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(P...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.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
BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.H...BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.However,previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure.AIM This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn’s perianal fistula(CPF)closure rates after stem cell transplantation with and without anti-TNF therapy,and to identify the factors affecting CPF closure and recurrence.METHODS The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled.Clinical data were compared according to anti-TNF therapy and CPF closure.RESULTS A total of 65 patients were included.The median age of females was 26 years(range:21-31)and that of males was 29(44.6%).The mean follow-up duration was 65.88±32.65 months,and complete closure was observed in 50(76.9%)patients.The closure rates were similar after stem cell transplantation with and without anti-TNF therapy(66.7%vs 81.6%at 3 year,P=0.098).The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture(P=0.027,0.002,and 0.008,respectively).Clinical factors such as complexity,number of fistulas,presence of concurrent abscess,and medication were not significant for closure.The cumulative 1-,2-,and 3-year closure rates were 66.2%,73.8%,and 75.4%,respectively.CONCLUSION Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation.However,both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy.Fistulous tract length,proctitis,and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.展开更多
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 injur...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.展开更多
BACKGROUND: Pulmonary complications after orthoto- pic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ische- mia and reperfusion are induced by pro-inflammat...BACKGROUND: Pulmonary complications after orthoto- pic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ische- mia and reperfusion are induced by pro-inflammatory cyto- kines. The high level of inflammatory cytokines might ad- ditionally influence pulmonary cappillary fluid filtration. The objectives of this study were to measure the concentra- tions of tumor necrotic factor-alpha (TNF-α), interleukin- 6 (IL-6) and interleukin-8 (IL-8) during OLT and to in- vestigate the relationship between these cytokines and post- operative pulmonary complications. METHODS: Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consis- ting of 8 patients with postoperative pulmonary complica- tions , and group B consisting of 14 patients without post- operative pulmonary complications. Enzyme-linked im- munoassay (ELISA) was used to determine serum TNF-α, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0 ), clamping and cross-clamping of the in- ferior cava and portal vein (T1, T2 ), 90 minutes and 3 hours after reperfusion (T3 , T4 ) and 24 hours after opera- tion (T5). RESULTS: The level of PaO2/FiO2 in group A was lower than that in group B ( P <0. 05 ). The concentrations of TNF-α, IL-6 and IL-8 in the two groups increased rapidly at T2 , peaked at T3 , decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-α, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4(P<0.05). CONCLUSION: After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-α, IL-6 and IL-8 increased may be related to pulmonary injury after he- patic ischemic reperfusion.展开更多
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 ...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.展开更多
AIM： To investigate the role of tumor necrosis factoralpha （TNF-α） in zebrafish retinal development and myelination. METHODS： Morpholino oligonucleotides （MO）, which are complementary to the translation start...AIM： To investigate the role of tumor necrosis factoralpha （TNF-α） in zebrafish retinal development and myelination. METHODS： Morpholino oligonucleotides （MO）, which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin （cp）, and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 （atoh7） mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein （mbp）was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS： Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization （hpf）. mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization （dpf） as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION： TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.展开更多
Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain,weight loss associated with diarrhea,and multiple inflammatory ulcerations and strictures of the small bowel.Ulcerative jejunoilei...Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain,weight loss associated with diarrhea,and multiple inflammatory ulcerations and strictures of the small bowel.Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo.Increased levels of tumor necrosis factor-alpha(TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder.No specific therapy has been shown to change the course of ulcerative jejunoileitis.We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies,including high dose corticosteroids and cyclosporine.The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody,infliximab(Remicade).展开更多
