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Sample records for plasma tumor necrosis

  1. The Relationship between Plasma Tumor Necrosis Factor and Pneumonia of Tibetan Neonates

    Institute of Scientific and Technical Information of China (English)

    ZHOU Cuojie; DEJI Meiduo; ZHAO Min

    2002-01-01

    This study was to discuss the changing characteristics of plasma tumor necrosis factor (TNF) in Tibetan neonates with pneumonia. Radioimmunoassay was applied to determine the plasma level of TNF in 48 tibetan neonates with pneumonia and 20 healthy term newborns. The results showed that the plasma level of TNF in severe group with pneumonia( 16.075 ± 13. 1603ug/mt) was higher than that in mild group(14.705 ± 13.0162), P < 0.001. The TNF level of these two groups were significantly higher than that of healthy control group(7. 8650 ± 2. 5173ug/mt), P < 0. 001. So, the plasma level of TNF was closely related with the severity of pneumonia. Severer pneumonia was, higher TNF level was.It suggested that TNF was involved in the regulating process in pneumonia.

  2. Mechanisms of tumor cell necrosis.

    Science.gov (United States)

    Proskuryakov, Sergey Y; Gabai, Vladimir L

    2010-01-01

    Until recently, necrosis, unlike apoptosis, was considered as passive and unregulated form of cell death. However, during the last decade a number of experimental data demonstrated that, except under extreme conditions, necrosis may be a well-regulated process activated by rather specific physiological and pathological stimuli. In this review, we consider mechanisms and the role of necrosis in tumor cells. It became recently clear that the major player in necrotic cascade is a protein kinase RIP1, which can be activated by number of stumuli including TNF, TRAIL, and LPS, oxidative stress, or DNA damage (via poly-ADP-ribose polymerase). RIP1 kinase directly (or indirectly via another kinase JNK) transduces signal to mitochondria and causes specific damage (mitochondrial permeability transition). Mitochondrial collapse activates various proteases (e.g., calpains, cathepsin) and phospholipases, and eventually leads to plasma membrane destruction, a hallmark of necrotic cell death. Necrosis, in contrast to apoptosis, usually evokes powerful inflammatory response, which may participate in tumor regression during anticancer therapy. On the other hand, excessive spontaneous necrosis during tumor development may lead to more aggressive tumors due to stimulatory role of necrosis-induced inflammation on their growth.

  3. 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.

  4. DIAGNOSTIC-VALUE OF PLASMA-LEVELS OF TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) AND INTERLEUKIN-6 (IL-6) IN NEWBORNS WITH SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; MARTENS, A; VANRAAN, J; SAMSON, G; FETTER, WPF; OKKEN, A; DELEIJ, LHFM; KIMPEN, J

    The aim of this study was to examine if TNF alpha and IL-6 plasma levels could be of value in diagnosing neonatal sepsis. Tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) plasma levels were determined in 15 newborn infants with confirmed sepsis (group I), 18 with suspected sepsis

  5. 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

    1997-01-01

    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 r

  6. TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1-BETA, AND INTERLEUKIN-6 PLASMA-LEVELS IN NEONATAL SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; MARTENS, A; VANRAAN, J; SAMSON, G; FETTER, WPF; OKKEN, A; DELEIJ, LHFM

    Tumor necrosis factor-alpha, IL-1beta, and IL-6 are thought to be involved in the pathogenesis of sepsis with gram-negative bacteria. We studied these cytokines during neonatal sepsis with mainly gram-positive bacteria. Ten newborns with clinical sepsis and 22 healthy controls were enrolled in the

  7. Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Obradović Dragana

    2012-01-01

    Full Text Available Background/Aim. Multiple sclerosis (MS is an immunemediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha and interleukin-4 (IL-4 in cerebrospinal fluid (CSF and plasma in the MS patients and the controls (other neurological non-inflammatory diseases and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. Methods. This study involved 60 consecutive MS patients - 48 patients with relapsing-remitting MS (RRMS and 12 patients with secondary progressive MS (SPMS. The control group consisted of 20, age and sex matched, nonimmunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7% patients had relapse (RRMS, 14 (23.3% were in remission (RRMS, while the rest of the patients, 12 (20.0%, were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS, albumin ratio and IgG index were determined in all MS patients. Results. The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples. IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001, however plasma levels were similar. The patients in relapse (RRMS and with progressive disease (SPMS had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001. IL-4 CSF levels in relapse (RRMS and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in

  8. The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; Keating, Michael J; Manshouri, Taghi; Giles, Francis J; Dey, Amanda; Estrov, Zeev; Koller, Charles A; Kurzrock, Razelle; Thomas, Deborah A; Faderl, Stefan; Lerner, Susan; O'Brien, Susan; Albitar, Maher

    2002-08-15

    Tumor necrosis factor-alpha (TNF-alpha), a cytokine possessing pleiotropic biological activities, is produced by leukemic lymphocytes in patients with chronic lymphocytic leukemia (CLL) and acts as an autocrine and paracrine growth factor in this disease. In this study, TNF-alpha levels were determined in 150 patients with CLL and correlated with disease characteristics, prognostic factors, and survival. The mean TNF-alpha plasma concentration in the patients with CLL was significantly higher than in the healthy control population (16.4 versus 8.7 pg/mL; P <.0001). Patients having an elevated TNF-alpha level had more advanced Rai and Binet stage disease, higher serum beta(2)-microglobulin (beta(2)M) levels, a greater percentage of cells expressing CD38, and lower hemoglobin and platelet levels. Patients having chromosomal abnormalities such as 11q deletion, trisomy 12, and chromosome 17 aberrations had a higher mean TNF-alpha level (27.5 pg/mL) than patients having a diploid karyotype or other miscellaneous cytogenetic abnormalities (14.2 pg/mL; P <.001). The TNF-alpha level was a predictor of survival when the Cox proportional hazards model was used with TNF-alpha entered as a continuous variable (P =.0001). Also, patients having a TNF-alpha level above the mean value of 14 pg/mL had significantly shorter survival duration (P =.00001). The TNF-alpha level remained predictive of survival in Cox multivariate analysis independent of Rai staging and beta(2)M, hemoglobin, prior therapy, white cell count, and platelet level (P =.005). We conclude that the TNF-alpha level serves as a prognostic factor in patients with CLL and that inhibition of TNF-alpha in these patients could have therapeutic importance.

