Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α

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Ceran Ceyhan

2012-10-01

Full Text Available Abstract Background One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-α (TNF-α. Methods Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-α, were tested for their effects on breast cancer cell proliferation. Results We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-α, antibodies acted synergistically on SK-BR-3 cells

Serum and Urinary Levels of Tumor Necrosis Factor-Alpha in Renal Transplant Patients.

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Senturk Ciftci, Hayriye; Demir, Erol; Savran Karadeniz, Meltem; Tefik, Tzevat; Yazici, Halil; Nane, Ismet; Savran Oguz, Fatma; Aydin, Filiz; Turkmen, Aydin

2017-12-18

Allograft rejection is an important cause of early and long-term graft loss in kidney transplant recipients. Tumor necrosis factor-alpha promotes T-cell activation, the key reaction leading to allograft rejection. Here, we investigated whether serum and urinary tumor necrosis factor-alpha levels can predict allograft rejection. This study included 65 living related-donor renal transplant recipients with mean follow-up of 26 ± 9 months. Serum and urinary tumor necrosis factor-alpha levels were measured at pretransplant and at posttransplant time points (days 1 and 7 and months 3 and 6); serum creatinine levels were also monitored during posttransplant follow-up. Standard enzyme-linked immunoabsorbent assay was used to detect tumor necrosis factor-alpha levels. Clinical variables were monitored. Nine of 65 patients (13.8%) had biopsy-proven rejection during follow-up. Preoperative serum and urinary tumor necrosis factor-alpha levels were not significantly different when we compared patients with and without rejection. Serum tumor necrosis factor-alpha levels (in pg/mL) were significantly higher in the allograft rejection versus nonrejection group at day 7 (11.5 ± 4.7 vs 15.4 ± 5.8; P = .029) and month 1 (11.1 ± 4.8 vs 17.8 ± 10.9; P =.003). Urinary tumor necrosis factor-alpha levels (in pg/mL) were also elevated in the allograft rejection versus the nonrejection group at days 1 (10.2 ± 2.5 vs 14.1 ± 6.8; P = .002) and 7 (9.8 ± 2.2 vs 14.5 ± 2.7; P tumor necrosis factor-alpha has a role in diagnosing renal transplant rejection. Serum and urinary tumor necrosis factor-alpha levels may be a possible predictor for allograft rejection.

Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter.

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Shinohara, Mayuka; Sumino, Yasuhiro; Sato, Fuminori; Kiyono, Tohru; Hashimoto, Naohiro; Mimata, Hiromitsu

2017-06-01

To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence. © 2017 The Japanese Urological Association.

Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab

DEFF Research Database (Denmark)

Bendtzen, Klaus; Geborek, Pierre; Svenson, Morten

2006-01-01

Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial...

Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

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Agarwal Pankaj

2007-01-01

Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

Tumor necrosis factor alpha polymorphism correlates with deleterious effects of ultraviolet B light on cutaneous immunity

NARCIS (Netherlands)

Vincek, V.; Kurimoto, I.; Medema, J. P.; Prieto, E.; Streilein, J. W.

1993-01-01

Intradermally injected tumor necrosis factor alpha (TNF-alpha) mimics the effects of UV B light (UVB) radiation and neutralizing anti-TNF-alpha antibodies abolish the deleterious effects of UVB on induction of contact hypersensitivity suggesting that TNF-alpha is the major mediator of UVB effects on

Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown

International Nuclear Information System (INIS)

Mahadevan, V.; Malik, S.T.; Meager, A.; Fiers, W.; Lewis, G.P.; Hart, I.R.

1990-01-01

Flavone acetic acid (FAA), a novel investigational antitumor agent, has been shown to cause early vascular shutdown in several experimental murine tumors, and this phenomenon is believed to be crucial to FAA's antitumor effects. However, the basis of this FAA-induced tumor vascular shutdown is unknown. In this study a radioactive tracer-clearance technique has been used as an objective indication of tumor blood flow to show that i.p. administered FAA induces a progressive and sustained reduction in blood flow in a colon 26 tumor growing s.c. in syngeneic mice. As early as 1 h after administration, there was a significant increase in the t1/2 clearance value for intratumorally injected 133Xe, reaching a peak at 3 h (117.3 +/- 36.4 versus 7.8 +/- 0.85 min for controls). Significant inhibition of blood flow was still apparent 48 h after a single injection of drug. This FAA-induced vascular shutdown was virtually abolished in tumor-bearing mice pretreated with an antiserum against tumor necrosis factor, while no such effect was observed in controls pretreated with nonimmune serum (t1/2 of 10.8 +/- 1.2 versus 65.6 +/- 8.0 min for controls). Furthermore, in vitro FAA was seen to induce tumor necrosis factor secretion from murine peritoneal cells and splenocytes. These studies suggest that FAA-induced tumor vascular shutdown in the colon 26 tumor is mediated by tumor necrosis factor

Arthritis is inhibited in Borrelia-primed and infected interleukin-17A-deficient mice after administration of anti-gamma-interferon, anti-tumor necrosis factor alpha and anti-interleukin-6 antibodies.

Science.gov (United States)

Kuo, Joseph; Warner, Thomas F; Schell, Ronald F

2017-08-31

The role that cytokines play in the induction of Lyme arthritis is gradually being delineated. We showed previously that severe arthritis developed in a T-cell-driven murine model, even in mice lacking interleukin-17A (IL-17A) and administered anti-gamma-interferon (IFN-γ) antibody. Increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two pro-inflammatory cytokines, were detected in cultures of popliteal lymph node cells obtained from these mice. We hypothesized that concomitantly administered anti-IL-6, anti-TNF-α and anti-IFN-γ antibodies would inhibit the development of arthritis in IL-17A-deficient mice. Our results showed that swelling of the hind paws and histopathological changes consistent with arthritis were significantly reduced in IL-17A-deficient mice that administered the three anti-cytokine antibodies. These results suggest that treatment with multiple anti-cytokine antibodies can abrogate the induction of Lyme arthritis in mice. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

El factor de necrosis de los tumores o caquectina

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Jorge Eliécer Ossa Londoño

1988-02-01

Full Text Available

Se presenta una revisión de la literatura sobre el Factor de Necrosis de los Tumores o Caquectina, con base en artículos publicados durante los anos 1986-1987, haciendo hincapié en las diferencias funcionales y moleculares entre el FNT Alfa, la Linfotoxina o FNT Beta y la Caquectina. Se enfatizan los mecanismos del shock, de la necrosis tumoral y de la caquexia; se Indican las propiedades antitumorales del FNT in vivo e in vitro y se esbozan esquemas terapéuticos experimentales que permiten colegir que el FNT tendrá un papel Importante en la Inmunoterapia del cáncer en el hombre.

This is a review of the 1986-1987 Literature on the Tumor Necrosis Factor (TNF or Cachectin, emphasizing functional and molecular differences among TNF alpha, Iymphotoxin or TNF beta and Cachectin. Mechanisms of shock, tumor necrosis and cachexia are discussed. In vivo and ín vítro antitumoral properties of TNF are indicated, as well as some experimental therapeutic regimens. These facts allow the suggestion that TNF might become an Important aid for Immunotherapy of cancer In humans.

Tumor necrosis factor related apoptosis inducing ligand triggers apoptosis in dividing but not in differentiating human epidermal keratinocytes

NARCIS (Netherlands)

Jansen, Bastiaan J. H.; van Ruissen, Fred; Cerneus, Stefanie; Cloin, Wendy; Bergers, Mieke; van Erp, Piet E. J.; Schalkwijk, Joost

2003-01-01

Using serial analysis of gene expression we have previously identified the expression of several pro-apoptotic and anti-apoptotic genes in cultured human primary epidermal keratinocytes, including tumor necrosis factor related apoptosis inducing ligand (TRAIL). TRAIL is a potent inducer of apoptosis

Anti-Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis

NARCIS (Netherlands)

Bloemendaal, Felicia M.; Levin, Alon D.; Wildenberg, Manon E.; Koelink, Pim J.; Mcrae, Bradford L.; Salfeld, Jochen; Lum, Jenifer; van der Neut Kolfschoten, Marijn; Claassens, Jill W.; Visser, Remco; Bentlage, Arthur; D'Haens, Geert R. A. M.; Verbeek, J. Sjef; Vidarsson, Gestur; van den Brink, Gijs R.

2017-01-01

Although tumor necrosis factor (TNF) antagonists reduce many clinical features of inflammatory bowel disease, complete mucosal healing occurs in fewer than 50% of patients. The Fc-region of monoclonal antibodies against TNF has immunosuppressive properties via effects on macrophage polarization. We

Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat

NARCIS (Netherlands)

Buttini, M; Appel, K; Sauter, A; GebickeHaerter, PJ; Boddeke, HWGM

Induction of tumor necrosis factor alpha was studied in the brain of rats after focal cerebral ischaemia by occlusion of the left middle cerebral artery. Using a specific antisense riboprobe for in situ hybridization histochemistry, cells positive for tumor necrosis factor alpha messenger RNA were

Capacity of tumor necrosis factor to augment lymphocyte-mediated tumor cell lysis of malignant mesothelioma

International Nuclear Information System (INIS)

Bowman, R.V.; Manning, L.S.; Davis, M.R.; Robinson, B.W.

1991-01-01

Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma

Anti-tumor necrosis factor (TNF drugs for the treatment of psoriatic arthritis: an indirect comparison meta-analysis

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Thorlund K

2012-12-01

Full Text Available Kristian Thorlund,1 Eric Druyts,2 J Antonio Aviña-Zubieta,3,4 Edward J Mills1,21Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 2Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; 3Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 4Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, CanadaObjective: To evaluate the comparative effectiveness of available tumor necrosis factor-a inhibitors (anti-TNFs for the management of psoriatic arthritis (PsA in patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs.Methods: We used an exhaustive search strategy covering randomized clinical trials, systematic reviews and health technology assessments (HTA published on anti-TNFs for PsA. We performed indirect comparisons of the available anti-TNFs (adalimumab, etanercept, golimumab, and infliximab measuring relative risks (RR for the psoriatic arthritis response criteria (PsARC, mean differences (MDs for improvements from baseline for the Health Assessment Questionnaire (HAQ by PsARC responders and non-responders, and MD for the improvements from baseline for the psoriasis area and severity index (PASI. When the reporting of data on intervention group response rates and improvements were incomplete, we used straightforward conversions based on the available data.Results: We retrieved data from 20 publications representing seven trials, as well as two HTAs. All anti-TNFs were significantly better than control, but the indirect comparison did not reveal any statistically significant difference between the anti-TNFs. For PsARC response, golimumab yielded the highest RR and etanercept the second highest; adalimumab and infliximab both yielded notably smaller RRs. For HAQ improvement, etanercept and infliximab yielded the largest MD among PsARC responders

Increase of tumor necrosis factor receptor 1 expression in women with unexplained early spontaneous abortion

Institute of Scientific and Technical Information of China (English)

YAN Chun-fang; YU Xue-wen; JIN Hui; LI Xu

2004-01-01

To investigate membrane tumor necrosis factor receptor 1 protein expression level in decidua andconcentration of soluble tumor necrosis factor receptor 1 in serum in women with unexplained early spontaneous abortion,threatened abortion, and compare the levels with healthy pregnant women. Methods: Thirty-seven women with unexplainedearly spontaneous abortion, 27 women with threatened abortion, and 34 healthy pregnant women undergoing artificial abortionof pregnancy at 6 - 10 weeks of gestation were selected. Decidual samples were collected when women were undergoing arti-ficial abortion, and blood samples were collected at the same time. The level of membrane tumor necrosis factor receptor 1 indecidua was detected by flow cytometer, and the concentration of soluble tumor necrosis factor receptor 1 in sera was mea-sured with an enzyme-linked immunosorbent assay. Results: The ercentages of membrane tumor necrosis factor receptor 1positive decidual cells were 16.42 ± 7.10 Mean ± SD for women with unexplained early spontaneous abortion and 13.14 ±6.30 for healthy pregnant women ( P ＜ 0.05). Serum oncentration of soluble tumor necrosis factor receptor 1 was signifi-cantly higher in women with unexplained early spontaneous abortion than in healthy pregnant women and in women withthreatened abortion, and no difference was found between healthy pregnant women and women with threatened abortion.Conclusion: Women with unexplained early spontaneous abortion present significantly higher expression of tumor necrosisfactor receptor 1 than healthy pregnant women, suggesting that over-expression of tumor necrosis factor receptor 1 may cont-ribute to the development of early spontaneous abortion.

Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma.

Science.gov (United States)

Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia

2016-12-06

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti-tumor necrosis factor treatment and disease activity.

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Karagiozoglou-Lampoudi, Thomais; Trachana, Maria; Agakidis, Charalampos; Pratsidou-Gertsi, Polyxeni; Taparkou, Anna; Lampoudi, Sotiria; Kanakoudi-Tsakalidou, Florentia

2011-10-01

Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non-anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research. Copyright © 2011 Elsevier Inc. All rights reserved.

B-lymfocytdepletring og andre biologiske behandlingsmuligheder ved Graves' oftalmopatiTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

DEFF Research Database (Denmark)

El, Fassi D.; Hegedus, L.; Nielsen, Claus Henrik

2008-01-01

The current medical treatment options for Graves' ophthalmopathy (GO) are unsatisfactory. Recent treatment of GO patients with the B-lymphocyte depleting monoclonal antibody rituximab or with the anti-tumor necrosis factor-alpha agents etanercept and infliximab has shown promising results. We...

Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients.

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Lew, Daniel; Yoon, Soon Man; Yan, Xiaofei; Robbins, Lori; Haritunians, Talin; Liu, Zhenqiu; Li, Dalin; McGovern, Dermot Pb

2017-10-28

To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations. This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure. Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn's disease, IgA ASCA ( P = 0.04) and IgG-ASCA ( P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions ( P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. Our study shows 1 in 5 IBD patients experience an adverse

Generation of truncated recombinant form of tumor necrosis factor ...

African Journals Online (AJOL)

7. Original Research Article. Generation of truncated recombinant form of tumor necrosis factor ... as 6×His tagged using E.coli BL21 (DE3) expression system. The protein was ... proapoptotic signaling cascade through TNFR1. [5] which is ...

Blockade of Tumor Necrosis Factor-Alpha: A Role for Adalimumab in Neovascular Age-Related Macular Degeneration Refractory to Anti-Angiogenesis Therapy

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Beatriz Fernández-Vega

2016-03-01

Full Text Available Aims: To report a case of wet age-related macular degeneration (wet-AMD refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF therapy in a patient who showed visual and anatomical improvement and stabilization after starting a subcutaneous treatment course with adalimumab, an anti-tumor necrosis factor-alpha (TNF-α drug, for concomitant Crohn's disease. Methods: Observational case report of a female patient. Ophthalmological evaluation was performed by slit lamp and ophthalmoscopy (posterior pole and anterior segment. Best-corrected visual acuity (BCVA was determined, and imaging was performed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT. Intravitreal therapies used and treatment with anti-TNF-α were recorded. Results: A 64-year-old woman with wet-AMD was treated with fourteen intravitreal injections of ranibizumab (0.5 mg for a period of 40 months with intervals of 1-6 months. She initially showed a good visual and anatomical response to periodic anti-VEGF treatment but during check visits, anatomical and functional responses deteriorated. At the 40-month follow-up, the patient had developed Crohn's disease, and her rheumatologist started treatment with adalimumab (40 mg subcutaneously every 2 weeks. During the 25 months of treatment with adalimumab, the patient did not require any additional intravitreal anti-VEGF treatments because her BCVA, clinical, and OCT findings improved and remained stable. Conclusions: We described a case of a patient with wet-AMD refractory to anti-VEGF therapy, which clinically benefited from subcutaneous adalimumab therapy. Treatment with subcutaneous anti-TNF-α in combination with anti-VEGF therapy avoids the high cost and risks related to multiple intravitreal anti-VEGF injections with good functional and anatomic outcomes.

Soluble tumor necrosis factor receptor-1 in preterm infants with chronic lung disease.

Science.gov (United States)

Sato, Miho; Mori, Masaaki; Nishimaki, Shigeru; An, Hiromi; Naruto, Takuya; Sugai, Toshiyuki; Shima, Yoshio; Seki, Kazuo; Yokota, Shumpei

2010-04-01

It is clear that inflammation plays an important role in developing chronic lung disease in preterm infants. The purpose of the present study is to investigate changes of serum soluble tumor necrosis factor receptor-1 levels over time in infants with chronic lung disease. The serum levels of soluble tumor necrosis factor receptor-1 were measured after delivery, and at 7, 14, 21 and 28 days of age in 10 infants with chronic lung disease and in 18 infants without chronic lung disease. The serum level of soluble tumor necrosis factor receptor-1 was significantly higher in infants with chronic lung disease than in infants without chronic lung disease after delivery. The differences between these two groups remained up to 28 days of age. Prenatal inflammation with persistence into postnatal inflammation may be involved in the onset of chronic lung disease.

Fibrinolytic response to tumor necrosis factor in healthy subjects

NARCIS (Netherlands)

van der Poll, T.; Levi, M. [=Marcel M.; Büller, H. R.; van Deventer, S. J.; de Boer, J. P.; Hack, C. E.; ten Cate, J. W.

1991-01-01

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men,

Anorectal stenosis after treatment with tumor necrosis factor α antibodies: a case series

Directory of Open Access Journals (Sweden)

Keegan Denise

2010-07-01

Full Text Available Abstract Introduction We identified three patients who developed anorectal stenosis after successful treatment with anti-tumor necrosis factor α (anti-TNF-α agents. Case presentation Two patients, a 24-year-old Irish Caucasian man and a 64-year-old Irish Caucasian woman, developed symptoms attributable to anorectal stenosis four to six weeks after treatment. A further patient, a 25-year-old Irish Caucasian male, presented three years after treatment with anorectal stenosis, having been asymptomatic with his stenosis for the preceding three years. No patients had evidence of active inflammation at time of representation or had previous anal canal surgery. Conclusion Anorectal stenosis in these patients appears to be independent of active inflammation. No other cause of new stenosis could be identified. We postulate that rapid clinical response to anti-TNF-α agents led to aberrant mucosal healing. This in turn led to anorectal stenosis. This is the first report of this complication in association with the use of biologic agents.

Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease

DEFF Research Database (Denmark)

Nielsen, Ole Haagen; Ainsworth, Mark Andrew

2013-01-01

A 35-year-old man presents with an exacerbation of Crohn's ileocolitis. He received a diagnosis of Crohn's disease 8 years ago and has been treated on three previous occasions with prednisone. Because of a recurrent need for glucocorticoids, treatment with azathioprine (150 mg per day) was starte...... colonoscopy show acute and chronic granulomatous inflammation, and the gastroenterologist recommends treatment with a tumor necrosis factor (TNF) inhibitor....

Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

Science.gov (United States)

Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

2016-06-21

Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies.

Paradoxical Reaction to Golimumab: Tumor Necrosis Factor α Inhibitor Inducing Psoriasis Pustulosa

Directory of Open Access Journals (Sweden)

Marien Siqueira Soto Lopes

2013-11-01

Full Text Available Importance: Golimumab is a human monoclonal antibody, used for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Adverse reactions are increasing with this class of medication (tumor necrosis factor α inhibitors. Observations: The authors present a case of a female patient who presented with psoriasis pustulosa after the use of golimumab for rheumatoid arthritis. Conclusions and Relevance: Paradoxically, in this case, golimumab, which is used for psoriasis, induced the pustular form of this disease. We are observing an increasing number of patients who develop collateral effects with tumor necrosis factor α inhibitors, and the understanding of the mechanism of action and how these adverse reactions occur may contribute to avoid these sometimes severe situations.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) participates in anti-lipopolysaccharide factors (ALFs) gene expression in mud crab.

Science.gov (United States)

Sun, Wan-Wei; Zhang, Xin-Xu; Wan, Wei-Song; Wang, Shu-Qi; Wen, Xiao-Bo; Zheng, Huai-Ping; Zhang, Yue-Ling; Li, Sheng-Kang

2017-02-01

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key cytoplasm signal adaptor that mediates signals activated by tumor necrosis factor receptor (TNFR) superfamily and the Interleukin-1 receptor/Toll-like receptor (IL-1/TLR) superfamily. The full-length 2492 bp TRAF6 (Sp-TRAF6) from Scylla paramamosain contains 1800 bp of open reading frame (ORF) encoding 598 amino acids, including an N-terminal RING-type zinc finger, two TRAF-type zinc fingers and a conserved C-terminal meprin and TRAF homology (MATH) domain. Multiple alignment analysis shows that the putative amino acid sequence of Sp-TRAf6 has highest identity of 88% with Pt-TRAF6 from Portunus trituberculatus, while the similarity of Sp-TRAF6 with other crustacean sequences was 54-55%. RT-PCR analysis indicated that Sp-TRAF6 transcripts were predominantly expressed in the hepatopancreas and stomach, whereas it was barely detected in the heart and hemocytes in our study. Moreover, Sp-TRAF6 transcripts were significantly up-regulated after Vibrio parahemolyticus and LPS challenges. RNA interference assay was carried out used by siRNA to investigate the genes expression patterns regulated by Sp-TRAF6. The qRT-PCR results showed that silencing Sp-TRAF6 gene could inhibit SpALF1, SpALF2, SpALF5 and SpALF6 expression in hemocytes, while inhibit SpALF1, SpALF3, SpALF4, SpALF5 and SpALF6 expression in hepatopancreas. Taken together, the acute-phase response to immune challenges and the inhibition of SpALFs gene expression indicate that Sp-TRAF6 plays an important role in host defense against pathogen invasions via regulation of ALF gene expression in S. paramamosain. Copyright © 2016. Published by Elsevier Ltd.

Generation of truncated recombinant form of tumor necrosis factor ...

African Journals Online (AJOL)

Purpose: To produce truncated recombinant form of tumor necrosis factor receptor 1 (TNFR1), cysteine-rich domain 2 (CRD2) and CRD3 regions of the receptor were generated using pET28a and E. coli/BL21. Methods: DNA coding sequence of CRD2 and CRD3 was cloned into pET28a vector and the corresponding ...

Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha

DEFF Research Database (Denmark)

Brock, C; Brock, B; Aziz, Q

2017-01-01

-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which...

Long-term survival of subcutaneous anti-tumor necrosis factor biological drugs administered between 2008 and 2012 in a cohort of rheumatoid arthritis patients.

Science.gov (United States)

Alvarez Rivas, Noelia; Vazquez Rodriguez, Tomas R; Miranda Filloy, Jose A; Garcia-Porrua, Carlos; Sanchez-Andrade Fernández, Amalia

2017-05-25

To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

Directory of Open Access Journals (Sweden)

Melanie Vincent

2010-09-01

Full Text Available Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease.Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown.Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy

NARCIS (Netherlands)

Bremer, Edwin

2013-01-01

The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective

Microglia protect neurons against ischemia by synthesis of tumor necrosis factor

DEFF Research Database (Denmark)

Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Babcock, Alicia

2009-01-01

Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical...

Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies

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Isabell Lang

2018-04-01

Full Text Available Progranulin (PGRN is a secreted anti-inflammatory protein which can be processed by neutrophil proteases to various granulins. It has been reported that at least a significant portion of the anti-inflammatory effects of PGRN is due to direct high affinity binding to tumor necrosis factor receptor-1 (TNFR1 and TNFR2 and inhibition of tumor necrosis factor (TNF-induced TNFR1/2 signaling. Two studies failed to reproduce the interaction of TNFR1 and TNFR2 with PGRN, but follow up reports speculated that this was due to varying experimental circumstances and/or the use of PGRN from different sources. However, even under consideration of these speculations, there is still a striking discrepancy in the literature between the concentrations of PGRN needed to inhibit TNF signaling and the concentrations required to block TNF binding to TNFR1 and TNFR2. While signaling events induced by 0.2–2 nM of TNF have been efficiently inhibited by low, near to equimolar concentrations (0.5–2.5 nM of PGRN in various studies, the reported inhibitory effects of PGRN on TNF-binding to TNFR1/2 required a huge excess of PGRN (100–1,000-fold. Therefore, we investigated the effect of PGRN on TNF binding to TNFR1 and TNFR2 in highly sensitive cellular binding studies. Unlabeled TNF inhibited >95% of the specific binding of a Gaussia princeps luciferase (GpL fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to >95%, too. Purified PGRN, however, showed in both assays no effect on TNF–TNFR1/2 interaction even when applied in huge excess. To rule out that tags and purification- or storage-related effects compromise the potential ability of PGRN to bind TNF receptors, we directly co-expressed PGRN, and as control TNF, in TNFR1- and TNFR2-expressing cells and looked for binding of GpL-TNF. While expression of TNF strongly inhibited binding of GpL-TNF to TNFR1/2, co

Regulation of Tumor Progression by Programmed Necrosis

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Su Yeon Lee

2018-01-01

Full Text Available Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose deprivation, which occurs because of insufficient blood supply. This results in necrotic cell death in the core region of solid tumors. Necrotic cells release their cellular cytoplasmic contents into the extracellular space, such as high mobility group box 1 (HMGB1, which is a nonhistone nuclear protein, but acts as a proinflammatory and tumor-promoting cytokine when released by necrotic cells. These released molecules recruit immune and inflammatory cells, which exert tumor-promoting activity by inducing angiogenesis, proliferation, and invasion. Development of a necrotic core in cancer patients is also associated with poor prognosis. Conventionally, necrosis has been thought of as an unregulated process, unlike programmed cell death processes like apoptosis and autophagy. Recently, necrosis has been recognized as a programmed cell death, encompassing processes such as oncosis, necroptosis, and others. Metabolic stress-induced necrosis and its regulatory mechanisms have been poorly investigated until recently. Snail and Dlx-2, EMT-inducing transcription factors, are responsible for metabolic stress-induced necrosis in tumors. Snail and Dlx-2 contribute to tumor progression by promoting necrosis and inducing EMT and oncogenic metabolism. Oncogenic metabolism has been shown to play a role(s in initiating necrosis. Here, we discuss the molecular mechanisms underlying metabolic stress-induced programmed necrosis that promote tumor progression and aggressiveness.

Safety and efficacy of anti-tumor necrosis factor α therapy in ten patients with recent-onset refractory reactive arthritis.

Science.gov (United States)

Meyer, Alain; Chatelus, Emmanuel; Wendling, Daniel; Berthelot, Jean-Marie; Dernis, Emmanuelle; Houvenagel, Eric; Morel, Jacques; Richer, Olivier; Schaeverbeke, Thierry; Gottenberg, Jacques-Eric; Sibilia, Jean

2011-05-01

There are few treatments for reactive arthritis (ReA). Since concentrations of tumor necrosis factor α (TNFα) are high in the serum and joints of patients with persistent ReA, this cytokine could be targeted in patients who do not respond to nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). We under-took this study to investigate the safety and efficacy of TNF antagonists in patients with recent-onset and refractory ReA. All French rheumatology and internal medicine practitioners registered on the Club Rhumatisme et Inflammation web site were asked to report on patients with ReA (defined by the criteria of the Third International Workshop on Reactive Arthritis) who had received anti-TNF therapy within the 12 months following the triggering infection. Tolerance and efficacy were retrospectively assessed using a standardized questionnaire. Ten patients with ReA previously refractory to NSAIDs and DMARDs, for which there was clinical and microbiologic evidence of a triggering bacterial infection, received anti-TNF therapy within a median of 6 months (range 2-12 months) between the beginning of ReA and the initiation of the treatment. The median followup was 20.6 months (range 6-50 months). We observed no severe adverse event and no infection related to the bacterium that triggered the ReA. Anti-TNF therapy was rapidly effective in 9 patients (90%), as shown by the rapid effect on a visual analog scale pain score, tender joint count, swollen joint count, and extraarticular manifestations, and by the corticosteroid-sparing effect. Anti-TNF therapy appears to be a safe and effective treatment of rheumatic and extraarticular manifestations in patients with recent-onset and refractory ReA, with a corticosteroid-sparing effect. Thus, TNFα could be a relevant target for ReA therapy.

Systemic use of tumor necrosis factor alpha as an anticancer agent

Science.gov (United States)

Roberts, Nicholas J.; Zhou, Shibin; Diaz, Luis A.; Holdhoff, Matthias

2011-01-01

Tumor necrosis factor-α (TNF-α) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-α with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-α in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-α as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-α. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-α in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors. PMID:22036896

Adverse events of anti-tumor necrosis factor α therapy in ankylosing spondylitis.

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Qiang Tong

Full Text Available This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS.The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers.Short-term adverse events occurred in 20.15% (81/402, including rash (3.5%; 14/402, pruritus (1.2%; 5/402, nausea (2.2%; 9/402, headache (0.7%; 3/402, skin allergies (4.0%; 16/402, fever (0.5%; 2/402, palpitations (3.0%; 12/402, dyspnea (0.5%; 2/402, chest pain (0.2%; 1/402, [corrected] abdominal pain (1.0%; 4/402, hypertension (2.2%; 9/402, papilledema (0.5%; 2/402, laryngeal edema (0.2%; 1/402 and premature ventricular contraction (0.2%; 1/402. Long-term adverse events occurred in 59 (34.3%; 59/172 patients, including pneumonia (7.6%; 13/172, urinary tract infections (9.9%; 17/172, otitis media (4.7%; 8/172, tuberculosis are (3.5%; 6/172 [corrected], abscess (1.2%; 2/172, oral candidiasis (0.6%; 1/172, elevation of transaminase (1.7%; 3/172, anemia (1.2%; 2/172, hematuresis (0.6%; 1/172, constipation (2.3%; 4/172, weight loss (0.6%; 1/172, exfoliative dermatitis (0.6%; 1/172. CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05. Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01.This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with anti-TNF-α therapy. Long

Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes

International Nuclear Information System (INIS)

Kim, Young Jun; Nam, Chang-Hoon; Jin, Young-Hyun; Stieglitz, Thomas; Salieb-Beugelaar, Georgette B

2014-01-01

This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. (paper)

The effect of anti-tumor necrosis factor alpha agents on the outcome in pediatric uveitis of diverse etiologies.

Science.gov (United States)

Deitch, Iris; Amer, Radgonde; Tomkins-Netzer, Oren; Habot-Wilner, Zohar; Friling, Ronit; Neumann, Ron; Kramer, Michal

2018-04-01

This study aimed to report the clinical outcome of children with uveitis treated with anti-tumor necrosis factor alpha (TNF-α) agents. This included a retrospective cohort study. Children with uveitis treated with infliximab or adalimumab in 2008-2014 at five dedicated uveitis clinics were identified by database search. Their medical records were reviewed for demographic data, clinical presentation, ocular complications, and visual outcome. Systemic side effects and the steroid-sparing effect of treatment were documented. The cohort included 24 patients (43 eyes) of whom 14 received infliximab and 10 received adalimumab after failing conventional immunosuppression therapy. Mean age was 9.3 ± 4.0 years. The most common diagnosis was juvenile idiopathic arthritis-related uveitis (n = 10), followed by Behçet's disease (n = 4), sarcoidosis (n = 1), and ankylosing spondylitis (n = 1); eight had idiopathic uveitis. Ocular manifestations included panuveitis in 20 eyes (46.5%), chronic anterior uveitis in 19 (44.2%), and intermediate uveitis in 4 (9.3%). The duration of biologic treatment ranged from 6 to 72 months. During the 12 months prior to biologic treatment, while on conventional immunosuppressive therapy, mean visual acuity deteriorated from 0.22 to 0.45 logMAR, with a trend of recovery to 0.25 at 3 months after initiation of biologic treatment, remaining stable thereafter. A full corticosteroid-sparing effect was demonstrated in 16 of the 19 patients (84.2%) for whom data were available. Treatment was well tolerated. Treatment of pediatric uveitis with anti-TNF-α agents may improve outcome while providing steroid-sparing effect, when conventional immunosuppression fails. The role of anti-TNF-α agents as first-line treatment should be further investigated in controlled prospective clinical trials.

Which factors influence radiographic progression during treatment with tumor necrosis factor inhibitors in clinical practice?

DEFF Research Database (Denmark)

Ørnbjerg, Lykke Midtbøll; Østergaard, Mikkel; Bøyesen, Pernille

2014-01-01

OBJECTIVE: To investigate baseline characteristics associated with radiographic progression and the effect of disease activity, drug, switching, and withdrawal on radiographic progression in tumor necrosis factor (TNF) inhibitor-naive patients with rheumatoid arthritis (RA) followed for about 2...

Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease

NARCIS (Netherlands)

Michelakakis, H.; Spanou, C.; Kondyli, A.; Dimitriou, E.; van Weely, S.; Hollak, C. E.; van Oers, M. H.; Aerts, J. M.

1996-01-01

Tumor necrosis factor-a (TNF-a) levels were measured in the plasma of patients with different types of Gaucher disease (GD) and patients with other lysosomal storage diseases. The highest TNF-a levels were observed in the most severe neuronopathic type of GD, exceeding those found in healthy

MutY DNA Glycosylase Protects Cells From Tumor Necrosis Factor Alpha-Induced Necroptosis.

Science.gov (United States)

Tran, An Hue Vy; Han, Se Hee; Kim, Joon; Grasso, Francesca; Kim, In San; Han, Ye Sun

2017-07-01

Numerous studies have implied that mutY DNA glycosylase (MYH) is involved in the repair of post-replicative mispairs and plays a critical role in the base excision repair pathway. Recent in vitro studies have shown that MYH interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD), a key effector protein of tumor necrosis factor receptor-1 (TNFR1) signaling. The association between MYH and TRADD is reversed during tumor necrosis factor alpha (TNF-α)- and camptothecin (CPT)-induced apoptosis, and enhanced during TNF-α-induced survival. After investigating the role of MYH interacts with various proteins following TNF-α stimulation, here, we focus on MYH and TRADD interaction functions in necroptosis and its effects to related proteins. We report that the level of the MYH and TRADD complex was also reduced during necroptosis induced by TNF-α and zVAD-fmk. In particular, we also found that MYH is a biologically important necrosis suppressor. Under combined TNF-α and zVAD-fmk treatment, MYH-deficient cells were induced to enter the necroptosis pathway but primary mouse embryonic fibroblasts (MEFs) were not. Necroptosis in the absence of MYH proceeds via the inactivation of caspase-8, followed by an increase in the formation of the kinase receptor- interacting protein 1 (RIP1)-RIP3 complex. Our results suggested that MYH, which interacts with TRADD, inhibits TNF-α necroptotic signaling. Therefore, MYH inactivation is essential for necroptosis via the downregulation of caspase-8. J. Cell. Biochem. 118: 1827-1838, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases.

Science.gov (United States)

Luan, Y Y; Yao, Y M; Sheng, Z Y

2013-01-01

Within the immune system homeostasis is maintained by a myriad of mechanisms that include the regulation of immune cell activation and programmed cell death. The breakdown of immune homeostasis may lead to fatal inflammatory diseases. We set out to identify genes of tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) family that has a functional role in the process of immune homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which functions as an oncogenic molecule, is also associated with enhanced cell survival and inhibition of apoptosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) governs immune homeostasis in both the innate and adaptive immune system and prevents hyper-responsiveness by negatively regulating signaling via T cell receptors and Toll-like receptors (TLRs). There also exist two highly homologous but uncharacterized proteins, TIPE1 and TIPE3. This review is an attempt to provide a summary of TNFAIP8 family associated with immune homeostasis and inflammatory cancer diseases.

Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.

Science.gov (United States)

Lavazza, Cristiana; Carlo-Stella, Carmelo; Giacomini, Arianna; Cleris, Loredana; Righi, Marco; Sia, Daniela; Di Nicola, Massimo; Magni, Michele; Longoni, Paolo; Milanesi, Marco; Francolini, Maura; Gloghini, Annunziata; Carbone, Antonino; Formelli, Franca; Gianni, Alessandro M

2010-03-18

Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 10(5) tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

Infective endocarditis following tumor necrosis factor-α antagonist therapy for management of psoriatic erythroderma: a case report.

Science.gov (United States)

Mizuno, Takuro; Kiyosawa, Jun; Fukuda, Akihiro; Watanabe, Seiji; Kurose, Nozomu; Nojima, Takayuki; Kanda, Tsugiyasu

2017-02-09

The introduction of biological agents, such as infliximab, which act against tumor necrosis factor-α was a major advance for the treatment of an increasing number of chronic diseases. Tumor necrosis factor-α antagonists represent a major therapeutic advance for the management of chronic inflammatory diseases, such as psoriasis. Previous studies have reported that the use of tumor necrosis factor-α antagonists increased the risk of opportunistic infections and reactivation of latent bacterial infections. Cardiac involvement, such as infective endocarditis, is very rare in the literature. A 77-year-old Asian man with a 10-year history of psoriatic erythroderma was referred due to high fever and general malaise. He was treated with Predonine (prednisolone) and infliximab. After treatment, cardiac echography showed mitral valve vegetation and brain magnetic resonance imaging indicated multiple fresh infarctions. He died from large brain infarction in October 2013. An autopsy showed fresh thrombosis in his left middle cerebral artery, mitral valve vegetations, and septic micro-embolisms in multiple organs. Lethal bacterial endocarditis was revealed after administration of tumor necrosis factor-α inhibitor, infliximab, for the treatment of psoriatic erythroderma. An autopsy showed vegetation in his mitral valve and brain infarction with fresh purulent embolism in his left middle cerebral artery and septic micro-embolisms.

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

Science.gov (United States)

Ward, Mark G; Irving, Peter M; Sparrow, Miles P

2015-10-28

In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

Proliferative and antiproliferative effects of interferon-gamma and tumor necrosis factor-alpha on cell lines derived from cervical and ovarian malignancies

International Nuclear Information System (INIS)

Mutch, D.G.; Massad, L.S.; Kao, M.S.; Collins, J.L.