AIM:To study the expression of tumor necrosis factor- alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo. METHODS: Male SD rats underwent 70% partial h...AIM:To study the expression of tumor necrosis factor- alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo. METHODS: Male SD rats underwent 70% partial hepatec- tomy. The remaining liver and spleen tissue samples were collected at indicated time points after hepatectomy. TACE expression was investigated by Western blotting, immunohistochemistry, and serial section immunostaining. RESULTS: Expression of TACE in liver and spleen tissues after partial hepatectomy was a time-dependent alteration, reaching a maximal level between 24 and 48 h and remaining elevated for more than 168 h. TACE protein was localized to mononuclear cells (MNC), which infiltrated the liver from the spleen after hepatectomy. The kinetics of TACE expression was in accordance with the number of TACE-staining MNCs and synchronized with those of transforming growth factor-α (TGFα). In addition, TACE-staining MNC partially overlapped with CD3+ T lymphocytes. CONCLUSION: TACE may be involved in liver regenera- tion by pathway mediated with TGFα-EGFR in the cell- cycle progressive phase in vivo. TACE production and effect by paracrine may be a pathway of involvement in liver regeneration for the activated CD3+ T lymphocytes.展开更多
BACKGROUND： Previous studies of curcumin have focused mainly on its cytotoxic properties for antitumor therapy. There are few studies addressing the application of curcumin in the prevention and treatment of nervous ...BACKGROUND： Previous studies of curcumin have focused mainly on its cytotoxic properties for antitumor therapy. There are few studies addressing the application of curcumin in the prevention and treatment of nervous system diseases. OBJECTIVE： To observe the protective effect of curcumin against tumor necrosis factor-alpha （TNF-α）-induced neuronal damage in the rat hippocampus and to explore the intervention effect of curcumin on Ca^2＋ influx following neuronal damage. DESIGN, TIME AND SETTING： A cell morphological and physiological study was performed at the Institute of Brain Research, Medical College of Jinan University, China, from December 2006 to June 2007. MATERIALS： Curcumin （Sigma, USA） and TNF-α （Sigma, USA） were used in this study. METHODS： Hippocampal neurons were isolated from one-day neonatal rats and primarily cultured for 5 days. Following this they received 1 pmol/L curcumin and 100 ng/mL TNF-a pre-treatment. Dynamic morphological changes were observed for 1 hour by inverted microscopy. At 48 hours post-treatment, static morphological characteristics of the neurons were observed using inverted microscopy. Subsequently, hippocampal neurons were primarily cultured for 7 days, after receiving 1 pmol/L curcumJn and 4.5 ng/mL TNF-a pre-treatment. Intracellular free Ca^2＋ was measured using Fluo 3/acetoxymethyl ester. MAIN OUTCOME MEASURES： Effects of curcumin on TNF-a-induced neuronal damage and Ca^2＋ influx in the rat hippocampus were measured. RESULTS： Following curcumin treatment, TNF-a-induced neurons grew as normal. TNF-a induced a rapid Ca^2＋ influx into the neuronal cytoplasm; however, Ca2＋ fluorescence intensity only slightly increased when neurons were co-perfused with curcumin and TNF-α. CONCLUSION： Curcumin has a protective effect on rat hippocampal neurons possibly by reducing the TNF-α-induced rapid Ca^2＋ influx into neuronal cytoplasm and by maintaining the Ca^2＋ homeostasis.展开更多
Low survival rate occurs in patients who initially experience a spontaneous return of circulation after cardiac arrest（CA）. In this study, we induced asphyxial CA in adult male Sprague-Daley rats, maintained their b...Low survival rate occurs in patients who initially experience a spontaneous return of circulation after cardiac arrest（CA）. In this study, we induced asphyxial CA in adult male Sprague-Daley rats, maintained their body temperature at 37 ± 0.5°C, and then observed the survival rate during the post-resuscitation phase. We examined neuronal damage in the hippocampus using cresyl violet（CV） and Fluore-Jade B（F-J B） staining, and pro-inflammatory response using ionized calcium-binding adapter molecule 1（Iba-1）, glial fibrillary acidic protein（GFAP）, and tumor necrosis factor-alpha（TNF-α） immunohistochemistry in the hippocampus after asphyxial CA in rats under normothermia. Our results show that the survival rate decreased gradually post-CA（about 63% at 6 hours, 37% at 1 day, and 8% at 2 days post-CA）. Rats were sacrificed at these points in time post-CA, and no neuronal damage was found in the hippocampus until 1 day post-CA. However, some neurons in the stratum pyramidale of the CA region in the hippocampus were dead 2 days post-CA. Iba-1 immunoreactive microglia in the CA1 region did not change until 1 day postCA, and they were activated（enlarged cell bodies with short and thicken processes） in all layers 2 days postCA. Meanwhile, GFAP-immunoreactive astrocytes did not change significantly until 2 days post-CA. TNF-α immunoreactivity decreased significantly in neurons of the stratum pyramidale in the CA1 region 6 hours post-CA, decreased gradually until 1 day post-CA, and increased significantly again 2 days post-CA. These findings suggest that low survival rate of normothermic rats in the early period of asphyxia-induced CA is related to increased TNF-α immunoreactivity, but not to neuronal damage in the hippocampal CA1 region.展开更多