  9. Imaging Tumor Necrosis with Ferumoxytol.

    Directory of Open Access Journals (Sweden)

    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.

  10. Plasma Tumor Necrosis Factor-alpha (TNF-α) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy.

    Science.gov (United States)

    Wu, Jianxian; Li, Xueming

    2015-12-11

    BACKGROUND Inflammatory responses in utero and in neonates have been involved in the development of white matter lesions. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) in spastic cerebral palsy. MATERIAL AND METHODS Plasma TNF-α was measured by ELISA in 54 children with spastic cerebral palsy and 28 aged-matched controls. Both groups were split into age subgroups (1-3 vs. 4-12). Gross motor function and activities of daily living were assessed on enrollment and after 6 months of rehabilitation. RESULTS TNF-α was higher in patients with cerebral palsy than in controls in young (Pcerebral palsy had significantly higher TNF-α levels compared with older ones (Pcerebral palsy showed higher plasma levels of TNF-α than controls. In addition, pre-treatment TNF-α levels were correlated with the improvements after rehabilitation therapy.

  11. Rat Tumor Response to the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging, Plasma 5-Hydroxyindoleacetic Acid Levels, and Tumor Necrosis

    Directory of Open Access Journals (Sweden)

    Lesley D. McPhail

    2006-03-01

    Full Text Available The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using Ktrans and the integrated area under the gadolinium time curve (IAUGC as response biomarkers. Highperformance liquid chromatography (HPLC was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor Ktrans and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in Ktrans or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.

  12. The Effect of a Prophylactic Dose of Ibuprofen on Plasma Level of Interleukin 1, Interleukin 6 and Tumor Necrosis Factor-Alpha in a 1500 m Running Practice

    Directory of Open Access Journals (Sweden)

    Gholamreza Sepehri

    2011-01-01

    Full Text Available Problem statement: there are controversies about the effects of anti-inflammatory drugs on exercised induced changes on plasma cytokines in untrained male athletes, so the primary purpose of this study was to measure the influence of a prophylactic dose of ibuprofen use on plasma cytokines during a 1500 m running race. Approach: Subjects were 10 untrained male Medical University students who consumed 400 mg ibuprofen two hours before the 1500 m running practice and 10 controls that competed in the race but avoided ibuprofen and all other medications. Blood samples were collected before, 1h and 24 h following the 1500 m exercise bout to measure plasma concentrations of interleukin-1 beta (IL-1β , interleukin-6(IL-6 and tumor necrosis factor alpha (TNF- α . Results: There were not any significant differences between plasma concentration of IL-1β, IL-6 and TNF- α during the study period. Also the data showed that there were not any significant differences between plasma level of IL-1β, IL-6 and TNF- α in ibuprofen and control group during the study period. Conclusions/Recommendation: Our result showed that a prophylactic dose of ibuprofen did not affect acute inflammatory cytokines levels (IL-1β, IL-6 and TNF- α in untrained healthy young males. So the etiology of the muscle soreness in athletes actively participating in sport races seems to be independent of inflammatory processes.

  13. The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol\\/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg\\/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.

  14. Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: a prospective longitudinal study.

    Science.gov (United States)

    Li, Zezhi; Qi, Dake; Chen, Jun; Zhang, Chen; Yi, Zhenghui; Yuan, Chengmei; Wang, Zuowei; Hong, Wu; Yu, Shunying; Cui, Donghong; Fang, Yiru

    2013-01-01

    Although tumor necrosis factor-alpha (TNF-α) has been recognized to be involved in the pathogenesis of major depressive disorder (MDD) for a long time, only few studies so far investigated the effects of antidepressant, venlafaxine on TNF-α and the results are inconsistent. Moreover, the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown. To elucidate these relationships, in the present study, 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited. Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17. Prior to venlafaxine treatment, both responders and non-responders shared a similar plasma TNF-α (p=0.33), which was significantly decreased following venlafaxine treatment (pTNF-α (p=0.01), which was associated with the greater reduction rate of HRSD-17 (B=1.02, p=0.01). In addition, the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients (p=0.84) compared to the healthy controls on admission (p=0.001, p=0.03, respectively). Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy. The extent of TNF-α reduction may be associated with the efficiency of venlafaxine.

  15. Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor alpha in obese women.

    Science.gov (United States)

    Polak, Jan; Klimcakova, Eva; Moro, Cedric; Viguerie, Nathalie; Berlan, Michel; Hejnova, Jindriska; Richterova, Blanka; Kraus, Ivan; Langin, Dominique; Stich, Vladimir