1990-01-01

Four human cell lines derived from cervical carcinomas (ME-180, SiHa, HT-3, and MS751) and three human cell lines derived from ovarian carcinomas (SK-OV-3, Caov-3, and NIH:OVCAR-3) were analyzed in vitro to determine the effect of recombinant interferon-gamma and recombinant human tumor necrosis factor-alpha on cell growth and survival. The effects of interferon-gamma, tumor necrosis factor-alpha, and both interferon-gamma and tumor necrosis factor-alpha on cell growth were measured after 24 and 72 hours of incubation by the incorporation of chromium 51. The results of this analysis showed that all seven cell lines were resistant to the antiproliferative action of tumor necrosis factor-alpha, that the growth of most cell lines was inhibited by interferon-gamma by 72 hours of incubation, and that after 72 hours of incubation all cell lines demonstrated a synergistic antiproliferative response to the combination of interferon-gamma and tumor necrosis factor-alpha. However, the effects of these cytokines on cell growth were found to differ among cell lines and varied with the concentration and the duration of incubation. The growth of one cell line (Caov-3) was stimulated by both tumor necrosis factor-alpha and interferon-gamma. These results suggest that the clinical effects of these cytokines on the growth of gynecologic cancers may be more complex than previously supposed

Role of tumor necrosis factor in macrophage leishmanicidal activity in vitro and resistance to cutaneous leishmaniasis in vivo.

Science.gov (United States)

Theodos, C M; Povinelli, L; Molina, R; Sherry, B; Titus, R G

1991-01-01

Recombinant human tumor necrosis factor (TNF) and purified murine TNF were both able to activate macrophages to destroy intracellular Leishmania major in vitro. In addition, parasitizing macrophages with L. major markedly increased the ability of the cells to produce TNF. Finally, when mice were vaccinated with an avirulent form of L. major, the animals produced large amounts of TNF but no gamma interferon in response to infection with virulent L. major. Treating these mice with a neutralizing anti-TNF antibody led to partial but not complete inhibition of the resistant state, which suggests that factors other than TNF and gamma interferon contribute to resistance to L. major. PMID:1906844

Low level tumor necrosis factor-alpha protects cardiomyocytes against high level tumor necrosis factor-alpha: brief insight into a beneficial paradox.

Science.gov (United States)

Cacciapaglia, Fabio; Salvatorelli, Emanuela; Minotti, Giorgio; Afeltra, Antonella; Menna, Pierantonio

2014-12-01

Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFα" helped cardiomyocyte to withstand toxicity from "high TNFα" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high

Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-α Inhibitors

OpenAIRE

Bradford, Russell D.; Pettit, April C.; Wright, Patty W.; Mulligan, Mark J.; Moreland, Larry W.; McLain, David A.; Gnann, John W.; Bloch, Karen C.

2009-01-01

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors for rheumatologic disorders. Although TNF-α inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti–TNF-α drugs and herpes simplex virus encephalitis has not been previously described.

Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series.

Science.gov (United States)

Umekita, Kunihiko; Umeki, Kazumi; Miyauchi, Shunichi; Ueno, Shiro; Kubo, Kazuyoshi; Kusumoto, Norio; Takajo, Ichiro; Nagatomo, Yasuhiro; Okayama, Akihiko

2015-09-01

Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60-96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.

Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis

DEFF Research Database (Denmark)

Fugger, L; Morling, N; Sandberg-Wollheim, M

1990-01-01

The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were...

Tumor necrosis factor alpha inhibitors in the treatment of toxic epidermal necrolysis.

Science.gov (United States)

Woolridge, Katelyn F; Boler, Patrick L; Lee, Brian D

2018-01-01

Toxic epidermal necrolysis (TEN) is a rare, life-threatening adverse drug reaction for which there is no standardized or consistently effective treatment. Due to a greater understanding of disease pathogenesis and the identification of tumor necrosis factor (TNF) α as a mediator of keratinocyte death, TNF-α antagonists have been used in the treatment of TEN. Specifically, infliximab and etanercept have been shown to be effective at halting disease progression. The objective of this study is to review published case reports and case series using anti-TNF-α medications in the treatment of TEN. Results of many of the articles reviewed support the use of TNF-α inhibitors in TEN in both adult and pediatric populations; however, the risks caused by these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-α inhibition in the treatment of TEN.

Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

Science.gov (United States)

DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

2016-01-01

Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils

NARCIS (Netherlands)

van den Berg, J. M.; Weyer, S.; Weening, J. J.; Roos, D.; Kuijpers, T. W.

2001-01-01

Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor alpha (TNF-alpha) was reported by some to have pro-apoptotic and by others to have antiapoptotic effects on neutrophils. The aim of this study was

Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

NARCIS (Netherlands)

Zwaveling, Jan Harm

1997-01-01

The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable

Tumor necrosis factor alpha production in irradiated cells in vitro

International Nuclear Information System (INIS)

Koeteles, G.J.; Bognar, G.; Kubasova, T.

1994-01-01

Normal and tumor cell lines were used to investigate tumor necrosis factor (TNFα) production and its radiation sensitivity. The cells were irradiated with gamma rays using different doses from 0.25 Gy up to 5 Gy. The number of plated cells, changes of proliferation and TNFα production were determined during the following four post-irradiation days. For TNFα quantity measurement immuno-radiometric assay (IRMA) and enzyme amplified sensitivity assay (EASIA) was used. The results suggest that though gamma irradiation decreased cell proliferation in a dose dependent manner, the quantity produced in the post-irradiation period increased considerably in each irradiated sample. (N.T.) 3 refs.; 2 figs.; 1 tab

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

NARCIS (Netherlands)

Bisoendial, Radjesh; Tabet, Fatiha; Tak, Paul P.; Petrides, Francine; Cuesta Torres, Luisa F.; Hou, Liming; Cook, Adam; Barter, Philip J.; Weninger, Wolfgang; Rye, Kerry-Anne

2015-01-01

Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo)

Tumor necrosis factor (TNF) biology and cell death.

Science.gov (United States)

Bertazza, Loris; Mocellin, Simone

2008-01-01

Tumor necrosis factor (TNF) was the first cytokine to be used in humans for cancer therapy. However, its role in the treatment of cancer patients is debated. Most uncertainties in this field stem from the knowledge that the pathways directly activated or indirectly affected upon TNF engagement with its receptors can ultimately lead to very different outcomes in terms of cell survival. In this article, we summarize the fundamental molecular biology aspects of this cytokine. Such a basis is a prerequisite to critically approach the sometimes conflicting preclinical and clinical findings regarding the relationship between TNF, tumor biology and anticancer therapy. Although the last decade has witnessed remarkable advances in this field, we still do not know in detail how cells choose between life and death after TNF stimulation. Understanding this mechanism will not only shed new light on the physiological significance of TNF-driven programmed cell death but also help investigators maximize the anticancer potential of this cytokine.

Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series.

Science.gov (United States)

Eisenberg, Elon; Sandler, Ifat; Treister, Roi; Suzan, Erica; Haddad, May

2013-11-01

Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-α adalimumab was assessed. Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira(®) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). These results suggest adalimumab, and possibly other anti-TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area. © 2013 World Institute of Pain.

Prognostic value of tumor necrosis at CT in diffuse large B-cell lymphoma

Energy Technology Data Exchange (ETDEWEB)

Adams, Hugo J.A., E-mail: h.j.a.adams@gmail.com [Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht (Netherlands); Klerk, John M.H. de [Department of Nuclear Medicine, Meander Medical Center, Amersfoort (Netherlands); Fijnheer, Rob [Department of Hematology, Meander Medical Center, Amersfoort (Netherlands); Dubois, Stefan V. [Department of Pathology, Meander Medical Center, Amersfoort (Netherlands); Nievelstein, Rutger A.J.; Kwee, Thomas C. [Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht (Netherlands)

2015-03-15

Highlights: •CT is compulsory for staging newly diagnosed DLBCL. •Approximately 13.7% of DLBCL patients have tumor necrosis at CT. •Tumor necrosis status at CT is not associated with any NCCN-IPI factor. •Patients with tumor necrosis at CT have a significantly worse outcome. -- Abstract: Objective: To determine the prognostic value of tumor necrosis at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Materials and methods: This retrospective study included 51 patients with newly diagnosed DLBCL who had undergone both unenhanced and intravenous contrast-enhanced CT before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone) chemo-immunotherapy. Presence of tumor necrosis was visually and quantitatively assessed at CT. Associations between tumor necrosis status at CT and the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI) factors were assessed. Cox regression analysis was used to determine the prognostic impact of NCCN-IPI scores and tumor necrosis status at CT. Results: There were no correlations between tumor necrosis status at CT and the NCCN-IPI factors categorized age (ρ = −0.042, P = 0.765), categorized lactate dehydrogenase (LDH) ratio (ρ = 0.201, P = 0.156), extranodal disease in major organs (φ = −0.245, P = 0.083), Ann Arbor stage III/IV disease (φ = −0.208, P = 0.141), and Eastern Cooperative Oncology Group (ECOG) performance status (φ = 0.015, P = 0.914). In the multivariate Cox proportional hazards model, only tumor necrosis status at CT was an independent predictive factor of progression-free survival (P = 0.003) and overall survival (P = 0.004). Conclusion: The findings of this study indicate the prognostic potential of tumor necrosis at CT in newly diagnosed DLBCL.

[Effect of vascular endothelial growth factor and tumor necrosis factor receptor for treatment of avascular necrosis of the femoral head in rabbits].

Science.gov (United States)

Hu, Zhi-ming; Zhou, Ming-qian; Gao, Ji-min

2008-12-01

To evaluate the therapeutic effect of vascular endothelial growth factor (VEGF) and tumor necrosis factor receptor (TNFR) on avascular necrosis of the femoral head in rabbits. Avascular necrosis of the femoral head was induced in 26 New Zealand white rabbits by injections of horse serum and prednisolone. The rabbits were then divided into VEGF/TNFR treatment group, VEGF treatment group, and untreated model group, with another 4 normal rabbits as the normal control group. In the two treatment groups, the therapeutic agents were injected percutaneously into the femoral head. Enzyme-linked immunosorbent assay was performed to determine the concentration of TNF-alpha in rabbit serum followed by pathological examination of the changes in the bone tissues, bone marrow hematopoietic tissue and the blood vessels in the femoral head. Compared with the model group, the rabbits with both VEGF and TNFR treatment showed decreased serum concentration of TNF-alpha with obvious new vessel formation, decreased empty bone lacunae in the femoral head and hematopoietic tissue proliferation in the bone marrow cavity. Percutaneous injection of VEGF and TNFR into the femoral head can significantly enhance bone tissue angiogenesis and ameliorate osteonecrosis in rabbits with experimental femoral head necrosis.

Treatment of therapy-resistant perineal metastatic Crohn's disease after proctectomy using anti-tumor necrosis factor chimeric monoclonal antibody, cA2 - Report of two cases

NARCIS (Netherlands)

van Dullemen, HM; de Jong, E; Slors, F; Tytgat, GNJ; van Denventer, SJH

PURPOSE: Two young females with well-documented Crohn's disease and nonhealing perineal wounds following proctectomy compatible with "metastatic Crohn's disease" are described, We hypothesized that metastatic Crohn's disease would be a tumor necrosis factor-dependent inflammatory-reaction and have

Curcumin Requires Tumor Necrosis Factor α Signaling to Alleviate Cognitive Impairment Elicited by Lipopolysaccharide

Directory of Open Access Journals (Sweden)

E.M. Kawamoto

2012-05-01

Full Text Available A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2 signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

Science.gov (United States)

Kok, Beverley; Lester, Erica L W; Lee, William M; Hanje, A James; Stravitz, R Todd; Girgis, Safwat; Patel, Vaishali; Peck, Joshua R; Esber, Christopher; Karvellas, Constantine J

2018-03-21

Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo

DEFF Research Database (Denmark)

Hansen, P R; Svendsen, Jesper Hastrup; Høyer, S

1994-01-01

Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100...... in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial...... ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline...

Investigation of Epidermal Growth Factor, Tumor Necrosis Factor-alpha and Thioredoxin System in Rats Exposed to Cerebral Ischemia

Directory of Open Access Journals (Sweden)

Erol-Demirbilek Melike

2016-09-01

Full Text Available Background: Thioredoxin reductase (TrxR, epidermal growth factor (EGF and tumor necrosis factor-α (TNF-α have neuroprotective/neurotoxic effects in cerebral ischemia. We aimed to investigate the TrxR activity, EGF and TNF-α levels in cerebral ischemic, sham-operated and non-ischemic rat brains.

Impact of Stopping Tumor Necrosis Factor inhibitors on Rheumatoid Arthritis Patients' Burden of Disease

NARCIS (Netherlands)

Ghiti Moghadam, Marjan; ten Klooster, Peter M.; Vonkeman, Harald Erwin; Kneepkens, Eva L.; Klaasen, Ruth; Stolk, Jan N.; Tchetverikov, Ilja; Vreugdenhil, Simone A.; van Woerkom, Jan M.; Goekoop-Ruiterman, Yvonne P.M.; Landewé, Robert B.M.; van Riel, Piet L.C.M.; van de Laar, Mart A F J; Jansen, Tim L.

OBJECTIVE: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability and fatigue in patients with established rheumatoid arthritis (RA). METHODS: In the pragmatic

Impact of Stopping Tumor Necrosis Factor-inhibitors on Rheumatoid Arthritis Patients' Burden of Disease

NARCIS (Netherlands)

Ghiti Moghadam, Marjan; ten Klooster, Peter M.; Vonkeman, Harald Erwin; Kneepkens, Eva L.; Klaasen, Ruth; Stolk, Jan N.; Tchetverikov, Ilja; Vreugdenhil, Simone A.; van Woerkom, Jan M.; Goekoop-Ruiterman, Yvonne P.M.; Landewé, Robert B.M.; van Riel, Piet L.C.M.; van de Laar, Mart A F J; Jansen, Tim L.

2017-01-01

OBJECTIVE: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability and fatigue in patients with established rheumatoid arthritis (RA). METHODS: In the pragmatic

Severe glandular tularemia in a patient treated with anti-tumour necrosis factor for psoriatic arthritis

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Ruxandra Calin

2017-07-01

Full Text Available A case of severe glandular tularemia in a patient receiving anti-tumour necrosis factor (TNF therapy is reported here. The patient required prolonged treatment with doxycycline–ciprofloxacin due to early relapse after ciprofloxacin was stopped. Tularemia may have a more severe course in patients receiving anti-TNF. This may thus be an indication for more aggressive treatment.

Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor α inhibitor therapy

DEFF Research Database (Denmark)

Glintborg, Bente; Ostergaard, Mikkel; Krogh, Niels Steen

2013-01-01

To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care.......To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care....

Impact of Stopping Tumor Necrosis Factor-inhibitors on Rheumatoid Arthritis Patients' Burden of Disease

NARCIS (Netherlands)

Ghiti Moghadam, Marjan; ten Klooster, Peter M.; Vonkeman, Harald E.; Kneepkens, Eva L.; Klaasen, Ruth; Stolk, Jan N.; Tchetverikov, Ilja; Vreugdenhil, Simone A.; van Woerkom, Jan M.; Goekoop-Ruiterman, Yvonne P. M.; Landewé, Robert B. M.; van Riel, Piet L. C. M.; van de Laar, Mart A. F. J.; Jansen, Tim L.

2017-01-01

To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability and fatigue in patients with established rheumatoid arthritis (RA). In the pragmatic 12-month POET trial,

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

Science.gov (United States)

Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

2009-12-01

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with

Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells.

NARCIS (Netherlands)

Paleolog, E.M.; Delasalle, S.A.; Buurman, W.A.; Feldmann, M.

1994-01-01

Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion

Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

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Nadia Belmellat

2017-11-01

Full Text Available Tumor necrosis factor-alpha (TNF-α blockade is an effective treatment for rheumatoid arthritis (RA and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management

Directory of Open Access Journals (Sweden)

Dong Il Park

2018-01-01

Full Text Available Because anti-tumor necrosis factor (anti-TNF therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Soluble receptors for tumor necrosis factor as markers of disease activity in visceral leishmaniasis

NARCIS (Netherlands)

Zijlstra, E. E.; van der Poll, T.; Mevissen, M.

1995-01-01

Serum concentrations of soluble receptors for tumor necrosis factor (sTNFRs) were measured before and after antimony therapy in 25 Sudanese patients with active visceral leishmaniasis (VL). Both sTNFR types I and II were significantly elevated in patients with VL compared with healthy controls from

Effect of tumor necrosis factor-alpha infusion on the incretin effect in healthy volunteers

DEFF Research Database (Denmark)

Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke

2013-01-01

Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumor necrosis factor-alpha (TNF-α). Whereas TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce...

Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

DEFF Research Database (Denmark)

Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

2005-01-01

Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO...... signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected...

Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome

DEFF Research Database (Denmark)

Coenen, Marieke J H; Enevold, Christian; Barrera, Pilar

2010-01-01

Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication.......Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication....

Severe glandular tularemia in a patient treated with anti-tumour necrosis factor for psoriatic arthritis.

Science.gov (United States)

Calin, Ruxandra; Caumes, Eric; Reibel, Florence; Ali Mohamed, Anzime; Brossier, Florence; Foltz, Violaine; Boussouar, Samia; Fautrel, Bruno; Maurin, Max; Katlama, Christine; Pourcher, Valérie

2017-07-01

A case of severe glandular tularemia in a patient receiving anti-tumour necrosis factor (TNF) therapy is reported here. The patient required prolonged treatment with doxycycline-ciprofloxacin due to early relapse after ciprofloxacin was stopped. Tularemia may have a more severe course in patients receiving anti-TNF. This may thus be an indication for more aggressive treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-α therapy in inflammatory arthropathies. Associations with aortic stiffness.

Science.gov (United States)

Angel, Kristin; Provan, Sella Aarrestad; Mowinckel, Petter; Seljeflot, Ingebjørg; Kvien, Tore Kristian; Atar, Dan

2012-11-01

Anti-Tumor Necrosis Factor (TNF)-α therapy improves vascular pathology in inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The l-arginine/ADMA ratio is important for modulation of the nitric oxide synthase activity. We examined the effect of TNF-α antagonists on ADMA and l-arginine/ADMA, and associations between ADMA, L-arginine/ADMA, aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies. Forty-eight patients who started with anti-TNF-α therapy were compared with a non-treated group of 32 patients. Plasma ADMA and L-arginine were assessed at baseline, 3 and 12 months. In a subgroup of 55 patients, aortic pulse wave velocity (aPWV) was measured at baseline, 3 and 12 moths, and CIMT was examined at baseline and 12 months. Anti-TNF-α therapy increased the L-arginine/ADMA ratio (mean [SD]) in the treatment group compared to the control group after 3 months (12 [29] vs. -13 [20], P < 0.001) and 12 months (7 [27] vs. -8 [19], P = 0.008), but did not affect ADMA (3 months: 0.00 [0.09] μmol/L vs. 0.02 [0.07] μmol/L, P = 0.42, 12 months: 0.01 [0.08] μmol/L vs. 0.01 [0.09] μmol/L, P = 0.88). Baseline aPWV was associated with ADMA (P = 0.02) and L-arginine/ADMA (P = 0.02) in multiple regression analyses, and the L-arginine/ADMA ratio was continuously associated with aPWV after initiation of anti-TNF-α therapy (P = 0.03). ADMA and L-arginine/ADMA were not correlated with CIMT. Anti-TNF-α therapy improved the L-arginine/ADMA ratio in patients with inflammatory arthropathies. ADMA and the L-arginine/ADMA ratio were associated with aPWV, and might have a mechanistic role in the aortic stiffening observed in these patients. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The dual role of tumor necrosis factor (TNF) in cancer biology.

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Bertazza, Loris; Mocellin, Simone

2010-01-01

Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting.

Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

Science.gov (United States)

Irwin, Michael R.; Olmstead, Richard; Valladares, Edwin M.; Breen, Elizabeth Crabb; Ehlers, Cindy L.

2009-01-01

Background In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-α (TNF-α) normalizes REM sleep in alcohol-dependent adults. Methods In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Results Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Conclusions Pharmacologic neutralization of TNF-α activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-α may have a physiologic role in the regulation of REM sleep in humans. PMID:19185287

Predictive value of histologic tumor necrosis after radiation.

Science.gov (United States)

Chen, Y; Taghian, A G; Rosenberg, A E; O'Connell, J; Okunieff, P; Suit, H D

2001-12-20

Postsurgical evaluation of histologic changes of tumors after preoperative chemotherapy and/or radiotherapy has been a routine clinical practice of pathologists and oncologists. There appears to be secure evidence that the extent of tumor necrosis vs. viable tumor cells postchemotherapy is a clinically useful predictor of outcome. The significance of histologic tumor necrosis after radiotherapy, however, has not been clearly established and deserves further investigation. We investigated the correlation between histological extent of tumor necrosis, survival of tumor transplants, and radiation doses in an experimental model using three human tumor xenografts. Three human tumor cell lines were investigated: STS-26, SCC-21, and HGL-21. Tumors were grown subcutaneously in athymic nude mice and received external beam radiation of different doses. Tumors were excised 2 weeks postirradiation. One-half of the tumor was divided into 1-mm(3) fragments and transplanted to naive mice. The other half was examined for histologic tumor necrosis. Transplant survival was strongly correlated with radiation dose, TCD(p) (radiation dose that results in local tumor control in proportion, p, to irradiated tumors). In contrast, there was no clear association between transplant survival rate and the extent of tumor necrosis. The experimental model demonstrated a strong inverse correlation between radiation doses and tumor transplant survival. Histologic tumor necrosis did not correlate well with radiation doses or transplant survival rates. Despite common practices in histologic examination of tumors posttherapy, clinical interpretations and implications of histologic tumor necrosis after radiotherapy should be considered with caution. Copyright 2001 Wiley-Liss, Inc.

Experiences and needs for work participation in employees with rheumatoid arthritis treated with anti-tumour necrosis factor therapy

NARCIS (Netherlands)

van der Meer, Marrit; Hoving, Jan L.; Vermeulen, Marjolein I. M.; Herenius, Marieke M. J.; Tak, Paul P.; Sluiter, Judith K.; Frings-Dresen, Monique H. W.

2011-01-01

To investigate the experiences and needs with respect to work participation of employees with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. Face-to-face interviews in 14 employees with RA on anti-TNF therapy focused on experiences, offered support and needs with

Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

NARCIS (Netherlands)

Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment

Directory of Open Access Journals (Sweden)

Dong Il Park

2018-01-01

Full Text Available Because anti-tumor necrosis factor (anti-TNF therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells.

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You, Bo Ra; Han, Bo Ram; Park, Woo Hyun

2017-03-14

Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.

Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells

NARCIS (Netherlands)

Eigler, A; Sinha, B; Endres, S

1993-01-01

In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF

Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense?

NARCIS (Netherlands)

van der Poll, T.; Lowry, S. F.

1995-01-01

Tumor necrosis factor-alpha (TNF) exerts numerous influences which, in association with severe infection, subserve both detrimental as well as beneficial host responses. The current review addresses recent insights into the structure and function of this pleiotropic cytokine, with a particular

Effectiveness of anti-tumour necrosis factor-α therapy in Danish patients with inflammatory bowel diseases

DEFF Research Database (Denmark)

Bank, Steffen; Andersen, Paal Skytt; Burisch, Johan

2015-01-01

Introduction: The objective of this study was to evaluate the outcome of anti-tumour necrosis factor-α (anti-TNF) treatment in a large cohort of patients with inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) in clinical practice and to establish a cohort...... in clinical trials. Funding: The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and the University of Aarhus (PhD grant). Trial registration: Clinicaltrials NCT02322008....

Current evidence of anti-tumor necrosis factor α treatment efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach of individual drugs.

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Simonini, Gabriele; Druce, Katie; Cimaz, Rolando; Macfarlane, Gary J; Jones, Gareth T

2014-07-01

To summarize evidence regarding the effectiveness of anti-tumor necrosis factor α (anti-TNFα) treatments in childhood autoimmune chronic uveitis (ACU), refractory to previous disease-modifying antirheumatic drugs (DMARDs). A systematic search between January 2000 and October 2012 was conducted using EMBase, Ovid Medline, Evidence-Based Medicine (EBM) Reviews: American College of Physicians Journal Club, Cochrane libraries, and EBM Reviews. Studies investigating the efficacy of anti-TNFα therapy, in children ages ≤16 years, as the first treatment with a biologic agent for ACU, refractory to topical and/or systemic steroid therapy and at least 1 DMARD, were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation, as defined by the Standardization of Uveitis Nomenclature Working Group criteria. We determined a combined estimate of the proportion of children responding to anti-TNFα treatment, including etanercept (ETA), infliximab (INF), or adalimumab (ADA). We initially identified 989 articles, of which 148 were potentially eligible. In total, 22 retrospective chart reviews and 1 randomized clinical trial were deemed eligible, thus including 229 children (ADA: n = 31, ETA: n = 54, and INF: n = 144). On pooled analysis of observational studies, the proportion of responding children was 87% (95% confidence interval [95% CI] 75-98%) for ADA, 72% (95% CI 64-79%) for INF, and 33% (95% CI 19-47%) for ETA. There was no difference in the proportion of responders between ADA and INF (χ(2) = 3.06, P = 0.08), although both showed superior efficacy compared with ETA (ADA versus ETA: χ(2) = 20.9, P < 0.001 and INF versus ETA: χ(2) = 20.9, P < 0.001). Although randomized controlled trials are needed, the available evidence suggests that INF and ADA provide proven similar benefits in the treatment of childhood ACU, and they are both superior to ETA. Copyright © 2014 by the American College of Rheumatology.

Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases

DEFF Research Database (Denmark)

Olesen, Caroline Meyer; Coskun, Mehmet; Peyrin-Biroulet, Laurent

2016-01-01

Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural ...... inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD....

Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients

International Nuclear Information System (INIS)

Gatanaga, Tetsuya; Whang, Chenduen; Cappuccini, F.; Lucci, J.A. III; Jeffes, E.W.B.; Kohr, W.; Lentz, R.; Tomich, J.; Yamamoto, R.S.; Granger, G.A.

1990-01-01

Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor α (TNF-α) in vitro. BF is a protein with a molecular mass of 28kDa on reducing sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE). The active material was purified to homogeneity by a combination of affinity chromatography, PAGE, and high-pressure liquid chromatography. Amino acid sequence analysis revealed that BF is derived from the membrane TNF receptor. Purified BF blocks the lytic activity of recombinant human and mouse TNF-α and recombinant human lymphotoxin activity of TNF-α and recombinant human lymphotoxin on murine L929 cells in vitro. However, BF inhibits the lytic activity of TNF-α more effectively than it does that of lymphotoxin. The BF also inhibits the necrotizing activity of recombinant human TNF-α when coinjected into established cutaneous Meth A tumors in BALB/c mice. The BF may have an important role in (i) the regulation and control of TNF-α and lymphotoxin activity in cancer patients, (ii) interaction between the tumor and the host antitumor mechanisms, and (iii) use of systemically administered TNF-α in clinical trials with human cancer patients

Studies on structural features of human tumor necrosis factor

International Nuclear Information System (INIS)

Yin Chuanyuan; Guo Donglin; Xi Tao; Xu Xianxiu; Gu Qingchao

1997-01-01

The microstructure of human tumor necrosis factor alpha (TNF-α) and its mutant (TNF-b) has been investigated by utilizing positron annihilation lifetime spectroscopy, radioiodination of human TNF and L929 cells assay. The experimental results show that the long lifetime (Τ 2 ) and corresponding intensity (I 2 ) of lower ortho-positronium annihilation in TNF-α are longer and less than those in the TNF-b, respectively. It suggests that the TNF-b is smaller in free volume and higher in density than the TNF-α. The TNF-b may maintain a more favorable conformation for binding to TNF receptors, thus increasing its biological activity. It is then concluded that the increases in the cytotoxicity and in the density for the TNF-b result from the decreases in the free volume in the TNF-b

Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity

DEFF Research Database (Denmark)

Ågren, Magnus S.; Andersen, Thomas L.; Andersen, Line

2011-01-01

Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-a (TNF-a) induces MMPs and may influence anastomosis repair....

Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance.

Science.gov (United States)

Qing, Zhou; Xiao-Hui, Wu; Xi-Mei, Wu; Chao-Chun, Zou

2018-06-15

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo -/- ) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo -/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo -/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Role of tumor necrosis factor-alpha and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis.

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Lupia, E; Montrucchio, G; Battaglia, E; Modena, V; Camussi, G

1996-08-01

The aim of the present study was to investigate in vivo in a mouse model the stimulation of neoangiogenesis by synovial fluids of patients with rheumatoid arthritis (RA) and to determine the role of tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) in the formation of new vessels. Angiogenesis was studied in a mouse model in which Matrigel, injected subcutaneously, was used as a vehicle for the delivery of potential angiogenic stimuli. Synovial fluids of patients with RA but not with osteoarthritis (OA) were shown to induce neoangiogenesis. Since synovial fluid of patients with RA contained significantly higher levels of TNF-alpha-like bioactivity and of PAF than that of patients with OA, the role of these mediators was evaluated by using an anti-TNF-alpha neutralizing monoclonal antibody (mAb) and a PAF receptor antagonist, WEB 2170. When added to Matrigel, anti-TNF-alpha mAb and particularly WEB 2170 significantly reduced neoangiogenesis induced by synovial fluids of RA patients. Moreover, PAF extracted and purified from synovial fluid induced angiogenesis. These results suggest that the neoangiogenesis observed in rheumatoid synovitis may be due, at least in part, to the angiogenic effect of locally produced TNF-alpha and PAF.

Polymorphisms in tumor necrosis factor genes and susceptibility to visceral leishmaniasis in Moroccan children

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Rajaa Ejghal

2015-05-01

Full Text Available Objective: To examine whether polymorphic alleles at these two loci are involved in the susceptibility to visceral leishmaniasis (VL in Moroccan children. Methods: We have genotyped polymorphisms by PCR-restricted fragment length polymorphisms in 102 patients with VL, 92 asymptomatic carriers [positive skin test delayedtype hypersensitivity (DTH+] and 40 healthy controls (negative skin test delayed-type hypersensitivity, with no history of Leishmania infection. Results: Regression analysis showed no significant association between polymorphisms of tumor necrosis factors-ααwhen comparing VL and DTH + group (P > 0.05. The associations were detected between VL and negative skin test delayed-type hypersensitivity for the heterozygote genotype (P = 0.021, the recessive model: 1/2 + 2/2 (P = 0.044 and the minor allele 2 (P = 0.019. The resistance to VL was found to be under the recessive model 1/2 + 2/2 of tumor necrosis factors-β, when comparing VL and DTH + group (odds ratios: 0.558, 95%; confidence interval: 0.316-0.987; P = 0.044. Conclusions: These results must be regarded to preliminary but suggestive that further study with larger populations is worthwhile.

CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

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Alessandra Citro

Full Text Available CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control. The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

Negative regulatory role of PI3-kinase in TNF-induced tumor necrosis.

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Matschurat, Susanne; Blum, Sabine; Mitnacht-Kraus, Rita; Dijkman, Henry B P M; Kanal, Levent; De Waal, Robert M W; Clauss, Matthias

2003-10-20

Tissue factor is the prime initiator of blood coagulation. Expression of tissue factor in tumor endothelial cells leads to thrombus formation, occlusion of vessels and development of hemorrhagic infarctions in the tumor tissue, often followed by regression of the tumor. Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor alpha (TNF alpha) and synergistically enhances the TNF-induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44/42 and p38 mitogen-activated protein (MAP) kinases, and stress-activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)-kinase, led to strongly enhanced expression of tissue factor in TNF- and VEGF-treated cells, implicating a negative regulatory role for PI3-kinase. In vivo, the application of wortmannin promoted the formation of TNF-induced hemorrhages and intratumoral necroses in murine meth A tumors. The co-injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF-sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF-treatment in combination with specific inhibition of PI3-kinase is a novel concept in anti-cancer therapy. Copyright 2003 Wiley-Liss, Inc.

Leonurine protects against tumor necrosis factor-α-mediated inflammation in human umbilical vein endothelial cells.

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Liu, Xinhua; Pan, Lilong; Wang, Xianli; Gong, Qihai; Zhu, Yi Zhun

2012-05-01

Leonurine, a bioactive alkaloid compound in Herba leonuri, has various pharmacological activities, including antioxidant and anti-apoptotic capacities. This study was conducted to test the hypothesis that leonurine was able to attenuate tumor necrosis factor (TNF)-α-induced human umbilical vein endothelial cells (HUVEC) activation and the underlying molecular mechanisms. Mitogen-activated protein kinases (MAPK) activation, nuclear factor-κB (NF-κB) activation, and inflammatory mediators expression were detected by Western blot or enzyme-liked immunosorbent assay, intracellular reactive oxygen species (ROS) and NF-κB p65 translocation were measured by immunofluorescence, endothelial cell-monocyte interaction was detected by microscope. Leonurine inhibited U937 cells adhesion to TNF-α-activated HUVEC in a concentration dependent manner. Treatment with leonurine blocked TNF-α-induced mRNA and protein expression of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), cyclooxygenase-2, and monocyte chemoattractant protein-1 in endothelial cells. In addition, leonurine attenuated TNF-α-induced intracellular ROS production in HUVEC. Furthermore, leonurine also suppressed the TNF-α-activated p38 phosphorylation and IκBα degradation. Subsequently, reduced NF-κB p65 phosphorylation, nuclear translocation, and DNA-binding activity were also observed. Our results demonstrated for the first time that the anti-inflammatory properties of leonurine in endothelial cells, at least in part, through suppression of NF-κB activation, which may have a potential therapeutic use for inflammatory vascular diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The correlation analysis of tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk: A meta-analysis.

Science.gov (United States)

Gao, Quangen; Zhang, Peijin; Wang, Wei; Ma, He; Tong, Yue; Zhang, Jing; Lu, Zhaojun

2016-10-01

Venous thromboembolism is a common complex disorder, being the resultant of gene-gene and gene-environment interactions. Tumor necrosis factor-alpha is a proinflammatory cytokine which has been implicated in venous thromboembolism risk. A promoter 308G/A polymorphism in the tumor necrosis factor-alpha gene has been suggested to modulate the risk for venous thromboembolism. However, the published findings remain inconsistent. In this study, we conducted a meta-analysis of all available data regarding this issue. Eligible studies were identified through search of Pubmed, EBSCO Medline, Web of Science, and China National Knowledge Infrastructure (CNKI, Chinese) databases up to June 2014. Pooled Odd ratios (ORs) with 95% confidence intervals were applied to estimating the strength of the genetic association in the random-effects model or fixed-effects model. A total of 10 studies involving 1999 venous thromboembolism cases and 2166 controls were included in this meta-analysis to evaluate the association between tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk. Overall, no significantly increased risk venous thromboembolism was observed in all comparison models when all studies were pooled into the meta-analysis. However, in stratified analyses by ethnicity, there was a pronounced association with venous thromboembolism risk among West Asians in three genetic models (A vs. G: OR = 1.82, 95%CI = 1.13-2.94; GA vs. GG: OR = 1.82, 95%CI = 1.08-3.06; AA/GA vs. GG: OR = 1.88, 95%CI = 1.12-3.16). When stratifying by source of controls, no significant result was detected in all genetic models. This meta-analysis demonstrates that tumor necrosis factor-alpha 308G/A polymorphism may contribute to susceptibility to venous thromboembolism among West Asians. Studies are needed to ascertain these findings in larger samples and different racial groups. © The Author(s) 2015.

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

Science.gov (United States)

Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph J H; Garbow, Joel R

2017-05-01

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

Microglia and macrophages express tumor necrosis factor receptor p75 following middle cerebral artery occlusion in mice

DEFF Research Database (Denmark)

Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Fenger, Claus

2007-01-01

The proinflammatory and potential neurotoxic cytokine tumor necrosis factor (TNF) is produced by activated CNS resident microglia and infiltrating blood-borne macrophages in infarct and peri-infarct areas following induction of focal cerebral ischemia. Here, we investigated the expression of the ...

Affinity Purification of Tumor Necrosis Factor-α Expressed in Raji Cells by Produced scFv Antibody Coupled CNBr-Activated Sepharose

Science.gov (United States)

Abdolalizadeh, Jalal; Majidi Zolbanin, Jafar; Nouri, Mohammad; Baradaran, Behzad; Movassaghpour, AliAkbar; Farajnia, Safar; Omidi, Yadollah

2013-01-01

Purpose: Recombinant tumor necrosis factor-alpha (TNF-α) has been utilized as an antineoplastic agent for the treatment of patients with melanoma and sarcoma. It targets tumor cell antigens by impressing tumor-associated vessels. Protein purification with affinity chromatography has been widely used in the downstream processing of pharmaceutical-grade proteins. Methods:In this study, we examined the potential of our produced anti-TNF-α scFv fragments for purification of TNF-α produced by Raji cells. The Raji cells were induced by lipopolysaccharides (LPS) to express TNF-α. Western blotting and Fluorescence-activated cell sorting (FACS) flow cytometry analyses were used to evaluate the TNF-α expression. The anti-TNF-α scFv selected from antibody phage display library was coupled to CNBr-activated sepharose 4B beads used for affinity purification of expressed TNF-α and the purity of the protein was assessed by SDS-PAGE. Results: Western blot and FACS flow cytometry analyses showed the successful expression of TNF-α with Raji cells. SDS-PAGE analysis showed the performance of scFv for purification of TNF-α protein with purity over 95%. Conclusion: These findings confirm not only the potential of the produced scFv antibody fragments but also this highly pure recombinant TNF-α protein can be applied for various in vitro and in vivo applications. PMID:24312807

Affinity Purification of Tumor Necrosis Factor-α Expressed in Raji Cells by Produced scFv Antibody Coupled CNBr-Activated Sepharose

Directory of Open Access Journals (Sweden)

Safar Farajnia

2013-02-01

Full Text Available Purpose: Recombinant tumor necrosis factor-alpha (TNF-α has been utilized as an antineoplastic agent for the treatment of patients with melanoma and sarcoma. It targets tumor cell antigens by impressing tumor-associated vessels. Protein purification with affinity chromatography has been widely used in the downstream processing of pharmaceutical-grade proteins. Methods: In this study, we examined the potential of our produced anti-TNF-scFv fragments for purification of TNF-α produced by Raji cells. he Raji cells were induced by lipopolysaccharides (LPS to express TNF-α. Western blotting and Fluorescence-activated cell sorting (FACS flow cytometry analyses were used to evaluate the TNF-α expression. The anti-TNF-α scFv selected from antibody phage display library was coupled to CNBr-activated sepharose 4B beads used for affinity purification of expressed TNF-α and the purity of the protein was assessed by SDS-PAGE. Results: Western blot and FACS flow cytometry analyses showed the successful expression of TNF-α with Raji cells. SDS-PAGE analysis showed the performance of scFv for purification of TNF-α protein with purity over 95%. Conclusion: These findings confirm not only the potential of the produced scFv antibody fragments but also this highly pure recombinant TNF-α protein can be applied for various in vitro and in vivo applications.