BACKGROUND： Cerebral infarction is poorly treated due to neuronal necrosis and secondary pathophysiological changes; for example, free radical production and inflammatory reactions. OBJECTIVE： To detect the levels o...BACKGROUND： Cerebral infarction is poorly treated due to neuronal necrosis and secondary pathophysiological changes; for example, free radical production and inflammatory reactions. OBJECTIVE： To detect the levels of high-sensitivity C-reactive protein （hs-CRP）, interleukin-6 （IL-6）, and tumor necrosis factor- a （TNF- α ） in elderly males with cerebral infarction. DESIGN： Non-randomized current control study. SETTING： Cadre Medical Department, Guizhou Provincial People＇s Hospital. PARTICIPANTS： Forty elderly males （65-89 years old） with cerebral infarction were selected from Cadre Medical Department, Guizhou Provincial People＇s Hospital from February 2004 to December 2006. All patients met the diagnostic criteria of cerebral infarction modified at the 4th National Cerebrovascular Disease Academic Meeting, and were diagnosed on the basis of CT or MRI tests. Furthermore, 35 elderly male inpatients （65-87 years old） without cerebral infarction were selected as the control group. Included subjects provided confirmed consent and did not have heart disease, diabetes mellitus, lipid disorder, acute trauma, infection, rheumatism, or other inflammatory diseases. The study was approved by the local ethics committee. There were no significant differences in age, blood pressure, and lipid levels between the cerebral infarction group and the control group （P 〉 0.05）, and this suggested that the baseline data of both groups were comparable. METHODS： Fasting venous blood was drawn from cerebral infarction patients 24 hours after cerebral infarction attack and from control subjects 24 hours after hospitalization. A latex-enhanced immunoturbidimetric assay and an enzyme-linked immunosorbent assay were used to detect the levels of hs-CRP, IL-6, and TNF- α in the serum. MAIN OUTCOME MEASURES： The levels of hs-CRP, 1L-6, and TNF- α in the serum in both groups. RESULTS： Forty cerebral infarction patients and thirty-five control subjects were included in the final analysis without any loss. Levels of hs-CRP, IL-6, and TNF-α in the cerebral infarction group were significantly higher than those in the control group （P 〈 0.01 ）. CONCLUSION： Levels of serum inflammatory reactive factors are increased in elderly males with cerebral infarction.展开更多
As an aquatic fish,the spotted halibut Verasper variegatus is highly susceptible to bacterial and virus infections.Tumor necrosis factor-alpha(TNF-α)as a cytokine could control the inflammatory responses.The function...As an aquatic fish,the spotted halibut Verasper variegatus is highly susceptible to bacterial and virus infections.Tumor necrosis factor-alpha(TNF-α)as a cytokine could control the inflammatory responses.The functions of TNF-αin many species have been widely studied,particularly in mammals.However,little is known about the TNF-αfunctions in V.variegatus.We first cloned and sequenced the TNF-αgene in V.variegatus(VvTNF-α).The two conserved cysteine residues,transmembrane sequence,Thr-Leu motif,and TNF family signature,as well as the TA-rich motifs of its proteins related to inflammatory responses had high similarity to those of the other teleost and mammalian TNF-α.The phylogenetic analysis showed that VvTNF-αwas consistent with TNF-αgenes of other vertebrates.The VvTNF-αtranscripts were extensively distributed in the peripheral blood leukocytes(PBLs),spleen,and gill,indicating that the VvTNF-αhad a role in immune function.Furthermore,treatment with pathogen-associated molecular patterns(PAMPs)could induce a rapid and significant increase of VvTNF-αin the PBLs,which reveals that VvTNF-αdoes participate in the host immune responses against bacterial and viral pathogens.We found that VvTNF-αhad an interesting expression pattern during metamorphosis,showing that the flatfish TNF-αmay have some novel functions during specific developmental stages.In addition,the 3 D structure prediction of VvTNF-αprovided an indication of how it is likely to interact with other proteins.Therefore,VvTNF-αhas multiple functions,and provides valuable information to explore novel functions of TNF-α.展开更多
Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are involved in the progression of coronary artery disease (CAD). The cytokines’ levels are associated with the severity of CAD. We have recently repor...Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are involved in the progression of coronary artery disease (CAD). The cytokines’ levels are associated with the severity of CAD. We have recently reported on the association of resistin, a relatively novel cytokine with the pathogenesis of cardiovascular disease (CVD). Although the inflammatory cytokines’ impact on atherosclerosis is widely accepted, yet some controversy exists regarding the involvement of these factors in atherogenesis. The current review highlights the potential association of TNF-alpha, IL-6 and resistin SNPs (single nucleotide polymorphisms) with CAD. Molecular genetics data along with the intracellular signaling cascade mechanisms may have important clinical implications in the treatment of CAD.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