    2006-10-01

    Adipocytokines secreted by adipose tissue are suggested to play a role in the development of obesity-related complications. Regular aerobic exercise has been shown to reduce the risk of metabolic complications in obese subjects. The aim of this study was to investigate the effect of aerobic training on gene expression in subcutaneous abdominal adipose tissue (SCAAT) and on plasma levels of several adipocytokines in obese women. Twenty-five obese sedentary premenopausal women (body mass index, 32.18 +/- 3.17 kg/m(2)) underwent a 12-week aerobic exercise program, with a frequency of 5 d/wk and intensity corresponding to 50% of individual maximal oxygen consumption (V(.-)(O(2)max)) consisting of 2 sessions per week of supervised aerobic exercise and 3 sessions per week of home-based exercise on a bicycle ergometer. Before and after the aerobic training, (V(.-)(O(2)max)) and body composition were measured and plasma and SCAAT biopsy samples (in a subgroup of 8 subjects) were obtained for determination of plasma and messenger RNA levels of adipocytokines (leptin, adiponectin, interleukin 6, tumor necrosis factor alpha). The aerobic training resulted in an increase of subjects' V o(2)max by 12.8% (24.6 +/- 3.9 vs 27.7 +/- 4.8 mL x min(-1) x kg(-1), P < .05). Body weight and fat mass were reduced by 5.9% (88.5 +/- 8.2 vs 83.3 +/- 7.7 kg, P < .001) and 6.4% (38.8 +/- 4.2% vs 36.3 +/- 4.6%, P < .001), respectively, and the revised QUantitative Insulin sensitivity ChecK Index (QUICKI) increased (0.43 +/- 0.06 vs 0.48 +/- 0.06, P < .05) during the aerobic training. No aerobic training-induced changes in messenger RNA levels of the investigated genes in SCAAT were observed. A decrease of plasma leptin (24.3 +/- 8.7 vs 18.1 +/- 8.3 ng/mL, P < .05) was detected, whereas plasma levels of other cytokines remained unchanged. In moderately obese females, 3 months' aerobic training did not promote changes in the adipose tissue gene expression or plasma levels of the adipocytokines

  16. Plasma Levels of Matrix Metalloproteinase (MMP)-2, MMP-9 and Tumor Necrosis Factor-α in Chronic Hepatitis C Virus Patients

    Science.gov (United States)

    Abdel-Latif, Mohamed S

    2015-01-01

    Background: In chronic HCV infection, pathological accumulation of the extracellular matrix is the main feature of liver fibrosis; that indicates the imbalanced rate of increased matrix synthesis to decreased breakdown of connective tissue proteins. Matrix metalloproteinases (MMPs) play a crucial role in remodeling of extracellular matrix. It is known that expression of MMPs is regulated by Tumor necrosis factor (TNF)-α. Also, levels of TNF-α in liver and serum are increased in chronic HCV patient. Accordingly, this study aimed to correlate the plasma levels of MMP-2, MMP-9 and TNF-α in chronic HCV patients with the pathogenesis of the liver. Methods: The current study was conducted on 15 fibrotic liver cases with detectable HCV RNA, 10 HCV cirrhotic liver cases, and 15 control subjects of matched age and sex. Plasma MMP-2, MMP-9 and TNF-α were measured by ELISA. Results: Data revealed that the MMP2, MMP9 and TNF-α levels showed a significant elevation in chronic HCV patients compared to control group (p= 0.001). But, no significant correlation was observed in levels of MMP-2, MMP-9, and TNF-α between fibrotic and cirrhotic cases. Conclusions: MMP-2, MMP-9 and TNF-α showed high reproducibility to differentiate chronic HCV patients from control group. On the contrary, MMP-2, MMP-9 and TNF-α were not able to differentiate fibrotic from cirrhotic liver cases. Thus, MMP-2, MMP-9 and TNF-α could not be correlated with the progression of liver disease. Rather they could be used as prognostic markers of liver fibrosis. PMID:26464613

  17. Changes of interleukin-1β, tumor necrosis factor α and interleukin-6 in brain and plasma after brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    朱涛; 姚智; 袁汉娜; 陆伯刚; 杨树源

    2004-01-01

    Objective: To study the changes of interleukin-1 β (IL-1β), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) levels in brain and plasma after brain injury and to assess the relationship between the cytokine levels and injury severity in rats. Methods: A total of 51 male Wistar rats, weighing 280-340 g, were anesthetized with chloral hydrate (400 mg/kg body weight) through intraperitoneal injection and fixed on a stereotaxic instrument. Severe brain injury was created in 16 rats (severe injury group) and moderate brain injury in 18 rats (moderate injury group) by a fluid percussion model, and cytokine levels of IL-1β, TNFα and IL-6 were measured with biological assay. And sham operation was made on the other 17 rats (control group). Results: In the control group, the levels of IL-1β, TNFα and IL-6 were hardly detected in the cortex of the rats, but in the ipsilateral cortex of the rats in both injury groups, they increased obviously at 8 hours after injury. The increasing degree of these cytokines had no significant difference between the two injury groups. The levels of IL-6 in the plasma of all the rats increased slightly, whereas the levels of IL-1β and TNFα were undetectable. Conclusions: The increase of IL-1β, TNFα and IL-6 levels is closely related to brain injury. The increased cytokine levels in the central nervous system are not parallel to those in the peripheral blood. It suggests that inflammatory cytokines play important roles in the secondary neural damage after brain injury.

  18. Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression.

    Science.gov (United States)

    Schoenberg, K M; Perfield, K L; Farney, J K; Bradford, B J; Boisclair, Y R; Overton, T R

    2011-11-01

    Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n=40) were administered 0, 2.0, or 4.0 mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples collected daily from 22 d before expected parturition through 21 d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d -14, -3, -1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d -14 but cows receiving 2.0 mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5±0.1 ng/mL for 0, 2.0, and 4.0 mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0±0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose)+log(insulin)+log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of

  19. Therapeutic approaches for tumor necrosis factor inhibition

    Directory of Open Access Journals (Sweden)

    Maria Letícia de Castro Barbosa

    2011-09-01

    Full Text Available Tumor necrosis factor (TNF consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.O fator de necrose tumoral (do inglês, tumor necrosis factor - TNF consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produ

  20. Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

    DEFF Research Database (Denmark)

    Madsen, Pernille M; Clausen, Bettina H; Degn, Matilda;

    2016-01-01

    Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor...

  1. Tumor necrosis factor interaction with gold nanoparticles

    Science.gov (United States)

    Tsai, De-Hao; Elzey, Sherrie; Delrio, Frank W.; Keene, Athena M.; Tyner, Katherine M.; Clogston, Jeffrey D.; Maccuspie, Robert I.; Guha, Suvajyoti; Zachariah, Michael R.; Hackley, Vincent A.