THE USE OF TUMOR NECROSIS FACTOR α INHIBITORS IN PATIENTS WITH WEBER-CHRISTIAN DISEASE

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Olga Nikolayevna Egorova

2013-01-01

Full Text Available Weber-Christian disease (WCD, also known as idiopathic lobular panniculitis, is a rare disease belonging to the group of diffuse connective tissue diseases. No therapy for WCD has been developed; empirical treatment is typically used. The first description of the use of tumor necrosis factor α inhibitors in a female patient with infiltrative WCD is presented. The tactics of managing this patient category are analyzed.

Molecular imaging of tumor photoimmunotherapy: Evidence of photosensitized tumor necrosis and hemodynamic changes

DEFF Research Database (Denmark)

Kishimoto, Shun; Oshima, Nobu; Yamamoto, Kazutoshi

2018-01-01

Near-infrared photoimmunotherapy (NIR PIT) employs the photoabsorbing dye IR700 conjugated to antibodies specific for cell surface epidermal growth factor receptor (EGFR). NIR PIT has shown highly selective cytotoxicity in vitro and in vivo. Cell necrosis is thought to be the main mode of cytotox......Near-infrared photoimmunotherapy (NIR PIT) employs the photoabsorbing dye IR700 conjugated to antibodies specific for cell surface epidermal growth factor receptor (EGFR). NIR PIT has shown highly selective cytotoxicity in vitro and in vivo. Cell necrosis is thought to be the main mode...... of cytotoxicity based mainly on in vitro studies. To better understand the acute effects of NIR PIT, molecular imaging studies were performed to assess its cellular and vascular effects.In addition to in vitro studies for cytotoxicity of NIR PIT, the in vivo tumoricidal effects and hemodynamic changes induced....... Following NIR PIT, metabolic MRI using hyperpolarized fumarate showed the production of malate in EGFR-expressing A431 tumor xenografts, providing direct evidence for photosensitized tumor necrosis induced by NIR PIT. R2* mapping studies showed temporal changes in oxygenation, with an accompanying increase...

A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma

NARCIS (Netherlands)

Wenzel, Sally E.; Barnes, Peter J.; Bleecker, Eugene R.; Bousquet, Jean; Busse, William; Dahlén, Sven-Erik; Holgate, Stephen T.; Meyers, Deborah A.; Rabe, Klaus F.; Antczak, Adam; Baker, James; Horvath, Ildiko; Mark, Zsuzsanna; Bernstein, David; Kerwin, Edward; Schlenker-Herceg, Rozsa; Lo, Kim Hung; Watt, Rosemary; Barnathan, Elliot S.; Chanez, Pascal; Chanez, P.; Tunon-de-Lara, M.; Antczak, A.; Pierzchala, W.; Bukowczan, Z.; Trawinska, E.; Baker, J.; Wenzel, S. E.; Katial, R.; Bernstein, D.; Kerwin, E.; Bensch, G.; Castro, M.; Noonan, M.; Nayak, A.; Chupp, G.; Kline, J.; Busse, W.; Kavuru, M. S.; Lang, D.; Wolfe, R.; Baughman, R.; Korenblat, P.; Mansfield, L.; Bleecker, E.; Lisberg, E.; Liu, M.; Panettieri, R.; Spangenthal, S.; Bel, E. H.

2009-01-01

RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. OBJECTIVES: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.

Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

DEFF Research Database (Denmark)

Bruun, Christine; Heding, Peter E; Rønn, Sif G

2009-01-01

Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction...

Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

DEFF Research Database (Denmark)

Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

2007-01-01

The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas......-mediated signaling during early implantation. Here we show that ESCs are primarily resistant to Fas-mediated apoptosis independently of their state of hormonal differentiation. Pre-treatment of ESCs with interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha sensitizes them to become apoptotic upon stimulation...... of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE...

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Science.gov (United States)

Hero, M; Suomalainen, A; Hagström, J; Stoor, P; Kontio, R; Alapulli, H; Arte, S; Toiviainen-Salo, S; Lahdenne, P; Mäkitie, O

2013-01-01

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism. Copyright © 2012 Elsevier Inc. All rights reserved.

Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients

NARCIS (Netherlands)

Feelders, R. A.; Swaak, A. J.; Romijn, J. A.; Eggermont, A. M.; Tielens, E. T.; Vreugdenhil, G.; Endert, E.; van Eijk, H. G.; Berghout, A.

1999-01-01

Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects

Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.

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Jacek Nikliński

2010-05-01

Full Text Available The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF-alpha and its receptors (TNF-Rs in the epithelial ovarian cancer (EOC and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively. Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001 and with reduced mean survival time (MST (p=0.002. The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.

The tumor necrosis factor-α inhibitor golimumab in the treatment of rheumatoid arthritis

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Natalia Vladimirovna Chichasova

2014-01-01

Full Text Available The tumor necrosis factor-α (TNF-α golimumab (GLM, that is a fully human monoclonal anti-body, was registered in Russia in 2012 to treat rheumatic diseases, such as rheumatoid arthritis (RA, ankylosing spondylitis, and psoriatic arthritis. Its distinguishing characteristics are a high affinity for TNF-α and easiness-to-use: the drug as a 0.5-ml solution is injected subcutaneously once monthly. The registration of the medication was followed by the implementation of a massive program of clinical trials. The randomized placebo-controlled GO-FORWARD, GO-BEFORE, and GO-AFTER studies have indicated that GLM is effective in patients with RA from different subgroups and has a favorable safety profile as compared to that of the entire class of biological agents. According to the data of these studies, GLM had a positive effect on the functional status and quality of life in patients with RA: there was a significantly greater decrease in HAQ scores in both the early and long open treatment phases (to 5 years and in fatigability than in the control group (p=0.032, physical and mental health improvements, as shown by the SF-36 questionnaire, and a significant reduction in disability.

Investigation of relationship between tumor necrosis factor α in gingival and periodontitis

International Nuclear Information System (INIS)

Zhao Jingjie; Yang Xia; Hou Guihua; Wang Weiyue; Wang Haodan; Jia Hongying; Li Yantao

1999-01-01

42 periodontitis patients and 15 health controls are selected to determine the amount of tumor necrosis factor-α (TNF-α) in inflamed gingival and the normal gingival by RIA. The elations between TNF-α and clinical parameters are analysed. The results show that the level of TNF-α in inflamed gingival is higher than that in the controls (P<0.01). The relationship between TNF-α and clinical parameters indicate that the level of TNF-α positively correlate to the degree of periodontitis and group damage. It indicates TNF-α may be one of the mechanism in the pathogenesis of periodontitis disease

Amperometric magnetoimmunoassay for the direct detection of tumor necrosis factor alpha biomarker in human serum

Energy Technology Data Exchange (ETDEWEB)

Eletxigerra, U. [Micro-NanoFabrication Unit, IK4-Tekniker, Eibar (Spain); CIC microGUNE, Arrasate-Mondragón (Spain); Martinez-Perdiguero, J. [CIC microGUNE, Arrasate-Mondragón (Spain); Merino, S. [Micro-NanoFabrication Unit, IK4-Tekniker, Eibar (Spain); CIC microGUNE, Arrasate-Mondragón (Spain); Villalonga, R.; Pingarrón, J.M. [Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Madrid (Spain); Campuzano, S., E-mail: susanacr@quim.ucm.es [Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Madrid (Spain)

2014-08-01

Highlights: • Electrochemical magnetoimmunosensor for tumor necrosis factor alpha (TNFα) biomarker. • Sensitive and selective detection of TNFα in undiluted serum. • LOD achieved lower than the cut-off value established for relevant illnesses. • Useful and affordable alternative to ELISAs for TNFα determination in serum. - Abstract: An amperometric immunoassay for the determination of tumor necrosis factor alpha (TNFα) protein biomarker in human serum based on the use of magnetic microbeads (MBs) and disposable screen-printed carbon electrodes (SPCEs) has been developed. The specifically modified microbeads were magnetically captured on the working electrode surface and the amperometric responses were measured at −0.20 V (vs. Ag pseudo-reference electrode), upon addition of hydroquinone (HQ) as electron transfer mediator and H{sub 2}O{sub 2} as the enzyme substrate. After a thorough optimization of the assay, extremely low limits of detection were achieved: 2.0 pg mL{sup −1} (36 fM) and 5.8 pg mL{sup −1} (105 fM) for standard solutions and spiked human serum, respectively. The simplicity, robustness and this clinically interesting LOD proved the developed TNFα immunoassay as a good contender for real clinical application.

Amperometric magnetoimmunoassay for the direct detection of tumor necrosis factor alpha biomarker in human serum

International Nuclear Information System (INIS)

Eletxigerra, U.; Martinez-Perdiguero, J.; Merino, S.; Villalonga, R.; Pingarrón, J.M.; Campuzano, S.

2014-01-01

Highlights: • Electrochemical magnetoimmunosensor for tumor necrosis factor alpha (TNFα) biomarker. • Sensitive and selective detection of TNFα in undiluted serum. • LOD achieved lower than the cut-off value established for relevant illnesses. • Useful and affordable alternative to ELISAs for TNFα determination in serum. - Abstract: An amperometric immunoassay for the determination of tumor necrosis factor alpha (TNFα) protein biomarker in human serum based on the use of magnetic microbeads (MBs) and disposable screen-printed carbon electrodes (SPCEs) has been developed. The specifically modified microbeads were magnetically captured on the working electrode surface and the amperometric responses were measured at −0.20 V (vs. Ag pseudo-reference electrode), upon addition of hydroquinone (HQ) as electron transfer mediator and H 2 O 2 as the enzyme substrate. After a thorough optimization of the assay, extremely low limits of detection were achieved: 2.0 pg mL −1 (36 fM) and 5.8 pg mL −1 (105 fM) for standard solutions and spiked human serum, respectively. The simplicity, robustness and this clinically interesting LOD proved the developed TNFα immunoassay as a good contender for real clinical application

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

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Hong-Mei Yang

2017-02-01

Full Text Available Bleomycin (BLM, a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22 tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

PROGNOSTIC VALUE OF TUMOR NECROSIS FACTOR-ALPHA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

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E. N. Zotina

2016-01-01

Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

Glioma-secreted soluble factors stimulate microglial activation: The role of interleukin-1β and tumor necrosis factor-α.

Science.gov (United States)

Hwang, Ji-Sun; Jung, Eun-Hye; Kwon, Mi-Youn; Han, Inn-Oc

2016-09-15

We aimed to elucidate the effect of soluble factors secreted by glioma on microglial activation. Conditioned medium (CM) from glioma cells, CRT-MG and C6, significantly induced nitric oxide (NO) production and stimulated the mRNA expression of inducible NO synthase (iNOS), interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2) in BV2 cells. Glioma CM stimulated p38 mitogen-activated protein kinase (MAPK) phosphorylation, and a p38 MAPK inhibitor, SB203580, suppressed CM-induced NO production in BV2 cells. In addition, CM stimulated nuclear factor-kappaB (NF-κB) DNA binding and transcriptional activity, which was repressed by SB203580. Gliomas displayed higher mRNA expression and release of TNF-α and IL-1β than primary astrocyte cells. Neutralization of TNF-α and IL-1β in C6-CM using a neutralizing antibody inhibited NO/iNOS expression in BV-2 cells. These results indicate potential contribution of diffusible tumor-derived factors to regulate microglial activation and subsequent tumor microenvironment. Copyright © 2016. Published by Elsevier B.V.

Inflammatory Cytokine Tumor Necrosis Factor α Confers Precancerous Phenotype in an Organoid Model of Normal Human Ovarian Surface Epithelial Cells

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Joseph Kwong

2009-06-01

Full Text Available In this study, we established an in vitro organoid model of normal human ovarian surface epithelial (HOSE cells. The spheroids of these normal HOSE cells resembled epithelial inclusion cysts in human ovarian cortex, which are the cells of origin of ovarian epithelial tumor. Because there are strong correlations between chronic inflammation and the incidence of ovarian cancer, we used the organoid model to test whether protumor inflammatory cytokine tumor necrosis factor α would induce malignant phenotype in normal HOSE cells. Prolonged treatment of tumor necrosis factor α induced phenotypic changes of the HOSE spheroids, which exhibited the characteristics of precancerous lesions of ovarian epithelial tumors, including reinitiation of cell proliferation, structural disorganization, epithelial stratification, loss of epithelial polarity, degradation of basement membrane, cell invasion, and overexpression of ovarian cancer markers. The result of this study provides not only an evidence supporting the link between chronic inflammation and ovarian cancer formation but also a relevant and novel in vitro model for studying of early events of ovarian cancer.

Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder.

Science.gov (United States)

Makinodan, Manabu; Iwata, Keiko; Ikawa, Daisuke; Yamashita, Yasunori; Yamamuro, Kazuhiko; Toritsuka, Michihiro; Kimoto, Sohei; Okumura, Kazuki; Yamauchi, Takahira; Yoshino, Hiroki; Tsujii, Masatsugu; Sugiyama, Toshiro; Tsuchiya, Kenji; Mori, Norio; Matsuzaki, Hideo; Kishimoto, Toshifumi

2017-03-01

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro-inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro-inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro-inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor-α mRNA expression level in peripheral blood mononuclear cells but not interleukin-1β or -6. Consistently, tumor necrosis factor-α mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor-α mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis

NARCIS (Netherlands)

Bos, W.H.; Bartelds, G.M.; Vis, M.; van der Horst, A.R.; Wolbink, G.J.; van de Stadt, R.J.; van Schaardenburg, D.; Dijkmans, B.A.C.; Lems, W.F.; Nurmohamed, M.T.; Aarden, L.; Hamann, D.

2009-01-01

Objective: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody ( ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis ( RA). Methods: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated

Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis

NARCIS (Netherlands)

Bos, W.H.; Bartelds, G.M.; Vis, M.; Horst, A.; Wolbink, G.; van de Stadt, R.J.; van Schaardenburg, D.; Dijkmans, B.A.C.; Lems, W.F.; Nurmohamed, M.T.; Aarden, L.; Hamann, D.

2009-01-01

Objective: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). Methods: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated

[Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells].

Science.gov (United States)

Zheng, Yongchang; Du, Shunda; Xu, Haifeng; Xu, Yiyao; Zhao, Haitao; Chi, Tianyi; Lu, Xin; Sang, Xinting; Mao, Yilei

2014-11-18

To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha (TNF-α)-induced hepatocellular carcinoma cells with bioinformatics tools. Published microarray dataset of TNF-α-induced HepG2, human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network. In the signal transduction network, MYC and SP1 were the key nodes of signaling transduction. Several genes from the network were closely related with cellular adhesion.Epidermal growth factor receptor (EGFR) is a possible key gene of effectively regulating cellular adhesion during the induction of TNF-α. EGFR is a possible key gene for TNF-α-induced metastasis of hepatocellular carcinoma.

Association of tumor necrosis factor alpha gene polymorphism G-308A with pseudoexfoliative glaucoma in the Pakistani population.

NARCIS (Netherlands)

Khan, M.I.; Micheal, S.; Rana, N.; Akhtar, F.; Hollander, A.I. den; Ahmed, A.; Qamar, R.

2009-01-01

PURPOSE: The purpose of the present study was to determine the role of the tumor necrosis factor alpha (TNF-alpha) gene polymorphism G-308A and total serum immunoglobulin E (TsIgE) levels in the onset of pseudoexfoliation glaucoma (PEXG) in Pakistani patients. METHODS: The TNF-alpha polymorphism

The proinflammatory cytokine tumor necrosis factor-α excites subfornical organ neurons.

Science.gov (United States)

Simpson, Nick J; Ferguson, Alastair V

2017-09-01

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNF-α -/- mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNF-α into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNF-α, while direct administration of TNF-α into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNF-α. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNF-α on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNF-α depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration dependent. Interestingly, following 24-h incubation with TNF-α, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNF-α elevates SFO neuron excitability. This effect was likely mediated by the transient sodium current, as TNF-α increased the magnitude of the current and lowered its threshold of activation. In contrast, TNF-α did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNF-α exposure elevates SFO neuron activity, providing a basis for TNF-α hypertensive and sympathetic effects. NEW & NOTEWORTHY Considerable recent evidence has suggested important links between inflammation and the pathological mechanisms underlying hypertension. The present study describes cellular mechanisms through which acute and long-term exposure of tumor necrosis factor-α (TNF-α) influences the activity of subfornical organ neurons by

Recombinant tumor necrosis factor alpha inhibits growth of methylcholanthrene-induced sarcoma and enhances natural killer activity of tumor-infiltrating lymphocytes in aging rats

International Nuclear Information System (INIS)

Ziolkowska, Maria; Nowak Joanna, J.; Janiak, Marek; Ryzewska, Alicja

1994-01-01

The effect of recombinant human tumor necrosis factors alpha (rHuTNF-α) on the growth of immunogenic, methylcholanthrene-induced sarcoma (MC-Sa) and natural killer (NK) cell activity of tumor-infiltrating lymphocytes (TIL) in adult and aging rats was investigated. In both groups of animals the growth of transplantable MC-Sa was markedly and similarly inhibited by multiple intratumoral (i.t.) injections of rHuTF-α. This effect was accompanied by stimulation of NK activity of tumor-infiltrating lymphocytes in adult as well as in aging rats. Studies ''in vitro'' demonstrated additionally that rHuTNF-α was a potent stimulator of NK but not of ADCC (antibody-dependent cellular cytotoxicity) activity of spleen lymphocytes from healthy animals. Our results indicate that the antitumor effect of TNF-α is comparable in adult and in aging rats bearing immunogenic MC-Sa. The inhibition of MC-Sa growth may be attributed not only to the TNF-α-induced necrosis of the neoplastic tissue but also to the ''in vivo'' stimulatory effect of this cytokine upon the NK-type function of lymphocytes infiltrating the tumor mass. (author). 31 refs, 5 figs, 2 tabs

Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis

NARCIS (Netherlands)

Bos, W. H.; Bartelds, G. M.; Vis, M.; van der Horst, A. R.; Wolbink, G. J.; van de Stadt, R. J.; van Schaardenburg, D.; Dijkmans, B. A. C.; Lems, W. F.; Nurmohamed, M. T.; Aarden, L.; Hamann, D.

2009-01-01

To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 :

Tumor-altered dendritic cell function: implications for anti-tumor immunity

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Kristian Michael Hargadon

2013-07-01

Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells

NARCIS (Netherlands)

van Kooten, C.; Rensink, I.; Aarden, L.; van Oers, R.

1992-01-01

The proliferative response of purified malignant B cells from 26 patients with chronic lymphocytic leukemia (CLL) was investigated in vitro. In the majority of these patients, a proliferative response could be induced by the combination of tumor necrosis factor (TNF)-alpha and PMA. The concentration

[C1q/tumor necrosis factor related protein 6 (CTRP6) is involved in gentamicin-induced acute kidney injury in rats].

Science.gov (United States)

Li, Rong; Yang, Xiaoxia; Yu, Yan; Zhou, Meilan; Tian, Xiujuan; Feng, Shidong; Wang, Hanmin

2016-11-01

Objective To explore the role of the anti-inflammatory cytokine C1q/tumor necrosis factor related protein 6 (CTRP6) in gentamicin-induced acute kidney injury in rats. Methods SD rats were divided into 5 groups including control group, model group and the other 3 experimental groups. The rats in model group and experimental groups were subcutaneously injected with gentamicin at the dose of 400 mg/(kg.d) for consecutive 2 days to induce acute renal injury. Two days before gentamicin injection, the rats in the 3 experimental groups were given pAd-CTRP6 at the doses of 0.5, 5 and 50 mg/kg, respectively. The serum levels of blood urea nitrogen (BUN) and creatinine (Cr) were respectively assayed with picric acid colorimetry and ultraviolet spectrophotometry; ELISA was used to detect serum CTRP6 content and the production of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the kidney homogenate; Western blotting was performed to detect the expressions of CTRP6, caspase-1 and pyrin domain containing 3 (NLRP3) proteins in the renal tissues of rats. Results Compared with control group, serum BUN and Cr contents increased in the model rats; the secretion of inflammatory factors IL-1β and TNF-α, as well as the expressions of caspase-1 and NLRP3 were also enhanced in the model group. Compared with the model group, serum BUN and Cr contents decreased in the experimental groups; the secretion of IL-1β and TNF-α, as well as the expressions of caspase-1 and NLRP3 were also attenuated in the experimental groups. Moreover, with the increase of the injection dosage of pAd-CTRP6, the suppressive effect was gradually strengthened. Conclusion CTRP6 can attenuate gentamicin-induced acute renal injury in rats in a dose-dependent manner.

Interleukin-10 to tumor necrosis factor-alpha ratio is a predictive biomarker in nonalcoholic fatty liver disease: interleukin-10 to tumor necrosis factor-alpha ratio in steatohepatitis.

Science.gov (United States)

Hashem, Reem M; Mahmoud, Mona F; El-Moselhy, Mohamed A; Soliman, Hala M

2008-10-01

Fatty liver disease is commonly associated with diabetes mellitus (DM). Insulin resistance (IR) as an investigative biomarker is only concerned with fatty liver that results from DM type 2 associated with metabolic syndrome. Irrespective of IR, DM is generally characterized by overproduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), whereas action of the latter is modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). The aim of this study was to investigate the efficacy of using TNF-alpha alone or IL-10/TNF-alpha ratio compared to IR, as a promising biomarker for fatty liver assessment in DM. Furthermore, we hypothesized that using garlic as an immunomodulator may decrease TNF-alpha and increase IL-10 production to improve steatohepatitis. DM was induced metabolically by a high-fat diet to bring about IR, or chemically by alloxan, producing insulin deficiency, in male albino rats. Garlic powder was supplemented (15 mg/kg per day) for 3 weeks. Fatty liver was depicted histologically and biochemically (aspartic aminotransferase, alanine aminotransferase, HOMA-IR, TNF-alpha, IL-10, IL-10/TNF-alpha ratio). We found that, in contrast to obese rats, garlic decreased IL-10/TNF-alpha ratio, despite decreasing TNF-alpha in alloxan diabetic rats in agreement with the histology, which revealed more prominent improvement in the obese group. Moreover, the effect of garlic was not linked to improvement of IR in obese rats. We conclude that IL-10/TNF-alpha ratio may be considered as a convenient biomarker for investigation of fatty liver of different grades, apart from being associated with IR, and immunomodulation of this ratio in favor of increasing it may exert significant improvement.

Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models

NARCIS (Netherlands)

Xie, Bangwen; Stammes, Marieke A.; van Driel, Pieter B. A. A.; Cruz, Luis J.; Knol-Blankevoort, Vicky T.; Löwik, Martijn A. M.; Mezzanotte, Laura; Que, Ivo; Chan, Alan; van den Wijngaard, Jeroen P. H. M.; Siebes, Maria; Gottschalk, Sven; Razansky, Daniel; Ntziachristos, Vasilis; Keereweer, Stijn; Horobin, Richard W.; Hoehn, Mathias; Kaijzel, Eric L.; van Beek, Ermond R.; Snoeks, Thomas J. A.; Löwik, Clemens W. G. M.

2015-01-01

Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF)

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

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Nishimon, Shohei; Ohnuma, Tohru; Takebayashi, Yuto; Katsuta, Narimasa; Takeda, Mayu; Nakamura, Toru; Sannohe, Takahiro; Higashiyama, Ryoko; Kimoto, Ayako; Shibata, Nobuto; Gohda, Tomohito; Suzuki, Yusuke; Yamagishi, Sho-Ichi; Tomino, Yasuhiko; Arai, Heii

2017-06-02

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. Copyright © 2017

Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels

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Pierangeli, Silvia S.; Sonnenfeld, Gerald

1989-01-01

Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

Increased risk of post-operative complications in patients with Crohn's disease treated with anti-tumour necrosis factor α agents - a systematic review

DEFF Research Database (Denmark)

El-Hussuna, Alaa; Theede, Klaus; Olaison, Gunnar

2014-01-01

INTRODUCTION: Tumour necrosis factor α (TNF-α) plays a role in the immune defence, angiogenesis and collagen synthesis. Inhibition of these pathways may increase the risk of infections and impair wound healing in patients after surgery. Biologic treatments including anti-TNF-α agents are increasi......INTRODUCTION: Tumour necrosis factor α (TNF-α) plays a role in the immune defence, angiogenesis and collagen synthesis. Inhibition of these pathways may increase the risk of infections and impair wound healing in patients after surgery. Biologic treatments including anti-TNF-α agents...... are increasingly used in the treatment of inflammatory bowel disease. Taking into consideration the biologics' mechanism of action, fears have been expressed that they might increase the rate of post-operative complications. Results from 18 retrospective studies were conflicting, and meta-analyses based...... an increased risk of overall post-operative complications and an increased rate of infectious or anastomosis-related complications in patients receiving anti-TNF-α. CONCLUSION: The use of anti-TNF-α agents in Crohn's disease patients is associated with an increased risk of post-operative complications after...

Critical roles of mucin-1 in sensitivity of lung cancer cells to tumor necrosis factor-alpha and dexamethasone.

Science.gov (United States)

Xu, Menglin; Wang, Xiangdong

2017-08-01

Lung cancer is the leading cause of death from cancer. Mucins are glycoproteins with high molecular weight, responsible for cell growth, differentiation, and signaling, and were proposed to be correlated with gene heterogeneity of lung cancer. Here, we report aberrant expression of mucin genes and tumor necrosis factor receptors in lung adenocarcinoma tissues compared with normal tissues in GEO datasets. Mucin-1 (MUC1) gene was selected and considered as the target gene; furthermore, the expression pattern of adenocarcinomic cells (A549, H1650, or H1299 cells) was validated under the stimulation with tumor necrosis factor-alpha (TNFα) or dexamethasone (DEX), separately. MUC1 gene interference was done to A549 cells to show its role in sensitivity of lung cancer cells to TNFα and DEX. Results of our experiments indicate that MUC1 may regulate the influence of inflammatory mediators in effects of glucocorticoids (GCs), as a regulatory target to improve therapeutics. It shows the potential effect of MUC1 and GCs in lung adenocarcinoma (LADC), which may help in LADC treatment in the future.

The effect of combining recombinant human tumor necrosis factor-alpha with local radiation on tumor control probability of a human glioblastoma multiforme xenograft in nude mice

International Nuclear Information System (INIS)

Huang, Peigen; Allam, Ayman; Perez, Luis A.; Taghian, Alphonse; Freeman, Jill; Suit, Herman D.

1995-01-01

Purpose: To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-α) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-α with local radiation on the tumor control probability of this tumor model. Methods and Materials: U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm 3 , mice were randomly assigned to treatment: rHuTNF-α alone compared with normal saline control; or local radiation plus rHuTNF-α vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-α on this tumor. The TCD 50 (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-α with local radiation. Results: Tumor growth in mice treated with a dose of 150 μg/kg body weight rHuTNF-α, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-α also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-α starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD 50 from the control value of 60.9 Gy to 50.5 Gy (p 50 value in the treatment vs. the control groups

Tumor necrosis factor-α enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway

International Nuclear Information System (INIS)

Song, Kai; Zhu, Fei; Zhang, Han-zhong; Shang, Zheng-jun

2012-01-01

Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-α (TNF-α) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-α-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer–endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-α could enhance cancer–endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer–endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis. -- Highlights: ► Spontaneous oral cancer–endothelial cell fusion. ► TNF-α enhanced cell fusions. ► VCAM-1/VLA-4 expressed in oral cancer. ► TNF-α increased expression of VCAM-1 on endothelial cells. ► VCAM-1/VLA-4 mediated TNF-α-enhanced cell fusions.

Tumor necrosis factor-{alpha} enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway

Energy Technology Data Exchange (ETDEWEB)

Song, Kai; Zhu, Fei; Zhang, Han-zhong [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); Shang, Zheng-jun, E-mail: shangzhengjun@hotmail.com [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); First Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan (China)

2012-08-15

Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-{alpha}-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer-endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-{alpha} could enhance cancer-endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer-endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis. -- Highlights: Black-Right-Pointing-Pointer Spontaneous oral cancer-endothelial cell fusion. Black-Right-Pointing-Pointer TNF-{alpha} enhanced cell fusions. Black-Right-Pointing-Pointer VCAM-1/VLA-4 expressed in oral cancer. Black-Right-Pointing-Pointer TNF-{alpha} increased expression of VCAM-1 on endothelial cells. Black

Plasma endothelin-1 and tumor necrosis factor-alpha concentrations in pregnant and cyclic rats after low-dose endotoxin infusion

NARCIS (Netherlands)

Faas, MM; Bakker, WW; Valkhof, N; Baller, JFW; Schuiling, GA

Plasma endothelin-1 and tumor necrosis factor-alpha were determined in pregnant and cyclic rats after infusion of either endotoxin (1.0 mu g/kg of body weight) or saline solution. After endotoxin, but not after saline solution, administration there was a transient endothelin-1 response in pregnant

Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study.

Science.gov (United States)

Curtis, Jeffrey R; Sarsour, Khaled; Napalkov, Pavel; Costa, Laurie A; Schulman, Kathy L

2015-11-11

Interstitial lung disease (ILD) is a common extra-articular condition in rheumatoid arthritis (RA), but few studies have systematically investigated its incidence and risk factors in patients receiving anti-tumor necrosis factor-alpha (anti-TNFα) agents or alternate mechanisms of action (MOAs) (e.g., T-cell, B-cell, and interleukin-6 inhibitors). RA patients at least 18 years old were selected from the MarketScan databases (2010-2012) if they had at least one prescription/administration of abatacept, rituximab, tocilizumab, or anti-TNF after having discontinued a different biologic agent and meeting enrollment criteria. Cox models estimated the risk of incident ILD and ILD-related hospitalization. Sensitivity analyses used an alternate ILD case definition. We identified 13,795 episodes of biologic exposure in 11,219 patients. Mean (standard deviation) follow-up was 0.7 (0.5) years. Patients receiving alternate MOA agents were more likely to have had recent exposure to steroids, prior exposure to a greater number of biologics, and history of ILD, anemia, chronic obstructive pulmonary disease, and other pulmonary conditions. When the sensitive definition was used, unadjusted ILD incidence rates (95% confidence interval, or CI) ranged from 4.0 (1.6-8.2, abatacept) to 12.2 (5.6-23.2, infliximab) per 1000 person-years. Being older (hazard ratio (HR) 3.5; 95% CI 2.1-6.0), being male (HR 3.1; 95% CI 1.2-8.4), and having another pulmonary condition (HR 4.8; 95% CI 1.7-13.7) were associated with increased ILD incidence in either sensitive and/or specific models. There were no significant differences by biologic class. Hospitalization rates (95% CI) when the sensitive definition was used ranged from 55.6 (6.7-200.7, tocilizumab) to 262.5 (71.5-672.2, infliximab). In Cox models, recent methotrexate exposure was associated with reduced ILD hospitalization (HR 0.16; 95% CI 0.06-0.46), whereas being male (HR 2.5; 95% CI 1.3-4.8) and having had a hospitalization for asthma (HR 3

Immunogenicity of anti-tumor necrosis factor antibodies-toward improved methods of anti-antibody measurement.

Science.gov (United States)

Aarden, Lucien; Ruuls, Sigrid R; Wolbink, Gertjan

2008-08-01

To date, millions of people have been treated with therapeutic monoclonal antibodies (TmAbs) for various indications. It is becoming increasingly clear that TmAbs can be immunogenic, which may reduce efficacy or induce adverse effects. Over the years, the importance of antibody formation has been questioned and sometimes minimized, as few antibody responses to TmAbs (HACA or HAHA) were reported. However, the methods to detect and quantify such antibodies used in the past have been problematic. Only recently, methods have been developed that have adequate sensitivity and are not seriously disturbed by false-positive reactions caused by rheumatoid factors, natural antibodies to Fab or F(ab')2 fragments, or Fc interactions of IgG4. The large number of treated patients, in combination with these new assays, presents a unique opportunity to study the anti-antibody immune response in man, possibly allowing us to manipulate immunogenicity in the future.

Tumor Necrosis Factor-Mediated Survival of CD169+ Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection

DEFF Research Database (Denmark)

Shinde, Prashant V; Xu, Haifeng C; Maney, Sathish Kumar

2018-01-01

Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169(+) cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169(+) cells during viral infections remain...... stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF) which signals via TNFR1 and promote "enforced virus replication" in CD169(+) macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance....

Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats.

Science.gov (United States)

Jedrzejewski, Tomasz; Piotrowski, Jakub; Wrotek, Sylwia; Kozak, Wieslaw

2014-08-01

Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. It improves quality of the patients' life by decreasing pain, fatigue, loss of appetite, nausea, and vomiting. However, the effect of PSP on body temperature has not thus far been studied, although it is well known that treatment with other polysaccharide adjuvants, such as lipopolysaccharides, may induce fever. The aim of the present study, therefore, was to investigate the influence of PSP on temperature regulation in rats. We report that intraperitoneal injection of PSP provoked a dose-dependent decrease of temperature in male Wistar rats equipped with biotelemetry devices to monitor deep body temperature (Tb). The response was rapid (i.e., with latency of 15-20min), transient (lasting up to 5h post-injection), and accompanied by a significant elevation of the blood tumor necrosis factor-α (TNF-α) level. Pretreatment of the rats with anti-TNF-α antibody prevented the PSP-induced drop in Tb. Based on these data, we conclude that rats may develop an anapyrexia-like response to the injection of peptidopolysaccharide rather than fever, and the response was TNF-α-dependent. Copyright © 2014 Elsevier Ltd. All rights reserved.

Study on radiation necrosis following intraoperative radiotherapy for brain tumors

International Nuclear Information System (INIS)

Tanaka, Yoshiaki; Takeshita, Nagayuki; Niwa, Kohkichi; Kamata, Noriko; Matsuda, Tadayoshi; Matsutani, Masao

1989-01-01

Ninety-five patients with primary or metastatic brain tumors were treated with the intraoperative radiotherapy (IORT). In seven cases, surgery was performed a second time because of suspected of tumor recurrence, later found to be a radiation necrosis. Tumorous lesions were irradiated by IORT in the range of 15 Gy to 20 Gy together with external radiotherapy in the 30 Gy to 72 Gy range. In follow-up postcontrast CT studies, irregularly-shaped lesions appeared at the IORT site and increased in size with the perifocal low density area on subsequent scans. The images resembled those seen in tumor recurrence. Histopathologic changes seen during the follow-up surgery were thought to be mainly the result of radiation necrosis, though viable tumor cells at the marginal tumor site were one possible etiology. A coagulation necrosis with a fibrin exudate was observed in the IORT portal area and the vascular walls exhibited marked degeneration which is symptomatic of delayed radiation necrosis. Thus, post-IORT radiation necrosis is thought to be a direct reaction to this technique, and the delayed absorption of necrotic tissue to be a direct reaction to this technique, and the delayed absorption of necrotic tissue clearly indicates the possibility of adverse effects in its use for treatment of brain tumors. (author)

Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab.

Science.gov (United States)

Kobayashi, Tetsuo; Yokoyama, Tomoko; Ito, Satoshi; Kobayashi, Daisuke; Yamagata, Akira; Okada, Moe; Oofusa, Ken; Narita, Ichiei; Murasawa, Akira; Nakazono, Kiyoshi; Yoshie, Hiromasa

2014-11-01

Tumor necrosis factor (TNF)-α inhibitor has been shown to affect the periodontal condition of patients with rheumatoid arthritis (RA). The aim of the present study is to assess the effect of a fully humanized anti-TNF-α monoclonal antibody, adalimumab (ADA), on the periodontal condition of patients with RA and to compare serum protein profiles before and after ADA therapy. The study participants consisted of 20 patients with RA treated with ADA. Clinical periodontal and rheumatologic parameters and serum cytokine levels were evaluated at baseline and 3 months later. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant difference in abundance before and after ADA therapy were found and identified using mass spectrometry and protein databases. The patients showed a significant decrease in gingival index (P = 0.002), bleeding on probing (P = 0.003), probing depth (P = 0.002), disease activity score including 28 joints using C-reactive protein (P protein spots obtained, nine spots were significantly decreased in abundance at reassessment, corresponding to complement factor H, phospholipase D, serum amyloid A, complement component 4, and α-1-acid glycoprotein (P periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

Science.gov (United States)

Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

1993-01-01

Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

El factor de necrosis tumoral-α, la resistencia a la insulina, el metabolismo de lipoproteínas y la obesidad en humanos Tumor necrosis factor-α, insulin resistance, the lipoprotein metabolism and obesity in humans

OpenAIRE

M.ª M. Ramírez Alvarado; C. Sánchez Roitz

2012-01-01

En la obesidad el tejido adiposo produce moléculas proinflamatorias como el Factor de Necrosis tumoral-α, que tiene efectos locales en la fisiología del adipocito y efectos sistémicos en otros órganos. Muchos estudios relacionando TNF-α, obesidad, resistencia a la insulina y metabolismo lipídico se han realizado en ratas, conejos y perros, pero los resultados observados en varios de estos estudios han sido contradictorios y muchos de ellos no se han logrado reproducir en humanos, lo...

Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy

Science.gov (United States)

Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

2013-01-01

Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections

Increased risk of post-operative complications in patients with Crohn’s disease treated with anti-tumour necrosis factor α agents - a systematic review

DEFF Research Database (Denmark)

El-Hussuna, Alaa; Theede, Klaus; Olaison, Per Olov Gunnar

2014-01-01

INTRODUCTION: Tumour necrosis factor α (TNF-α) plays a role in the immune defence, angiogenesis and collagen synthesis. Inhibition of these pathways may increase the risk of infections and impair wound healing in patients after surgery. Biologic treatments including anti-TNF-α agents are increasi......INTRODUCTION: Tumour necrosis factor α (TNF-α) plays a role in the immune defence, angiogenesis and collagen synthesis. Inhibition of these pathways may increase the risk of infections and impair wound healing in patients after surgery. Biologic treatments including anti-TNF-α agents...... are increasingly used in the treatment of inflammatory bowel disease. Taking into consideration the biologics' mechanism of action, fears have been expressed that they might increase the rate of post-operative complications. Results from 18 retrospective studies were conflicting, and meta-analyses based...... an increased risk of overall post-operative complications and an increased rate of infectious or anastomosis-related complications in patients receiving anti-TNF-α. CONCLUSION: The use of anti-TNF-α agents in Crohn's disease patients is associated with an increased risk of post-operative complications after...