TNF-α was found originally In sera of Bacillus Calmette Guerln infected mice as a macrophage derived factor. It Is cytotoxlc for tumor cell and less or not toxic to normal cells in vitor. The gene for human TNF-α wi...TNF-α was found originally In sera of Bacillus Calmette Guerln infected mice as a macrophage derived factor. It Is cytotoxlc for tumor cell and less or not toxic to normal cells in vitor. The gene for human TNF-α with E. coli-preferred codons has been designed according to the amino acid sequence deduced from the cDNA. The gene with 504 bp was divided into 27 oligonucleotide fragments having 30. to 40 nucleotides each. The solid phase phosphotriester method was used for the synthesis of these oligonucleotides. The 27 fragments were annealed to three segments and then linked by T4 DNA ligase. The entire gene was incorporated into plasmld PDR540 with Tac promoter which was used to transform E. coli 7118. The expressed protein was estimated by SDSPAGE with a molecular weight of 1. 7×104Da. The cytotoxlc activity of the product against L-929 cell was 1. 0×107units/ml culture.展开更多
Objective Secoemestrin C(SC),an epitetrathiodioxopiperazine isolated from Aspergillus nidulans,has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis.Howe...Objective Secoemestrin C(SC),an epitetrathiodioxopiperazine isolated from Aspergillus nidulans,has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis.However,the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear.This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo.Methods In vitro,HaCaT cells were induced with tumor necrosis factor-alpha(TNF-α,10 ng/mL)to establish an inflammatory injury model,and the expression of nuclear transcription factor-κB(NF-κB)pathway components was measured using qRT-PCR and Western blotting.An in vivo mouse model of imiquimod(IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis.Results SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells.In addition,systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model.SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions.Conclusion The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.展开更多
AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cas...AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms,which are TNF-α-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A. The TNF-α genotype frequencies,genotype combinations and haplotypes were analyzed to disclose the association with HCC.RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However,nine genotype combinations had associations with increased likelihood of HCC. Among them,TNF-α-1031/-857/-238 TT/CC/GA(AOR = 18.849,95%CI: 2.203-161.246,P = 0.007),TNF-α-1031/-308/-238 TT/GG/GA(AOR = 26.956,95%CI: 3.071-236.584,P = 0.003),and TNF-α-1031/-238 TT/GA(AOR = 21.576,95%CI: 2.581-180.394,P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α-1031/-863/-857/-308/-238 T-C-C-G-A(OR = 25.824,95%CI: 1.491-447.223,P = 0.0005),TNF-α-1031/-857/-308/-238 T-C-G-A(OR = 12.059,95%CI: 2.747-52.950,P < 0.0001),TNF-α-1031/-857/-238 T-C-A(OR = 10.696,95%CI: 2.428-47.110,P = 0.0001),TNF-α-1031/-308/-238 T-G-A(OR = 7.556,95%CI: 2.173-26.280,P = 0.0002) and TNF-α-1031/-238 T-A(OR = 10.865,95%CI: 2.473-47.740,P = 0.0001). Moreover,HCC Okuda stage Ⅲ cases with the TNF-α-1031 CC genotype had better survival than those with the TT genotype(AOR = 5.795,95%CI: 1.145-29.323). CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study,some TNF-α genotype combinations and haplotypes are associated with HCC. In addition,HCC Okuda stage Ⅲ cases with the TNF-α-1031 TT genotype may have a better prognosis than those with the CC genotype.展开更多
AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis(TB) infection in Crohn's disease(CD) patients treated with tumor necrosis factoralpha(TNFα) inhibitors.METHODS A meta-analysis o...AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis(TB) infection in Crohn's disease(CD) patients treated with tumor necrosis factoralpha(TNFα) inhibitors.METHODS A meta-analysis of randomized, double-blind, placebocontrolled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction(EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028(95%CI: 0.0011-0.055). The odds ratio was 4.85(95%CI: 1.02-22.99) with EBC and 5.85(95%CI: 1.13-30.38) without EBC.CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.展开更多
Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders.Tumor necrosis ...Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders.Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases.Therefore,a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy.Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics,and anti-inflammatory features.Recently,phytochemicals including flavonoids,terpenoids,alkaloids,and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system.In this review,we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration.展开更多
基金Supported by the National Natural Science Foundation of China,No.81871568,No.32100643COVID-19 Infection and Prevention Emergency Special Project of Chongqing Education Commission,No.KYYJ202009.