    2012-05-01

    We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis, attenuated total reflectance-Fourier transform infrared spectroscopy, fluorescence assay, and enzyme-linked immunosorbent assay. The native TNF used in this study exists in the active homotrimer configuration prior to conjugation. After binding to AuNPs, the maximum surface density of TNF is (0.09 +/- 0.02) nm-2 with a binding constant of 3 × 106 (mol L-1)-1. Dodecyl sulfate ions induce desorption of monomeric TNF from the AuNP surface, indicating a relatively weak intermolecular binding within the AuNP-bound TNF trimers. Anti-TNF binds to both TNF-conjugated and citrate-stabilized AuNPs, showing that non-specific binding is significant. Based on the number of anti-TNF molecules adsorbed, a substantially higher binding affinity was observed for the TNF-conjugated surface. The inclusion of thiolated polyethylene glycol (SH-PEG) on the AuNPs inhibits the binding of anti-TNF, and the amount of inhibition is related to the number ratio of surface bound SH-PEG to TNF and the way in which the ligands are introduced. This study highlights the challenges in quantitatively characterizing complex hybrid nanoscale conjugates, and provides insight on TNF-AuNP formation and activity.We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis

  2. The Link Between Oxidative Stress Response and Tumor Necrosis ...

    African Journals Online (AJOL)

    The Link Between Oxidative Stress Response and Tumor Necrosis Factor-Alpha ... Also, to investigate how this can affect normal hepatic tissues. ... A complex relationship exists between the thyroid gland and the liver in health and disease.

  3. ROLE OF TUMOR NECROSIS FACTOR IN NEONATAL SEPSIS

    Institute of Scientific and Technical Information of China (English)

    史源; 沈际臬; 汪江淮; 李华强; 覃世文; 刘韧

    1994-01-01

    In order to assess the role of tumor necrosis factor (TNF) in neonatal sepsis,plasma TNF levels were deter-mined by a method using L929 cells at the time of septic work-up in 67 neonates.Thirty-three patients with sepsis were found to have significantly higher TNF levels (533.33±468.74U/ml;1U corresponding to 1.67 pg re-combinant TNF)as compared with 34 non-sepsis patients (100.0±188,974U/ml)and 30 healthy newborns (27.33±16.17U/ml,P<0.05,respectively),The upper limit of normal plasma TNF levels was 60U/ml and the best cutoff value for predicting neonatal sepsis was 160U/ml.This had remarkable sensitivity (88%).Plasma TNF levels were significantly associated with the occurrence of shock,organ failure,sclerema and outcome.Thus,anti-TNF anti-bodies might be used in protecting newborns from septic death.

  4. Diagnostic Value of Plasma Tumor Necrosis Factor-α Concentration for Chronic Urticaria%血浆TNF-α浓度对慢性荨麻疹的诊断价值

    Institute of Scientific and Technical Information of China (English)

    雷素珍

    2012-01-01

    Objective To investigate the changes of plasma necrosis factor-α concentration in patients with chronic urticaria and analyze its diagnostic value. Methods 86 patients with chronic urticaria and 86 healthy controls were enrolled in this study. Determining plasma tumor necrosis factor-α (TNF-α) concentration with ELISA. Statistical analysis was taken. Results Plasma TNF-α concentration was significantly higher in patients than those of healthy controls (4.2 ±1.8 ng/ml vs 1.8 ±0.7)ng/ml, P2.8 ng/ml) that dignosed chronic urticaria with high sensitivity (83.1% ) and specificity (79. 1% ) respectively. Conclusion TNF-α may be involved in pathogenesis of chronic urticaria, and its concentration can effectively in diagnosis of chronic urticaria.%目的:揭示慢性荨麻疹患者血浆肿瘤坏死因子-α(TNF-α)浓度的变化,分析其对慢性荨麻疹的诊断价值.方法:选取门诊治疗的慢性荨麻疹患者及健康体检者各86例,ELISA检测血浆TNF-α浓度,对数据进行统计分析.结果:慢性荨麻疹患者血浆TNF-α浓度(4.2±1.8)ng/ml显著高于对照组(1.8±0.7)ng/ml(P2.8 ng/ml),对诊断慢性荨麻疹有较高的灵敏度(83.7%)和特异度(79.1%).结论:TNF-α可能参与慢性荨麻疹的发病机制,其浓度可有效诊断慢性荨麻疹.

  5. [The effect of tumor necrosis factor alpha on hepatic necrosis in viral hepatitis].

    Science.gov (United States)

    Yu, Y; Si, C; Lang, Z

    1996-01-01

    In order to investigate the effect of tumor necrosis factor alpha (TNF alpha) on hepatocyte necrosis in viral hepatitis, TNF alpha with or without D-galactosamine (D-Gal) was injected into the abdominal cavity of rats. No effect was observed after injection of TNF alpha alone. After injection of TNF alpha with D-Gal, the total bilirubin level in rat blood increased and hepatocyte necrosis appeared (P hepatic tissue were stained with anti-TNF alpha McAb by using ABC immunohistochemistry method. It was found that more severe the hepatocyte necrosis, more the positive cells expressing TNF alpha. There were more TNF alpha positive cells in the tissue of severe hepatitis. These results suggested that TNF alpha is a mediator in hepatocyte necrosis.

  6. 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...

  7. El factor de necrosis de los tumores o caquectina

    Directory of Open Access Journals (Sweden)

    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.

  8. Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis

    DEFF Research Database (Denmark)

    Ciurea, A.; Weber, U.; Stekhoven, D.

    2015-01-01

    Objective. To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. The Journal of Rheumatology, Methods.We compared newly initiated TNF inhibition for axSpA in 363 patients...

  9. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

    Directory of Open Access Journals (Sweden)

    Claudia Hernández-Jiménez

    Full Text Available The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5, mechanical ventilation with dry oxygen dispensation, and Group II (n = 5, mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77. This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05. Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02. Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  10. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

    Science.gov (United States)

    Hernández-Jiménez, Claudia; García-Torrentera, Rogelio; Olmos-Zúñiga, J Raúl; Jasso-Victoria, Rogelio; Gaxiola-Gaxiola, Miguel O; Baltazares-Lipp, Matilde; Gutiérrez-González, Luis H

    2014-01-01

    The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5), mechanical ventilation with dry oxygen dispensation, and Group II (n = 5), mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77). This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05). Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02). Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  11. Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.