Correlation of MRI Biomarkers with Tumor Necrosis in Hras5 Tumor Xenograft in Athymic Rats

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Daniel P. Bradley

2007-05-01

Full Text Available Magnetic resonance imaging (MRI can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relationship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24 bearing 1.94 ± 0.2-cm3 subcutaneous Hras5 tumors (ATCC 41000 before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0-10 mg/kg, i.v.. We measured effective transverse relaxation rate (R2*, initial area under the gadolinium concentration-time curve (IAUGC60/150, equivalent enhancing fractions (EHF60/150, time constant (Ktrans, proportion of hypoperfused voxels as estimated from fit failures in Ktrans analysis, and signal intensity (SI in T2-weighted MRI (T2W. ZD6126 treatment induced < 90% dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evident from T2W MRI. Although R2* did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of ≥ 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypoperfused voxels might provide a useful biomarker of tumor necrosis.

Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo

NARCIS (Netherlands)

Hinsbergh, V.W.M. van; Kooistra, T.; Berg, E.A. van den; Princen, H.M.G.; Fiers, W.; Emeis, J.J.

1988-01-01

The vascular endothelium plays an important role in fibrinolysis by producing tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). The monokine tumor necrosis factor (human recombinant TNF) increased the production of PAI by cultured human endothelial cells from

Tratamiento de Artritis reumatoide con antagonistas del factor de necrosis tumoral alfa y su asociación con el desarrollo de melanoma cutáneo: revisión sistemática de la literatura y meta-análisis.

OpenAIRE

Aldana Silva, Carolina; Chaparro Reyes, Laura Daniela

2015-01-01

Introducción: El tratamiento con antagonistas del factor de necrosis tumoral alfa (anti TNF) ha impactado el pronóstico y la calidad de vida de los pacientes con artritis reumatoide (AR) positivamente, sin embargo, se interroga un incremento en el riesgo de desarrollar melanoma. Objetivo: Conocer la asociación entre el uso de anti TNF y el desarrollo de melanoma maligno en pacientes con AR. Metodología: Se realizó una búsqueda sistemática en MEDLINE, EMBASE, COCHRANE LIBRARY y ...

Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

Directory of Open Access Journals (Sweden)

Kyung-A Hwang

2012-04-01

Full Text Available Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1. In addition, I. japonicus increased the production of interferon (IFN-γ and tumor necrosis factor (TNF-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562 by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

In vitro inhibition of enterobacteria-reactive CD4+Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

DEFF Research Database (Denmark)

Mangano, K.; Sardesai, N.; D'Alcamo, M.

2008-01-01

VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role...

The effect of combining recombinant human tumor necrosis factor-alpha with local radiation on tumor control probability of a human glioblastoma multiforme xenograft in nude mice

Energy Technology Data Exchange (ETDEWEB)

Huang, Peigen; Allam, Ayman; Perez, Luis A; Taghian, Alphonse; Freeman, Jill; Suit, Herman D

1995-04-30

Purpose: To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-{alpha}) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-{alpha} with local radiation on the tumor control probability of this tumor model. Methods and Materials: U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm{sup 3}, mice were randomly assigned to treatment: rHuTNF-{alpha} alone compared with normal saline control; or local radiation plus rHuTNF-{alpha} vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-{alpha} on this tumor. The TCD{sub 50} (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-{alpha} with local radiation. Results: Tumor growth in mice treated with a dose of 150 {mu}g/kg body weight rHuTNF-{alpha}, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-{alpha} also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-{alpha} starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD{sub 50} from the control value of 60.9 Gy to 50.5 Gy (p < 0.01). Conclusion: rHuTNF-{alpha} exhibits an antitumor effect against U87 xenograft in nude mice, as evidenced by an increased delay in tumor growth as well as cell loss factor. Also, there was an augmentation of tumor curability when given in combination with radiotherapy, resulting in a significantly lower TCD{sub 50} value in the treatment vs. the

Tumor necrosis factor-α regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells

NARCIS (Netherlands)

Giraudo, E.; Primo, L.; Audero, E.; Gerber, H.-P.; Koolwijk, P.; Soker, S.; Klagsbrun, M.; Ferrara, N.; Bussolino, F.

1998-01-01

Tumor necrosis factor-α (TNF-α) modulates gene expression in endothelial cells and is angiogenic in vivo. TNF-α does not activate in vitro migration and proliferation of endothelium, and its angiogenic activity is elicited by synthesis of direct angiogenic inducers or of proteases. Here, we show

A randomized, double-blind, phase I/II trial of tumor necrosis factor and interferon-gamma for treatment of AIDS-related complex (Protocol 025 from the AIDS Clinical Trials Group).

Science.gov (United States)

Agosti, J M; Coombs, R W; Collier, A C; Paradise, M A; Benedetti, J K; Jaffe, H S; Corey, L

1992-05-01

To determine safety and efficacy of tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-related complex, a randomized, double-blind study was conducted. Twenty-five patients with AIDS-related complex and CD4 lymphocytes less than or equal to 500 x 10(6)/L attended an AIDS Clinical Trials Unit of a tertiary referral center. Patients were administered tumor necrosis factor (TNF) (10 micrograms/m2) or IFN gamma (10 micrograms/m2), or both intramuscularly three times weekly for 16 weeks. Side effects from all three preparations included fever, constitutional symptoms, and local reactions. No significant hematologic, hepatic, renal, or coagulation abnormalities were observed. CD4 lymphocyte counts, beta 2-microglobulin, p24 antigen levels, and anti-p24 antibody did not change significantly during therapy. Similarly, no significant change was noted in rates of HIV isolation from peripheral blood mononuclear cells or plasma. TNF and IFN gamma were tolerable after premedication with acetaminophen; however, no significant change in markers of human immunodeficiency virus infection was demonstrated. These cytokines alone do not appear to be of benefit, nor do they appear to hasten the progression of HIV infection.

Hantaan Virus Nucleocapsid Protein Binds to Importin alpha Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B

Science.gov (United States)

2008-11-19

Microbiology . All Rights Reserved. Hantaan Virus Nucleocapsid Protein Binds to Importin Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced...Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702,1 and Department of Microbiology , Mount Sinai...34–36. 32. Prescott , J., C. Ye, G. Sen, and B. Hjelle. 2005. Induction of innate immune response genes by Sin Nombre hantavirus does not require

Interleukin-6 and tumor necrosis factor-alpha values in elk neonates

Science.gov (United States)

Barber-Meyer, S. M.; Johnson, C.R.; Murtaugh, M.P.; Mech, L.D.; White, P.J.

2007-01-01

Serological indicators of general condition would be helpful for monitoring or assessing ungulate wildlife. Toward that end, we report the 1st reference values for 2 cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-??), in neonatal elk (Cervus elaphus). We obtained blood samples from 140 calves ??? 6 days old in Yellowstone National Park during summer 2003-2005. TL-6 values ranged from 0 to 1.21 pg/ml with a median of 0.03 pg/ml. TNF-?? values ranged from 0 to 225.43 pg/ml with a median of 1.85 pg/ml. IL-6 and TNF-?? concentrations were not significant predictors of elk calf survival through 21 days. Development of ungulate-based IL-6 and TNF-?? assays that provide greater sensitivity than cross-reacting human-based assays could be helpful in monitoring ungulate condition and health status comparisons among herds. Such information could provide indirect assessments of range quality or environmental influences among herds. 

Elevated levels of tumor necrosis factor alpha and mortality in centenarians

DEFF Research Database (Denmark)

Bruunsgaard, Helle; Andersen-Ranberg, Karen; Hjelmborg, Jacob v B

2003-01-01

BACKGROUND: Aging is accompanied by low-grade inflammation. Tumor necrosis factor (TNF) alpha initiates the cytokine cascade, and high levels are associated with dementia and atherosclerosis in persons aged 100 years. We hypothesized that TNF-alpha was also a prognostic marker for all......-cause mortality in these persons. METHODS: We enrolled 126 subjects at or around the time of their 100th birthday. Plasma levels of TNF-alpha, interleukin (IL)-6, IL-8, and C-reactive protein were measured at baseline, and we determined the associations between the markers of inflammation and mortality during...... the subsequent 5 years. RESULTS: Only 9 subjects were alive after 5 years. Elevated levels of TNF-alpha were associated with mortality in both men and women (hazard ratio = 1.34 per SD of 2.81 pg/mL; 95% confidence interval: 1.12 to 1.60, P = 0.001). Levels of IL-6 and IL-8 did not affect survival; levels of C...

Levels of inhibitors of tumor necrosis factor alpha and interleukin 1beta in urine and sera of patients with urosepsis

NARCIS (Netherlands)

Olszyna, D. P.; Prins, J. M.; Buis, B.; van Deventer, S. J.; Speelman, P.; van der Poll, T.

1998-01-01

The antiinflammatory cytokine response during urosepsis was determined by measurement of concentrations of soluble tumor necrosis factor receptor (sTNFR) types I and II, interleukin 1 receptor antagonist (IL-1ra), soluble IL-1 receptor type II (sIL-1RII), and interleukin 10 in sera and urine of 30

A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide

Czech Academy of Sciences Publication Activity Database

Dulebo, A.; Ettrich, Rüdiger; Lucas, R.; Kaftan, D.

2012-01-01

Roč. 18, č. 27 (2012), s. 4236-4243 ISSN 1381-6128 Institutional support: RVO:67179843 Keywords : lectin-like domain * tumor necrosis factor * TIP peptide * oligosaccharides * molecular docking * molecular dynamics simulation * alveolar liquid clearance Subject RIV: CE - Biochemistry Impact factor: 3.311, year: 2012

Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : The value of adjuvant radiotherapy

NARCIS (Netherlands)

Thijssens, KMJ; van Ginkel, RJ; Pras, E; Suurmeijer, AJH; Hoekstra, HJ

Background: The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan followed by limb-saving surgery. Methods: From 1991 to 2003, 73 patients (median age, 54

Tumor Necrosis Factors, Interferons and Matrix Metalloproteinase-9 in Sera of Non-Hodgkin's Lymphoma Patients

International Nuclear Information System (INIS)

Abdel Malak, C.A.; Karawya, E.M.; Hammouda, G.A.; Zakhary, N.I.

2003-01-01

In the present study, the serum levels of some cytokines and the matrix metalloproteinase-9 (MMP-9) were studied in an attempt to find suitable markers for early diagnosis of non- Hodgkin's lymphoma (NHL) and to assess their role in differentiating between disseminated and non disseminated cases. The present study was conducted on 60 patients with non disseminated NHL, 14 patients with disseminated NHL, in addition to 10 healthy controls. Their sera were used to determine tumor necrosis factor-α (TNF--α), tumor necrosis factor--β (TNF-β), interferon---α), (IFN--α), interferon-γ (IFN--γ) and Matrix Metalloproteinase-9 (MMP-9) using the ELISA technique. The results showed that the serum level of TNF---α), and IFN---α), can be used to differentiate between the control group and the group of NHL patients. However, they could not differentiate between non disseminated NHL (nd- NHL) and disseminated NHL (d- NHL). On the other hand, the serum level of TNF-β) can be used to differentiate between nd- NHL and d- NHL, but not between the control group and nd-NHL. Each of [FN--γ and MMP-9 were not useful in discrimination between the control group and the diseased ones. Our data revealed no correlation between serum level of the parameters investigated and the gender of the patients. The present results revealed that TNF-α) and INF-α), can be used as diagnostic tools for NHL. On the other hand, TNF-β) is useful in the differentiation between nd-NHL and d-NHL

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with schizophrenia

Directory of Open Access Journals (Sweden)

Kadasah S

2017-04-01

Full Text Available Saeed Kadasah,1 Misbahul Arfin,2 Sadaf Rizvi,2 Mohammed Al-Asmari,2 Abdulrahman Al-Asmari2 1Department of Psychiatry, 2Division of Molecular Biology & Genetics, Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Background: Schizophrenia is one of the most common devastating psychiatric disorders that negatively affects the quality of life and psychosocial functions. Its etiology involves the interplay of complex polygenic influences and environmental risk factors. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia. Objective: The aim of this study was to investigate the association of proinflammatory cytokine genes, tumor necrosis factor (TNF-α (-308G/A and TNF-β (+252A/G polymorphisms with schizophrenia susceptibility. Subjects and methods: TNF-α and TNF-β genes were amplified using amplification refractory mutation system primers in 180 schizophrenia patients and 200 healthy matched controls recruited from the Psychiatry Clinic of Prince Sultan Military Medical City, Riyadh. The frequencies of alleles and genotypes of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms in patients were compared with those in controls. Results: The frequencies of TNF-α (-308 allele A and genotype GA were significantly higher, while those of allele G and genotype GG were lower in schizophrenia patients as compared to controls, indicating that genotype GA and allele A of TNF-α (-308G/A may increase susceptibility to schizophrenia, while genotype GG and allele G may reduce it. On the other hand, the distribution of alleles and genotypes of TNF-β (+252A/G polymorphism does not differ significantly in patients from controls; however, the frequency of genotype GG of TNF-β (+252A/G was significantly higher in male patients than in female patients. The distribution of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms was almost similar in schizophrenia patients with

Tumor necrosis factor and its receptors in the neuroretina and retinal vasculature after ischemia-reperfusion injury in the pig retina

DEFF Research Database (Denmark)

Gesslein, Bodil; Håkansson, Gisela; Gustafsson, Lotta

2010-01-01

Numerous studies have been performed aimed at limiting the extent of retinal injury after ischemia, but there is still no effective pharmacological treatment available. The aim of the present study was to examine the role of tumor necrosis factor (TNF)α and its receptors (TNF-R1 and TNF-R2), espe...

Concise Review: Mesenchymal Stem Cells Ameliorate Tissue Injury via Secretion of Tumor Necrosis Factor-α Stimulated Protein/Gene 6

Directory of Open Access Journals (Sweden)

Zhigang He

2014-01-01

Full Text Available Numerous reports have described therapeutic benefits in various disease models after administration of the adult stem/progenitor cells from bone marrow or other tissues referred to as mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs. They all showed that one of the important effects of MSCs is to act against excessive inflammatory responses and repair the damaged tissues. The therapeutic benefits of MSCs were initially interpreted by their migration, engraftment, and differentiation into target tissues. However, remarkable anatomical structural repairs and functional improvements were increasingly observed with a small number of or even no MSCs in the injured tissues. This suggests that most beneficial effects are largely due to paracrine secretions or cell-to-cell contacts that have multiple effects involving modulation of inflammatory and immune responses. Currently, the therapeutic benefits of MSCs are in part explained by the cells being activated by signals from injured tissues to express an anti-inflammatory protein, tumor-necrosis-factor-α-induced protein 6. This important mechanism of action has attracted increasing attention, and therefore we conducted this review to summarize the latest research.

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

Science.gov (United States)

Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

2016-09-01

Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

Science.gov (United States)

Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

2016-08-01

Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

Expression of human soluble tumor necrosis factor (TNF)-related ...

African Journals Online (AJOL)

DR NJ TONUKARI

2011-06-06

Jun 6, 2011 ... bio-technique in bacterial (Lin et al., 2007), yeast (Xu et al., 2003) ... biological activity, such as human somatotropin (hST) .... sion way with chloroplast transit peptide (Wang et al., .... chloroplast protein synthesis capacity by massive expression of a ... necrosis factor-related apoptosis-inducing ligand in vivo.

In vitro cytotoxicity of human recombinant tumor necrosis factor alpha in association with radiotherapy in a human ovarian carcinoma cell line

International Nuclear Information System (INIS)

Manetta, A.; Lucci, J.; Soopikian, J.; Granger, G.; Berman, M.L.; DiSaia, P.J.

1990-01-01

It has been speculated that tumor necrosis factor alpha (TNF-alpha) may decrease the cytotoxicity of radiotherapy by increasing the scavenging of toxic superoxide radicals. Because of the possible clinical implications, the cytotoxicity of TNF-alpha in combination with radiotherapy (RT) was compared with that of RT alone in a human ovarian cancer cell line. NIH:OVCAR-3 cells were incubated with TNF-alpha at 10.0, 1.0, 0.1, and 0.01 microgram/ml. Plates were divided into two groups; one received 150 cGy of radiotherapy and the other received no further therapy. Seventy-two hours later, supernatants were aspirated and viable cells were stained with a 1% solution of crystal violet. Survival of cells treated with RT plus TNF-alpha was expressed as a percentage of surviving irradiated controls. Analysis of results revealed minimal additive cell killing effect between TNF-alpha and radiotherapy at all concentrations of tumor necrosis factor, with the greatest difference noted in the group treated with 10 micrograms/ml TNF-alpha. A continued radiotherapy dose-response study with TNF-alpha showed a similar additive, not radioprotective, effect. This may have implication as a potentiator of RT in some human tumors

Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity

DEFF Research Database (Denmark)

Engelmann, H; Holtmann, H; Brakebusch, C

1990-01-01

Immunological cross-reactivity between tumor necrosis factor (TNF) binding proteins which are present in human urine (designated TBPI and TBPII) and two molecular species of the cell surface receptors for TNF is demonstrated. The two TNF receptors are shown to be immunologically distinct, to differ....... These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin E2. Monovalent F(ab) fragments of the polyclonal antibodies...

Choice of therapeutic tactics after failure of the first tumor necrosis factor-α inhibitor

Directory of Open Access Journals (Sweden)

N. V. Chichasova

2017-01-01

Full Text Available The paper discusses whether the effect of different biological agents (BAs can be achieved in patients with active rheumatoid arthritis (RA when they inadequately respond to therapy with tumor necrosis factor-α (TNF-α inhibitors. It gives data on the efficacy of BAs with another mechanism of action (abatacept, tocilizumab, and rituximab and on the comparable efficacy of golimumab (GLM in this group of patients. It is shown that the effect of GLM therapy does not depend on the reasons for discontinuation of a previously used TNF-α inhibitors (inefficacy, adverse events, etc.. It is conclusion that GLM is effective after failure of one or two TNF-α inhibitors.

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

International Nuclear Information System (INIS)

Voigt, Susann; Kalthoff, Holger; Adam, Dieter; Philipp, Stephan; Davarnia, Parvin; Winoto-Morbach, Supandi; Röder, Christian; Arenz, Christoph; Trauzold, Anna; Kabelitz, Dieter; Schütze, Stefan

2014-01-01

The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may

Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

DEFF Research Database (Denmark)

Clausen, Bettina H; Lambertsen, Kate L; Babcock, Alicia A

2008-01-01

BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We inv...

Anti-plasmodial and anti-inflammatory activities of cyclotide-rich ...

African Journals Online (AJOL)

2017-09-03

Sep 3, 2017 ... orthodox anti-malarial treatments, and in search of relief, people living in ... the world today are still derived from natural sources.5. An important role in ..... each assay plate. Effect of CRF on LPS-evoked tumor necrosis factor ..... to contribute to the inflammatory cascade by increasing vascular permeability.

Vasculitis Associated With Tumor Necrosis Factor-α Inhibitors

Science.gov (United States)

Sokumbi, Olayemi; Wetter, David A.; Makol, Ashima; Warrington, Kenneth J.

2012-01-01

Objective To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors. Patients and Methods This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti–TNF-α therapy. Results Of 8 patients with vasculitis associated with anti–TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti–TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation. Conclusion Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed. PMID:22795634

Hepatocellular carcinoma: IVIM diffusion quantification for prediction of tumor necrosis compared to enhancement ratios

International Nuclear Information System (INIS)

Kakite, Suguru; Dyvorne, Hadrien A.; Lee, Karen M.; Jajamovich, Guido H.; Knight-Greenfield, Ashley; Taouli, Bachir

2015-01-01

To correlate intra voxel incoherent motion (IVIM) diffusion parameters of liver parenchyma and hepatocellular carcinoma (HCC) with degree of liver/tumor enhancement and necrosis; and to assess the diagnostic performance of diffusion parameters vs. enhancement ratios (ER) for prediction of complete tumor necrosis. In this IRB approved HIPAA compliant study, we included 46 patients with HCC who underwent IVIM diffusion-weighted (DW) MRI in addition to routine sequences at 3.0 T. True diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (PF) and apparent diffusion coefficient (ADC) were quantified in tumors and liver parenchyma. Tumor ER were calculated using contrast-enhanced imaging, and degree of tumor necrosis was assessed using post-contrast image subtraction. IVIM parameters and ER were compared between HCC and background liver and between necrotic and viable tumor components. ROC analysis for prediction of complete tumor necrosis was performed. 79 HCCs were assessed (mean size 2.5 cm). D, PF and ADC were significantly higher in HCC vs. liver (p < 0.0001). There were weak significant negative/positive correlations between D/PF and ER, and significant correlations between D/PF/ADC and tumor necrosis (for D, r 0.452, p < 0.001). Among diffusion parameters, D had the highest area under the curve (AUC 0.811) for predicting complete tumor necrosis. ER outperformed diffusion parameters for prediction of complete tumor necrosis (AUC > 0.95, p < 0.002). D has a reasonable diagnostic performance for predicting complete tumor necrosis, however lower than that of contrast-enhanced imaging

Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy

DEFF Research Database (Denmark)

Larsson, S; Englund, M; Struglics, A

2015-01-01

concentrations of interleukin (IL)-6, -8 and tumor necrosis factor (TNF)-α by multiplex immunoassay, graded radiographic features of tibiofemoral and patellofemoral OA according to the Osteoarthritis Research Society International (OARSI) atlas, scored patient-reported outcomes using the Knee Injury...

Emerging Roles of Tumor Necrosis Factor-Stimulated Gene-6 in the Pathophysiology and Treatment of Atherosclerosis

Directory of Open Access Journals (Sweden)

Rena Watanabe

2018-02-01

Full Text Available Tumor necrosis factor-stimulated gene-6 (TSG-6 is a 35-kDa glycoprotein that has been shown to exert anti-inflammatory effects in experimental models of arthritis, acute myocardial infarction, and acute cerebral infarction. Several lines of evidence have shed light on the pathophysiological roles of TSG-6 in atherosclerosis. TSG-6 suppresses inflammatory responses of endothelial cells, neutrophils, and macrophages as well as macrophage foam cell formation and vascular smooth muscle cell (VSMC migration and proliferation. Exogenous TSG-6 infusion and endogenous TSG-6 attenuation with a neutralizing antibody for four weeks retards and accelerates, respectively, the development of aortic atherosclerotic lesions in ApoE-deficient mice. TSG-6 also decreases the macrophage/VSMC ratio (a marker of plaque instability and promotes collagen fibers in atheromatous plaques. In patients with coronary artery disease (CAD, plasma TSG-6 levels are increased and TSG-6 is abundantly expressed in the fibrous cap within coronary atheromatous plaques, indicating that TSG-6 increases to counteract the progression of atherosclerosis and stabilize the plaque. These findings indicate that endogenous TSG-6 enhancement and exogenous TSG-6 replacement treatments are expected to emerge as new lines of therapy against atherosclerosis and related CAD. Therefore, this review provides support for the clinical utility of TSG-6 in the diagnosis and treatment of atherosclerotic cardiovascular diseases.

Tumor necrosis factor alpha of teleosts: in silico characterization and homology modeling

Directory of Open Access Journals (Sweden)

Tran Ngoc Tuan

2016-10-01

Full Text Available Tumor necrosis factor alpha (TNF- is known to be crucial in many biological activities of organisms. In this study, physicochemical properties and modeling of TNF- protein of fish was analyzed using in silico approach. TNF- proteins selected from fish species, including grass carp (Ctenopharyngodon idella, zebra fish (Danio rerio, Nile tilapia (Oreochromis niloticus, goldfish (Carassius auratus, and rainbow trout (Oncorhynchus mykiss were used in this study. Physicochemical characteristics with molecular weight, theoretical isoelectric point, extinction coefficient, aliphatic index, instability index, total number of negatively charged residues and positively charged residues, and grand average of hydropathicity were computed. All proteins were classified as transmembrane proteins. The “transmembrane region” and “TNF” domain were identified from protein sequences. The function prediction of proteins was also performed. Alpha helices and random coils were dominating in the secondary structure of the proteins. Three-dimensional structures were predicted and verified as good structures for the investigation of TNF- of fish by online server validation.

UVEITIS INA RHEUMATOLOGISTS PRACTICE: A ROLE OF TUMOR NECROSIS FACTOR-а INHIBITORS

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Sergey Valentinovich Moiseyev

2009-01-01

Full Text Available Uveitis frequently develops in patients with ankylosing spondylitis (AS and other autoimmune diseases. It is occasionally characterized by a severe recurrent course and untreatable with systemic glucocorticoids (GC and standard immunosuppressive agents. The results of (mainly small clinical trials, as well as some observations suggest that therapy with tumor necrosis factor-а (TNF-а inhibitors is effective in such patients. There is the strongest evidence that they are beneficial in treating recurrent uveitis in patients with AS, infliximab having some efficacy advantages over etanercept and adalimumab. Accordingly, chronic uveitis in AS can be considered as an additional argument in favor of the use of TNF-а inhibitors. Furthermore, treatment with drugs of this group is warranted in severe uveitis refractory to GC and immunosuppressants. It is conceivable that in some forms of uveitis, for example, in patients with Behcet's disease, treatment with TNF-а inhibitors should be initiated at an earlier stage as the efficacy of standard immunosuppressants is generally limited

Tumor necrosis factor-alpha induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor

NARCIS (Netherlands)

van der Poll, T.; Jansen, P. M.; van Zee, K. J.; Welborn, M. B.; de Jong, I.; Hack, C. E.; Loetscher, H.; Lesslauer, W.; Lowry, S. F.; Moldawer, L. L.

1996-01-01

Tumor necrosis factor-alpha (TNF-alpha) can bind to two distinct transmembrane receptors, the p55 and p75 TNF receptors. We compared the capability of two mutant TNF proteins with exclusive affinity for the p55 or p75 TNF receptor with that of wild type TNF, to activate the hemostatic mechanism in

Effect of Tumor Necrosis Factor-α on Neutralization of Ventricular Fibrillation in Rats with Acute Myocardial Infarction

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Yu Chen

2011-01-01

Full Text Available The purpose of this study was to explore the effects of tumor necrosis factor-α (TNF-α on ventricular fibrillation (VF in rats with acute myocardial infarction (AMI. Rats were randomly classified into AMI group, sham operation group and recombinant human tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc group. Spontaneous and induced VFs were recorded. Monophasic action potentials (MAPs among different zones of myocardium were recorded at eight time points before and after ligation and MAP duration dispersions (MAPDds were calculated. Then expression of TNF-α among different myocardial zones was detected. After ligation of the left anterior descending coronary artery, total TNF-α expression in AMI group began to markedly increase at 10 min, reached a climax at 20–30min, and then gradually decreased. The time-windows of VFs and MAPDds in the border zone performed in a similar way. At the same time-point, the expression of TNF-α in the ischemia zone was greater than that in the border zone, and little in the non-ischemia zone. Although the time windows of TNF-α expression, the MAPDds in the border zone and the occurrence of VFs in the rhTNFR:Fc group were similar to those in the AMI group, they all decreased in the rhTNFR:Fc group. Our findings demonstrate that TNF-α could enlarge the MAPDds in the border zone, and promote the onset of VFs.

Lowering Interleukin-12 Activity Improves Myocardial and Vascular Function Compared With Tumor Necrosis Factor-a Antagonism or Cyclosporine in Psoriasis.

Science.gov (United States)

Ikonomidis, Ignatios; Papadavid, Evangelia; Makavos, George; Andreadou, Ioanna; Varoudi, Maria; Gravanis, Kostas; Theodoropoulos, Kostas; Pavlidis, George; Triantafyllidi, Helen; Moutsatsou, Paraskevi; Panagiotou, Christina; Parissis, John; Iliodromitis, Efstathios; Lekakis, John; Rigopoulos, Dimitrios

2017-09-01

Interleukin (IL)-12 activity is involved in the pathogenesis of psoriasis and acute coronary syndromes. We investigated the effects of IL-12 inhibition on vascular and left ventricular (LV) function in psoriasis. One hundred fifty psoriasis patients were randomized to receive an anti-IL-12/23 (ustekinumab, n=50), anti-tumor necrosis factor-a (TNF-α; etanercept, n=50), or cyclosporine treatment (n=50). At baseline and 4 months post-treatment, we measured (1) LV global longitudinal strain, twisting, and percent difference between peak twisting and untwisting at mitral valve opening (%untwMVO) using speckle-tracking echocardiography, (2) coronary flow reserve, (3) pulse wave velocity and augmentation index, (4) circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide), TNF-α, IL-6, IL-12, IL-17, malondialdehyde, and fetuin-a. Compared with baseline, all patients had improved global longitudinal strain (median values: -17.7% versus -19.5%), LV twisting (12.4° versus 14°), %untwMVO (27.8% versus 35%), and coronary flow reserve (2.8 versus 3.1) and reduced circulating NT-proBNP, IL-17, TNF-α, and IL-6 post-treatment ( P psoriasis, IL-12/23 inhibition results in a greater improvement of coronary, arterial, and myocardial function than TNF-α inhibition or cyclosporine treatment. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02144857. © 2017 American Heart Association, Inc.

Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

Science.gov (United States)

Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

2014-01-08

Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

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Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj

2003-01-01

BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow....... Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (Palpha...

99m Tc-anti-epidermal growth factor receptor nanobody for tumor imaging.

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Piramoon, Majid; Hosseinimehr, Seyed Jalal; Omidfar, Kobra; Noaparast, Zohreh; Abedi, Seyed Mohammad

2017-04-01

Nanobodies are important biomolecules for tumor targeting. In this study, we synthesized and labeled anti-epidermal growth factor receptor (EGFR) nanobody OA-cb6 with 99m Tc(CO) 3 + and evaluated its characteristics for targeting the EGFR in the A431 human epidermal carcinoma cell line. Nanobody radiolabeling was achieved with high yield and radiochemical purity, and the radioconjugate was stable. Biodistribution results in nude mice exhibited a favorable tumor-to-muscle ratio at 4-hr postinjection, and tumor location was visualized at 4 hr after injection of radiolabeled nanobody. Our result showed that the OA-cb6- 99m Tc-tricarbonyl radiolabeled nanobody is a promising radiolabeled biomolecule for tumor imaging in cancers with high EGFR overexpression. © 2016 John Wiley & Sons A/S.

Cytologic anaplasia is a prognostic factor in osteosarcoma biopsies, but mitotic rate or extent of spontaneous tumor necrosis are not: a critique of the College of American Pathologists Bone Biopsy template.

Science.gov (United States)

Cates, Justin Mm; Dupont, William D

2017-01-01

The current College of American Pathologists cancer template for reporting biopsies of bone tumors recommends including information that is of unproven prognostic significance for osteosarcoma, such as the presence of spontaneous tumor necrosis and mitotic rate. Conversely, the degree of cytologic anaplasia (degree of differentiation) is not reported in this template. This retrospective cohort study of 125 patients with high-grade osteosarcoma was performed to evaluate the prognostic impact of these factors in diagnostic biopsy specimens in predicting the clinical outcome and response to neoadjuvant chemotherapy. Multivariate Cox regression was performed to adjust survival analyses for well-established prognostic factors. Multivariate logistic regression was used to determine odds ratios for good chemotherapy response (≥90% tumor necrosis). Osteosarcomas with severe anaplasia were independently associated with increased overall and disease-free survival, but mitotic rate and spontaneous necrosis had no prognostic impact after controlling for other confounding factors. Mitotic rate showed a trend towards increased odds of a good histologic response, but this effect was diminished after controlling for other predictive factors. Neither spontaneous necrosis nor the degree of cytologic anaplasia observed in biopsy specimens was predictive of a good response to chemotherapy. Mitotic rate and spontaneous tumor necrosis observed in pretreatment biopsy specimens of high-grade osteosarcoma are not strong independent prognostic factors for clinical outcome or predictors of response to neoadjuvant chemotherapy. Therefore, reporting these parameters for osteosarcoma, as recommended in the College of American Pathologists Bone Biopsy template, does not appear to have clinical utility. In contrast, histologic grading schemes for osteosarcoma based on the degree of cytologic anaplasia may have independent prognostic value and should continue to be evaluated.

Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosis

OpenAIRE

HARRIS, JAMES; HARRIS, JAMES

2008-01-01

PUBLISHED umor necrosis factor (TNF)?? is a proinflammatory cytokine that mediates inflammation in response to various pathogens, including Mycobacterium tuberculosis, but is also a key factor in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Three TNF???suppressing drugs have been approved to treat selected autoimmune diseases; 2 are monoclonal antibodies against TNF?? (adalimumab and infliximab), and the other is a soluble TNF receptor/Fc fusion protein (etanerce...

Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma.

Science.gov (United States)

Griffith, Thomas S; Fialkov, Jonathan M; Scott, David L; Azuhata, Takeo; Williams, Richard D; Wall, Nathan R; Altieri, Dario C; Sandler, Anthony D

2002-06-01

The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-O) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-O with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.

Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis.

Science.gov (United States)

Fredriksson, Lisa; Herpers, Bram; Benedetti, Giulia; Matadin, Quraisha; Puigvert, Jordi C; de Bont, Hans; Dragovic, Sanja; Vermeulen, Nico P E; Commandeur, Jan N M; Danen, Erik; de Graauw, Marjo; van de Water, Bob

2011-06-01

Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but the exact mechanism at the cellular hepatocyte level is not well understood. Here we studied the mechanism of crosstalk in hepatocyte apoptosis caused by diclofenac and the proinflammatory cytokine tumor necrosis factor α (TNF-α). HepG2 cells were treated with diclofenac followed by TNF-α challenge and subsequent evaluation of necrosis and apoptosis. Diclofenac caused a mild apoptosis of HepG2 cells, which was strongly potentiated by TNF-α. A focused apoptosis machinery short interference RNA (siRNA) library screen identified that this TNF-α-mediated enhancement involved activation of caspase-3 through a caspase-8/Bid/APAF1 pathway. Diclofenac itself induced sustained activation of c-Jun N-terminal kinase (JNK) and inhibition of JNK decreased both diclofenac and diclofenac/TNF-α-induced apoptosis. Live cell imaging of GFPp65/RelA showed that diclofenac dampened the TNF-α-mediated nuclear factor kappaB (NF-κB) translocation oscillation in association with reduced NF-κB transcriptional activity. This was associated with inhibition by diclofenac of the TNF-α-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα). Finally, inhibition of IκB kinase β (IKKβ) with BMS-345541 as well as stable lentiviral short hairpin RNA (shRNA)-based knockdown of p65/RelA sensitized hepatocytes towards diclofenac/TNF-α-induced cytotoxicity. Together, our data suggest a model whereby diclofenac-mediated stress signaling suppresses TNF-α-induced survival signaling routes and sensitizes cells to apoptosis. Copyright © 2011 American Association for the Study of Liver Diseases.

Characterization of receptors for recombinant human tumor necrosis factor-alpha from human placental membranes

International Nuclear Information System (INIS)

Aiyer, R.A.; Aggarwal, B.B.

1990-01-01

High affinity receptors for recombinant human tumor necrosis factor-alpha (rhTNF-alpha) were identified on membranes prepared from full term human placenta. Highly purified rhTNF-alpha iodinated by the iodogen method was found to bind placental membranes in a displaceable manner with an approximate dissociation constant (KD) of 1.9 nM. The membrane bound TNF-alpha receptor could be solubilized by several detergents with optimum extraction being obtained with 1% Triton X-100. The binding of 125I-rhTNF-alpha to the solubilized receptor was found to be time and temperature dependent, yielding maximum binding within 1 h, 24 h and 48 h at 37 degrees C, 24 degrees C and 4 degrees C, respectively. However, the maximum binding obtainable at 4 degrees C was only 40% of that at 37 degrees C. The binding 125I-rhTNF-alpha to solubilized placental membrane extracts was displaceable by unlabeled rhTNF-alpha, but not by a related protein recombinant human tumor necrosis factor-beta (rhTNF-beta; previously called lymphotoxin). This is similar to the behavior of TNF-alpha receptors derived from detergent-solubilized cell extracts, although on intact cells, both rhTNF-alpha and rhTNF-beta bind with equal affinity to TNF receptors. The Scatchard analysis of the binding data of the solubilized receptor revealed high affinity binding sites with a KD of approximately 0.5 nM and a receptor concentration of about 1 pmole/mg protein. Gel filtration of the solubilized receptor-ligand complexes on Sephacryl S-300 revealed two different peaks of radioactivity at approximate molecular masses of 50,000 Da and 400,000 Da. The 400,000 dalton peak corresponded to the receptor-ligand complex. Overall, our results suggest that high affinity receptors for TNF-alpha are present on human placental membranes and provide evidence that these receptors may be different from that of rhTNF-beta

Experiences and needs for work participation in employees with rheumatoid arthritis treated with anti-tumour necrosis factor therapy.

Science.gov (United States)

Van der Meer, Marrit; Hoving, Jan L; Vermeulen, Marjolein I M; Herenius, Marieke M J; Tak, Paul P; Sluiter, Judith K; Frings-Dresen, Monique H W

2011-01-01

To investigate the experiences and needs with respect to work participation of employees with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. Face-to-face interviews in 14 employees with RA on anti-TNF therapy focused on experiences, offered support and needs with respect to work participation. Experiences regarding work participation varied and ranged from fatigue at work, having no job control, not being understood by the work environment or difficulty dealing with emotions as a result of interaction within the work environment. Support by health care professionals for work participation was considered important, especially concerning social or psychological issues. Advice in becoming aware of one's changes in abilities was highly appreciated, as was the availability of professional advice in times of an urgent work issue due to RA. Employees mentioned an increase in social support at work and job control as important facilitating factors for work participation. Although patients with RA report improvement in their work functioning after starting anti-TNF therapy, employees continue facing challenges in working life due to RA. For support concerning work participation, it is recommended that health care professionals are more aware of work-related problems in patients with RA treated with anti-TNF therapy.

Histopathological investigation of radiation necrosis. Coagulation necrosis in the irradiated and non-irradiated brain tumors and in the normal brain tissue

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Nakamura, N [Niigata Univ. (Japan). Brain Research Inst.