文摘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.
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.
基金Supported by the grants from the Asan Institute for Life Sciences,Asan Medical Center,Seoul,Korea,No.2019IF0593 and No.2020IP0039.
文摘BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn’s disease(CD).Anti-tumor necrotic factor(TNF)therapy combined with drainage procedure is effective as well.However,previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure.AIM This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn’s perianal fistula(CPF)closure rates after stem cell transplantation with and without anti-TNF therapy,and to identify the factors affecting CPF closure and recurrence.METHODS The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled.Clinical data were compared according to anti-TNF therapy and CPF closure.RESULTS A total of 65 patients were included.The median age of females was 26 years(range:21-31)and that of males was 29(44.6%).The mean follow-up duration was 65.88±32.65 months,and complete closure was observed in 50(76.9%)patients.The closure rates were similar after stem cell transplantation with and without anti-TNF therapy(66.7%vs 81.6%at 3 year,P=0.098).The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture(P=0.027,0.002,and 0.008,respectively).Clinical factors such as complexity,number of fistulas,presence of concurrent abscess,and medication were not significant for closure.The cumulative 1-,2-,and 3-year closure rates were 66.2%,73.8%,and 75.4%,respectively.CONCLUSION Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation.However,both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy.Fistulous tract length,proctitis,and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.
文摘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.
文摘BACKGROUND: Pulmonary complications after orthoto- pic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ische- mia and reperfusion are induced by pro-inflammatory cyto- kines. The high level of inflammatory cytokines might ad- ditionally influence pulmonary cappillary fluid filtration. The objectives of this study were to measure the concentra- tions of tumor necrotic factor-alpha (TNF-α), interleukin- 6 (IL-6) and interleukin-8 (IL-8) during OLT and to in- vestigate the relationship between these cytokines and post- operative pulmonary complications. METHODS: Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consis- ting of 8 patients with postoperative pulmonary complica- tions , and group B consisting of 14 patients without post- operative pulmonary complications. Enzyme-linked im- munoassay (ELISA) was used to determine serum TNF-α, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0 ), clamping and cross-clamping of the in- ferior cava and portal vein (T1, T2 ), 90 minutes and 3 hours after reperfusion (T3 , T4 ) and 24 hours after opera- tion (T5). RESULTS: The level of PaO2/FiO2 in group A was lower than that in group B ( P <0. 05 ). The concentrations of TNF-α, IL-6 and IL-8 in the two groups increased rapidly at T2 , peaked at T3 , decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-α, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4(P<0.05). CONCLUSION: After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-α, IL-6 and IL-8 increased may be related to pulmonary injury after he- patic ischemic reperfusion.
文摘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.
基金Supported by the National Natural Science Foundation of China (No.81301080)the Tianjin Natural Science Foundation (No.15JCYBJC24400, No.15JCQNJC10900)the Scientific Research Foundation for the Returned Overseas Chinese Scholars (No.2012-1707)
文摘AIM： To investigate the role of tumor necrosis factoralpha （TNF-α） in zebrafish retinal development and myelination. METHODS： Morpholino oligonucleotides （MO）, which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin （cp）, and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 （atoh7） mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein （mbp）was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS： Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization （hpf）. mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization （dpf） as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION： TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.
文摘Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain,weight loss associated with diarrhea,and multiple inflammatory ulcerations and strictures of the small bowel.Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo.Increased levels of tumor necrosis factor-alpha(TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder.No specific therapy has been shown to change the course of ulcerative jejunoileitis.We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies,including high dose corticosteroids and cyclosporine.The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody,infliximab(Remicade).