    Directory of Open Access Journals (Sweden)

    Eiji Kakazu

    Full Text Available BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys and secrete substantial amounts of L-Glutamate (L-Glu via the transport system Xc- (4F2hc+xCT, and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM, and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19, the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.

  12. High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan

    NARCIS (Netherlands)

    Zwaveling, JH; Maring, JK; Clarke, FL; vanGinkel, RJ; Limburg, PC; Hoekstra, HJ; Girbes, ARJ; Schraffordt Koops, H.

    1996-01-01

    Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreat ment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissu

  13. High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes

    DEFF Research Database (Denmark)

    Sandmand, Marie; Bruunsgaard, Helle; Kemp, Kåre

    2003-01-01

    BACKGROUND: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-alpha are strongly associated with morbidity an...

  14. Biochemical characterization and metabolic effects of the tumor necrosis factor

    OpenAIRE

    Martins e Silva, J.

    1991-01-01

    The tumor necrosis factor, preliminary identified because of its antitumor properties, refers to two kinds of similar polypeptides (TNF or cachectin, and TNF-fl or lymphotoxin), which share some biolo gical effects. Both substances, as members of the class of cytokines, play a role as mediators of inflam mation and the celiular immune response. Human cachectin is produced as a prohormone and activated by cleavage of a 76 residue peptide. Mature cachectin (with comprises 157 aminoa...

  15. Modulation of tumor necrosis factor by microbial pathogens.

    OpenAIRE

    Rahman, Masmudur M.; Grant McFadden

    2006-01-01

    In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor) is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcom...

  16. Molecular mechanism of signaling by tumor necrosis factor

    Institute of Scientific and Technical Information of China (English)

    ZHA; Jikun(查纪坤); SHU; Hongbing(舒红兵)

    2002-01-01

    Tumor necrosis factor (TNF) is an important cytokine with multiple biological effects,including cell growth,differentiation,apoptosis,immune regulation and induction of inflammation. The effects of TNF are mediated by two receptors,TNF-R1 and TNF-R2. The major signal transduction pathways triggered by TNF include those that lead to apoptosis,activation of transcription factor NF-??B and protein kinase JNK. This review will discuss the molecular mechanisms of these signaling pathways.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats.

    NARCIS (Netherlands)

    Hoenig, M.; McGoldrick, J.B.; Beer, M. de; Demacker, P.N.M.; Ferguson, D.C.

    2006-01-01

    Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with r

  19. The relationship between tumor necrosis factor-α gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome

    Institute of Scientific and Technical Information of China (English)

    刘辉国

    2006-01-01

    Objective To investigate the relationship between tumor necrosis factor-α(TNF-α) gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods The plasma TNF-αlevel of OSAHS group and non-OSAHS group was detected by enzyme-linked immunosorbent assay (ELISA). Eighteen patients with severe OSAHS were treated with continuous

  20. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats.

    NARCIS (Netherlands)

    Hoenig, M.; McGoldrick, J.B.; Beer, M. de; Demacker, P.N.M.; Ferguson, D.C.

    2006-01-01

    Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with r

  1. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats.

    NARCIS (Netherlands)

    Hoenig, M.; McGoldrick, J.B.; Beer, M. de; Demacker, P.N.M.; Ferguson, D.C.

    2006-01-01

    Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with

  2. Disassociated relation between plasma tumor necrosis factor-α, interleukin-6 and increased body weight in Amerindian women: A long-term prospective study of natural body weight variation and impaired glucose tolerance

    Directory of Open Access Journals (Sweden)

    Lindgärde Folke

    2010-06-01

    Full Text Available Abstract Background Inflammatory cytokines are linked to obesity-related insulin resistance and may predict type 2 diabetes independently of obesity. We previously reported that a majority of a cohort of 73 non-diabetic women with normal plasma (p-glucose with Amerindian heritage in Lima, Peru, during a 5-year period increased both body weight and p-glucose levels, yet p-insulin was unaltered. A high proportion of palmitoleic acid (16:1n-7 in serum (s and systolic blood pressure (SBP were independent predictors of high p-glucose. Whether cytokines also contributed is, however, not known. Methods During 5 years we prospectively investigated the relation between changed concentrations of p-tumor necrosis factor (TNF-α, p-interleukin (IL-6 and circulating insulin and glucose in relation to the natural variation of body weight. Study variables included anthropometric measurements, p-insulin, TNF-α, IL-6, SBP and the proportion of 16:1n-7 in s-fatty acid composition. Results Weight and waist differences correlated negatively to the difference in p-TNF-α but positively to differences in p-IL-6 and p-insulin, whereas the increase of p-glucose from baseline to follow-up did not correlate with changes in levels of the two cytokines. In multiple regression analysis changes of TNF-α and insulin contributed independently to the variance in weight. P-insulin at baseline and weight change were determinants of fasting p-insulin at follow-up. Multiple regression analysis revealed that weight change (t-value = - 2.42; P = 0.018 and waist change (t-value = 2.41; P = 0.019 together with S-16:1n-7 (p Conclusion Our prospective study of Amerindian women revealed disassociations between changes in p-TNF-α and p-IL-6 in relation to variation in body weight. A high proportion of s-16:1n-7, SBP at baseline together with weight and waist changes were independent predictors of p-glucose at follow-up. The exact role of the opposite effects and clinical impact of p

  3. NO ASSOCIATION BETWEEN TUMOR NECROSIS FACTOR ALPHA AND OBSESSIVE COMPULSIVE DISORDER IN CHINESE HAN POPULATION

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Objective To investigate association between tumor necrosis factor alpha (TNF-α) and obsessive compulsive disorder (OCD) in Chinese Han population.Methods Plasma concentrations of TNF-α were measured in 61 drug-free patients who fulfilled DSM-Ⅳ criteria for OCD and 93 healthy controls.TNF-α concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA).Two polymorphisms of TNF-α gene were investigated in the same patients and healthy controls:-308 G/A and-238 G/A.The allelic and genoty...