1977-01-01

Eighty four irradiated tumors (including 59 gliomas) and the surrounding brain tissue were analyzed. In 'normal' brain tissue, typical coagulation necrosis attributable to irradiation was observed in the cerebral white matter, presenting a whitish-yellow color but no remarkable changes in volume. Histologically there was complete desintegration of myelin and axon. Vascular changes included hyalinous thickening, concentric cleavage, fibrinoid degeneration, adventitial fibrosis and edema of small arteries, fibrin thrombi or occlusion of arterioles and capillaries, and telangiectasia of small veins and venules. While other tumors showed hyalinous or fibrous scar tissue and decrease in volume, the gliomas maintained their original volume without residual tumor cells. Massive coagulation necrosis was occasionally found even in full volume, non-irradiated gliomas (controls), although the changes were fewer and not so varied as in typical radiation necrosis. With small dosages, it was difficult to judge whether the necrosis was caused by irradiation or occurred spontaneously. Coagulation necrosis in tumor tissue was found in 25 of 59 cases (42%) of irradiated gliomas, but in only 2 of 49 cases (4%) of the nonirradiated gliomas. In 49 cases no coagulation necrosis of the surrounding tissue was found. Although histopathological judgement is difficult, it is suggested that there is a significant correlation between coagulation necrosis and irradiation. Discussion of the relationship between coagulation necrosis and NSD (nominal standard dose) led to the conclusion that coagulation necrosis will not be caused by irradiation of less than 1400 rets in NSD.

Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensisTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors

DEFF Research Database (Denmark)

Lobner, M.; Walsted, A.; Larsen, R.

2008-01-01

tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and interferon (IFN)-gamma was increased after Immunlina...... administration for 3 days (P alpha, IFN-gamma, and IL-6 responses to TT were enhanced after 8 and 14 days (P ...) and fell below baseline levels after 14 days (P alpha...

Percentage tumor necrosis following chemotherapy in neuroblastoma correlates with MYCN status but not survival.

Science.gov (United States)

Bomken, Simon; Davies, Beverley; Chong, Leeai; Cole, Michael; Wood, Katrina M; McDermott, Michael; Tweddle, Deborah A

2011-03-01

The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma.

Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.

Science.gov (United States)

Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

2017-06-01

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II -/- ) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II -/- ) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. © 2017 by the American Diabetes Association.

Tumor Necrosis Factor-α-Induced Ototoxicity in Mouse Cochlear Organotypic Culture.

Directory of Open Access Journals (Sweden)

Qian Wu

Full Text Available Tumor necrosis factor (TNF-α is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-α can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-α to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-α treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters' and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF-α treatment, and provide an in vitro model of inflammatory-induced ototoxicity.

Radioprotection by murine and human tumor-necrosis factor; Dose-dependent effects on hematopoiesis in the mouse

Energy Technology Data Exchange (ETDEWEB)

Sloerdal, L; Muench, M O; Warren, D J; Moore, M A.S. [James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York (USA)

1989-01-01

Tumor-necrosis factor (TNF) has been shown to confer significant radioprotection in murine models. Herein, we demonstrate a dose-dependent enhancement of hematological recovery when single doses of either murine or human recombinant TNF are administered prior to irradiation. In addition to its action upon leukocytes and erythocytes, TNF also alleviates radiation-induced thrombocytopenia in the mouse. These effects on circulating blood constituents are further reflected in increased numbers of both primitive (CFU-S) and more differentiated (CFU-GM, CFU-Mega) hematopoietic progenitors in TNF-treated animals. This suggests that TNF exerts it radioprotective effects on a pool of primitive multi-potential hematopoietic cells. (author).

Prognostic factors of tumor recurrence in completely resected non-small cell lung cancer

International Nuclear Information System (INIS)

Tantraworasin, Apichat; Saeteng, Somcharoen; Lertprasertsuke, Nirush; Arreyakajohn, Nuttapon; Kasemsarn, Choosak; Patumanond, Jayanton

2013-01-01

Patients with completely resected non-small cell lung cancer (NSCLC) have an excellent outcome; however tumor recurs in 30%–77% of patients. This study retrospectively analyzed the clinicopathologic features of patients with any operable stage of NSCLC to identify the prognostic factors that influence tumor recurrence, including intratumoral blood vessel invasion (IVI), tumor size, tumor necrosis, and intratumoral lymphatic invasion. From January 2002 to December 2011, 227 consecutive patients were enrolled in this study. They were divided into two groups: the “no recurrence” group and the “recurrence” group. Recurrence-free survival was analyzed by multivariable Cox regression analysis, stratified by tumor staging, chemotherapy, and nodal involvement. IVI, tumor necrosis, tumor diameter more than 5 cm, and nodal involvement were identified as independent prognostic factors of tumor recurrence. The hazard ratio (HR) of patients with IVI was 2.1 times higher than that of patients without IVI (95% confident interval [CI]: 1.4–3.2) (P = 0.001).The HR of patients with tumor necrosis was 2.1 times higher than that of patients without tumor necrosis (95% CI: 1.3–3.4) (P = 0.001). Patients who had a maximum tumor diameter greater than 5 cm had significantly higher risk of recurrence than patients who had a maximum tumor diameter of less than 5 cm (HR 1.9, 95% CI: 1.0–3.5) (P = 0.033). IVI, tumor diameter more than 5 cm, and tumor necrosis are prognostic factors of tumor recurrence in completely resected NSCLC. Therefore, NSCLC patients, with or without nodal involvement, who have one or more prognostic factors of tumor recurrence may benefit from adjuvant chemotherapy for prevention of tumor recurrence

Modulators of Response to Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

National Research Council Canada - National Science Library

Behbakht, Kian

2008-01-01

.... More effective therapies are urgently needed. One of the most promising therapies in development for ovarian cancer is the use of either the Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL...

Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : Three time periods at risk for amputation

NARCIS (Netherlands)

van Ginkel, Robert J.; Thijssens, Katja M. J.; Pras, Elisabeth; van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; Hoekstra, Harald J.

Background: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods: From 1991 to 2003, 73 patients (36 men, 37 women,

Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors

Directory of Open Access Journals (Sweden)

Tanaka T

2014-04-01

Full Text Available Toshio Tanaka,1,2 Yoshihiro Hishitani,3 Atsushi Ogata2,3 1Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan; 2Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; 3Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan Abstract: Rheumatoid arthritis (RA is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF-α and interleukin (IL-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs. Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients. Keywords: interleukin-6, rheumatoid arthritis, adalimumab, biologic

Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression

International Nuclear Information System (INIS)

Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A.

1990-01-01

Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand of leukocyte function-associated antigen-1 (LFA-1), as well as a receptor for human picorna virus, and its regulation thus affects various immunologic and inflammatory reactions. The weak, constitutive ICAM-1 expression on human keratinocytes (KC) can be up-regulated by cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). In order to further examine the regulation of KC ICAM-1 expression, normal human KC or epidermoid carcinoma cells (KB) were incubated with different cytokines and/or exposed to ultraviolet (UV) radiation. Subsequently, ICAM-1 expression was monitored cytofluorometrically using a monoclonal anti-ICAM-1 antibody. Stimulation of cells with recombinant human (rh) interleukin (IL) 1 alpha, rhIL-4, rhIL-5, rhIL-6, rh granulocyte/macrophage colony-stimulating factor (GM-CSF), rh interferon alpha (rhIFN alpha), and rh transforming growth factor beta (TGF beta) did not increase ICAM-1 surface expression. In contrast, rhTNF beta significantly up-regulated ICAM-1 expression in a time- and dose-dependent manner. Moreover, the combination of rhTNF beta with rhIFN gamma increased the percentage of ICAM-1-positive KC synergistically. This stimulatory effect of rhTNF beta was further confirmed by the demonstration that rhTNF beta was capable of markedly enhancing ICAM-1 mRNA expression in KC. Finally, exposure of KC in vitro to sublethal doses of UV radiation (0-100 J/m2) prior to cytokine (rhIFN tau, rhTNF alpha, rhTNF beta) stimulation inhibited ICAM-1 up-regulation in a dose-dependent fashion. These studies identify TNF beta and UV light as potent regulators of KC ICAM-1 expression, which may influence both attachment and detachment of leukocytes and possibly viruses to KC

Tumor Necrosis Factor-α Produced in Cardiomyocytes Mediates a Predominant Myocardial Inflammatory Response to Stretch in Early Volume Overload

OpenAIRE

Chen, Yuanwen; Pat, Betty; Zheng, Junying; Cain, Laura; Powell, Pamela; Shi, Ke; Sabri, Abdelkarim; Husain, Ahsan; Dell’Italia, Louis J

2010-01-01

Acute stretch caused by volume overload (VO) of aorto-caval fistula (ACF) induces a variety of myocardial responses including mast cell accumulation, matrix metalloproteinase (MMP) activation and collagen degradation, all of which are critical in dictating long term left ventricle (LV) outcome to VO. Meanwhile, these responses can be part of myocardial inflammation dictated by tumor necrosis factor-α (TNF-α) which is elevated after acute ACF. However, it is unknown whether TNF-α mediates a ma...

Characterization of a Canine Tetranucleotide Microsatellite Marker Located in the First Intron of the Tumor Necrosis Factor Alpha Gene

OpenAIRE

WATANABE, Masashi; TANAKA, Kazuaki; TAKIZAWA, Tatsuya; SEGAWA, Kazuhito; NEO, Sakurako; TSUCHIYA, Ryo; MURATA, Michiko; MURAKAMI, Masaru; HISASUE, Masaharu

2013-01-01

ABSTRACT A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic informatio...

Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes

DEFF Research Database (Denmark)

Dominguez, Helena; Storgaard, Heidi; Rask-Madsen, Christian

2005-01-01

OBJECTIVE: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic...... glucose uptake remained unchanged as well. Beta-cell function tended to improve. CONCLUSION: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed....

Anti-tumor effects of (1→3)-β-d-glucan from Saccharomyces cerevisiae in S180 tumor-bearing mice.

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Mo, Li; Chen, Yafei; Li, Wenjian; Guo, Shuai; Wang, Xuzhao; An, Hailong; Zhan, Yong

2017-02-01

(1→3)-β-d-Glucan from Saccharomyces cerevisiae is a typical polysaccharide with various biological effects and is considered a candidate for the prevention and treatment of cancer in vitro. Research into the function of (1→3)-β-d-glucan in tumor-bearing animals in vivo, however, is limited. Here, we investigated the effects of (1→3)-β-d-glucan from S. cerevisiae on S180 tumor-bearing mice and on the immunity of the tumor-bearing host. The molecular mechanisms underlying the observed effects were investigated. (1→3)-β-d-Glucan was shown to exert anti-tumor effects without toxicity in normal mouse cells. The volume and weight of S180 tumors decreased dramatically following treatment with (1→3)-β-d-glucan, and treatment with the polysaccharide was furthermore shown to increase the tumor inhibition rate in a dose-dependent manner. Spleen index, T lymphocyte subsets (CD 4 and CD 8 ), as well as interleukins (IL)-2, (IL-2, IL-6), and tumor necrosis factor-α were assayed to detect the immunoregulatory and anti-tumor effects after (1→3)-β-d-glucan intragastrical administration. (1→3)-β-d-Glucan was shown to significantly potentiate the mouse immune responses by, among other effects, decreasing the ratio of CD 4 to CD 8 . The expression levels of IL-2, IL-6, and TNF-α were also significantly increased by (1→3)-β-d-glucan. These results suggest that (1→3)-β-d-glucan enhances the host's immune function during the tumor inhibition process. S180 tumor cells treated with (1→3)-β-d-glucan also exhibited significant apoptotic characteristics. (1→3)-β-d-glucan increased the ratio of Bax to Bcl-2 at the translation level by up-regulating Bax expression and down-regulating Bcl-2 expression, resulting in the initiation of cell apoptosis in S180 tumor-bearing mice. Taken together, these results indicate that the anti-tumor effects exerted by (1→3)-β-d-glucan may be attributed to the polysaccharide's immunostimulating properties and apoptosis

Tumor necrosis factor-α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase (MMP)-1 and MMP-3 ex vivo

DEFF Research Database (Denmark)

Ågren, Magnus S; Schnabel, Reinhild; Christensen, Lise H

2015-01-01

Tumor necrosis factor (TNF)-α induces matrix metalloproteinases (MMPs) that may disrupt skin integrity. We have investigated the effects and mechanisms of exogenous TNF-α on collagen degradation by incubating human skin explants in defined serum-free media with or without TNF-α (10ng/ml) in the a......Tumor necrosis factor (TNF)-α induces matrix metalloproteinases (MMPs) that may disrupt skin integrity. We have investigated the effects and mechanisms of exogenous TNF-α on collagen degradation by incubating human skin explants in defined serum-free media with or without TNF-α (10ng...... tissue-derived collagenolytic activity with TNF-α exposure was blocked by neutralizing MMP-1 monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase-1. TNF-α increased production (pendogenous MMP-1...

The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-α or isoproterenol.

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Takahashi, N; Yoshizaki, T; Hiranaka, N; Kumano, O; Suzuki, T; Akanuma, M; Yui, T; Kanazawa, K; Yoshida, M; Naito, S; Fujiya, M; Kohgo, Y; Ieko, M

2015-05-01

A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear. We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation. C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays. The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The β-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes. Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.

[Effects of occupational stress on serum tumor necrosis factor-α and interleukins].

Science.gov (United States)

Zhou, Wen-Hui; Yu, Shan-Fa; Jiang, Kai-You

2010-12-01

To explore the effect of occupational stress on serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2 and IL-4. A cross-sectional epidemiological study was conducted in 200 workers from the refrigerator assembly line in Henan province in China. Psychosocial work conditions were measured by using the job demand-control model, the effort-reward imbalance model questionnaires and occupational stress measurement scale. Serum TNF-α, IL-1β, IL-2, and IL-4 concentrations were measured by radioimmunoassay or immunoradiometric assay method respectively. Serum TNF-α concentration was statistically significantly different between workers with higher affective balance level and control groups [(1.947 ± 0.173) and (2.029 ± 0.240) fmol/ml] (P life stress level and control groups [(1.759 ± 0.361) and (1.606 ± 0.381) ng/ml] (P life stress and role ambiguity were the predictors of serum IL-2 (R(2) was 0.040, 0.078 and 0.104, respectively). Reward was the predictor of serum IL-4 (R(2) = 0.030). Unhealthy psychological stress factor might be induce a marked increase in the concentrations of serum TNF-α, IL-1β, IL-2, as well as IL-4.

(+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.

Science.gov (United States)

Choi, Hyeon-Jae; Lee, Jin-Hwee; Jung, Yi-Sook

2014-05-02

Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors

DEFF Research Database (Denmark)

Pedersen, Susanne Juhl; Sørensen, Inge Juul; Lambert, Robert G W

2011-01-01

To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix...... metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy....

Feline Toxoplasmosis: Tumor Necrosis Factor, Nitric Oxide, and Free Radicals in Seropositive Cats.

Science.gov (United States)

Faria, Joice L M; Couto, Caroline do; Wierzynski, Sheron L; Bottari, Nathieli B; Baldissera, Matheus D; Pereira, Wanderson A B; Da Silva, Aleksandro S

2018-02-01

Toxoplasma gondii is a cosmopolitan protozoan that causes disease in several species, including humans. In cats, these infections are usually asymptomatic, but in other species they can lead to high levels of inflammatory and cell damage markers, causing cellular damage. Therefore, the aim of this study was to measure levels of tumor necrosis factor (TNF-α), reactive oxygen species (ROS), and nitric oxide (nitrite/nitrate-NO x ) in the serum of cats seropositive for T. gondii. Initially, we investigated the presence of antibodies against T. gondii in cats in the city of Concordia, Santa Catarina, Brazil, with the use of indirect immunofluorescence (IFA), and found 30 cats seropositive for T. gondii and 30 seronegative cats. In this study, seropositive cats showed higher levels of TNF-α, ROS, and NO x compared to seronegative cats. Although cats do not show clinical signs of disease, constant inflammatory response can cause cell damage, which over time may adversely affect the animal.

Differential Effects of Self-Reported Lifetime Marijuana Use on Interleukin-1 Alpha and Tumor Necrosis Factor in African American Adults

OpenAIRE

Keen, Larry; Turner, Arlener D.; Callender, Clive; Campbell, Alfonso

2015-01-01

It is unknown how lifetime marijuana use affects different proinflammatory cytokines. The purpose of the current study is to explore potential differential effects of lifetime marijuana use on interleukin-1 alpha (IL-1α) and tumor necrosis factor (TNF) in a community based sample. Participants included 168 African American adults (51% female, median age= 47 years). Upon study entry, blood was drawn and the participants completed questions regarding illicit drug use history whose answers were ...

Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system.

Science.gov (United States)

Walsh, Matthew C; Lee, JangEun; Choi, Yongwon

2015-07-01

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of interleukin-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the Toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T-cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system but also for maintaining immune tolerance, and more recent work has begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tumor necrosis factor receptor associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system

Science.gov (United States)

Walsh, Matthew C.; Lee, JangEun; Choi, Yongwon

2016-01-01

Summary Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of IL-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor (IRF) pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system, but also for maintaining immune tolerance, and more recent works have begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. PMID:26085208

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.

Science.gov (United States)

Bredholt, Geir; Mannelqvist, Monica; Stefansson, Ingunn M; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B; Wik, Elisabeth; Akslen, Lars A

2015-11-24

Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.

Effect of disrupted mitochondria as a source of damage-associated molecular patterns on the production of tumor necrosis factor α by splenocytes from dogs.

Science.gov (United States)

Friedenberg, Steven G; Strange, Heather R; Guillaumin, Julien; VanGundy, Zachary C; Crouser, Elliott D; Papenfuss, Tracey L

2016-06-01

OBJECTIVE To evaluate the effects of damage-associated molecular patterns (DAMPs) derived from disrupted mitochondria on canine splenocytes and other immune cells. SAMPLES Liver, spleen, and bone marrow samples obtained from 8 cadavers of healthy research Beagles that had been euthanized for other purposes. PROCEDURES Mitochondria were obtained from canine hepatocytes, and mitochondrial DAMPs (containing approx 75% mitochondrial proteins) were prepared. Mitochondrial DAMPs and the nuclear cytokine high-mobility group box protein 1 were applied to splenocytes, bone marrow-differentiated dendritic cells, and a canine myelomonocytic cell (DH82) line for 6 or 24 hours. Cell culture supernatants from splenocytes, dendritic cells, and DH82 cells were assayed for tumor necrosis factor α with an ELISA. Expression of tumor necrosis factor α mRNA in splenocytes was evaluated with a quantitative real-time PCR assay. RESULTS In all cell populations evaluated, production of tumor necrosis factor α was consistently increased by mitochondrial DAMPs at 6 hours (as measured by an ELISA). In contrast, high-mobility group box protein 1 did not have any independent proinflammatory effects in this experimental system. CONCLUSIONS AND CLINICAL RELEVANCE The study revealed an in vitro inflammatory effect of mitochondrial DAMPs (containing approx 75% mitochondrial proteins) in canine cells and validated the use of an in vitro splenocyte model to assess DAMP-induced inflammation in dogs. This experimental system may aid in understanding the contribution of DAMPs to sepsis and the systemic inflammatory response syndrome in humans. Further studies in dogs are needed to validate the biological importance of these findings and to evaluate the in vivo role of mitochondrial DAMPs in triggering and perpetuating systemic inflammatory states.

IMPACT OF THE THERAPY WITH TUMOR NECROSIS FACTOR α INHIBITORS ON THE FREQUENCY OF UVEITIS EXACERBATIONS IN PATIENTS WITH ANKYLOSING SPONDYLITIS

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Alla A Godzenko

2014-01-01

Full Text Available The course of uveitis in patients with ankylosing spondylitis (AS does not always correlate with inflammation in the axial skeleton and peripheral joints. Effect of tumor necrosis factor α (TNFα inhibitors on uveitis has been insufficiently studied yet, unlike their effect on the peripheral joints and spine.Objective. To compare the frequency of uveitis attacks in patients with AS during treatment with TNFα inhibitors and the conventional anti-inflammatory therapy.Materials and Methods. The study included 48 patients with AS and recurrent uveitis treated with TNFα inhibitors: 25 – infliximab, 15 – adalimumab, 9 – etanercept; 7 patients received two or more drugs sequentially. Median [25th, 75th percentiles] of the treatment duration was 3 [3.5; 5] years. The duration of treatment since the first attack of uveitis until administration of TNFα inhibitors was 5 [5; 9.7] years. Eighteen patients received only nonsteroidal anti-inflammatory drugs (NSAIDs, 30 patients received NSAIDs and basic anti-inflammatory drugs (DMARDs, including sulfasalazine (n = 23, methotrexate (n = 4, and cyclosporine (n = 4.Results. The median number of uveitis exacerbations during the standard anti-inflammatory therapy was 1 [0.4; 3] per year; during treatment with TNFα inhibitors – 0 [0; 0.5] per year (p = 0.0007. In 19 of 48 patients (40%, no exacerbations of uveitis were registered during therapy with these drugs. The frequency of uveitis attacks in patients treated with infliximab decreased from 1 [0.2; 2.75] to 0.1 [0; 0.8] episodes per year (p = 0.002, adalimumab – from 1.75 [1; 4.5] to 0 [0; 0.07] (p = 0.04, etanercept – from 0.95 [0.5; 1.75] to 0 [0; 0.07] (p = 0.001.Conclusion. Administration of TNFα inhibitors significantly reduces the frequency of uveitis attacks in patients with AS.

Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells.

Science.gov (United States)

Ma, Hak-Ling; Napierata, Lee; Stedman, Nancy; Benoit, Stephen; Collins, Mary; Nickerson-Nutter, Cheryl; Young, Deborah A

2010-02-01

Patients with psoriasis and psoriatic arthritis respond well to tumor necrosis factor alpha (TNFalpha) blockers in general; however, there is now mounting evidence that a small cohort of patients with rheumatoid arthritis who receive TNFalpha blockers develop psoriasis. This study was undertaken to explore the mechanisms underlying TNFalpha blockade-induced exacerbation of skin inflammation in murine psoriasis-like skin disease. Skin inflammation was induced in BALB/c scid/scid mice after they received CD4+CD45RB(high)CD25- (naive CD4) T cells from donor mice. These mice were treated with either anti-interleukin-12 (anti-IL-12)/23p40 antibody or murine TNFRII-Fc fusion protein and were examined for signs of disease, including histologic features, various cytokine levels in the serum, and cytokine or FoxP3 transcripts in the affected skin and draining lymph node (LN) cells. In a separate study, naive CD4+ T cells were differentiated into Th1 or Th17 lineages with anti-CD3/28 magnetic beads and appropriate cytokines in the presence or absence of TNFalpha. Cytokine gene expression from these differentiated cells was also determined. Neutralization of TNFalpha exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1beta, IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs. TNFalpha also demonstrated a divergent role during priming and reactivation of naive T cells. These results reveal a novel immunoregulatory role of TNFalpha on Th17 and Treg cells in some individuals, which may account for the exacerbation of skin inflammation in some patients who receive anti-TNF treatments.

A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

International Nuclear Information System (INIS)

Chang, M.P.

1988-01-01

The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNF is not directly lytic for membranes. In susceptible target cells, DTx induces the release of 51 Cr- and 75 Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH 4 Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors

Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab in psoriasis

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Sridhar J

2006-01-01

Full Text Available Background: Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF-a being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. Aim: To study the efficacy of chimeric monoclonal antibody to TNF-a (infliximab in Indian patients with recalcitrant psoriasis vulgaris. Materials and Methods: Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. Results: Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. Conclusions: This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.

The influence of X-radiation on production of interleukin-6 and alpha-tumor necrosis factor by perepheral blood mononuclears

International Nuclear Information System (INIS)

Komarovskaya, M.E.; Dryk, S.I.; Krivenko, S.I.; Karkanitsa, L.V.

1993-01-01

The influence of X-radiation on production of interleurin-6 (IL-6) and α-tumor necrosis factor (TNF) has been investigated. Irradiation with doses of 45, 90 and 900 cGy was shown to increase considerably TNF and IL-6 production both in intact mononuclear cultures of human peripheral blood and in cultures stimulated by phytohemagglutinin. In addition to an absolute increase in the production, the stimulatory effect was manifested by earlier accumulation of IL-6 and TNF activities in supernatant fractions of the cultures under study

Is tumor necrosis factor - 376a promoter polymorphism associated with susceptibility to multiple sclerosis? ¿El polimorfismo-376A del promotor del gen del factor de necrosis tumoral se asocia con una mayor susceptibilidad a padecer esclerosis múltiple?

Directory of Open Access Journals (Sweden)

Marcelo A. Kauffman

2007-10-01

Full Text Available A single nucleotide polymorphism (SNP at position -376 of the tumor necrosis factor á gene (TNFA has been associated with susceptibility to multiple sclerosis (MS in Spain. However, no association was found in populations from the USA and The Netherlands. Here we investigate the association between the TNFA - 376A SNP and MS susceptibility in Argentinean patients with MS. The A/G genotype was found in 4.4% of patients (n=90 and in 4.8% of healthy individuals (n=84; p=0.92; odds ratio=0.93; confidence interval: 0.23- 3.84. Thus, no significant differences in genotype and allele frequencies were found between healthy individuals and patients with MS in Argentina.Un polimorfismo de nucleótido único (SNP, por sus iniciales en inglés en la posición -376 del gen codificante del factor de necrosis tumoral á (TNFA ha sido asociado en España con un mayor riesgo a padecer esclerosis múltiple (EM. Sin embargo, esta asociación no fue encontrada en estudios hechos en poblaciones provenientes de los EE.UU. y Holanda. Aquí investigamos la asociación entre el SNP TNFA -376A y el desarrollo de EM en una población de pacientes argentinos con EM. El genotipo A/G fue encontrado en 4.4% de los pacientes (n=90 y en 4.8% de los controles sanos (n=84; p=0.92; odds ratio=0.93; intervalo de confianza: 0.23-3.84. En consecuencia, no encontramos diferencias en las frecuencias alélicas y genotípicas entre los sujetos enfermos y los controles sanos en Argentina.

Tumor necrosis factor alpha selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation

International Nuclear Information System (INIS)

Wong, G.H.; McHugh, T.; Weber, R.; Goeddel, D.V.

1991-01-01

We report here that infection of the human T-cell line HUT-78 with human immunodeficiency virus (HIV) increases its sensitivity to heat and radiation toxicity. A possible explanation for this result may be the reduced expression of manganous superoxide dismutase (MnSOD) in HIV-infected cells compared to uninfected cells. Tumor necrosis factor alpha (TNF-alpha) further sensitizes HIV-infected cells but not uninfected cells to heat and radiation. This is consistent with the ability of TNF-alpha to induce the expression of MnSOD in uninfected but not in HIV-infected cells. HIV-infected HUT-78 cell lines engineered to overexpress MnSOD are more resistant to heat and radiation than HIV-infected cells that do not overexpress MnSOD. However, treatment with TNF-alpha still sensitizes these cells to heat and radiation

DNA fragmentation and cytotoxicity by recombinant human tumor necrosis factor in L929 fibroblast cells

International Nuclear Information System (INIS)

Kosaka, T.; Kuwabara, M.; Koide, F.

1992-01-01

Induction of cell DNA fragmentation by treatment of recombinant human Tumor Necrosis Factor alpha (rhTNF alpha) was examined by using mouse L929 cells derived from mouse fibroblast cells. The amount of DNA fragments derived from rhTNF alpha-treated cells, detected by alkaline elution technique, was smaller than that derived from X-irradiated cells. The rhTNF alpha caused the DNA fragmentation depending on its incubation time and concentration. The DNA damage caused by rhTNF alpha treatment correlated with its cytotoxicity. This result suggested that the DNA fragmentation is one of causes of cell death. The treatment with proteinase K of DNA obtained from rhTNF alpha-treated cells did not increase the amount of DNA fragmentation, which indicates that rhTNF alpha causes DNA-fragmentation but not DNA-protein cross-linking

Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo

Czech Academy of Sciences Publication Activity Database

Weber, T.; Lu, M.; Anděra, Ladislav; Lahm, H.; Gellert, N.; Fariss, M. W.; Kořínek, Vladimír; Sattler, W.; Ucker, D. S.; Terman, A.; Schroder, A.; Erl, W.; Brunk, U. T.; Coffey, R. J.; Weber, C.; Neuzil, J.

2002-01-01

Roč. 8, - (2002), s. 863-869 ISSN 1078-0432 R&D Projects: GA ČR GA312/99/0348 Institutional research plan: CEZ:AV0Z5052915 Keywords : Vitamin E, Antineoplastic Agent, Tumor Necrosis Factor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.991, year: 2002

Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha.

Science.gov (United States)

Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.

1997-01-01

We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

Directory of Open Access Journals (Sweden)

Ge Li

2016-04-01

Full Text Available Tumor necrosis factor alpha (TNFα plays a key role in the pathogenesis of rheumatoid arthritis (RA. Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.

Molecular and functional characterization of pigeon (Columba livia) tumor necrosis factor receptor-associated factor 3.

Science.gov (United States)

Zhou, Yingying; Kang, Xilong; Xiong, Dan; Zhu, Shanshan; Zheng, Huijuan; Xu, Ying; Guo, Yaxin; Pan, Zhiming; Jiao, Xinan

2017-04-01

Tumor necrosis factor receptor-associated factor 3 (TRAF3) plays a key antiviral role by promoting type I interferon production. We cloned the pigeon TRAF3 gene (PiTRAF3) according to its predicted mRNA sequence to investigate its function. The 1704-bp full-length open reading frame encodes a 567-amino acid protein. One Ring finger, two TRAF-type Zinc fingers, one Coiled coil, and one MATH domain were inferred. RT-PCR showed that PiTRAF3 was expressed in all tissues, with relatively weak expression in the heart and liver. In HEK293T cells, over-expression of wild-type, △Ring, △Zinc finger, and △Coiled coil PiTRAF3, but not a △MATH form, significantly increased IFN-β promoter activity. Zinc finger and Coiled coil domains were essential for NF-κB activation. In chicken HD11 cells, PiTRAF3 increased IFN-β promoter activity and four domains were all contributing. R848 stimulation of pigeon peripheral blood mononuclear cells and splenocytes significantly increased expression of PiTRAF3 and the inflammatory cytokine genes CCL5, IL-8, and IL-10. These data demonstrate TRAF3's innate immune function and improve understanding of its involvement in poultry antiviral defense. Copyright © 2016 Elsevier Ltd. All rights reserved.

Regulation of bitter taste responses by tumor necrosis factor.

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Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

2015-10-01

Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells

OpenAIRE

Lim, Sung-Chul; Jeon, Ho Jong; Kee, Keun Hong; Lee, Mi Ja; Hong, Ran; Han, Song Iy

2017-01-01

Andrographolide, a natural compound isolated from Andrographis paniculata, has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL)....

Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors*

Science.gov (United States)

Pontejo, Sergio M.; Alejo, Ali; Alcami, Antonio

2015-01-01

The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. PMID:25940088

Granulocyte-Macrophage Colony-Stimulating Factor Amplification of Interleukin-1β and Tumor Necrosis Factor Alpha Production in THP-1 Human Monocytic Cells Stimulated with Lipopolysaccharide of Oral Microorganisms

OpenAIRE

Baqui, A. A. M. A.; Meiller, Timothy F.; Chon, Jennifer J.; Turng, Been-Foo; Falkler, William A.

1998-01-01

Cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are used to assist in bone marrow recovery during cancer chemotherapy. Interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) play important roles in inflammatory processes, including exacerbation of periodontal diseases, one of the most common complications in patients who undergo this therapy. A human monocyte cell line (THP-1) was utilized to investigate IL-1β and TNF-α production following GM-CSF suppl...

Tumor necrosis factor-α inhibits effects of aryl hydrocarbon receptor ligands on cell death in human lymphocytes.

Science.gov (United States)

Ghatrehsamani, Mahdi; Soleimani, Masoud; Esfahani, Behjat A Moayedi; Shirzad, Hedayatollah; Hakemi, Mazdak G; Mossahebimohammadi, Majid; Eskandari, Nahid; Adib, Minoo

2015-01-01

Activation of aryl hydrocarbon receptor (AhR) leads to diverse outcome in various kinds of cells. AhR activation may induce apoptosis or prevent of apoptosis and cell death. Recent studies suggest that apoptosis effects of AhR can be modulated by inflammatory cytokine like tumor necrosis factor alpha (TNF-α). In this study, we try to investigate the possible interaction of TNF-α with the 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR, on peripheral lymphocytes. Human peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by discontinuous density gradient centrifugation on ficoll. Isolated PBMCs were divided into four groups: Control group, TNF-α administered group, TCDD administered group, co-administered group with TCDD and TNF-α. Cells were maintained for a week in lymphocyte culture condition. Then, TNF-α was added to group 2 and 4. Finally, apoptosis and necrosis were analyzed in all samples using flowcytometry. In group 4, the mean percent of necrosis and apoptosis in TCDD treatment groups was significantly larger than other groups; (P 0.05). However, the mean percent of cell death in co-administered group with TCDD and TNF-α was significantly lower than other groups; (P < 0.05). TNF-α could significantly inhibit effects of TCDD on lymphocytes apoptosis. Combination effects of TNF-α and TCDD on lymphocyte increase cell survival.

ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5.

Science.gov (United States)

Hsu, H; Solovyev, I; Colombero, A; Elliott, R; Kelley, M; Boyle, W J

1997-05-23

Members of tumor necrosis factor receptor (TNFR) family signal largely through interactions with death domain proteins and TRAF proteins. Here we report the identification of a novel TNFR family member ATAR. Human and mouse ATAR contain 283 and 276 amino acids, respectively, making them the shortest known members of the TNFR superfamily. The receptor is expressed mainly in spleen, thymus, bone marrow, lung, and small intestine. The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2. This TRAF interaction domain resides at the C-terminal 20 amino acids. Like most other TRAF-interacting receptors, overexpression of ATAR activates the transcription factor NF-kappaB. Co-expression of ATAR with TRAF5, but not TRAF2, results in synergistic activation of NF-kappaB, suggesting potentially different roles for TRAF2 and TRAF5 in post-receptor signaling.

An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles

NARCIS (Netherlands)

Wilson, A. G.; de Vries, N. [=Niek; Pociot, F.; di Giovine, F. S.; van der Putte, L. B.; Duff, G. W.

1993-01-01

The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies

Soluble tumor necrosis factor receptor-I in preterm infants with chorioamnionitis.

Science.gov (United States)

Sato, Miho; Nishimaki, Shigeru; An, Hiromi; Shima, Yoshio; Naruto, Takuya; Sugai, Toshiyuki; Iwasaki, Shiho; Seki, Kazuo; Imagawa, Tomoyuki; Mori, Masaaki; Yokota, Shumpei

2009-04-01

The aim of our study was (i) to determine whether chorioamnionitis (CAM) is associated with an elevated soluble tumor necrosis factor receptor I (sTNFR-I) level and (ii) to examine the time course of the concentration of sTNFR-I in preterm infants after birth. We measured sTNFR-I levels in the cord blood of 112 preterm infants (gestational age < or =34 weeks), and those in peripheral blood of 30 preterm infants on days 7, 14, 21 and 28. The median value for the sTNFR-I was significantly elevated in 33 infants with CAM at stage 3 (4618 pg/mL) compared with the 52 infants without CAM (2866 pg/mL), or the 13 infants with CAM at stage 1 (3638 pg/mL) and the 14 infants at stage 2 (3242 pg/mL). The severity of CAM is an independent factor for the elevation of cord blood sTNFR-I. The sTNFR-I level on day 0 was significantly higher in eight infants with CAM at stage 3 than in the 22 infants without CAM or with CAM at stage 1 and 2; however there were no significant differences on days 7, 14, 21 and 28. The serum level of sTNFR-I showed a significant gradual decline with time. We suggest that there is an association between elevated sTNFR-I levels in cord blood and maternal CAM, and this elevation may reflect the fetal inflammation. However the elevation of sTNFR-I could not persist postnatally for a long time.

Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

Science.gov (United States)

Lin, Marie C; Lee, Nikki P; Zheng, Ning; Yang, Pai-Hao; Wong, Oscar G; Kung, Hsiang-Fu; Hui, Chee-Kin; Luk, John M; Lau, George Ka-Kit

2005-01-01

AIM: To compare the gene expression profile in a pair of HBV-infected twins. METHODS: The gene expression profile was compared in a pair of HBV-infected twins. RESULTS: The twins displayed different disease outcomes. One acquired natural immunity against HBV, whereas the other became a chronic HBV carrier. Eighty-eight and forty-six genes were found to be up- or down-regulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RT-PCR. However, upon HBV core antigen stimulation, TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+ channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins. CONCLUSION: TNF-αIP1 may play a role in the innate immunity against HBV. PMID:16437679

Tumor Necrosis Factor-Alpha in Peripical Tissue Exudates of Teeth with Apical Periodontitis

Directory of Open Access Journals (Sweden)

Sonja Pezelj-Ribaric

2007-01-01

Full Text Available Aim. The aim of this study was to determine tumor necrosis factor-alpha (TNF-α levels in periapical exudates and to evaluate their relationship with radiological findings. Methodology. Periapical exudates were collected from root canals of 60 single-rooted teeth using absorbent paper points. TNF-α levels were determined by enzyme-linked immunosorbent assays. The samples were divided into three groups according to the periapical radiolucent area. Results. Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentrations in control group (40, 57±28, 15 pg/mL and group with larger radiolucent areas (2365, 79±582, 95 pg/mL, as well as between control and canals with small radiolucent areas (507, 66±278, 97 (P<.05. Conclusions. The levels of TNF-α increase significantly in teeth with periapical pathosis, from smaller to bigger lesions. This research and its results have shown that objective analysis of the TNF-α levels enables establishment of a relationship between different concentrations of TNF-α and different radiological changes.

Protective specific immunity induced by cyclophosphamide plus tumor necrosis factor alpha combination treatment of EL4-lymphoma-bearing C57BL/6 mice.

