blocking anti-human tumor necrosis factor alpha antibodies,while they were mimicked by recombinant human tumor necrosis factor alpha cytokine.Conclusions:Present work shows that phagocytosis of hemozoin promotes monocyte degranulation and enhances active lysozyme release.The effect requires tumor necrosis factor alpha mediation.
文摘AIM To investigate the association of tumor necrosis factor alpha(TNFα)-G308 A polymorphism with different liver pathological changes in treatment-na?ve Egyptian patients infected with hepatitis C virus(HCV) genotype 4.METHODS This study included 180 subjects,composed of 120 treatment-na?ve chronic HCV patients with different fibrosis grades(F0-F4) and 60 healthy controls. The TNFα-G308 A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα-G308 A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence.RESULTS Current data showed that the TNFα-G308 A SNP frequency was significantly different between controls and HCV infected patients(P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients(F2-F4,n = 60) than in early fibrosis patients(F0-F1,n = 60)(P = 0.05,0.04 respectively). Moreover,the GA or AA genotypes increased the TNFα serum level greater than the GG genotype(P = 0.002). The results showed a clear association between severe liver pathological conditions(inflammation,steatosis and fibrosis) and(GA + AA) genotypes(P = 0.035,0.03,0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes(GA + AA) were significantly associated with liver inflammation(OR = 3.776,95%CI: 1.399-10.194,P = 0.009),severe steatosis(OR = 4.49,95%CI: 1.441-14.0,P = 0.010) and fibrosis progression(OR = 2.84,95%CI: 1.080-7.472,P = 0.034). Also,the A allele was an independent risk factor for liver inflammation(P = 0.003),steatosis(P = 0.003) and fibrosis(P = 0.014). CONCLUSION TNFα SNP at nucleotide-308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected
文摘BACKGROUND Inflammatory cytokines play a vital role in the occurrence of osteoarticular injury and inflammation. Whether inflammation-associated factors interleukin-1β(IL- 1β), IL-6, tumor necrosis factor-α(TNF-α) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of keen articular cartilage injury remains poorly understood. AIM To measure the levels of inflammatory factors [IL-1β, IL-6, TNF-α and VEGF] in patients with knee articular cartilage injury. METHODS Fifty-five patients with knee articular cartilage injury were selected as patient groups, who were divided into three grades [mild (n = 20), moderate (n = 19) and severe (n = 16)] according to disease severity and X-ray examinations. Meanwhile, 30 healthy individuals who underwent physical examination were selected as the control group. The levels of IL-1β, IL-6, TNF-α and VEGF were measured by ELISA and immunohistochemical staining. RESULTS Compared with the control group, patient groups displayed significantly higher levels of IL-1β, IL-6, TNF-α and VEGF, and the extent of increase was directly proportional to the severity of injury (P < 0.05). In addition, the number of cells with positive staining of IL-1β, IL-6, TNF-α and VEGF in the synovial membrane were significantly increased, along with increased disease severity (P < 0.05). After treatment, the scores of visual analogue scale and the Western Ontario and McMaster University of Orthopaedic Index in patient groups were 2.26 ± 1.13 and 15.56 ± 7.12 points, respectively, which were significantly lower than those before treatment (6.98 ± 1.32 and 49.48 ± 8.96). Correlation analysis suggested that IL-1β and TNF-α were positively correlated with VEGF. CONCLUSION IL-1β, IL-6, TNF-α and VEGF levels are increased in patients with knee articular cartilage injury, and are associated with the disease severity, indicating they might play an important role in the occurrence and development of knee articular cartilage injury. Furthermore, therapeutically targeting them might be a novel approach for the treatment of keen articular cartilage injury.