  4. Herceptin conjugates linked by EDC boost direct tumor cell death via programmed tumor cell necrosis.

    Directory of Open Access Journals (Sweden)

    Jiemiao Hu

    Full Text Available Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride, are capable of engendering human epidermal growth factor receptor 2 (Her2 positive tumor cells death. Using a high-performance liquid chromatography (HPLC system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also induced Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism that often results from antibody treatment, the Herceptin trimer elicited effective and direct tumor cell death via a novel mechanism: programmed cell necrosis. In Her2-positive cells, inhibition of necrosis pathways significantly reversed Herceptin trimer-induced cell death. In summary, the Herceptin trimer reported herein harbors great potential for overcoming tumor cell resistance to Herceptin treatment.

  5. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  6. Tumor necrosis factor and cancer, buddies or foes?

    Institute of Scientific and Technical Information of China (English)

    Xia WANG; Yong LIN

    2008-01-01

    Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory eytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-κB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.

  7. Soluble and cell surface receptors for tumor necrosis factor

    DEFF Research Database (Denmark)

    Wallach, D; Engelmann, H; Nophar, Y

    1991-01-01

    Tumor necrosis factor (TNF) initiates its multiple effects on cell function by binding at a high affinity to specific cell surface receptors. Two different molecular species of these receptors, which are expressed differentially in different cells, have been identified. The cDNAs of both receptor...... have recently been cloned. Antibodies to one of these receptor species (the p55, type I receptor) can trigger a variety of TNF like effects by cross-linking of the receptor molecules. Thus, it is not TNF itself but its receptors that provide the signal for the response to this cytokine...... in certain pathological situations. Release of the soluble receptors from the cells seems to occur by proteolytic cleavage of the cell surface forms and appears to be a way of down-regulating the cell response to TNF. Because of their ability to bind TNF, the soluble receptors exert an inhibitory effect...

  8. Role of mononuclear phagocyte function in endotoxin-induced tumor necrosis

    NARCIS (Netherlands)

    Hofhuis, F.M.A.; Bloksma, N.; Willers, J.M.N.

    1984-01-01

    The temporal susceptibility of tumors to induction of necrosis and regression by endotoxin was investigated further with a focus on the role of the putative mediator, tumor necrosis factor (TNF). Production of this factor was shown earlier to require prior activation of the mononuclear phagocytic sy

  9. Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria

    OpenAIRE

    Stoelcker, Benjamin; Hehlgans, Thomas; Weigl, Karin; Bluethmann, Horst; Grau, Georges E.; Männel, Daniela N

    2002-01-01

    Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.

  10. Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice

    OpenAIRE

    Knight, Belinda; Yeoh, George C.T.; Husk, Kirsten L.; Ly, Tina; Abraham, Lawrence J; Yu, Changpu; Rhim, Jonathan A.; Fausto, Nelson

    2000-01-01

    Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TN...

  11. 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.

  12. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

    OpenAIRE

    Spriggs, D; Imamura, K; Rodriguez, C; Horiguchi, J; Kufe, D W

    1987-01-01

    Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production...

  13. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB;

    2006-01-01

    Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients...

  14. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor.

    Science.gov (United States)

    Farma, Jeffrey M; Puhlmann, Markus; Soriano, Perry A; Cox, Derrick; Paciotti, Giulio F; Tamarkin, Lawrence; Alexander, H Richard

    2007-06-01

    Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.

  15. Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

    Science.gov (United States)

    Torres, David; Janot, Laure; Quesniaux, Valerie F.J.; Grivennikov, Sergei I.; Maillet, Isabelle; Sedgwick, Jonathon D.; Ryffel, Bernhard; Erard, Francois

    2005-01-01

    Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF−/−) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (104 CFU) but succumbed at a higher dose of infection (105 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF−/−, mice protected TNF−/− mice from fatal infection. Taken together the data suggest that in the absence of soluble TNF, the presence of membrane-expressed TNF on phagocytes and lymphocytes partially restores host defense to LM infection. PMID:16314479

  16. Tumor necrosis factor-alpha inhibitor treatment for sarcoidosis

    Directory of Open Access Journals (Sweden)

    José Luis Callejas-Rubio

    2008-12-01

    Full Text Available José Luis Callejas-Rubio, Lourdes López-Pérez, Norberto Ortego-CentenoUnit of Autoimmune Systemic Diseases, Hospital Clinico San Cecilio, Granada, SpainAbstract: Sarcoidosis is a chronic multisystem disease of unknown etiology, characterized by noncaseating granulomatous infiltration of virtually any organ system. Treatment is often undertaken in an attempt to resolve symptoms or prevent progression to organ failure. Previous studies have suggested a prominent role for tumor necrosis factor-alpha (TNF-α in the inflammatory process seen in sarcoidosis. TNF-α and interleukin-1 are released by alveolar macrophages in patients with active lung disease. Corticosteroids have proved to be efficacious in the treatment of sarcoidosis, possibly by suppressing the production of TNF-α and other cytokines. Three agents are currently available as specific TNF antagonists: etanercept, infliximab, and adalimumab. Although data from noncomparative trials suggest that all three have comparable therapeutic effects in rheumatoid arthritis, their effects in a granulomatous disease such as sarcoidosis are less consistent. In this review, current data on the effectiveness are summarized.Keywords: sarcoidosis, infliximab, etanercept, adalimumab, anti-TNA alpha

  17. Modulation of tumor necrosis factor by microbial pathogens.

    Directory of Open Access Journals (Sweden)

    2006-02-01

    Full Text Available In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcome or deflect the host responses mediated by TNF. For example, modulatory proteins encoded by multiple families of viruses can block TNF and TNF-mediated responses at multiple levels, such as the inhibition of the TNF ligand or its receptors, or by modulating key transduction molecules of the TNF signaling pathway. Bacteria, on the other hand, tend to modify TNF-mediated responses specifically by regulating components of the TNF signaling pathway. Investigation of these diverse strategies employed by viral and bacterial pathogens has significantly advanced our understanding of both host TNF responses and microbial pathogenesis. This review summarizes the diverse microbial strategies to regulate TNF and how such insights into TNF modulation could benefit the treatment of inflammatory or autoimmune diseases.