Science.gov (United States)

Krawczyk, C M; Verstovsek, S; Ujházy, P; Maccubbin, D; Ehrke, M J

1995-06-01

A combination treatment protocol initiated 12 days after tumor injection, when the tumor was large, by administering cyclophosphamide (CY, 150 or 250 mg/kg) intraperitoneally followed by intravenous tumor necrosis factor alpha (TNF alpha, 1000 units injection) on days 13, 16, 18, 21, and 23, resulted in about 60% long-term survival (i.e., survival for at least 60 days) in the syngeneic C57BL/6 mouse/EL4 lymphoma model system. The establishment of a specific antitumor immune memory and its possible therapeutic relevance was verified by reinjecting 60-day survivors with EL4 cells; all 60-day survivors that had received the combination treatments rejected the implants and survived for a further 60 days. Thymic cellularity was reduced during treatment and its recovery appeared to correlate with long-term survival and immunity. Thymocytes from mice treated with the combination were found to express significant levels of specific anti-EL4 cytolytic activity following a 4-day stimulation culture with X-irradiated EL4 cells and low concentrations of interleukin-2. This response could not be generated with thymocytes from naive animals. In each case the effect seen with the combination of a moderate CY dose (150 mg/kg) with TNF alpha was better than that seen with either dose of CY alone and equal to or better than that seen with the higher dose of CY combined with TNF alpha. These results indicate that treatment with a single moderate dose of CY in combination with TNF alpha is effective against a large, established tumor in this murine model. Furthermore, all the long-term survivors induced by this treatment developed protective immunity against reimplanted tumor and demonstrated a long-term specific immune memory in the thymus.

Intermitted pharmacologic pretreatment by xenon, isoflurane, nitrous oxide, and the opioid morphine prevents tumor necrosis factor alpha-induced adhesion molecule expression in human umbilical vein endothelial cells

NARCIS (Netherlands)

Weber, Nina C.; Kandler, Jennis; Schlack, Wolfgang; Grueber, Yvonne; Frädorf, Jan; Preckel, Benedikt

2008-01-01

BACKGROUND: The barrier properties of the endothelium are of critical importance during pathophysiologic processes. These barrier properties depend on an intact cytoskeleton and are regulated by cell adhesion molecules. Tumor necrosis factor alpha (TNF-alpha) is known to induce cell adhesion

Supernatants from Staphylococcus epidermidis grown in the presence of different antibiotics induce differential release of tumor necrosis factor alpha from human monocytes.

OpenAIRE

Mattsson, E; Van Dijk, H; Verhoef, J; Norrby, R; Rollof, J

1996-01-01

Bacterial products from gram-positive bacteria, such as peptidoglycan, teichoic acid, and toxins, activate mononuclear cells to produce tumor necrosis factor alpha (TNF). The present study evaluated the release of soluble cell wall components from Staphylococcus epidermidis capable of inducing TNF after exposure of the bacteria to various antibiotics. A clinical S. epidermidis isolate (694) was incubated with either penicillin, oxacillin, vancomycin, or clindamycin at five times the MIC. Supe...

Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery.

Science.gov (United States)

Lu, Alex Y; Turban, Jack L; Damisah, Eyiyemisi C; Li, Jie; Alomari, Ahmed K; Eid, Tore; Vortmeyer, Alexander O; Chiang, Veronica L

2017-08-01

OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.

Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.

Science.gov (United States)

Aggarwal, Bharat B; Gupta, Subash C; Kim, Ji Hye

2012-01-19

Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.

The tumor necrosis factor alpha - 308G>A polymorphism is associated with dementia in the oldest-old

DEFF Research Database (Denmark)

Bruunsgaard, Helle; Benfield, Thomas L; Andersen-Ranberg, Karen

2004-01-01

OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One...... was investigated (Fischer exact test). Furthermore, whether the TNF -308 G>A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-alpha (analysis of variance), and mortality in the following 5 years (Cox regression analysis) within the cohort...... higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype. CONCLUSION: It is possible that the TNF -308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory...

Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta

DEFF Research Database (Denmark)

Issazadeh-Navikas, Shohreh; Ljungdahl, A; Höjeberg, B

1995-01-01

in cryosections of spinal cords using in situ hybridization technique with synthetic oligonucleotide probes. Three stages of cytokine mRNA expression could be distinguished: (i) interleukin (IL)-12, tumor necrosis factor (TNF)-beta (= lymphotoxin-alpha) and cytolysin appeared early and before onset of clinical...... signs of EAE; (ii) TNF-alpha peaked at height of clinical signs of EAE; (iii) IL-10 appeared increasingly at and after clinical recovery. The early expression of IL-12 prior to the expression of interferon-gamma (IFN-gamma) mRNA shown previously is consistent with a role of IL-12 in promoting...... proliferation and activation of T helper 1 (Th1) type cells producing IFN-gamma. The TNF-beta mRNA expression prior to onset of clinical signs favours a role for this cytokine in disease initiation. A pathogenic effector role of TNF-alpha was suggested from these observations that TNF-alpha mRNA expression...

Mechanisms of tumor necrosis in photodynamic therapy with a chlorine photosensitizer: experimental studies

Science.gov (United States)

Privalov, Valeriy A.; Lappa, Alexander V.; Bigbov, Elmir N.

2011-02-01

A photodynamic therapy experiment on 118 inbred white mice with transplanted Ehrlich's tumor (mouse mammary gland adenocarcinoma) is performed to reveal mechanisms of necrosis formation. In 7-10 days the tumor of 1-1.5 cm diameter is formed under skin at the injection point, and PDT procedure is applied. There were used a chlorine type photosensitizer RadachlorineTM and 662 nm wavelength diode laser. The drug is injected by intravenously at the dose of 40 mg/kg; the irradiation is executed in 2-2.5 hours at the surface dose of about 200 J/cm2. Each of the mice had a photochemical reaction in form of destructive changes at the irradiation region with subsequent development of dry coagulation necrosis. After rejection of the necrosis there occurred epithelization of defect tissues in a tumor place. Histological investigations were conducted in different follow-up periods, in 5 and 30 min, 1, 3, 6, and 12 hours, 1, 3, 7 and 28 days after irradiation. They included optical microscopy, immune marker analysis, morphometry with measurements of volume density of epithelium, tumor stroma and necroses, vascular bed. The investigations showed that an important role in damaging mechanisms of photodynamic action belongs to hypoxic injuries of tumor mediated by micro vascular disorders and blood circulatory disturbances. The injuries are formed in a few stages: microcirculation angiospasm causing vessel paresis, irreversible stases in capillaries, diapedetic hemorrhages, thromboses, and thrombovasculitis. It is marked mucoid swelling and fibrinoid necrosis of vascular tissue. Progressive vasculitises result in total vessel obliteration and tumor necrosis.

Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL Combination Therapy.

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Pi Chu Liu

Full Text Available Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5 in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

Infections and treatment of patients with rheumatic diseasesTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

DEFF Research Database (Denmark)

Atzeni, F.; Bendtzen, K.; Bobbio-Pallavicini, F.

2008-01-01

/inflammatory conditions, and current therapies have the aim of providing adequate (low) compensatory doses, the timing of GC administration, such as during the nocturnal turning-on phase of tumour necrosis factor (TNF) secretion, can be extremely important. The use of the lowest possible GC dose, at night......, and for the shortest possible time should therefore greatly reduce the risk of infections. Infection is a major co-morbidity in rheumatoid arthritis (RA), and conventional disease-modifying anti-rheumatic drugs (DMARDs) can increase the risk of their occurrence, including tuberculosis. TNF-alpha plays a key role...

Regulatory role of tumor necrosis factor receptor-associated factor 6 in breast cancer by activating the protein kinase B/glycogen synthase kinase 3β signaling pathway.

Science.gov (United States)

Shen, Hongyu; Li, Liangpeng; Yang, Sujin; Wang, Dandan; Zhou, Siying; Chen, Xiu; Tang, Jinhai

2017-08-01

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll‑like/interleukin‑1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription‑quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki‑67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor β‑activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF‑7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3β phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6‑TAK1 axis and its corresponding downstream AKT/GSK3β signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer.

Cost of tumor necrosis factor blockers per patient with rheumatoid arthritis in a multistate Medicaid population

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Bonafede M

2014-09-01

Full Text Available Machaon Bonafede,1 George J Joseph,2 Neel Shah,2 Nicole Princic,1 David J Harrison2 1Truven Health Analytics, Cambridge, MA, 2Amgen Inc., Thousand Oaks, CA, USA Background: The purpose of this study was to estimate the annual cost per treated patient for the tumor necrosis factor (TNF blockers, etanercept, adalimumab, and infliximab in rheumatoid arthritis (RA patients covered by Medicaid. Methods: The MarketScan Medicaid Multistate Database was used to identify adult RA patients who used etanercept, adalimumab, or infliximab (index agents from 2007 to 2011. The index date was the first claim preceded by 180 days and followed by 360 days of continuous enrollment. Patients with other conditions for which these agents are approved by the US Food and Drug Administration were excluded. “Continuing” patients had one or more pre-index claim for their index biologic, and "new" patients did not. Cost per treated patient was calculated in the 360 day post-index period for each index agent as the total index drug and administration cost to the payer and the costs of switched-to agents divided by the number of patients who received the index agent. Results: A total of 1,085 patients met the study criteria. Forty-eight percent received etanercept (n=521; 37% received adalimumab (n=405; and 15% received infliximab (n=159. Patient characteristics were similar across groups (mean age 47.4 years, 83% female. The annual cost per treated patient was lowest for etanercept ($18,466, followed by adalimumab ($20,983 and infliximab ($26,516. For all agents, annual costs were lower for new patients ($17,996 for etanercept, $18,992 for adalimumab, and $24,756 for infliximab than for continuing patients ($19,004 for etanercept, $24,438 for adalimumab, and $28,127 for infliximab. Conclusion: Etanercept had lower costs per treated patient than adalimumab or infliximab in both new and continuing Medicaid enrollees with RA. Keywords: cost, tumor necrosis factor

Tumor necrosis factor α triggers proliferation of adult neural stem cells via IKK/NF-κB signaling

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Kaltschmidt Christian

2006-09-01

Full Text Available Abstract Background Brain inflammation has been recognized as a complex phenomenon with numerous related aspects. In addition to the very well-described neurodegenerative effect of inflammation, several studies suggest that inflammatory signals exert a potentially positive influence on neural stem cell proliferation, migration and differentiation. Tumor necrosis factor alpha (TNF-α is one of the best-characterized mediators of inflammation. To date, conclusions about the action of TNF on neural stem or progenitor cells (NSCs, NPCs have been conflicting. TNF seems to activate NSC proliferation and to inhibit their differentiation into NPCs. The purpose of the present study was to analyze the molecular signal transduction mechanisms induced by TNF and resulting in NSC proliferation. Results Here we describe for the first time the TNF-mediated signal transduction cascade in neural stem cells (NSCs that results in increased proliferation. Moreover, we demonstrate IKK-α/β-dependent proliferation and markedly up-regulated cyclin D1 expression after TNF treatment. The significant increase in proliferation in TNF-treated cells was indicated by increased neurosphere volume, increased bromodeoxyuridin (BrdU incorporation and a higher total cell number. Furthermore, TNF strongly activated nuclear factor-kappa B (NF-κB as measured by reporter gene assays and by an activity-specific antibody. Proliferation of control and TNF-treated NSCs was strongly inhibited by expression of the NF-κB super-repressor IκB-AA1. Pharmacological blockade of IκB ubiquitin ligase activity led to comparable decreases in NF-κB activity and proliferation. In addition, IKK-β gene product knock-down via siRNA led to diminished NF-κB activity, attenuated cyclin D1 expression and finally decreased proliferation. In contrast, TGFβ-activated kinase 1 (TAK-1 is partially dispensable for TNF-mediated and endogenous proliferation. Understanding stem cell proliferation is crucial

Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

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Choi, Yoon Seok; Jung, Min Kyung; Lee, Jeewon; Choi, Seong Jin; Choi, Sung Hoon; Lee, Hyun Woong; Lee, Jong-Joo; Kim, Hyung Joon; Ahn, Sang Hoon; Lee, Dong Hyeon; Kim, Won; Park, Su-Hyung; Huh, Jun R; Kim, Hyoung-Pyo; Park, Jun Yong; Shin, Eui-Cheol

2018-03-01

CD4 + CD25 + Foxp3 + T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4 + CD25 + Foxp3 + ) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORγt inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. A higher proportion of CD4 + CD25 + Foxp3 + Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. Treg cells from patients with AHA have altered functions compared with Treg cells from healthy

Serum Levels of Anticyclic Citrullinated Peptide Antibodies, Interleukin-6, Tumor Necrosis Factor-α, and C-Reactive Protein Are Associated with Increased Carotid Intima-Media Thickness: A Cross-Sectional Analysis of a Cohort of Rheumatoid Arthritis Patients without Cardiovascular Risk Factors

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Vázquez-Del Mercado, Mónica; Nuñez-Atahualpa, Lourdes; Figueroa-Sánchez, Mauricio; Gómez-Bañuelos, Eduardo; Rocha-Muñoz, Alberto Daniel; Martín-Márquez, Beatriz Teresita; Martínez-García, Erika Aurora; Macias-Reyes, Héctor; Gamez-Nava, Jorge Ivan; Navarro-Hernandez, Rosa Elena; Nuñez-Atahualpa, María Alejandra; Andrade-Garduño, Javier

2015-01-01

The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients. Methods. Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Results. The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNFα (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03). Conclusions. Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events. PMID:25821796

Serum Levels of Anticyclic Citrullinated Peptide Antibodies, Interleukin-6, Tumor Necrosis Factor-α, and C-Reactive Protein Are Associated with Increased Carotid Intima-Media Thickness: A Cross-Sectional Analysis of a Cohort of Rheumatoid Arthritis Patients without Cardiovascular Risk Factors

Directory of Open Access Journals (Sweden)

Mónica Vázquez-Del Mercado

2015-01-01

Full Text Available The main cause of death in rheumatoid arthritis (RA is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP antibody levels with increased carotid intima-media thickness (cIMT in RA patients. Methods. Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC were studied. All groups were assessed for atherogenic index of plasma (AIP and cIMT. Anti-CCP, C-reactive protein (CRP, and levels of tumor necrosis factor alpha (TNFα and interleukin-6 (IL-6 were measured by enzyme-linked immunosorbent assay (ELISA. Results. The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P<0.001. Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P<0.01, and lower levels of high density lipoprotein cholesterol (HDL-c (P=0.02. The cIMT correlated with levels of anti-CCP (r=0.513, P=0.001, CRP (r=0.799, P<0.001, TNFα (r=0.642, P=0.001, and IL-6 (r=0.751, P<0.001. In multiple regression analysis, cIMT was associated with CRP (P<0.001 and anti-CCP levels (P=0.03. Conclusions. Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.

Tumor necrosis factor (TNF-alpha) and C-reactive protein (CRP) are positively associated with the risk of chronic kidney disease in patients with type 2 diabetes.

Science.gov (United States)

Yeo, Eun-Sil; Hwang, Ji-Yun; Park, Ji Eun; Choi, Young Ju; Huh, Kap Bum; Kim, Wha Young

2010-07-01

Chronic low-grade inflammation may induce chronic kidney disease in patients with type 2 diabetes. This study investigated the relation between inflammatory biomarkers and chronic kidney disease in patients with type 2 diabetes, which has not yet been reported in Asian populations. A cross-sectional study was performed in 543 patients recruited from diabetic clinics for an ongoing, prospective study. Multivariate logistic regression was used to evaluate the association between inflammatory biomarkers and the presence of chronic kidney disease (estimated glomerular filtration rate Disease equation using plasma creatinine). The risk of chronic kidney disease increased in the highest quartiles of C-reactive protein (CRP) [multivariate odds ratio (OR) = 3.73; 95% CI = 1.19-1.70] and tumor necrosis factor-alpha (multivariate OR = 4.45; 95% CI = 1.63-12.11) compared to the lowest quartiles after adjustments for age, sex, zinc intake, and other putative risk factors for chronic kidney disease. Our results suggest that CRP and tumor necrosis factor-alpha may be independent risk factors for chronic kidney disease in patients with type 2 diabetes. A causal mechanism of this association should be evaluated in a followup study of Korean patients with type 2 diabetes.

Reactivation of pulmonary tuberculosis (TBC) with the use of antagonist of the tumor necrosis factor alpha (FNTα) in rheumatoid arthritis: On purpose of a case

International Nuclear Information System (INIS)

Martinez V, Jose B; Medina V, Yimy F; Parga, Roberto; Restrepo, Jose Felix; Iglesias G, Antonio; Rondon, Federico

2005-01-01

Woman 56 years old, with history of rheumatoid arthritis who develops reactivation of pulmonary tuberculosis (TBC) after 1 year of treatment with biological therapy (antagonist of the tumor necrosis factor alpha). It is discussed pathophysiologic mechanisms, diagnostic approach, treatment of TBC and some recommendations for the use of biological therapy in patients with rheumatic disease

Model-Based Radiation Dose Correction for Yttrium-90 Microsphere Treatment of Liver Tumors With Central Necrosis

International Nuclear Information System (INIS)

Liu, Ching-Sheng; Lin, Ko-Han; Lee, Rheun-Chuan; Tseng, Hsiou-Shan; Wang, Ling-Wei; Huang, Pin-I; Chao, Liung-Sheau; Chang, Cheng-Yen; Yen, Sang-Hue; Tung, Chuan-Jong; Wang, Syh-Jen; Oliver Wong, Ching-yee; Liu, Ren-Shyan

2011-01-01

Purpose: The objectives of this study were to model and calculate the absorbed fraction φ of energy emitted from yttrium-90 ( 90 Y) microsphere treatment of necrotic liver tumors. Methods and Materials: The tumor necrosis model was proposed for the calculation of φ over the spherical shell region. Two approaches, the semianalytic method and the probabilistic method, were adopted. In the former method, the range--energy relationship and the sampling of electron paths were applied to calculate the energy deposition within the target region, using the straight-ahead and continuous-slowing-down approximation (CSDA) method. In the latter method, the Monte Carlo PENELOPE code was used to verify results from the first method. Results: The fraction of energy, φ, absorbed from 90 Y by 1-cm thickness of tumor shell from microsphere distribution by CSDA with complete beta spectrum was 0.832 ± 0.001 and 0.833 ± 0.001 for smaller (r T = 5 cm) and larger (r T = 10 cm) tumors (where r is the radii of the tumor [T] and necrosis [N]). The fraction absorbed depended mainly on the thickness of the tumor necrosis configuration, rather than on tumor necrosis size. The maximal absorbed fraction φ that occurred in tumors without central necrosis for each size of tumor was different: 0.950 ± 0.000, and 0.975 ± 0.000 for smaller (r T = 5 cm) and larger (r T = 10 cm) tumors, respectively (p 90 Y microsphere treatment of hepatic tumors with central necrosis. With this model, important information is provided regarding the absorbed fraction applicable to clinical 90 Y microsphere treatment.

A matrix of cholesterol crystals, but not cholesterol alone, primes human monocytes/macrophages for excessive endotoxin-induced production of tumor necrosis factor-alpha. Role in atherosclerotic inflammation?

DEFF Research Database (Denmark)

Bendtzen, Klaus; Christensen, Ole; Nielsen, Claus Henrik

2014-01-01

When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower...

HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia

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Mishra Ritu

2012-06-01

Full Text Available Abstract Background HIV-1 Tat protein is known to be associated with neuroinflammation, a condition that develops in almost half of patients infected with HIV-1. HIV-1 Tat can alter glial neuroprotective functions, leading to neurotoxicity within the CNS. HIV-1 Tat is known to be secreted from productively infected cells and can affect neighboring uninfected cells by modulating cellular gene expression in a bystander fashion. Methods We were interested to study whether exogenous exposure to HIV-1 Tat-C protein perturbs the microRNA (miRNA expression profile of human microglial cells, leading to altered protein expression. We used protein expression and purification, miRNA overexpression, miRNA knockdown, transfection, site-directed mutagenesis, real-time PCR, luciferase assay and western blotting techniques to perform our study. Results HIV-1 Tat-C treatment of human microglial cells resulted in a dose-dependent increase in miR-32 expression. We found that tumor necrosis factor-receptor–associated factor 3 TRAF3 is a direct target for miR-32, and overexpression of miR-32 in CHME3 cells decreased TRAF3 both at the mRNA and the protein level. Recovery of TRAF3 protein expression after transfection of anti-miR-32 and the results of the luciferase reporter assay provided direct evidence of TRAF3 regulation by miR-32. We found that the regulation of interferon regulatory factor 3 (IRF3 and IRF7 is controlled by cellular levels of TRAF3 protein in microglial cells, as after overexpression of miR-32 and application of anti-miR-32, expression levels of IRF3 and IRF7 were inversely regulated by expression levels of TRAF3. Thus, our results suggest a novel miRNA mediated mechanism for regulation of TRAF3 in human microglial cells exposed to HIV-1 Tat C protein. These results may help to elucidate the detrimental neuroinflammatory consequences of HIV-1 Tat C protein in bystander fashion. Conclusion HIV-1 Tat protein can modulate TRAF3 expression through

Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate resistant polycystic ovary disease

OpenAIRE

Seyam, Emaduldin; Hasan, Momen; Khalifa, Eissa M.; Ramadan, Ahmad; Hefzy, Enas

2017-01-01

Objective: The aim of this work was to investigate the level of the serum level of tumor necrosis factor alpha (TNF-α) as an inflammatory biomarker in lean and obese women with polycystic ovary disease (PCOD), who are resistant to clomiphene citrate (CCR-PCOD). Patients and design: It is a case controlled study, where one hundred and fifty (n = 150) PCOD women (study group), who are resistant to clomiphene citrate (CCR-PCOD) had been recruited, in addition to one hundred (n = 100) women wi...

Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt

DEFF Research Database (Denmark)

Trebicka, Jonel; Krag, Aleksander; Gansweid, Stefan

2011-01-01

In cirrhosis portal hypertension can promote bacterial translocation and increase serum endotoxin levels. Vice versa, endotoxin aggravates portal hypertension by induction of systemic and splanchnic vasodilation, and by triggering hepatic inflammatory response via tumor necrosis factor α (TNFα......). However, the hepatic elimination of endotoxin in cirrhotic patients with severe portal hypertension, in the absence of acute complications, has not been investigated so far....

How real is the long-lasting effect of tumor necrosis factor α inhibitors? Focus on immunogenicity

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D.E. Karateev

2014-01-01

Full Text Available Tumor necrosis factor (TNF α inhibitors are the most commonly used agents to treat rheumatoid arthritis (RA and other inflammatory arthropathies. Five drugs belonging to the family of TNFα inhibitors have been certified in Russia for treating RA: infliximab (INF, adali- mumab (ADA, golimumab, certolizumab pegol, and etanercept (ETN. These drugs have different compositions. ETN does not belong to the family of monoclonal antibodies (mAbs and has a different mechanism of action. It is a dimeric molecule of synthetic fusion protein contain- ing TNF receptor and bound to the Fc-fragment of human Ig1. ETN can inhibit both TNFα and lymphotoxin α. ETN contains only the pro- tein identical to human protein. All TNFα inhibitors exhibit a virtually identical anti-inflammatory activity. The data from the registries show that the risk of discontinuation of therapy with TNFα during the first 2–3 years is appreciably high; there is a trend toward increased frequency of therapy discontinuation because of loss of effectiveness. It was found that the risk of therapy discontinuation because of insufficient effectiveness and adverse events (AEs is minimal for ETN and maximal for INF. The structure of biological drugs (which also affects their immunogenicity has the key neg- ative effect on maintaining the response to therapy and frequency of AEs. However, since ETN is a fusion molecule and contains less poten- tially immunogenic epitopes compared to mAbs, the frequency of detecting anti-drug antibodies (ADAbs is appreciably lower. The fact that ETN has a lower immunogenicity can be used to explain the significantly lower probability of discontinuing therapy using this drug as compared to INF and ADA. The risk that the need to increase the dose because of gradual loss of effectiveness of therapy with ADA and INF, was 4.9- and 28-fold higher, respectively, as compared to ETN. Therapeutic algorithms make it possible to control therapy with TGFα inhibitors

How real is the long-lasting effect of tumor necrosis factor α inhibitors? Focus on immunogenicity

Directory of Open Access Journals (Sweden)

D.E. Karateev

2014-05-01

Full Text Available Tumor necrosis factor (TNF α inhibitors are the most commonly used agents to treat rheumatoid arthritis (RA and other inflammatory arthropathies. Five drugs belonging to the family of TNFα inhibitors have been certified in Russia for treating RA: infliximab (INF, adali- mumab (ADA, golimumab, certolizumab pegol, and etanercept (ETN. These drugs have different compositions. ETN does not belong to the family of monoclonal antibodies (mAbs and has a different mechanism of action. It is a dimeric molecule of synthetic fusion protein contain- ing TNF receptor and bound to the Fc-fragment of human Ig1. ETN can inhibit both TNFα and lymphotoxin α. ETN contains only the pro- tein identical to human protein. All TNFα inhibitors exhibit a virtually identical anti-inflammatory activity. The data from the registries show that the risk of discontinuation of therapy with TNFα during the first 2–3 years is appreciably high; there is a trend toward increased frequency of therapy discontinuation because of loss of effectiveness. It was found that the risk of therapy discontinuation because of insufficient effectiveness and adverse events (AEs is minimal for ETN and maximal for INF. The structure of biological drugs (which also affects their immunogenicity has the key neg- ative effect on maintaining the response to therapy and frequency of AEs. However, since ETN is a fusion molecule and contains less poten- tially immunogenic epitopes compared to mAbs, the frequency of detecting anti-drug antibodies (ADAbs is appreciably lower. The fact that ETN has a lower immunogenicity can be used to explain the significantly lower probability of discontinuing therapy using this drug as compared to INF and ADA. The risk that the need to increase the dose because of gradual loss of effectiveness of therapy with ADA and INF, was 4.9- and 28-fold higher, respectively, as compared to ETN. Therapeutic algorithms make it possible to control therapy with TGFα inhibitors

(+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells

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Choi, Hyeon-Jae; Lee, Jin-Hwee [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Jung, Yi-Sook, E-mail: yisjung@ajou.ac.kr [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 443-749 (Korea, Republic of)

2014-05-02

Highlights: • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced TARC and MDC expression in HaCaT cells. • PKCζ, p38 MAPK, or NF-κB mediate TNF-α/IFN-γ-induced TARC and MDC expression. • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced activation of PKCζ, p38 MAPK, or NF-κB. • (+)-Nootkatone suppresses chemokine expression by inhibiting of PKCζ and p38 pathways. - Abstract: Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.

Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors.

Science.gov (United States)

Pontejo, Sergio M; Alejo, Ali; Alcami, Antonio

2015-06-26

The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Effects of Tumor Necrosis Factor Blocker on Salicylate-Induced Tinnitus in Mice.

Science.gov (United States)

Hwang, Juen-Haur; Huang, David Chang-Wei; Lu, Yin-Chang; Yang, Wei-Shiung; Liu, Tien-Chen

2017-06-01

Neuroinflammation is considered a novel mechanism for acute tinnitus. Here, we investigated the effects of a tumor necrosis factor (TNF) blocker on the gene expression of inflammatory-cytokine in the cochlea in a tinnitus animal model. Enbrel® (30 mg/kg, intraperitoneally (i.p.)) were administrated to the mice with the salicylate induced tinnitus for 3 days. Tinnitus score and mRNA expression levels of TNFR1, TNFR2, and N-methyl-d-aspartate receptor subunit 2B (NR2B) and its downstream regulatory element antagonist modulator (DREAM) in the cochlea of mice were measured and compared to the control. The tinnitus score significantly decreased in the Enbrel® treated group. The mRNA levels of both TNFR1 and TNFR2 were significantly lower in the treatment than in the control group. The mRNA levels of NR2B and DREAM followed a similar trend. we found that treatment with 30 mg/ kg Enbrel® decreased salicylate-induced behavior associated with tinnitus and reduced the mRNA expression levels of TNFR1/R2, NR2B, and DREAM in the cochlea of mice. These findings supported the hypothesis that neuroinflammation might be a novel mechanism for salicylate-induced tinnitus.

Predisposing Factors of Liver Necrosis after Transcatheter Arterial Chemoembolization in Liver Metastases from Neuroendocrine Tumor

Energy Technology Data Exchange (ETDEWEB)

Joskin, Julien, E-mail: j.joskin@gmail.com; Baere, Thierry de, E-mail: Thierry.DEBAERE@igr.fr [Institut Gustave Roussy, Department of Interventional Radiology (France); Auperin, Anne, E-mail: Anne.AUPERIN@igr.fr [Institut Gustave Roussy, Department of Epidemiology (France); Tselikas, Lambros, E-mail: lambros.tselikas@gmail.com; Guiu, Boris, E-mail: boris.guiu@chu-dijon.fr; Farouil, Geoffroy, E-mail: g.farouil@gmail.com [Institut Gustave Roussy, Department of Interventional Radiology (France); Boige, Valérie, E-mail: boige@igr.fr; Malka, David, E-mail: david.malka@igr.fr [Institut Gustave Roussy, Department of Digestive Oncology (France); Leboulleux, Sophie, E-mail: sophie.leboulleux@igr.fr [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Ducreux, Michel, E-mail: ducreux@igr.fr [Institut Gustave Roussy, Department of Digestive Oncology (France); Baudin, Eric, E-mail: baudin@igr.fr [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Deschamps, Frédéric, E-mail: frederic.deschamps@igr.fr [Institut Gustave Roussy, Department of Interventional Radiology (France)

2015-04-15

PurposeTo investigate predictive factors for liver necrosis after transcatheter arterial chemoembolization (TACE) of neuroendocrine liver metastases.MethodsA total of 164 patients receiving 374 TACE were reviewed retrospectively to analyze predictive factors of liver necrosis. We analyzed patient age and sex; metastasis number and location; percentage of liver involvement; baseline liver function test; and pretreatment imaging abnormalities such as bile duct dilatation (BDD), portal vein narrowing (PVN), and portal vein thrombosis (PVT). We analyzed TACE technique such as Lipiodol or drug-eluting beads (DEB) as the drug’s vector; dose of chemotherapy; diameter of DEB; and number, frequency, and selectivity of TACE.ResultsLiver necrosis developed after 23 (6.1 %) of 374 TACE. In multivariate analysis, DEB > 300 μm in size induced more liver necrosis compared to Lipiodol (odds ratio [OR] 35.20; p < 0.0001) or with DEB < 300 μm in size (OR 19.95; p < 0.010). Pretreatment BDD (OR 119.64; p < 0.0001) and PVT (OR 9.83; p = 0.030) were predictive of liver necrosis. BDD or PVT responsible for liver necrosis were present before TACE in 59 % (13 of 22) and were induced by a previous TACE in 41 % (9 of 22) of cases.ConclusionDEB > 300 μm in size, BDD, and PVT are responsible for increased rate of liver necrosis after TACE. Careful analysis of BDD or PVT on pretreatment images as well as images taken between two courses can help avoid TACE complications.

Modified model of VX2 tumor overexpressing vascular endothelial growth factor.

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Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre

2012-06-01

To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (ρ = .883, P = .012). The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

Ionizing radiation induced production of tumor necrosis factor α in the Ewing's sarcoma cell line RM 82 in vitro and in vivo

International Nuclear Information System (INIS)

Ruebe, C.; Schaefer, K.L.; Dockhorn-Dworniczak, B.; Willich, N.

1997-01-01

Aim: The expression of cytokines plays an important role in the transmission of the effects of ionizing radiation to tumor cells and normal tissue. Tumor necrosis factor alpha (TNF α), a pleiotropic monokine, is of special interest because of its cytotoxic effect on tumor cells and the induction of hemorrhagic necrosis in tumors. We examined the influence of ionizing radiation on TNF α production in a human Ewing's sarcoma cell line in vitro and in vivo. Methods: The protein and mRNA levels of the Ewing's sarcoma cell line RM 82 were examined in vitro with 'Enhanced Amplified Sensitivity Immunoassay' (EASIA) and semiquantitative RT-PCR before and after treatment with single doses of 2 to 40 Gy, 1 to 72 hours after irradiation. After successful transplantation to nude mice, the time and dose correlation of TNF α mRNA production was examined in vivo. Results: In vitro, RM 82 had a basal protein level of TNF α of 20.1 ± 4.3 pg/ml/10 6 cells. We observed a time- and dose-dependent increase of TNF α expression with a maximum of 125 pg/ml/10 6 (5.9fold) 24 hours after irradiation with 20 Gy. At the mRNA level, the maximal up-regulation occurred 6 to 12 hours after 10 Gy. In vivo, the xenograft tumor maintained the capacity of TNF α expression. Time- and dose-dependency in mRNA production showed a maximum increase 6 hours after treatment with 10 Gy. (orig.) [de

An update on anti-TNF agents in ulcerative colitis

NARCIS (Netherlands)

Samaan, Mark A.; Bagi, Preet; Vande Casteele, Niels; D'Haens, Geert R.; Levesque, Barrett G.

2014-01-01

Anti-tumor necrosis factor-α agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their

Effect of ascorbic acid and alpha-tocopherol supplementations on serum leptin, tumor necrosis factor alpha, and serum amyloid A levels in individuals with type 2 diabetes mellitus

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Mostafa Jamalan

2015-10-01

Full Text Available Objective: Diabetes mellitus Type 2 is one of the most widespread chronic metabolic diseases. In most cases, this type of diabetes is associated with alterations in levels of some inflammatory cytokines and hormones. Considering anti-inflammatory properties of plant extracts rich in ascorbic acid (vitamin C and alpha-tocopherol (vitamin E, anti-diabetic properties of these two well-known antioxidant vitamins were investigated through measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP, insulin, leptin, tumor necrosis factor alpha (TNF-α, and serum amyloid A (SAA in patients with diabetes mellitus type 2. Methods: Male patients (n=80 were randomly divided into two groups each consisted of 40 subjects. Test groups were supplemented with ascorbic acid (1000 mg/day or alpha-tocopherol (300 mg/day orally during four weeks. Before and after treatment, serum biochemical factors of subjects were measured and compared. Results: Our results showed that both ascorbic acid and alpha-tocopherol could induce significant anti-inflammatory effects by decreasing the level of inflammatory factors such as TNF-α, SAA, and hs-CRP in diabetes mellitus type 2 patients. Effects of alpha-tocopherol and ascorbic acid in decreasing serum leptin level were similar. Ascorbic acid in contrast to alpha-tocopherol diminished fasting insulin and HOMA index but had no effect on LDL serum level. Conclusion: Concerning the obtained results, it is concluded that consumption of supplementary vitamins C and E could decrease induced inflammatory response in patients with diabetes mellitus type 2.  It is also possible that vitamin C and vitamin E supplementation can attenuate incidence of some proposed pathological effects of diabetes mellitus.

11-Hydroxy-β-steroid dehydrogenase gene expression in canine adipose tissue and adipocytes: stimulation by lipopolysaccharide and tumor necrosis factor α.

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Ryan, V H; Trayhurn, P; Hunter, L; Morris, P J; German, A J

2011-10-01

The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1) is expressed in a number of tissues in rodents and humans and is responsible for the reactivation of inert cortisone into cortisol. Its gene expression and activity are increased in white adipose tissue (WAT) from obese humans and may contribute to the adverse metabolic consequences of obesity and the metabolic syndrome. The extent to which 11β-HSD-1 contributes to adipose tissue function in dogs is unknown; the aim of the present study was to examine 11β-HSD-1 gene expression and its regulation by proinflammatory and anti-inflammatory agents in canine adipocytes. Real-time PCR was used to examine the expression of 11β-HSD-1 in canine adipose tissue and canine adipocytes differentiated in culture. The mRNA encoding 11β-HSD-1 was identified in all the major WAT depots in dogs and also in liver, kidney, and spleen. Quantification by real-time PCR showed that 11β-HSD-1 mRNA was least in perirenal and falciform depots and greatest in subcutaneous, omental, and gonadal depots. Greater expression was seen in the omental depot in female than in male dogs (P=0.05). Gene expression for 11β-HSD-1 was also seen in adipocytes, from both subcutaneous and visceral depots, differentiated in culture; expression was evident throughout differentiation but was generally greatest in preadipocytes and during early differentiation, declining as cells progressed to maturity. The inflammatory mediators lipopolysaccharide and tumor necrosis factor α had a main stimulatory effect on 11β-HSD-1 gene expression in canine subcutaneous adipocytes, but IL-6 had no significant effect. Treatment with dexamethasone resulted in a significant time- and dose-dependent increase in 11β-HSD-1 gene expression, with greatest effects seen at 24 h (2 nM: approximately 4-fold; 20 nM: approximately 14-fold; P=0.010 for both). When subcutaneous adipocytes were treated with the peroxisome proliferator activated receptor γ agonist rosiglitazone

Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk.

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Li, Ming; Wang, Yinping; Gu, Yahong

2014-02-01

Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations.