文摘AIM:To study the expression of tumor necrosis factor- alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo. METHODS: Male SD rats underwent 70% partial hepatec- tomy. The remaining liver and spleen tissue samples were collected at indicated time points after hepatectomy. TACE expression was investigated by Western blotting, immunohistochemistry, and serial section immunostaining. RESULTS: Expression of TACE in liver and spleen tissues after partial hepatectomy was a time-dependent alteration, reaching a maximal level between 24 and 48 h and remaining elevated for more than 168 h. TACE protein was localized to mononuclear cells (MNC), which infiltrated the liver from the spleen after hepatectomy. The kinetics of TACE expression was in accordance with the number of TACE-staining MNCs and synchronized with those of transforming growth factor-α (TGFα). In addition, TACE-staining MNC partially overlapped with CD3+ T lymphocytes. CONCLUSION: TACE may be involved in liver regenera- tion by pathway mediated with TGFα-EGFR in the cell- cycle progressive phase in vivo. TACE production and effect by paracrine may be a pathway of involvement in liver regeneration for the activated CD3+ T lymphocytes.
基金the grant from Medical Science Foundation of Guangdong Province,No.A2006334the Natural Science Foundation of Guangdong Province,No.06105246,No.9151040701000008the Science and Technology Project of Guangzhou City,No.2007J1-C0041
文摘BACKGROUND： Previous studies of curcumin have focused mainly on its cytotoxic properties for antitumor therapy. There are few studies addressing the application of curcumin in the prevention and treatment of nervous system diseases. OBJECTIVE： To observe the protective effect of curcumin against tumor necrosis factor-alpha （TNF-α）-induced neuronal damage in the rat hippocampus and to explore the intervention effect of curcumin on Ca^2＋ influx following neuronal damage. DESIGN, TIME AND SETTING： A cell morphological and physiological study was performed at the Institute of Brain Research, Medical College of Jinan University, China, from December 2006 to June 2007. MATERIALS： Curcumin （Sigma, USA） and TNF-α （Sigma, USA） were used in this study. METHODS： Hippocampal neurons were isolated from one-day neonatal rats and primarily cultured for 5 days. Following this they received 1 pmol/L curcumin and 100 ng/mL TNF-a pre-treatment. Dynamic morphological changes were observed for 1 hour by inverted microscopy. At 48 hours post-treatment, static morphological characteristics of the neurons were observed using inverted microscopy. Subsequently, hippocampal neurons were primarily cultured for 7 days, after receiving 1 pmol/L curcumJn and 4.5 ng/mL TNF-a pre-treatment. Intracellular free Ca^2＋ was measured using Fluo 3/acetoxymethyl ester. MAIN OUTCOME MEASURES： Effects of curcumin on TNF-a-induced neuronal damage and Ca^2＋ influx in the rat hippocampus were measured. RESULTS： Following curcumin treatment, TNF-a-induced neurons grew as normal. TNF-a induced a rapid Ca^2＋ influx into the neuronal cytoplasm; however, Ca2＋ fluorescence intensity only slightly increased when neurons were co-perfused with curcumin and TNF-α. CONCLUSION： Curcumin has a protective effect on rat hippocampal neurons possibly by reducing the TNF-α-induced rapid Ca^2＋ influx into neuronal cytoplasm and by maintaining the Ca^2＋ homeostasis.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)the Ministry of Education(NRF-2014R1A1A2057263)+2 种基金by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(NRF-2017R1A2B4009079&NRF-2017R1A2B4008403)by the Bio-Synergy Research Project(NRF-2015M3A9C4076322)of the Ministry of ScienceICT and Future Planning through the National Research Foundation
文摘Low survival rate occurs in patients who initially experience a spontaneous return of circulation after cardiac arrest（CA）. In this study, we induced asphyxial CA in adult male Sprague-Daley rats, maintained their body temperature at 37 ± 0.5°C, and then observed the survival rate during the post-resuscitation phase. We examined neuronal damage in the hippocampus using cresyl violet（CV） and Fluore-Jade B（F-J B） staining, and pro-inflammatory response using ionized calcium-binding adapter molecule 1（Iba-1）, glial fibrillary acidic protein（GFAP）, and tumor necrosis factor-alpha（TNF-α） immunohistochemistry in the hippocampus after asphyxial CA in rats under normothermia. Our results show that the survival rate decreased gradually post-CA（about 63% at 6 hours, 37% at 1 day, and 8% at 2 days post-CA）. Rats were sacrificed at these points in time post-CA, and no neuronal damage was found in the hippocampus until 1 day post-CA. However, some neurons in the stratum pyramidale of the CA region in the hippocampus were dead 2 days post-CA. Iba-1 immunoreactive microglia in the CA1 region did not change until 1 day postCA, and they were activated（enlarged cell bodies with short and thicken processes） in all layers 2 days postCA. Meanwhile, GFAP-immunoreactive astrocytes did not change significantly until 2 days post-CA. TNF-α immunoreactivity decreased significantly in neurons of the stratum pyramidale in the CA1 region 6 hours post-CA, decreased gradually until 1 day post-CA, and increased significantly again 2 days post-CA. These findings suggest that low survival rate of normothermic rats in the early period of asphyxia-induced CA is related to increased TNF-α immunoreactivity, but not to neuronal damage in the hippocampal CA1 region.