  18. Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

    Directory of Open Access Journals (Sweden)

    Gabriel Olmos

    2014-01-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; this de novo production of TNF-α is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca+2 permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons. Thus, the net effect of TNF-α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS. As microglial activation and upregulation of TNF-α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-α signaling may represent a valuable target for intervention.

  19. Modulation of topoisomerase activities by tumor necrosis factor.

    Science.gov (United States)

    Baloch, Z; Cohen, S; Fresa, K; Coffman, F D

    1995-01-01

    A number of chemotherapeutic agents which inhibit the DNA topoisomerases markedly potentiate cell death mediated by tumor necrosis factor, suggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were assayed following TNF addition to murine L929 cells. Topoisomerase I and II activities increased within 15 min of TNF addition and returned to baseline levels within 1 and 2 hr, respectively. The increases in both topoisomerase activities were blocked by H-7 (but not H-8) and similar increases were seen following PMA addition. However, concentrations of H-7 which blocked the increased topoisomerase activities had no effect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity by topoisomerase inhibitors. Thus, in these cells topoisomerase activities are directly modified by TNF during the initial phases of a cytotoxic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the TNF-mediated increases in topoisomerase activities.

  20. Purification of human immunoglobulin G autoantibodies to tumor necrosis factor using affinity chromatography and magnetic separation.

    Science.gov (United States)

    Sennikov, S V; Golikova, E A; Kireev, F D; Lopatnikova, J A

    2013-04-30

    Autoantibodies to cytokines are important biological effector molecules that can regulate cytokine activities. The aim of the study was to develop a protocol to purify autoantibodies to tumor necrosis factor from human serum, for use as a calibration material to determine the absolute content of autoantibodies to tumor necrosis factor by enzyme-linked immunosorbent assay. The proposed protocol includes a set of affinity chromatography methods, namely, Bio-Gel P6DG sorbent to remove albumin from serum, Protein G Sepharose 4 Fast Flow to obtain a total immunoglobulin G fraction of serum immunoglobulins, and Affi-Gel 15 to obtain specifically antibodies to tumor necrosis factor. The addition of a magnetic separation procedure to the protocol eliminated contaminant tumor necrosis factor from the fraction of autoantibodies to tumor necrosis factor. The protocol generated a pure fraction of autoantibodies to tumor necrosis factor, and enabled us to determine the absolute concentrations of different subclasses of immunoglobulin G autoantibodies to tumor necrosis factor in apparently healthy donors.

  1. Effects of endotoxin and tumor necrosis factor alpha on regional brain neurotransmitters in mice.

    Science.gov (United States)

    Cho, L; Tsunoda, M; Sharma, R P

    1999-01-01

    Alterations in regional brain concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites were investigated in male BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS, 2 mg kg(-1)) or recombinant murine tumor necrosis factor alpha (TNFalpha, 0.1 mg kg(-1)) at 2, 6, 12 and 24 h after the injection. At 2 h post-injection the LPS administration resulted in hypothermia, which was not apparent at later time points. No consistent effects were observed by either LPS or TNFalpha on peripheral leukocyte counts or plasma transaminase levels. Both LPS and TNFalpha slightly elevated NE metabolism in the striatum at 2-12 h. Concentrations of DA and its metabolites were significantly elevated only in the hypothalamus following TNFalpha at 24 h. Tumor necrosis factor alpha exerted pronounced effects on 5-HT metabolism in most brain regions at 2 h. Results suggest that the effect of LPS is more complex compared with TNFalpha because of the endogenous production of other cytokines including the TNFalpha.

  2. 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 morta...... as confounders. CONCLUSION: TNF-alpha was an independent prognostic marker for mortality in persons aged 100 years, suggesting that it has specific biological effects and is a marker of frailty in the very elderly.......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...

  3. 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.

  4. 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

  5. Tumor necrosis factor gene expression in regular hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Hemmat E El Haddad

    2015-01-01

    Full Text Available This study evaluates tumor necrosis factor (TNF-alfa gene expression in patients with end-stage renal disease (ESRD on regular hemodialysis as an expression of cardiovascular disease (CVD risk even on a sub-clinical level and its relation to some of the parameters incriminated in the pathogenesis and the establishment of uremic arteriopathy. A total of 51 patients with ESRD on regular hemodialysis and 20 healthy subjects matching in age and gender as a control group were recruited. All selected cases were subjected to serum lipid profile, Creactive protein (CRP, TNF-alfa gene expression and Doppler study of carotid arteries to estimate carotid intimal media thickness (cIMT. Serum triglycerides (TGS level (P <0.001, CRP positivity (P = 0.002, relative quantification (RQ of TNF-alfa gene expression (P = 0.007 and cIMT (P = 0.02 were significantly higher while high-density lipoprotein (HDL level (P <0.001 was significantly lower among cases compared with controls. RQ showed a significant positive correlation with CRP titer (rho = 0.583, P = 0.011. Results also showed a significant strong negative correlation between with CRP titer and cIMT (rho = -0.590, P = 0.010. CRP titer showed only a significant strong negative correlation with age (rho = -0.589, P = 0.01 and positive correlation with HDL (rho = 0.51, P = 0.031. Patients with ESRD have increased gene expression of TNF-alfa and CRP titer together with increased atherosclerosis as expressed by increased cIMT.