Prognostic factors of tumor recurrence in completely resected non-small cell lung cancer

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Tantraworasin A

2013-06-01

Full Text Available Apichat Tantraworasin,1 Somcharean Seateang,1 Nirush Lertprasertsuke,2 Nuttapon Arreyakajohn,3 Choosak Kasemsarn,4 Jayanton Patumanond5 1General Thoracic Unit, Department of Surgery, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand; 2Department of Pathology, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand; 3Cardiovascular Thoracic Unit, Department of Surgery, Lampang Hospital, Lampang, Thailand; 4Cardiovascular Thoracic Unit, Department of Surgery, Chest Institute, Nonthaburi, Thailand; 5Department of Community Medicine, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand Background: Patients with completely resected non-small cell lung cancer (NSCLC have an excellent outcome; however tumor recurs in 30%-77% of patients. This study retrospectively analyzed the clinicopathologic features of patients with any operable stage of NSCLC to identify the prognostic factors that influence tumor recurrence, including intratumoral blood vessel invasion (IVI, tumor size, tumor necrosis, and nodal involvement. Methods: From January 2002 to December 2011, 227 consecutive patients were enrolled in this study. They were divided into two groups: the “no recurrence” group and the “recurrence” group. Recurrence-free survival was analyzed by multivariable Cox regression analysis, stratified by tumor staging, chemotherapy, and lymphatic invasion. Results: IVI, tumor necrosis, tumor diameter more than 5 cm, and nodal involvement were identified as independent prognostic factors of tumor recurrence. The hazard ratio (HR of patients with IVI was 2.1 times higher than that of patients without IVI (95% confident interval [CI]: 1.4–3.2 (P = 0.001.The HR of patients with tumor necrosis was 2.1 times higher than that of patients without tumor necrosis (95% CI: 1.3–3.4 (P = 0.001. Patients who had a maximum tumor diameter greater than 5 cm had significantly higher risk of recurrence than

Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation

Energy Technology Data Exchange (ETDEWEB)

Saber, Anne T.; Bornholdt, Jette; Dybdahl, Marianne; Sharma, Anoop K.; Vogel, Ulla; Wallin, Haakan [National Institute of Occupational Health, Copenhagen (Denmark); Loft, Steffen [Copenhagen University, Institute of Public Health, Copenhagen (Denmark)

2005-03-01

Particle-induced carcinogenicity is not well understood, but might involve inflammation. The proinflammatory cytokine tumor necrosis factor (TNF) is considered to be an important mediator in inflammation. We investigated its role in particle-induced inflammation and DNA damage in mice with and without TNF signaling. TNF-/- mice and TNF+/+ mice were exposed by inhalation to 20 mg m{sup -3} carbon black (CB), 20 mg m{sup -3} diesel exhaust particles (DEP), or filtered air for 90 min on each of four consecutive days. DEP, but not CB particles, induced infiltration of neutrophilic granulocutes into the lung lining fluid (by the cellular fraction in the bronchoalveolar lavage fluid), and both particle types induced interleukin-6 mRNA in the lung tissue. Surprisingly, TNF-/- mice were intact in these inflammatory responses. There were more DNA strand breaks in the BAL cells of DEP-exposed TNF-/- mice and CB-exposed mice compared with the air-exposed mice. Thus, the CB-induced DNA damage in BAL-cells was independent of neutrophil infiltration. The data indicate that an inflammatory response was not a prerequisite for DNA damage, and TNF was not required for the induction of inflammation by DEP and CB particles. (orig.)

Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review.

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Alijotas-Reig, Jaume; Esteve-Valverde, Enrique; Ferrer-Oliveras, Raquel; Llurba, Elisa; Gris, Josep Maria

2017-08-01

Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic

Relationship between increased serum tumor necrosis factor levels and insulin resistance in patients with essential hypertension

International Nuclear Information System (INIS)

Wang Weimin; Li Jinliang; Huang Yongqiang

2010-01-01

Objective: To investigate the relationship between serum tumor necrosis factor-α (TNF-α) levels and insulin resistance (IR) in patients with essential by pertension. Methods: Serum TNF-α and free insulin (fINS)levels were measured with RIA in 41 patients with essential hypertension and 38 controls. Insulin resistance was calculated with insulin resistance index (HOMA-IR). Results: The serum TNF-α levels were significantly higher in patients with essential hypertension than those in the controls (P<0.001). The HOMA-IR was also significantly higher in hypertension group than that in controls (P<0.001). Serum TNF-α levels was positively correlated with BMI, HOMA-IR and SBP both in hypertension group and control group (P<0.05). Conclusion: Serum TNF-α level was increased in hypertensive patients and positively correlated with obesity and IR. (authors)

Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells

Czech Academy of Sciences Publication Activity Database

Umannová, Lenka; Zatloukalová, Jiřina; Machala, M.; Krčmář, P.; Májková, Z.; Hennig, B.; Kozubík, Alois; Vondráček, Jan

2007-01-01

Roč. 99, č. 1 (2007), s. 79-89 ISSN 0388-1350 R&D Projects: GA ČR(CZ) GA524/05/0595 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : tumor necrosis factor-alpha * xenobiotic metabolizing enzymes * dioxin Subject RIV: BO - Biophysics

The repeatability of interleukin-6, tumor necrosis factor-α, and C-reactive protein in COPD patients over one year

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Umme Kolsum

2009-04-01

Full Text Available Umme Kolsum, Kay Roy, Cerys Starkey, Zoë Borrill, Nick Truman, Jørgen Vestbo, Dave SinghNorth West Lung Research Centre, University of Manchester, South Manchester University Hospitals Trust, Wythenshawe, Manchester, UKBackground: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and C-reactive protein (CRP over one year and examined the relationships between these systemic markers in COPD.Methods: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-α were measured. Repeatability was expressed by intraclass correlation coefficient (Ri and the Bland–Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits.Results: There was moderate repeatability with a very high degree of statistical significance (p ≤ 0.001 between the two visits for all the systemic biomarkers (IL-6, CRP, and TNF-α. CRP was significantly associated with IL-6 at both visits (r = 0.55, p = 0.0001, r = 0.51, p = 0.0002, respectively. There were no other significant associations between the systemic markers at either of the visits.Conclusions: Systemic inflammatory biomarkers IL-6, CRP, and TNF-α were moderately repeatable over a twelve month period in COPD patients. We have also shown that a robust and repeatable association between IL-6 and CRP exists.Keywords: interleukin-6, tumor necrosis factor-α, C-reactive protein, repeatability, COPD   

Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes

Science.gov (United States)

Li, Y. P.; Atkins, C. M.; Sweatt, J. D.; Reid, M. B.; Hamilton, S. L. (Principal Investigator)

1999-01-01

Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.

Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-a-induced epithelial-mesenchymal transition of MCF-7 cells

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R. Dong

2007-08-01

Full Text Available The microenvironment of the tumor plays an important role in facilitating cancer progression and activating dormant cancer cells. Most tumors are infiltrated with inflammatory cells which secrete cytokines such as tumor necrosis factor-a (TNF-a. To evaluate the role of TNF-a in the development of cancer we studied its effects on cell migration with a migration assay. The migrating cell number in TNF-a -treated group is about 2-fold of that of the control group. Accordingly, the expression of E-cadherin was decreased and the expression of vimentin was increased upon TNF-a treatment. These results showed that TNF-a can promote epithelial-mesenchymal transition (EMT of MCF-7 cells. Further, we found that the expression of Snail, an important transcription factor in EMT, was increased in this process, which is inhibited by the nuclear factor kappa B (NFkB inhibitor aspirin while not affected by the reactive oxygen species (ROS scavenger N-acetyl cysteine. Consistently, specific inhibition of NFkB by the mutant IkBa also blocked the TNF-a-induced upregulation of Snail promoter activity. Thus, the activation of NFkB, which causes an increase in the expression of the transcription factor Snail is essential in the TNF-a-induced EMT. ROS caused by TNF-a seemed to play a minor role in the TNF-a-induced EMT of MCF-7 cells, though ROS per se can promote EMT. These findings suggest that different mechanisms might be responsible for TNF-a - and ROS-induced EMT, indicating the need for different strategies for the prevention of tumor metastasis induced by different stimuli.

The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis.

Science.gov (United States)

Camussi, G; Lupia, E

1998-05-01

Tumour necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine which is overproduced in rheumatoid joints primarily by macrophages. This cytokine has a potential pathogenic role in the establishment of rheumatoid synovitis, in the formation of pannus tissue and in the process of joint destruction, as it increases synoviocyte proliferation and triggers a cascade of secondary mediators involved in the recruitment of inflammatory cells, in neo-angiogenesis and in the process of joint destruction. These findings made TNF alpha a potential target for anticytokine therapy. Experimental studies have shown that TNF alpha blockade by monoclonal antibodies or by soluble TNF receptor reduced the extent and severity of arthritis both in collagen-induced arthritis in mice and in transgenic mice overexpressing TNF alpha, which develop a rheumatoid-like destructive arthritis. Clinical studies based on the use of anti-TNF alpha antibodies or soluble receptors have suggested a potential beneficial effect of TNF alpha-blocking therapy in inducing amelioration of inflammatory parameters in patients with long-standing active disease. In these patients anti-TNF alpha therapy induces a rapid improvement in multiple clinical assessment of disease activity, including morning stiffness, pain score, Ritchie articular index and swollen joint count. The clinical benefits are associated with an improvement in some serological parameters, such as C-reactive protein and serum amyloid-A, erythrocyte sedimentation rate, blood cytokine levels, haemoglobin, white cells and platelet counts, rheumatoid factor titre and histological features of the synovium. However, it remains to be determined whether anti-TNF alpha therapy may be useful in the long term management of rheumatoid patients and in the achievement of better outcomes of disease. Because TNF alpha production also serves a specific function in host defence against infections and tumours, the adverse effects of long term anti-TNF alpha

Magnetic resonance imaging for differentiating of torsion of the ovarian tumor with or without necrosis

International Nuclear Information System (INIS)

Kim, Jong Wook; Lee, Young Rae; Park, Hae Won

2000-01-01

The purpose of this study is to determine whether MRI is helpful for differentiating torsion of ovarian tumor, with or without necrosis. We retrospectively evaluated the MRI findings of nine patients with surgically confirmed torsion of the ovarian tumor, comparing them with the surgical and pathologic findings. The MRI findings were analyzed for contrast enhancement of twisted tumor, and the presence, signal intensity and contrast enhancement of twisted vascular pedicle. In all nine patients, MRI revealed a twisted vascular pedicle. Six patients with necrotic ovaries showed either no enhancement (n=3D4) or linear peripheral enhancement of twisted tumors (n=3D2), and lack of enhancement (n=3D5) or peripheral enhancement (n=3D1) of twisted vascular pedicles. In four of six patients with necrosis, T1-weighted MR images demonstrated a hyperintense pedicle; in three without necrosis, postcontrast T1-weighted MR images revealed well-enhanced twisted tumors (n=3D2) and twisted vascular pedicles (n=3D3). By depicting a lack of contrast enhancement and high signal intensity within a twisted vascular pedicle, MRI can help differentiate torsion of ovarian tumor with or without necrosis. (author)

Tumor necrosis factor alpha inhibits in vitro bovine embryo development through a prostaglandin mediated mechanism

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Jackson Lauren R

2012-03-01

Full Text Available Abstract Mastitis or other infectious diseases have been related to reduced fertility in cattle. Inflammatory cytokines such as tumor necrosis factor α (TNFα are released in response to infection and may have negative effects on embryo development. In the current study the effect of exposure to TNFα on the development of in vitro fertilized bovine embryos was examined. Indomethacin, a prostaglandin synthesis inhibitor, was used to determine if blockade of prostaglandin synthesis would alter the effects of TNFα. Ovaries were obtained from a local abattoir and immature COC were isolated from 2-10 mm follicles, in vitro matured and fertilized. After fertilization, groups of presumptive zygotes were randomly placed into either control development medium, medium containing 25 ng/mL TNFα or medium containing 25 ng/mL TNFα plus 1 μg/mL indomethacin. The proportion of blastocysts formed was assessed at day 7 of culture. Fewer embryos exposed to TNFα alone reached the blastocyst stage (17.5 ± 2.4%, P

Imaging Tumor Necrosis with Ferumoxytol.

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Maryam Aghighi

high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.

Phospholipase C-{delta}{sub 1} regulates interleukin-1{beta} and tumor necrosis factor-{alpha} mRNA expression

Energy Technology Data Exchange (ETDEWEB)

Chung, Eric; Jakinovich, Paul; Bae, Aekyung [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States); Rebecchi, Mario, E-mail: Mario.rebecchi@SBUmed.org [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States)

2012-10-01

Phospholipase C-{delta}{sub 1} (PLC{delta}{sub 1}) is a widely expressed highly active PLC isoform, modulated by Ca{sup 2+} that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLC{delta}{sub 1} modulated expression of the pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLC{delta}{sub 1} was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT-PCR) results showed that PLC{delta}{sub 1} knockdown enhanced expression IL-1{beta} and tumor necrosis factor-{alpha} (TNF-{alpha}) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLC{delta}{sub 1} knock down caused persistently high Nf{kappa}b levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLC{delta}{sub 1} knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS-induced increases of IL-1{beta} and TNF-{alpha} mRNA's induced by PLC{delta}{sub 1} knockdown. Our results show that loss of PLC{delta}{sub 1} enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nf{kappa}b pathway. Our findings are consistent with the idea that PLC{delta}{sub 1} is a

Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α

International Nuclear Information System (INIS)

Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki

2007-01-01

In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol α from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol α with IC 50 value of 0.5 μM, and did not influence the activities of other replicative pols such as pols δ and ε, but also showed no effect on pol α activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD 50 values of 38.0-44.4 μM. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol α-specific inhibitor, but also as a candidate drug for anti-cancer treatment

Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum

NARCIS (Netherlands)

Prins, J. M.; Kuijper, E. J.; Mevissen, M. L.; Speelman, P.; van Deventer, S. J.

1995-01-01

The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production

Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells

International Nuclear Information System (INIS)

Tsujimoto, M.; Yip, Y.K.; Vilcek, J.

1985-01-01

Highly purified, Escherichia coli-derived recombinant human tumor necrosis factor (TNF) was labeled with 125 I and employed to determine receptor binding, internalization, and intracellular degradation in murine L929 cells (highly sensitive to the cytotoxic action of TNF) and in diploid human FS-4 cells (resistant to TNF cytotoxicity). 125 I-labeled TNF bound specifically to high-affinity receptors on both L929 and FS-4 cells. Scatchard analysis of the binding data indicated the presence of 2200 binding sites per L929 cell and 7500 binding sites per FS-4 cell. The calculated dissociation constants are 6.1 x 10 -10 M and 3.2 x 10 -10 M for L929 and FS-4 cells, respectively. In both L929 and FS-4 cells, incubation at 37 0 C resulted in a rapid internalization of the bulk of the cell-bound TNF, followed by the appearance of trichloroacetic acid-soluble 125 I radioactivity in the tissue culture medium, due to degradation of TNF. Degradation but not cellular uptake of TNF was inhibited in the presence of chloroquine (an inhibitor of lysosomal proteases) in both L929 and FS-4 cells, suggesting that degradation occurs intracellularly, probably within lysosomes. These results show that resistance of FS-4 cells to TNF cytotoxicity is not due to a lack of receptors or their inability to internalize and degrade TNF

Effects of a Tumor Necrosis Factor-α Antagonist on Experimentally Induced Rhinosinusitis

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Dong-Hyun Kim

2011-01-01

Full Text Available This prospective, randomized, and controlled study examined the effects of tumor necrosis factor soluble receptor type I (sTNFRI, a TNF-α antagonist on experimentally induced rhinosinusitis in rats. The experimental groups received an instillation of lipopolysaccharide (LPS plus an intramuscular injection of amoxicillin/clavulanate (antibiotic group, an instillation of sTNFRI (sTNFRI group, an instillation of sTNFRI and an injection of amoxicillin/clavulanate (sTNFRI/antibiotic group, or no additional treatment (LPS group. Histopathological changes were determined using hematoxylin-eosin and periodic acid-Schiff (PAS staining. Leakage of exudate was determined using fluorescence microscopy. Vascular permeability was measured using the Evans blue dye technique. Expression of MUC5AC was measured using reverse transcriptase PCR. The sTNFRI, antibiotic, and sTNFRI/antibiotic groups had significantly less capillary permeability, mucosal edema, PAS staining, and expression of MUC5AC than the LPS group. There were no differences in capillary permeability, mucosal edema, PAS staining, and MUC5AC expression between the sTNFRI and sTNFRI/antibiotic groups. The antibiotic group had PAS staining similar to that of the sTNFRI and sTNFRI/antibiotic groups but had a greater increase in capillary permeability, mucosal edema, and MUC5AC expression. This study shows that sTNFRI reduces inflammatory activity and mucus hypersecretion in LPS-induced rhinosinusitis in rats.

Inhibitory effects of tocopherols on expression of the cyclooxygenase-2 gene in RAW264.7 cells stimulated by lipopolysaccharide, tumor necrosis factor-α or Porphyromonas gingivalis fimbriae.

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Murakami, Yukio; Kawata, Akifumi; Koh, Teho; Seki, Yuya; Tamura, Seiko; Katayama, Tadashi; Fujisawa, Seiichiro

2013-01-01

Tocopherols, which include α-, β-, γ-, and δ-tocopherol, protect cells against harmful free radicals and play an important role in preventing many human diseases such as cancer, inflammatory disorders, and ageing itself. However, the causal relationships between periodontal or oral chronic diseases and tocopherols have not been sufficiently studied. The present study investigated the inhibitory effects of these compounds on the expression of cyclooxygenase-2 (COX2) mRNA in RAW264.7 cells stimulated with lipopolysaccharide (LPS), tumor necrosis factor-α (TNFα) or fimbriae of Poryphyromonas gingivalis (Pg), an oral anaerobe. The cytotoxicity (EC₅₀) of tocopherols toward RAW cells was determined using a cell counting kit (CCK-8). The regulatory effect of these compounds on the expression of COX2 mRNA stimulated with LPS, TNFα or Pg fimbriae was investigated using real-time polymerase chain reaction (PCR). Each tocopherol had similarly low cytotoxicity. COX2 gene expression in RAW cells after exposure to the three different macrophage activators was inhibited by the tocopherols (ptocopherol, β-, γ- and δ-tocopherol exhibited greater inhibitory effects (pTocopherols exhibit anti-inflammatory activity, and β-, γ- and δ-tocopherol have particularly more potent anti-inflammatory activity than α-tocopherol. Tocopherols may have potential utility for prevention of periodontal and chronic oral diseases.

CHANGES IN TUMOR NECROSIS FACTOR ALFA DURING TREATMENT OF PATIENTS WITH MULTIPLE SCLEROSIS BY TRANSIMMUNIZATION METHOD

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A. V. Kil'dyushevskiy

2016-01-01

Full Text Available Background: Despite the availability of a  large number of treatments for multiple sclerosis with various targets, these treatments are not always effective. According to the literature, experimental studies have shown a  significant decrease in tumor necrosis factor alfa (TNF-α with the use of extracorporeal photochemotherapy. Aim: To assess changes in TNF-α in patients with multiple sclerosis during treatment with transimmunization. Materials and methods: The study recruited 13 adult patients with multiple sclerosis. Serum TNF-α was measured by immunochemiluminescence analysis (IMMULITE 1000, Siemens. The patients were treated by transimmunization, i.e. a  modified photopheresis. Two hours before the procedure, Ammifurin (8-methoxypsoralene was administered to all the patients, then their mononuclear cells were isolated under PBSC protocol with Haemonetics MCS+ cell separator. Thereafter, mononuclear cells were irradiated with ultraviolet for 90  minutes and incubated for 20 hours at 37 °С. The next day the cells were re-infused to the patients. The procedure was performed 2  times per week for 6  months, then once per 4  months. Results: Before transimmunization, mean TNF-α level in adult patients with multiple sclerosis was 9.958±0.812  pg/mL (normal, below 8.1 pg/mL. After transimmunization, its level was 6.992±0.367  pg/mL (р<0.05. Conclusion: Ultraviolet irradiation of peripheral blood monocytes with their subsequent incubation (transimmunization led to a 30% decrease of serum TNF-α in patients with multiple sclerosis. This indicates a suppressive effect of transimmunization on TNF-α. Hence, in patients with multiple sclerosis transimmunization exerts an anti-inflammatory effect.

The reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent does not influence the effect of a second TNF blocking agent in patients with rheumatoid arthritis.

NARCIS (Netherlands)

Blom, M.; Kievit, W.; Fransen, J.; Kuper, I.H.; Broeder, A. den; Gendt, C.M. de; Jansen, T.L.Th.A.; Brus, H.L.; Laar, M.A. van der; Riel, P.L.C.M. van

2009-01-01

OBJECTIVE: To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent. METHODS: Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking

The reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent does not influence the effect of a second TNF blocking agent in patients with rheumatoid arthritis

NARCIS (Netherlands)

Blom, Marlies; Kievit, Wietske; Fransen, Jaap; Kuper, Ina H.; den Broeder, Alfons A.; De Gendt, Carla M.A.; Jansen, Tim L.; Brus, Herman L.M.; van de Laar, Mart A.F.J.; van Riel, Piet L.C.M.

2009-01-01

OBJECTIVE:To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent. METHODS:Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking

El factor de necrosis tumoral-α, la resistencia a la insulina, el metabolismo de lipoproteínas y la obesidad en humanos

OpenAIRE

M.ª M. Ramírez Alvarado; C. Sánchez Roitz

2012-01-01

En la obesidad el tejido adiposo produce moléculas proinflamatorias como el Factor de Necrosis tumoral-α, que tiene efectos locales en la fisiología del adipocito y efectos sistémicos en otros órganos. Muchos estudios relacionando TNF-α, obesidad, resistencia a la insulina y metabolismo lipídico se han realizado en ratas, conejos y perros, pero los resultados observados en varios de estos estudios han sido contradictorios y muchos de ellos no se han logrado reproducir en humanos, lo que hace ...

Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.

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Chen, Yu-Ying; Hsu, Ming-Jen; Hsieh, Cheng-Ying; Lee, Lin-Wen; Chen, Zhih-Cherng; Sheu, Joen-Rong

2014-01-01

Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

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Yu-Ying Chen

2014-01-01

Full Text Available Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α. Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK, Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis

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Lim Sung-Chul

2011-09-01

Full Text Available Abstract Background In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1, and its presence in tumor patients is associated with poor prognosis. Thus, necrosis has important clinical implications in tumor development; however, its molecular mechanism remains poorly understood. Results In the present study, we show that Distal-less 2 (Dlx-2, a homeobox gene of the Dlx family that is involved in embryonic development, is induced in cancer cell lines dependently of reactive oxygen species (ROS in response to glucose deprivation (GD, one of the metabolic stresses occurring in solid tumors. Increased Dlx-2 expression was also detected in the inner regions, which experience metabolic stress, of human tumors and of a multicellular tumor spheroid, an in vitro model of solid tumors. Dlx-2 short hairpin RNA (shRNA inhibited metabolic stress-induced increase in propidium iodide-positive cell population and HMGB1 and lactate dehydrogenase (LDH release, indicating the important role(s of Dlx-2 in metabolic stress-induced necrosis. Dlx-2 shRNA appeared to exert its anti-necrotic effects by preventing metabolic stress-induced increases in mitochondrial ROS, which are responsible for triggering necrosis. Conclusions These results suggest that Dlx-2 may be involved in tumor progression via the regulation of metabolic stress-induced necrosis.

Delayed brain radiation necrosis: pathological review and new molecular targets for treatment.

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Furuse, Motomasa; Nonoguchi, Naosuke; Kawabata, Shinji; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko

2015-12-01

Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell-cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.

Culture of Dendritic Cells in vitro and Its Anti-tumor Immonotherapy

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Yanwen ZHOU

2010-05-01

Full Text Available Background and objective Immunocompromised patients with malignant tumor always lack of strong anti-tumor immune response, because the antigenicity of tumor cells is weak, and antigen-presenting cell function is low, so that can not be effectively presenting tumor antigens to the lymphocytes. Therefore, how to effectively induce anti-tumor immune response is the key issue. Through the study on establishing a method to culture dendritic cells (DC in vitro and to observe the anti-lung cancer immunological effect induced by DC, we provided definite experiment basis for the clinic application of vaccine based on DC. Methods Through the experiment we get the soluble antigen polypeptide from lung cancer cells GLC-82 by 3 mol/L potassium chloride. DCs are cultured and obtained from peripheral blood mononuclear cell by GM-CSF, IL-4 and TNF-a. DCs are identified by flow cytometer (FCM and immunostaining. DCs modified by lung cancer tumor soluble antigen (TSA and staphylococcal enterotox in A (SEA, DCs modified by TSA or DCs modified by SEA or DCs modified by nothing were cultivated together with T lymphocyte, and the obtained cells are named TSA-SEA-DCL or TSA-DCL or SEA-DCL or DCL as effector cells. The anti-tumor activity of every effector cells against target cells was assayed with MTT method. Shape of DCs and effector cells, and the process of killing target cells were observed in microscope. Results Induced DCs expressed more CD1a, CD80 and HLA-DR, which had typical cell traits such as tree branch. The killing ratio of the TSA-SEA-DCL in vitro to GLC-82 is larger than TSA-DCL, SEA-DCL and DCL, also larger than to K562. When the effector cells cultivate with target cells, we can observe the CTL approach and gather to the cancer cell, induce it necrosis and apoptosis. Conclusion Ripe DCs that have typical characteristic and phenotype could be induced successfully. High potency and relatively specific antilung caner effect can be prepared in virtue of

Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis.

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Acar, Leyla; Atalan, Nazan; Karagedik, E Hande; Ergen, Arzu

2018-01-20

The humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha. To investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels. Case-control study. Seventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay. We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05). Our results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.

Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions

DEFF Research Database (Denmark)

Schuchmann, M; Hess, S; Bufler, P

1995-01-01

Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however......, demonstrates that TNF and LT alpha differ significantly with regard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically...... inactive monomers, the LT alpha trimer remained stable for several days. Accordingly, LT alpha more effectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only short-term impact of the cytokine, could be attributed to a distinct...

In vivo tumor targeting and imaging with anti-vascular endothelial growth factor antibody-conjugated dextran-coated iron oxide nanoparticles

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Hsieh WJ

2012-06-01

Full Text Available Wan-Ju Hsieh,1 Chan-Jung Liang,1 Jen-Jie Chieh,4 Shu-Huei Wang,1 I-Rue Lai,1 Jyh-Horng Chen,2 Fu-Hsiung Chang,3 Wei-Kung Tseng,4–6 Shieh-Yueh Yang,4 Chau-Chung Wu,7 Yuh-Lien Chen11Institute of Anatomy and Cell Biology, College of Medicine, 2Department of Electrical Engineering, 3Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan; 4Institute of Electro-Optical Science and Technology, National Taiwan Normal University, Taipei, Taiwan; 5Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Taipei, Taiwan; 6Department of Medical Imaging and Radiological Sciences, I-Shou University, Taipei, Taiwan; 7Department of Internal Medicine and Primary Care Medicine, National Taiwan University Hospital, Taipei, TaiwanBackground: Active targeting by specific antibodies combined with nanoparticles is a promising technology for cancer imaging and detection by magnetic resonance imaging (MRI. The aim of the present study is to investigate whether the systemic delivery of antivascular endothelial growth factor antibodies conjugating to the surface of functionalized supermagnetic iron oxide nanoparticles (anti-VEGF-NPs led to target-specific accumulation in the tumor.Methods: The VEGF expression in human colon cancer and in Balb/c mice bearing colon cancers was examined by immunohistochemistry. The distribution of these anti-VEGF-NPs particles or NPs particles were evaluated by MRI at days 1, 2, or 9 after the injection into the jugular vein of Balb/c mice bearing colon cancers. Tumor and normal tissues (liver, spleen, lung, and kidney were collected and were examined by Prussian blue staining to determine the presence and distribution of NPs in the tissue sections.Results: VEGF is highly expressed in human and mouse colon cancer tissues. MRI showed significant changes in the T*2 signal and T2 relaxation in the anti-VEGF-NP- injected-mice, but not in mice injected with NP alone. Examination of paraffin

miR-19a promotes colitis-associated colorectal cancer by regulating tumor necrosis factor alpha-induced protein 3-NF-κB feedback loops.

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Wang, T; Xu, X; Xu, Q; Ren, J; Shen, S; Fan, C; Hou, Y

2017-06-08

Chronic inflammation is believed to have a crucial role in colon cancer development. MicroRNA (miRNA) deregulation is common in human colorectal cancers, but little is known regarding whether miRNA drives tumor progression by regulating inflammation. Here, we showed that miR-19a can promote colitis and colitis-associated colon cancer (CAC) development using a CAC mouse model and an acute colitis mouse model. Tumor necrosis factor-α (TNF-α) stimulation can increase miR-19a expression, and upregulated miR-19a can in turn activate nuclear factor (NF)-κB signaling and TNF-α production by targeting TNF alpha-induced protein 3 (TNFAIP3). miR-19a inhibition can also alleviate CAC in vivo. Moreover, the regulatory effects of miR-19a on TNFAIP3 and NF-κB signaling were confirmed using tumor samples from patients with colon cancer. These new findings demonstrate that miR-19a has a direct role in upregulating NF-κB signaling and that miR-19a has roles in inflammation and CAC.

Grazing dairy cows had decreased interferon-γ, tumor necrosis factor, and interleukin-17, and increased expression of interleukin-10 during the first week after calving.

Science.gov (United States)

Heiser, Axel; McCarthy, Allison; Wedlock, Neil; Meier, Susanne; Kay, Jane; Walker, Caroline; Crookenden, Mallory A; Mitchell, Murray D; Morgan, Stuart; Watkins, Kate; Loor, Juan J; Roche, John R

2015-02-01

Peripartum, and especially during the transition period, dairy cows undergo dramatic physiological changes. These coincide with an increased risk of disease during the first 2 wk after calving and have been linked to dairy cows failing to achieve production as well as reproductive targets. Previous evidence suggests that these physiological changes affect the immune system and that transition dairy cows experience some form of reduced immunocompetence. However, almost all of these studies were undertaken in high-production, housed dairy cows. Grazing cows have much lower levels of production and this study aimed to provide clarity whether or not the dysfunctional attributes of the peripartum immune system reported in high production housed cows are evident in these animals. Therefore, cell culture techniques, flow cytometry, and quantitative PCR were applied to analyze the cellular composition of peripheral blood mononuclear cells from transition dairy cows as well as the performance of these cells in an in vitro assay. First, a combination of in vitro stimulation and quantitative PCR for cytokines was validated as a quantifiable immunocompetence assay in 29 cattle and a correlation of quantitative PCR and ELISA demonstrated. Second, the relative number of T helper cells, cytotoxic T cells, B cells, γδ T cells, natural killer cells, and monocytes in peripheral blood was measured, of which B cells and natural killer cells increased in number postcalving (n=29) compared with precalving. Third, following in vitro stimulation cytokine profiles indicated decreased expression of IFNγ, tumor necrosis factor, and IL-17 and increased expression of IL-10 wk 1 after calving, which later all returned to precalving values (n=39). Additionally, treatment of transition cows with a nonsteroidal anti-inflammatory drug (i.e., carprofen) administered on d 1, 3, and 5 postcalving (n=19; untreated control n=20) did not affect the cytokine expression at any time point. In conclusion

Expression of tumor necrosis factor receptor-associated protein 1 and its clinical significance in kidney cancer.

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Si, Tong; Yang, Guosheng; Qiu, Xiaofu; Luo, Youhua; Liu, Baichuan; Wang, Bingwei

2015-01-01

To investigate the expression and clinical significance of TRAP1 (tumor necrosis factor receptor-associated protein 1) in kidney cancer. TRAP1 expression was detected in kidney cancer and normal kidney tissues by qRT-PCR and immunohistochemistry (IHC), respectively. Then, the correlation of TRAP1 expression with clinicopathological characters and patients' prognosis was evaluated in kidney cancer. IHC results revealed that the high-expression rates of TRAP1 in kidney cancer tissues and normal kidney tissues were 51.3% (41/80), 23.3% (7/30), and the difference was statistically significant (P=0.01). Also, TRAP1 mRNA level in kidney cancer was found to be significantly greater compared with those in normal kidney by qRT-PCR. In addition, TRAP1 expression in kidney cancer significantly correlated with lymph node metastasis and clinical stage (Pkidney cancer and correlates with patients prognosis, which may be served as a potential marker for the diagnosis and treatment of kidney cancer.

Ultrasound Elasticity Imaging Predicts Therapeutic Outcomes of Patients With Crohn's Disease Treated With Anti-Tumour Necrosis Factor Antibodies.

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Orlando, Stefania; Fraquelli, Mirella; Coletta, Marina; Branchi, Federica; Magarotto, Andrea; Conti, Clara Benedetta; Mazza, Stefano; Conte, Dario; Basilisco, Guido; Caprioli, Flavio

2018-01-05

Ultrasound elasticity imaging is a non-invasive technique developed to evaluate fibrosis. Measuring tissue strain by ultrasound elasticity imaging can reliably detect severe ileal fibrosis in patients with Crohn's disease [CD]. We have hypothesised that a more severe range of fibrosis might influence the therapeutic response to anti-tumour necrosis factor [TNF] treatment. The aim of this study was to assess the ability of ultrasound elasticity imaging to predict the therapeutic outcome for CD patients. Consecutive patients with ileal/ileocolonic CD, starting anti-TNF treatment, were enrolled for the study. These patients underwent bowel ultrasound and ultrasound elasticity imaging at baseline and at 14 and 52 weeks after anti-TNF treatment. Bowel wall stiffness was quantified by calculating the strain ratio between the mesenteric tissue and the bowel wall. Strain ratio ≥ 2 was used to identify severe ileal fibrosis. Transmural healing at 14 and 52 weeks was defined as bowel wall thickness ≤ 3 mm. Thirty patients with CD were enrolled. Five patients underwent surgery for bowel obstruction. The frequency of surgeries was significantly greater in patients with a strain ratio ≥ 2 at baseline [p = 0.003]. A significant reduction of the bowel thickness was observed after 14 and 52 weeks of anti-TNF treatment [p < 0.005]. A significant inverse correlation was observed between the strain ratio values at baseline and the thickness variations following anti-TNF therapy [p = 0.007]; 27% of patients achieved transmural healing at 14 weeks. The baseline strain ratio was significantly lower in patients with transmural healing [p < 0.05]. This study shows that ultrasound elasticity imaging predicts therapeutic outcomes for CD patients treated with anti-TNF. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance.

Science.gov (United States)

Huntington, M O; Krell, K E; Armour , W E; Liljenquist, J E

2001-06-01

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor. We report here a remarkable degree of insulin resistance in a patient with adult respiratory distress syndrome and myelodysplasia.

Delayed radiation necrosis of the brain simulating a brain tumor

International Nuclear Information System (INIS)

Ikeda, Hiroya; Kanai, Nobuhiro; Kamikawa, Kiyoo

1976-01-01

Two cases of delayed radiation necrosis of the brain are reported. Case 1 was a 50-year-old man who had right hemiparesis and disorientation 26 months after Linac irradiation (5,000 rad), preceded by an operation for right maxillar carcinoma. A left carotid angiogram demonstrated a left temporal mass lesion, extending to the frontal lobe. Case 2 was a 41-year-old man who had previously had an operation for right intraorbital plasmocytoma, followed by two Co irradiations (6,400 rad, and 5,000 rad). He had the signs and symptoms of intracranial hypertension 36 months after his last irradiation. A left carotid angiogram demonstrated a left temporal mass lesion. Both cases were treated by administration of steroid hormone (which alleviated the signs and symptoms) and by temporal lobectomy. Microscopic examinations showed necrosis of the brain tissues associated with hyaline degeneration of blood vessel walls and perivascular cell infiltration. The signs and symptoms of intracranial hypertension subsided postoperatively. Thirteen other cases the same as ours were collected from literature. They showed the signs and symptoms simulating a brain tumor (like a metastatic brain tumor) after irradiation to extracranial malignant tumors. Diagnosis of radiation necrosis was made by operation or autopsy. A follow-up for a long time is necessary, because the pathological changes in the brain may be progressive and extending in some cases, although decompressive operations for mass lesions give excellent results. (auth.)

Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein

International Nuclear Information System (INIS)

Gray, P.W.; Barrett, K.; Chantry, D.; Turner, M.; Feldmann, M.

1990-01-01

The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNFα with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surface proteins that includes the nerve growth factor receptor, the human B-cell surface antigen CD40, and the rat T-cell surface antigen OX40. The TNF receptor contains four cysteine-rich subdomains in the extracellular portion. Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNFα with an affinity of 2.5 x 10 -9 M. This binding can be competitively inhibited with unlabeled TNFα or lymphotoxin (TNFβ)

Cloning of Human Tumor Necrosis Factor (TNF) Receptor cDNA and Expression of Recombinant Soluble TNF-Binding Protein

Science.gov (United States)

Gray, Patrick W.; Barrett, Kathy; Chantry, David; Turner, Martin; Feldmann, Marc

1990-10-01

The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNFα with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surface proteins that includes the nerve growth factor receptor, the human B-cell surface antigen CD40, and the rat T-cell surface antigen OX40. The TNF receptor contains four cysteine-rich subdomains in the extra-cellular portion. Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNFα with an affinity of 2.5 x 10-9 M. This binding can be competitively inhibited with unlabeled TNFα or lymphotoxin (TNFβ).

Infection of Human Fallopian Tube Epithelial Cells with Neisseria gonorrhoeae Protects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis

Science.gov (United States)

Morales, Priscilla; Reyes, Paz; Vargas, Macarena; Rios, Miguel; Imarai, Mónica; Cardenas, Hugo; Croxatto, Horacio; Orihuela, Pedro; Vargas, Renato; Fuhrer, Juan; Heckels, John E.; Christodoulides, Myron; Velasquez, Luis

2006-01-01

Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-α). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-α was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in naïve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-α antibodies; and (iii) the addition of exogenous TNF-α induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-α-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-α-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease. PMID:16714596

Multivoxel proton MRS for differentiation of radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for brain metastases

International Nuclear Information System (INIS)

Chernov, M.F.; Hayashi, Motohiro; Izawa, Masahiro

2006-01-01

Multivoxel proton magnetic resonance spectroscopy (MRS) was used for differentiation of radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for intracranial metastases in 33 consecutive cases. All patients presented with enlargement of the treated lesion, increase of perilesional brain edema, and aggravation or appearance of neurological signs and symptoms on average 9.3±4.9 months after primary treatment. Metabolic imaging defined four types of lesions: pure tumor recurrence (11 cases), partial tumor recurrence (11 cases), radiation-induced tumor necrosis (10 cases), and radiation-induced necrosis of the peritumoral brain (1 case). In 1 patient, radiation-induced tumor necrosis was diagnosed 9 months after radiosurgery; however, partial tumor recurrence was identified 6 months later. With the exception of midline shift, which was found to be more typical for radiation-induced necrosis (P<0.01), no one clinical, radiologic, or radiosurgical parameter either at the time of primary treatment or at the time of deterioration showed a statistically significant association with the type of the lesion. Proton MRS-based diagnosis was confirmed histologically in all surgically treated patients (7 cases) and corresponded well to the clinical course in others. In conclusion, multivoxel proton MRS is an effective diagnostic modality for identification of radiation-induced necrosis and tumor recurrence that can be used for monitoring of metabolic changes in intracranial neoplasms after radiosurgical treatment. It can be also helpful for differentiation of radiation-induced necrosis of the tumor and that of the peritumoral brain, which may have important clinical and medicolegal implications. (author)

Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

DEFF Research Database (Denmark)

Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

2010-01-01

by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine...