基金Educational and Technological Foundation for Excellent Talents of Guizhou Province, No. 2005(25)
文摘BACKGROUND： Cerebral infarction is poorly treated due to neuronal necrosis and secondary pathophysiological changes; for example, free radical production and inflammatory reactions. OBJECTIVE： To detect the levels of high-sensitivity C-reactive protein （hs-CRP）, interleukin-6 （IL-6）, and tumor necrosis factor- a （TNF- α ） in elderly males with cerebral infarction. DESIGN： Non-randomized current control study. SETTING： Cadre Medical Department, Guizhou Provincial People＇s Hospital. PARTICIPANTS： Forty elderly males （65-89 years old） with cerebral infarction were selected from Cadre Medical Department, Guizhou Provincial People＇s Hospital from February 2004 to December 2006. All patients met the diagnostic criteria of cerebral infarction modified at the 4th National Cerebrovascular Disease Academic Meeting, and were diagnosed on the basis of CT or MRI tests. Furthermore, 35 elderly male inpatients （65-87 years old） without cerebral infarction were selected as the control group. Included subjects provided confirmed consent and did not have heart disease, diabetes mellitus, lipid disorder, acute trauma, infection, rheumatism, or other inflammatory diseases. The study was approved by the local ethics committee. There were no significant differences in age, blood pressure, and lipid levels between the cerebral infarction group and the control group （P 〉 0.05）, and this suggested that the baseline data of both groups were comparable. METHODS： Fasting venous blood was drawn from cerebral infarction patients 24 hours after cerebral infarction attack and from control subjects 24 hours after hospitalization. A latex-enhanced immunoturbidimetric assay and an enzyme-linked immunosorbent assay were used to detect the levels of hs-CRP, IL-6, and TNF- α in the serum. MAIN OUTCOME MEASURES： The levels of hs-CRP, 1L-6, and TNF- α in the serum in both groups. RESULTS： Forty cerebral infarction patients and thirty-five control subjects were included in the final analysis without any loss. Levels of hs-CRP, IL-6, and TNF-α in the cerebral infarction group were significantly higher than those in the control group （P 〈 0.01 ）. CONCLUSION： Levels of serum inflammatory reactive factors are increased in elderly males with cerebral infarction.
基金Supported by the National High Technology Research and Development Program of China(863 Program)(No.31101891)the Hitech Research and Development Program of China(No.2012AA10A408)
文摘As an aquatic fish,the spotted halibut Verasper variegatus is highly susceptible to bacterial and virus infections.Tumor necrosis factor-alpha(TNF-α)as a cytokine could control the inflammatory responses.The functions of TNF-αin many species have been widely studied,particularly in mammals.However,little is known about the TNF-αfunctions in V.variegatus.We first cloned and sequenced the TNF-αgene in V.variegatus(VvTNF-α).The two conserved cysteine residues,transmembrane sequence,Thr-Leu motif,and TNF family signature,as well as the TA-rich motifs of its proteins related to inflammatory responses had high similarity to those of the other teleost and mammalian TNF-α.The phylogenetic analysis showed that VvTNF-αwas consistent with TNF-αgenes of other vertebrates.The VvTNF-αtranscripts were extensively distributed in the peripheral blood leukocytes(PBLs),spleen,and gill,indicating that the VvTNF-αhad a role in immune function.Furthermore,treatment with pathogen-associated molecular patterns(PAMPs)could induce a rapid and significant increase of VvTNF-αin the PBLs,which reveals that VvTNF-αdoes participate in the host immune responses against bacterial and viral pathogens.We found that VvTNF-αhad an interesting expression pattern during metamorphosis,showing that the flatfish TNF-αmay have some novel functions during specific developmental stages.In addition,the 3 D structure prediction of VvTNF-αprovided an indication of how it is likely to interact with other proteins.Therefore,VvTNF-αhas multiple functions,and provides valuable information to explore novel functions of TNF-α.