Production of tumor necrosis factor-a is increased in urinary tract infections

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Neni Susilaningsih

2015-12-01

Full Text Available BACKGROUND Urinary tract infection (UTI is a common source of bacteriemia. The most common cause of UTI is Escherichia coli (E. coli. Tumor Necrosis Factor (TNF-á gene polymorphism has been reported to be responsible for an excessive production of TNF-á and eventual disruption of pro-inflammatory cytokine regulation. The aim of this study was to compare TNF-á serum levels and TNF-á allele polymorphisms in patients with UTI due to E.coli and in non- UTI controls. METHODS A cross-sectional study was conducted at Dr. Kariadi Central Hospital and the Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang. In 68 patients with UTI the TNF-á serum levels were determined by means of ELISA and compared to those of non-UTI controls (n=55. TNFá- 308G>A gene polymorphism was analyzed by polymerase chain reaction restriction fragment length using the NcoI enzyme. Fragments were visualized on polyacrylamide gel with silver staining. RESULTS TNF-á serum level in patients with UTI had a median of 8.9 pg/mL, which was significantly higher than the median of 3.7 pg/mL in the control group (pA gene polymorphisms found in the patient group were G/G=61 (90%, G/A=7(10% and A/A=0, while in the control group were G/G=48 (87%, G/A=7 (13% and A/A =0. There was no significant differences (p=0.578 in gene polymorphisms between the two groups. CONCLUSIONS TNF-á serum levels in patients with UTI due to E. coli were significantly higher than in non-UTI controls, but for the TNF-á-380 gene polymorphisms no significant difference was found between the two groups. There are presumably more important factors than host genotype that influence UTI pathogenesis.

Production of tumor necrosis factor-á is increased in urinary tract infections

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Neni Susilaningsih

2012-12-01

Full Text Available Background Urinary tract infection (UTI is a common source of bacteriemia. The most common cause of UTI is Escherichia coli (E. coli. Tumor Necrosis Factor (TNF-á gene polymorphism has been reported to be responsible for an excessive production of TNF-á and eventual disruption of pro-inflammatory cytokine regulation. The aim of this study was to compare TNF-á serum levels and TNF-á allele polymorphisms in patients with UTI due to E.coli and in non-UTI controls. Methods A cross-sectional study was conducted at Dr. Kariadi Central Hospital and the Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang. In 68 patients with UTI the TNF-á serum levels were determined by means of ELISA and compared to those of non-UTI controls (n=55. TNF-á-308G>A gene polymorphism was analyzed by polymerase chain reaction restriction fragment length using the NcoI enzyme. Fragments were visualized on polyacrylamide gel with silver staining. Results TNF-á serum level in patients with UTI had a median of 8.9 pg/mL, which was significantly higher than the median of 3.7 pg/mL in the control group (pA gene polymorphisms found in the patient group were G/G=61 (90%, G/A=7(10% and A/A=0, while in the control group were G/G=48 (87%, G/A=7 (13% and A/A =0. There was no significant differences (p=0.578 in gene polymorphisms between the two groups. Conclusions TNF-á serum levels in patients with UTI due to E. coli were significantly higher than in non-UTI controls, but for the TNF-á-380 gene polymorphisms no significant difference was found between the two groups. There are presumably more important factors than host genotype that influence UTI pathogenesis.

Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia.

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Hill, M R; Clarke, S; Rodgers, K; Thornhill, B; Peters, J M; Gonzalez, F J; Gimble, J M

1999-07-01

Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other

The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

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Kolsum, Umme; Roy, Kay; Starkey, Cerys

2009-01-01

BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

DEFF Research Database (Denmark)

Kolsum, Umme; Roy, Kay; Starkey, Cerys

2009-01-01

BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

Association between Interleukin-10-1082 G/A and Tumor Necrosis Factor-α 308 G/A Gene Polymorphisms and Respiratory Distress Syndrome in Iranian Preterm Infants

OpenAIRE

Khoshdel, Abolfazl; Kheiri, Soleiman; Omidvari, Peyman; Moradi, Fahimeh; Hamidi, Majid; Teimori, Hossein

2017-01-01

Cytokine polymorphisms may contribute to the prevalence of respiratory distress syndrome. The present study was done to investigate the frequency of interleukin- (IL-) 10 and tumor necrosis factor- (TNF-) ? gene polymorphisms and their association with the risk of RDS in preterm infants. One-hundred and nineteen patients with RDS and 119 healthy preterm infants were enrolled. PCR restriction fragment length polymorphism was used to determine the frequency of IL-10 and TNF-? genotypes at -1082...

Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer

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Moretto, Roberto; Cremolini, Chiara; Rossini, Daniele; Pietrantonio, Filippo; Battaglin, Francesca; Mennitto, Alessia; Bergamo, Francesca; Loupakis, Fotios; Marmorino, Federica; Berenato, Rosa; Marsico, Valentina Angela; Caporale, Marta; Antoniotti, Carlotta; Masi, Gianluca; Salvatore, Lisa; Borelli, Beatrice; Fontanini, Gabriella; Lonardi, Sara; De Braud, Filippo

2016-01-01

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09–7.53; p < .0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. Implications for Practice: Right- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices

Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate.

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Prasad, Ananda S; Beck, Frances W J; Bao, Bin; Snell, Diane; Fitzgerald, James T

2008-03-15

Zinc lozenges have been used for treatment of the common cold; however, the results remain controversial. Fifty ambulatory volunteers were recruited within 24 h of developing symptoms of the common cold for a randomized, double-blind, placebo-controlled trial of zinc. Participants took 1 lozenge containing 13.3 mg of zinc (as zinc acetate) or placebo every 2-3 h while awake. The subjective scores for common cold symptoms were recorded daily. Plasma zinc, soluble interleukin (IL)-1 receptor antagonist (sIL-1ra), soluble tumor necrosis factor receptor 1, soluble vascular endothelial cell adhesion molecule, and soluble intercellular adhesion molecule (sICAM)-1 were assayed on days 1 and 5. Compared with the placebo group, the zinc group had a shorter mean overall duration of cold (4.0 vs. 7.1 days; P cold symptoms. We related the improvement in cold symptoms to the antioxidant and anti-inflammatory properties of zinc.

ANTI-INFLAMMATORY ACTIVITY OF EUCALYPTUS SPP. AND PISTASCIA LENTISCUS LEAF EXTRACTS.

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Qabaha, Khaled; Ras, Sari Abu; Abbadi, Jehad; Al-Rimawi, Fuad

2016-01-01

Eucalyptus spp. and Pistascia lentiscus are among the Palestinian trees that are traditionally used in folkloric medicine in treating many diseases; leaves of which are thought to have anti-inflammatory, antibacterial and antioxidant effects. The goal of this study is to evaluate the in vitro inhibitory effect of Eucalyptus spp . and Pistascia lentiscus extracts on Lipopolysacaride (LPS)-induced Interlukin-6 (Il-6) and Tumor Necrosis Factor-α (TNF-α) by polymorphonuclear Cells (PMNCs). Polymorphonuclear cells were isolated from the whole blood using Histopaque (Ficol-1077) method and then cultured in an enriched Roswell Park Memorial Institute (RBMI) medium. Supernatants' Interlukin-6 (IL-6) and Tumor Necrosis Factor (TNF-α) levels were determined 24 hour after LPS stimulation. HPLC was employed to determine the concentration of phenolic compounds in the extracts. The concentrations of TNF-α and IL-6 were compared using paired-samples t test. Eucalyptus spp . and Pistascia lentiscus leaves extracts have shown significant reduction in the levels of both Il-6 and TNF-α Gallic acid; a strong anti-inflammatory agent was found to be the major phenolic compound in both leaf extracts. However, other anti-inflammatory phenolic compounds were detected in Pitascia lentiscus extract including syringic acid and p-coumaric acid, while chlorogenic acid was detected in Eucalyptus spp . leaf extract. Reduction in the levels of Il-6 and TNF-α upon the effect of both Eucalyptus spp . and Pistascia lentiscus extract is an indication of their anti-inflammatory effects. Our results may also indicate that the observed anti-inflammatory effect of the above extracts may be due to the presence of gallic acid and other phenolic compounds. List of Abbreviations and Nomenclature: LPS: Lipopolysacaride, Il-6: Interlukin-6, TNF-α: Tumor Necrosis Factor-α, PMNCs: Polymorphonuclear Cells, HPLC: High Performance Liquid Chromatography, ELISA: Enzyme Linked Immune Sorbent Assay, EDTA

Implication of snail in metabolic stress-induced necrosis.

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Cho Hee Kim

2011-03-01

Full Text Available Necrosis, a type of cell death accompanied by the rupture of the plasma membrane, promotes tumor progression and aggressiveness by releasing the pro-inflammatory and angiogenic cytokine high mobility group box 1. It is commonly found in the core region of solid tumors due to hypoxia and glucose depletion (GD resulting from insufficient vascularization. Thus, metabolic stress-induced necrosis has important clinical implications for tumor development; however, its regulatory mechanisms have been poorly investigated.Here, we show that the transcription factor Snail, a key regulator of epithelial-mesenchymal transition, is induced in a reactive oxygen species (ROS-dependent manner in both two-dimensional culture of cancer cells, including A549, HepG2, and MDA-MB-231, in response to GD and the inner regions of a multicellular tumor spheroid system, an in vitro model of solid tumors and of human tumors. Snail short hairpin (sh RNA inhibited metabolic stress-induced necrosis in two-dimensional cell culture and in multicellular tumor spheroid system. Snail shRNA-mediated necrosis inhibition appeared to be linked to its ability to suppress metabolic stress-induced mitochondrial ROS production, loss of mitochondrial membrane potential, and mitochondrial permeability transition, which are the primary events that trigger necrosis.Taken together, our findings demonstrate that Snail is implicated in metabolic stress-induced necrosis, providing a new function for Snail in tumor progression.

Effects of escitalopram, R-citalopram, and reboxetine on serum levels of tumor necrosis factor-α, interleukin-10, and depression-like behavior in mice after lipopolysaccharide administration.

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Dong, Chao; Zhang, Ji-chun; Yao, Wei; Ren, Qian; Yang, Chun; Ma, Min; Han, Mei; Saito, Ryo; Hashimoto, Kenji

2016-05-01

Inflammation plays a role in the pathophysiology of depression. The purpose of this study is to examine whether the selective serotonin reuptake inhibitor (SSRI) escitalopram, its inactive enantiomer R-citalopram, and selective noradrenaline reuptake inhibitor (NRI) reboxetine, show anti-inflammatory and antidepressant effects in an inflammation-induced model of depression. Pretreatment with escitalopram (1, 3, or 10mg/kg, i.p.) markedly blocked an increase in the serum levels of pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after a single administration of lipopolysaccharide (LPS; 0.5mg/kg). Furthermore, escitalopram (3 or 10mg/kg) significantly increased the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) by a single administration of LPS. In contrast, pretreatment with R-citalopram (10mg/kg, i.p.) or reboxetine (10mg/kg, i.p.) did not affect the alterations in serum levels of TNF-α and IL-10 after LPS administration. Co-administration of reboxetine with escitalopram did not show anti-inflammatory effects. Pretreatment with escitalopram (10mg/kg) significantly attenuated LPS-induced increase of the immobility time in the tail-suspension test (TST) and forced swimming test (FST). In contrast, pretreatment with R-citalopram (10mg/kg), or reboxetine (10mg/kg) did not alter LPS-induced increase of immobility time of TST and FST. Interestingly, co-administration of reboxetine with escitalopram did not show antidepressant effect in this model. These findings suggest that escitalopram, but not R-citalopram and reboxetine, has anti-inflammatory and antidepressant effects in LPS-treated model of depression, and that reboxetine can antagonize the effects of escitalopram in the inflammation model. Therefore, it is likely that serotonergic system plays a key role in the pathophysiology of inflammation-induced depression. Copyright © 2016 Elsevier Inc. All rights reserved.

Recurrent abdominal pain as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in an Asian girl: a case report and review of the literature.

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Chen, Yun-Ju; Yu, Hsin-Hui; Yang, Yao-Hsu; Lau, Yu-Lung; Lee, Wen-I; Chiang, Bor-Luen

2014-12-01

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14-year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-α inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS. Copyright © 2012. Published by Elsevier B.V.

The role of soluble tumor necrosis factor like weak inducer of apoptosis and interleukin-17A in the etiopathogenesis of celiac disease

Science.gov (United States)

Yuksel, Mahmut; Kaplan, Mustafa; Ates, Ihsan; Kilic, Zeki Mesut Yalın; Kilic, Hasan; Suna, Nuretdin; Ates, Hale; Kayacetin, Ertugrul

2016-01-01

Abstract Our aim in this study was to determine soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) and interleukin-17A (IL-17A) levels in celiac disease, and their association with the gluten diet and autoantibodies. Eighty patients with celiac diagnosis and 80 healthy control individuals with similar age, gender and body mass index to the patient group were included in the study. Serum sTWEAK and IL-17A levels were measured by the serum enzyme-linked immunosorbent assay kit. The median IL-17A (117.5 pg/mL vs. 56.7 pg/mL; P = 0.001) level in celiac patients was higher than in the control group, while the median sTWEAK (543 pg/mL vs. 643 pg/mL; P = 0.016) level in patients was determined to be lower. In the patient group, patients who complied with the gluten diet had a lower level of median IL-17A (98.1 pg/mL vs. 197.5 pg/mL; P = 0.034) and a higher level of sTWEAK (606 pg/mL vs. 522.8 pg/mL; P = 0.031) than those who did not adhere. Furthermore, the IL-17A level was higher and the sTWEAK level was lower in celiac patients with positive antibody than those with negative antibody. A positive correlation was determined among anti-gliadin antibody IgA, anti-gliadin antibody IgG, anti-tissue transglutaminase IgG levels and the IL-17A level, and a negative correlation was determined with the sTWEAK level. In celiac disease, the sTWEAK and IL-17A levels differ between patients who cannot adapt to the gluten diet and who are autoantibody positive, and patients who adapt to the diet and are autoantibody negative. We believe that sTWEAK and IL-17A are associated with the inflammation in celiac pathogenesis. PMID:27367991

10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease

DEFF Research Database (Denmark)

Carlsson, Axel C; Ruge, Toralph; Kjøller, Erik

2018-01-01

BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease. METHODS AND RESULTS: CLARICOR (Effect of Clarithromycin on Mortality...... and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all...... factors improved prediction only modestly (concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk...

Evaluating the cellular targets of anti-4-1BB agonist antibody during immunotherapy of a pre-established tumor in mice.

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Gloria H Y Lin

2010-06-01

Full Text Available Manipulation of the immune system represents a promising avenue for cancer therapy. Rational advances in immunotherapy of cancer will require an understanding of the precise correlates of protection. Agonistic antibodies against the tumor necrosis factor receptor family member 4-1BB are emerging as a promising tool in cancer therapy, with evidence that these antibodies expand both T cells as well as innate immune cells. Depletion studies have suggested that several cell types can play a role in these immunotherapeutic regimens, but do not reveal which cells must directly receive the 4-1BB signals for effective therapy.We show that re-activated memory T cells are superior to resting memory T cells in control of an 8-day pre-established E.G7 tumor in mice. We find that ex vivo activation of the memory T cells allows the activated effectors to continue to divide and enter the tumor, regardless of antigen-specificity; however, only antigen-specific reactivated memory T cells show any efficacy in tumor control. When agonistic anti-4-1BB antibody is combined with this optimized adoptive T cell therapy, 80% of mice survive and are fully protected from tumor rechallenge. Using 4-1BB-deficient mice and mixed bone marrow chimeras, we find that it is sufficient to have 4-1BB only on the endogenous host alphabeta T cells or only on the transferred T cells for the effects of anti-4-1BB to be realized. Conversely, although multiple immune cell types express 4-1BB and both T cells and APC expand during anti-4-1BB therapy, 4-1BB on cells other than alphabeta T cells is neither necessary nor sufficient for the effect of anti-4-1BB in this adoptive immunotherapy model.This study establishes alphabeta T cells rather than innate immune cells as the critical target in anti-4-1BB therapy of a pre-established tumor. The study also demonstrates that ex vivo activation of memory T cells prior to infusion allows antigen-specific tumor control without the need for

Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine

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Kathryn S. Brown

2014-01-01

Full Text Available Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1 mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC.

A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus.

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Alejo, Alí; Ruiz-Argüello, M Begoña; Ho, Yin; Smith, Vincent P; Saraiva, Margarida; Alcami, Antonio

2006-04-11

Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis.

Soluble Prokaryotic Expression and Purification of Bioactive Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand.

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Do, Bich Hang; Nguyen, Minh Tan; Song, Jung-A; Park, Sangsu; Yoo, Jiwon; Jang, Jaepyeong; Lee, Sunju; So, Seoungjun; Yoon, Yejin; Kim, Inki; Lee, Kyungjin; Jang, Yeon Jin; Choe, Han

2017-12-28

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as an antitumor agent owing to its ability to induce apoptosis of cancer cells without imparting toxicity toward most normal cells. TRAIL is produced in poor yield because of its insoluble expression in the cytoplasm of E. coli . In this study, we achieved soluble expression of TRAIL by fusing maltose-binding protein (MBP), b'a' domain of protein disulfide isomerase (PDIb'a'), or protein disulfide isomerase at the N-terminus of TRAIL. The TRAIL was purified using subsequent immobilized metal affinity chromatography and amylose-binding chromatography, with the tag removal using tobacco etch virus protease. Approximately 4.5 mg of pure TRAIL was produced from 125 ml flask culture with a purification yield of 71.6%. The endotoxin level of the final product was 0.4 EU/μg, as measured by the Limulus amebocyte lysate endotoxin assay. The purified TRAIL was validated and shown to cause apoptosis of HeLa cells with an EC₅₀ and Hill coefficient of 0.6 ± 0.03 nM and 2.41 ± 0.15, respectively. The high level of apoptosis in HeLa cells following administration of purified TRAIL indicates the significance and novelty of this method for producing high-grade and high-yield TRAIL.

A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus

Science.gov (United States)

Alejo, Alí; Ruiz-Argüello, M. Begoña; Ho, Yin; Smith, Vincent P.; Saraiva, Margarida; Alcami, Antonio

2006-01-01

Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis. PMID:16581912

Plasma Levels of Tumor Necrosis Factor-Alpha and Interleukin-6 in Obsessive Compulsive Disorder

Directory of Open Access Journals (Sweden)

N. Konuk

2007-01-01

Full Text Available Aim. Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD. Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-α and interleukin-6 (IL-6 in OCD patients. Methods. Plasma concentrations of TNF-α and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-α and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA. Results. Both TNF-α and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P<.000, P<.001, resp.. In addition, the age of onset was negatively correlated with TNF-α level (r=−.402, P=.025 and duration of illness was weakly correlated with IL-6 levels (r:.357; P:.048 in patients group. Conclusion. OCD patients showed increases in TNF-α and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflamatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

Improvement of macrophage dysfunction by administration of anti-transforming growth factor-beta antibody in EL4-bearing hosts.

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Maeda, H; Tsuru, S; Shiraishi, A

1994-11-01

An experimental therapy for improvement of macrophage dysfunction caused by transforming growth factor-beta (TGF-beta) was tried in EL4 tumor-bearing mice. TGF-beta was detected in cell-free ascitic fluid from EL4-bearers, but not in that from normal mice, by western blot analysis. The ascites also showed growth-suppressive activity against Mv1Lu cells, and the suppressive activity was potentiated by transient acidification. To investigate whether the functions of peritoneal macrophages were suppressed in EL4-bearers, the abilities to produce nitric oxide and tumor necrosis factor-alpha (TNF-alpha) upon lipopolysaccharide (LPS) stimulation were measured. Both abilities of macrophages in EL4-bearing mice were suppressed remarkably on day 9, and decreased further by day 14, compared with non-tumor-bearing controls. TGF-beta activity was abrogated by administration of anti-TGF-beta antibody to EL4-bearing mice. While a large amount of TGF-beta was detected in ascitic fluid from control EL4-bearers, little TGF-beta was detectable in ascites from EL4-bearers given anti-TGF-beta antibody. Furthermore, while control macrophages exhibited little or no production of nitric oxide and TNF-alpha on LPS stimulation in vitro, macrophages from EL4-bearers administered with anti-TGF-beta antibody showed the same ability as normal macrophages. These results clearly indicate that TGF-beta contributes to macrophage dysfunction and that the administration of specific antibody for TGF-beta reverses macrophage dysfunction in EL4-bearing hosts.

Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha ) mRNA induction. Evidence for selective destabilization of TNF-alpha transcripts.

Science.gov (United States)

Rutault, K; Hazzalin, C A; Mahadevan, L C

2001-03-02

Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine whose synthesis and secretion are implicated in diverse pathologies. Hence, inhibition of TNF-alpha transcription or translation and neutralization of its protein product represent major pharmaceutical strategies to control inflammation. We have studied the role of ERK and p38 mitogen-activated protein (MAP) kinase in controlling TNF-alpha mRNA levels in differentiated THP-1 cells and in freshly purified human monocytes. We show here that it is possible to produce virtually complete inhibition of lipopolysaccharide-stimulated TNF-alpha mRNA accumulation by using a combination of ERK and p38 MAP kinase inhibitors. Furthermore, substantial inhibition is achievable using combinations of 1 microm of each inhibitor, whereas inhibitors used individually are incapable of producing complete inhibition even at high concentrations. Finally, addressing mechanisms involved, we show that inhibition of p38 MAP kinase selectively destabilizes TNF-alpha transcripts but does not affect degradation of c-jun transcripts. These results impinge on the controversy in the literature surrounding the mode of action of MAP kinase inhibitors on TNF-alpha mRNA and suggest the use of combinations of MAP kinase inhibitors as an effective anti-inflammatory strategy.

Model for breast cancer survival: relative prognostic roles of axillary nodal status, TNM stage, estrogen receptor concentration, and tumor necrosis.

Science.gov (United States)

Shek, L L; Godolphin, W

1988-10-01

The independent prognostic effects of certain clinical and pathological variables measured at the time of primary diagnosis were assessed with Cox multivariate regression analysis. The 859 patients with primary breast cancer, on which the proportional hazards model was based, had a median follow-up of 60 months. Axillary nodal status (categorized as N0, N1-3 or N4+) was the most significant and independent factor in overall survival, but inclusion of TNM stage, estrogen receptor (ER) concentration and tumor necrosis significantly improved survival predictions. Predictions made with the model showed striking subset survival differences within stage: 5-year survival from 36% (N4+, loge[ER] = 0, marked necrosis) to 96% (N0, loge[ER] = 6, no necrosis) in TNM I, and from 0 to 70% for the same categories in TNM IV. Results of the model were used to classify patients into four distinct risk groups according to a derived hazard index. An 8-fold variation in survival was seen with the highest (greater than 3) to lowest index values (less than 1). Each hazard index level included patients with varied combinations of the above factors, but could be considered to denote the same degree of risk of breast cancer mortality. A model with ER concentration, nodal status, and tumor necrosis was found to best predict survival after disease recurrence in 369 patients, thus confirming the enduring biological significance of these factors.

Increased pulmonary secretion of tumor necrosis factor-alpha in calves experimentally infected with bovine respiratory syncytial virus

DEFF Research Database (Denmark)

Rontved, C. M.; Tjørnehøj, Kirsten; Viuff, B.

2000-01-01

, of which 23 were experimentally infected with BRSV and five were given a mock inoculum. The presence of the cytokine tumor necrosis factor alpha (TNF-alpha) in the BAL fluids was detected and quantified by a capture ELISA. TNF-alpha was detected in 21 of the infected animals. The amount of TNF-alpha...... in the BAL fluid of calves killed post inoculation day (PID) 2 and 4 was at the same very low level as in the uninfected control animals. Large amounts of TNF-alpha were detected on PID 6, maximum levels of TNF-alpha were reached on PID 7, and smaller amounts of TNF-alpha were seen on PID 8. The high levels...... of TNF-alpha appeared on the days where severe lung lesions and clinical signs were obvious and the amounts of BRSV-antigen were at their greatest. Although Pasteurellaceae were isolated from some of the BRSV-infected calves, calves treated with antibiotics before and through the whole period...

Peri-implant parameters, tumor necrosis factor-alpha, and interleukin-1 beta levels in vaping individuals.

Science.gov (United States)

Al-Aali, Khulud A; Alrabiah, Mohammed; ArRejaie, Aws S; Abduljabbar, Tariq; Vohra, Fahim; Akram, Zohaib

2018-03-25

To the author's knowledge, there has been no study that has assessed clinical, radiographic, and immunological peri-implant parameters among individuals vaping e-cigarette (e-cig). This pilot study aimed to compare clinical and radiographic peri-implant parameters and levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β levels among individuals vaping e-cigs and never smoker (NS). Forty-seven individuals vaping e-cigs (group-1) and 45 NS (group-2) were included. Demographic and implant-related data were collected using a structured baseline questionnaire. Peri-implant plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were recorded and peri-implant bone loss (PIBL) were assessed using standardized digital radiographs. Enzyme-linked immunosorbent assay was used to assess the levels of TNF-α and IL-1β in peri-implant sulcular fluid. Bleeding on probing showed statistically significantly higher values in group-2 patients as compared to group-1 patients (P vaping individuals. Increased levels of proinflammatory cytokines in peri-implant sulcular fluid may suggest greater local inflammatory response in vaping individuals for peri-implant inflammation. © 2018 Wiley Periodicals, Inc.

Characterization of a canine tetranucleotide microsatellite marker located in the first intron of the tumor necrosis factor alpha gene.

Science.gov (United States)

Watanabe, Masashi; Tanaka, Kazuaki; Takizawa, Tatsuya; Segawa, Kazuhito; Neo, Sakurako; Tsuchiya, Ryo; Murata, Michiko; Murakami, Masaru; Hisasue, Masaharu

2014-01-01

A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic information content (PIC) value of this microsatellite locus varied from 0.389 to 0.749 and from 0.333 to 0.682, respectively, among the 6 breeds. The allelic frequency differed greatly among breeds, but this microsatellite marker was highly polymorphic and could be a useful marker for the canine TNFA gene.

Association Study of Tumor Necrosis Factor Receptor 1 (TNFR1 Gene Polymorphisms with Schizophrenia in the Polish Population

Directory of Open Access Journals (Sweden)

Renata Suchanek-Raif

2017-01-01

Full Text Available Schizophrenia is a devastating mental disorder with undetermined aetiology. Previous research has suggested that dysregulation of proinflammatory cytokines and their receptors plays a role in developing schizophrenia. We examined the association of the three single nucleotide polymorphisms (SNPs; rs4149576, rs4149577, and rs1860545 in the tumor necrosis factor receptor 1 (TNFR1 gene with the development and psychopathology of paranoid schizophrenia in the Polish Caucasian sample consisting of 388 patients and 657 control subjects. The psychopathology was assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS. SNPs were genotyped using the TaqMan 5′-exonuclease allelic discrimination assay. The SNPs tested were not associated with a predisposition to paranoid schizophrenia in either the entire sample or after stratification according to gender. However, rs4149577 and rs1860545 SNPs were associated with the intensity of the PANSS excitement symptoms in men, which may contribute to the risk of violent behavior. Polymorphisms in the TNFR1 gene may have an impact on the symptomatology of schizophrenia in men.

Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease.

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Shamim, Daniah; Laskowski, Michael

2017-01-01

Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents.

Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis.

Science.gov (United States)

Qiu, Yun; Mao, Ren; Chen, Bai-Li; Zhang, Sheng-Hong; Guo, Jing; He, Yao; Zeng, Zhi-Rong; Ben-Horin, Shomron; Chen, Min-Hu

2017-09-01

It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I 2  = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Anti-tumor activity of polysaccharides extracted from Senecio ...

African Journals Online (AJOL)

Purpose: To optimize the extraction conditions of polysaccharides from the root of Senecio scandens Buch,-Ham. (PRS) and evaluate its anti-tumor effect on hepatocellular carcinoma. Methods: Response surface methodology (RSM) applied with a Box-Behnken design (BBD, three levels and three factors) was employed to ...

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis.

Science.gov (United States)

Bisoendial, Radjesh; Tabet, Fatiha; Tak, Paul P; Petrides, Francine; Cuesta Torres, Luisa F; Hou, Liming; Cook, Adam; Barter, Philip J; Weninger, Wolfgang; Rye, Kerry-Anne

2015-11-01

Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature. © 2015 American Heart Association, Inc.

Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

International Nuclear Information System (INIS)

Konnai, Satoru; Usui, Tatsufumi; Ikeda, Manabu; Kohara, Junko; Hirata, Toh-ichi; Okada, Kosuke; Ohashi, Kazuhiko; Onuma, Misao

2005-01-01

Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-α and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-α-induced responses, in this study we examined the TNF-α-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-α (rTNF-α) was significantly higher than those from AL cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5 + or sIgM + cells and these cells showed resistance to TNF-α-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-α-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection

Selective cytotoxicity of transformed cells but not normal cells by a sialoglycopeptide growth regulator in the presence of tumor necrosis factor

Science.gov (United States)

Woods, K. M.; Fattaey, H.; Johnson, T. C.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

The tumor necrosis factor-alpha (TNF)-resistant, SV40-transformed, murine fibroblast cell lines, F5b and F5m, became sensitive to TNF-mediated cytolysis after treatment with a biologically active 18 kDa peptide fragment (SGP) derived from a 66-kDa parental cell surface sialoglycoprotein. Neither TNF nor the SGP alone exhibited cytotoxicity to the two SV40-transformed cell lines. However, Balb/c 3T3 cells, incubated with SGP alone or with SGP and TNF, were not killed. Therefore, SGP can selectively sensitize cells for TNF alpha-mediated cytotoxicity. This selective sensitization may be due to the previously documented ability of the SGP to selectively mediate cell cycle arrest.

Macrophages control vascular stem/progenitor cell plasticity through tumor necrosis factor-α-mediated nuclear factor-κB activation.

Science.gov (United States)

Wong, Mei Mei; Chen, Yikuan; Margariti, Andriani; Winkler, Bernhard; Campagnolo, Paola; Potter, Claire; Hu, Yanhua; Xu, Qingbo

2014-03-01

Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process. We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation. Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

Anti-tumor effect of a recombinant plasmid expressing human interleukin-12: an initial research

International Nuclear Information System (INIS)

Zheng Chuansheng; Xia Xiangwen; Feng Gansheng; Li Xin; Liang Huimin; Liang Bin

2010-01-01

Objective: To study the anti-tumor effect of a recombinant plasmid expressing human interleukin-12 (pEGFP-CI I L- 12) in vivo and in vitro. Methods: We transduct the recombinant gene (pEGFP-CI I L-12) to liver cancer cell HepG 2 in vitro, and detect reproductive activity of the cell using MTT and the activity of expressing vascular endothelial growth factor(VEGF) using semiquantitative PCR. And then, we deliver the gene to rabbit liver tumor tissue intraarterial and combine with chemoembolization to observe the anti- tumor effect to VX 2 tumor in vivo. Results: There are no statistical difference compared With control group in activity of reproductive and expressing VEGF in vitro. In vivo, tumor growth rate significantly reduce in gene therapy combined with chemoembolization group. Conclusion: Recombinant gene (pEGFP-Cl I L-12) exhibit significant anti-tumor effect in vivo but not in vitro, perhaps the anti-tumor effect is associated with an indirect pathway instead of a direct pathway. (authors)

Effect of Mirtazapine Treatment on Serum Levels of Brain-Derived Neurotrophic Factor and Tumor Necrosis Factor-α in Patients of Major Depressive Disorder with Severe Depression.

Science.gov (United States)

Gupta, Rachna; Gupta, Keshav; Tripathi, A K; Bhatia, M S; Gupta, Lalit K

2016-01-01

This study evaluated the clinical efficacy of mirtazapine and its effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-α (TNF-α) levels in patients of major-depressive disorder (MDD) with severe depression. Patients (aged 18-60) with MDD diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥25 were included (n = 30). Mirtazapine was given in the doses of 30 mg/day. All patients were followed up for 12 weeks for the evaluation of clinical efficacy, safety along with serum BDNF and TNF-α levels. HAM-D score at the start of treatment was 30.1 ± 1.92, which significantly (p depressed patients and treatment response is associated with an increase in serum BDNF and a decrease in serum TNF-α levels. © 2016 S. Karger AG, Basel.

Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α

Directory of Open Access Journals (Sweden)

Anna Janowska-Wieczorek

2012-07-01

Full Text Available Membrane type-1 matrix metalloproteinase (MT1-MMP has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML cells. Because tumor necrosis factor (TNF-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML.

Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α

International Nuclear Information System (INIS)

Marquez-Curtis, Leah A.; Shirvaikar, Neeta; Turner, A. Robert; Mirza, Imran; Surmawala, Amir; Larratt, Loree M.; Janowska-Wieczorek, Anna

2012-01-01

Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML

Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α

Energy Technology Data Exchange (ETDEWEB)

Marquez-Curtis, Leah A.; Shirvaikar, Neeta [Canadian Blood Services R& D, Edmonton, Alberta T6G 2R8 (Canada); Turner, A. Robert [Departments of Medicine and Oncology, University of Alberta, Edmonton, Alberta T6G 2G3 (Canada); Mirza, Imran [Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2B7 (Canada); Surmawala, Amir; Larratt, Loree M. [Departments of Medicine and Oncology, University of Alberta, Edmonton, Alberta T6G 2G3 (Canada); Janowska-Wieczorek, Anna, E-mail: anna.janowska@blood.ca [Canadian Blood Services R& D, Edmonton, Alberta T6G 2R8 (Canada); Departments of Medicine and Oncology, University of Alberta, Edmonton, Alberta T6G 2G3 (Canada)

2012-07-25

Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML.

Necrosis targeted radiotherapy with iodine-131-labeled hypericin to improve anticancer efficacy of vascular disrupting treatment in rabbit VX2 tumor models.

Science.gov (United States)

Shao, Haibo; Zhang, Jian; Sun, Ziping; Chen, Feng; Dai, Xu; Li, Yaming; Ni, Yicheng; Xu, Ke

2015-06-10

A viable rim of tumor cells surrounding central necrosis always exists and leads to tumor recurrence after vascular disrupting treatment (VDT). A novel necrosis targeted radiotherapy (NTRT) using iodine-131-labeled hypericin (131I-Hyp) was specifically designed to treat viable tumor rim and improve tumor control after VDT in rabbit models of multifocal VX2 tumors. NTRT was administered 24 hours after VDT. Tumor growth was significantly slowed down by NTRT with a smaller tumor volume and a prolonged tumor doubling time (14.4 vs. 5.7 days), as followed by in vivo magnetic resonance imaging over 12 days. The viable tumor rims were well inhibited in NTRT group compared with single VDT control group, as showed on tumor cross sections at day 12 (1 vs. 3.7 in area). High targetability of 131I-Hyp to tumor necrosis was demonstrated by in vivo SPECT as high uptake in tumor regions lasting over 9 days with 4.26 to 98 times higher radioactivity for necrosis versus the viable tumor and other organs by gamma counting, and with ratios of 7.7-11.7 and 10.5-13.7 for necrosis over peri-tumor tissue by autoradiography and fluorescence microscopy, respectively. In conclusion, NTRT improved the anticancer efficacy of VDT in rabbits with VX2 tumors.

Anti-tumor and anti-angiogenic ergosterols from Ganoderma lucidum

Science.gov (United States)

Chen, Shaodan; Yong, Tianqiao; Zhang, Yifang; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen

2017-10-01

This study was carried out to isolate chemical constituents from the lipid enriched fraction of Ganoderma lucidum extract and to evaluate their anti-proliferative effect on cancer cell lines and human umbilical vein endothelial cells. Ergosterol derivatives (1-14) were isolated from the lipid enriched fraction of G. lucidum. Their structures were established on the basis of spectroscopic analyses or by comparison of mass and NMR spectral data with those reported previously. Amongst, compound 1 was isolated and identified as a new compound. All the compounds were evaluated for their inhibitory effect on tumor cells and human umbilical vein endothelial cells in vitro. Compounds 9-13 displayed inhibitory activity against two tumor cell lines and human umbilical vein endothelial cells, which indicated that these four compounds had both anti-tumor and anti-angiogenesis activities. Compound 2 had significant selective inhibition against two tumor cell lines, while 3 exhibited selective inhibition against human umbilical vein endothelial cells. The structure–activity relationships for inhibiting human HepG2 cells were revealed by 3D-QASR. Ergosterol content in different parts of the raw material and products of G. lucidum was quantified. This study provides a basis for further development and utilization of ergosterol derivatives as natural nutraceuticals and functional food ingredients, or as source of new potential antitumor or anti-angiogenesis chemotherapy agent.

Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes.

Science.gov (United States)

Carrillo, Eddy H; Gordon, Laura E; Richardson, J David; Polk, Hiram C

2002-03-01

A systemic inflammatory response (SIR) is seen in approximately 75% of patients with complex blunt liver injuries treated nonoperatively. Many feel this response is caused by blood, bile, and necrotic tissue accumulation in the peritoneal cavity. Our current treatment for these patients is a delayed laparoscopic washout of the peritoneal cavity, resulting in a dramatic resolution of the SIR. Spectrophotometric analysis of the intraperitoneal fluid has confirmed the presence of high concentrations of free hemoglobin (Hb). We hypothesize that free Hb enhances the local peritoneal response by increasing tumor necrosis factor-alpha (TNF-alpha) production by monocytes, contributing to the local inflammatory response and SIR. Monocytes from five healthy volunteers were isolated and cultured in RPMI-1640 for 24 hours. Treatment groups included saline controls, lipopolysaccharide ([LPS], 10 ng/mL, from Escherichia coli), human Hb (25 microg/mL), and Hb + LPS. Supernatants were analyzed by enzyme-linked immunosorbent assay. Student's t test with Mann-Whitney posttest was used for statistical analysis with p < or = 0.05 considered significant. Free Hb significantly increased TNF-alpha production 915 +/- 223 pg/mL versus saline (p = 0.02). LPS and Hb + LPS further increased TNF-alpha production (2294 pg/mL and 2501 pg/mL, respectively, p < 0.001) compared with saline controls. These data confirm that free Hb is a proinflammatory mediator resulting in the production of significant amounts of TNF-alpha. These in vitro findings support our clinical data in which timely removal of intraperitoneal free hemoglobin helps prevent its deleterious local and systemic inflammatory effects in patients with complex liver injuries managed nonoperatively.

Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection

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Jintao Xu