文摘Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are involved in the progression of coronary artery disease (CAD). The cytokines’ levels are associated with the severity of CAD. We have recently reported on the association of resistin, a relatively novel cytokine with the pathogenesis of cardiovascular disease (CVD). Although the inflammatory cytokines’ impact on atherosclerosis is widely accepted, yet some controversy exists regarding the involvement of these factors in atherogenesis. The current review highlights the potential association of TNF-alpha, IL-6 and resistin SNPs (single nucleotide polymorphisms) with CAD. Molecular genetics data along with the intracellular signaling cascade mechanisms may have important clinical implications in the treatment of CAD.
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TNF-α was found originally In sera of Bacillus Calmette Guerln infected mice as a macrophage derived factor. It Is cytotoxlc for tumor cell and less or not toxic to normal cells in vitor. The gene for human TNF-α with E. coli-preferred codons has been designed according to the amino acid sequence deduced from the cDNA. The gene with 504 bp was divided into 27 oligonucleotide fragments having 30. to 40 nucleotides each. The solid phase phosphotriester method was used for the synthesis of these oligonucleotides. The 27 fragments were annealed to three segments and then linked by T4 DNA ligase. The entire gene was incorporated into plasmld PDR540 with Tac promoter which was used to transform E. coli 7118. The expressed protein was estimated by SDSPAGE with a molecular weight of 1. 7×104Da. The cytotoxlc activity of the product against L-929 cell was 1. 0×107units/ml culture.
文摘Objective Secoemestrin C(SC),an epitetrathiodioxopiperazine isolated from Aspergillus nidulans,has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis.However,the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear.This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo.Methods In vitro,HaCaT cells were induced with tumor necrosis factor-alpha(TNF-α,10 ng/mL)to establish an inflammatory injury model,and the expression of nuclear transcription factor-κB(NF-κB)pathway components was measured using qRT-PCR and Western blotting.An in vivo mouse model of imiquimod(IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis.Results SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells.In addition,systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model.SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions.Conclusion The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.
基金Supported by Basic Science Research Program through National Research Foundation of Korea Grants funded by the Korean GovernmentNo.NRF-2012R1A1A2007033 and No.2009-0093821South Korea
文摘AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms,which are TNF-α-1031 T>C,-863 C>A,-857 C>T,-308 G>A,and-238 G>A. The TNF-α genotype frequencies,genotype combinations and haplotypes were analyzed to disclose the association with HCC.RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However,nine genotype combinations had associations with increased likelihood of HCC. Among them,TNF-α-1031/-857/-238 TT/CC/GA(AOR = 18.849,95%CI: 2.203-161.246,P = 0.007),TNF-α-1031/-308/-238 TT/GG/GA(AOR = 26.956,95%CI: 3.071-236.584,P = 0.003),and TNF-α-1031/-238 TT/GA(AOR = 21.576,95%CI: 2.581-180.394,P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α-1031/-863/-857/-308/-238 T-C-C-G-A(OR = 25.824,95%CI: 1.491-447.223,P = 0.0005),TNF-α-1031/-857/-308/-238 T-C-G-A(OR = 12.059,95%CI: 2.747-52.950,P < 0.0001),TNF-α-1031/-857/-238 T-C-A(OR = 10.696,95%CI: 2.428-47.110,P = 0.0001),TNF-α-1031/-308/-238 T-G-A(OR = 7.556,95%CI: 2.173-26.280,P = 0.0002) and TNF-α-1031/-238 T-A(OR = 10.865,95%CI: 2.473-47.740,P = 0.0001). Moreover,HCC Okuda stage Ⅲ cases with the TNF-α-1031 CC genotype had better survival than those with the TT genotype(AOR = 5.795,95%CI: 1.145-29.323). CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study,some TNF-α genotype combinations and haplotypes are associated with HCC. In addition,HCC Okuda stage Ⅲ cases with the TNF-α-1031 TT genotype may have a better prognosis than those with the CC genotype.
文摘AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis(TB) infection in Crohn's disease(CD) patients treated with tumor necrosis factoralpha(TNFα) inhibitors.METHODS A meta-analysis of randomized, double-blind, placebocontrolled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction(EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028(95%CI: 0.0011-0.055). The odds ratio was 4.85(95%CI: 1.02-22.99) with EBC and 5.85(95%CI: 1.13-30.38) without EBC.CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.
文摘Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders.Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases.Therefore,a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy.Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics,and anti-inflammatory features.Recently,phytochemicals including flavonoids,terpenoids,alkaloids,and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system.In this review,we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration.