  6. Determination of Plasma L-selectin and Tumor Necrosis Factor-αConcentrations in Patients with Chronic Bronchitis and Its Clinical Values%慢性支气管炎患者血浆L-selectin和TNF-α的检测及临床价值

    Institute of Scientific and Technical Information of China (English)

    汪清

    2013-01-01

    Objective To explore plasma L-selectin and tumor necrosis factor-a levels in patients with chronic bronchitis and their clinical values were evaluated. Methods Ninety-eight patients and equal number of healthy controls were enrolled into this stud-y. Plasma L-selectin and tumor necrosis factor-a concentrations were measured by ELISA. Results Plasma L-selectin and TNF-α levels were markedly higher in patients with chronic bronchitis than those in healthy controls (all P<0.01) , and in acute exacerbation than in clinical recovery (all P<0.01). They were significantly associated with diverse variables of arterial blood gas (all P<0.01). Conclusion L-selectin and tumor necrosis factor-a are involved in the pathophysiological process of chronic bronchitis and their determination can be beneficial to evaluate severity and prognostication of chronic bronchitis.%目的:揭示慢性支气管炎患者血浆L-选择素(L-selectin)和肿瘤坏死因子-α(TNF-α)浓度的变化,探讨其临床价值.方法:收集慢性支气管炎患者和同期体检健康者各98例.ELISA检测血浆L-selectin和TNF-α浓度.结果:慢性支气管炎患者血浆L-selectin和TNF-α浓度均显著高于健康体检正常者(均P<0.01),急性发作期患者血浆L-selectin和TNF-α浓度均显著高于临床缓解期患者(均P<0.01),慢性支气管炎患者血浆L-selectin和TNF-α浓度与动脉血气指标显著相关(均P<0.01).结论:L-selectin和TNF-α参与慢性支气管炎的病理生理过程,指标测定有助于评估慢性支气管炎病情轻重及预后.

  7. Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

    NARCIS (Netherlands)

    M.A. Stammes (Marieke A.); Knol-Blankevoort, V.T. (Vicky T.); Cruz, L.J. (Luis J.); Feitsma, H.R.I.J. (Hans R. I. J.); L. Mezzanotte (Laura); Cordfunke, R.A. (Robert A.); Sinisi, R. (Riccardo); Dubikovskaya, E.A. (Elena A.); Maeda, A. (Azusa); DaCosta, R.S. (Ralph S.); Bierau, K. (Katja); Chan, A. (Alan); E.L. Kaijzel (Eric); T.J.A. Snoeks (thomas); E.R. van Beek (Ermond); C.W.G.M. Löwik (Clemens)

    2016-01-01

    textabstractPurpose: Recently we showed that a number of carboxylated near-infrared fluorescent (NIRF) cyanine dyes possess strong necrosis avid properties in vitro as well as in different mouse models of spontaneous and therapy-induced tumor necrosis, indicating their potential use for cancer diagn

  8. Factor de necrosis tumoral alfa en una población infanto-juvenil con sobrepeso

    National Research Council Canada - National Science Library

    Teresita del R. Carrizo; Elba I. Díaz; María S. Velarde; María M. Prado; María C. Bazán; Adela V. Abregú

    2013-01-01

    El sobrepeso infantil está asociado a sobrepeso/obesidad en la edad adulta. El tejido adiposo en obesos produce una cantidad incrementada de citoquinas proinflamatorias como el factor de necrosis tumoral alfa (TNF...

  9. Testicular Seminoma With Pseudocyst and Coagulation Necrosis Like Burned-out Tumor: A Case Report

    Directory of Open Access Journals (Sweden)

    Tatsuhiko Hoshii

    2016-07-01

    Full Text Available Testicular seminoma is a relatively common testicular cancer; however, testicular seminoma with pseudocyst is an extremely rare. The ‘burned-out’ phenomenon in germ cell tumors refers to a germ cell tumor in extra-gonadal tissues with spontaneous regression of an intra-gonadal tumor. We present a case of the testicular seminoma with pseudocyst and coagulation necrosis like burned-out tumor without metastasis.

  10. 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.

  11. A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis.

    Science.gov (United States)

    Delahunt, Brett; McKenney, Jesse K; Lohse, Christine M; Leibovich, Bradley C; Thompson, Robert Houston; Boorjian, Stephen A; Cheville, John C

    2013-03-01

    Grading of renal cell carcinoma (RCC) has prognostic significance, and there is recent consensus by the International Society of Urological Pathology (ISUP) that for clear cell and papillary RCC, grading should primarily be based on nucleolar prominence. Microscopic tumor necrosis also predicts outcome independent of tumor grading. This study was undertaken to assess whether the incorporation of microscopic tumor necrosis into the ISUP grading system provides survival information superior to ISUP grading alone. Data on 3017 patients treated surgically for clear cell RCC, 556 for papillary RCC, and 180 for chromophobe RCC were retrieved from the Mayo Clinic Registry. Median follow-up periods were 8.9, 9.7, and 8.5 years, respectively. Four proposed grades were defined: grade 1: ISUP grade 1+ISUP grade 2 without necrosis; grade 2: ISUP grade 2 with necrosis+ISUP grade 3 without necrosis; grade 3: ISUP grade 3 with necrosis+ISUP grade 4 without necrosis; grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors. There was a significant difference in survival between each of the grades for clear cell RCC, and the concordance index was superior to that of ISUP grading. The proposed grading system also outperformed the ISUP grading system when cases were stratified according to the TNM stage. Similar results were not obtained for papillary RCC or chromophobe RCC. We conclude that grading for clear cell RCC should be based on nucleolar prominence and necrosis, that ISUP grading should be used for papillary RCC, and that chromophobe RCC should not be graded.

  12. Tumor Necrosis Factor-Superfamily 15 Gene Expression in Patients with Sickle Cell Disease

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    Ahmet Ata Özçimen

    2014-09-01

    Full Text Available OBJECTIVE: The aim of this study was to investigate the relation between tumor necrosis factor-superfamily 15 (TNFSF15 gene expression and clinical findings in children with sickle cell disease (SCD. METHODS: Forty-nine patients with SCD and 38 healthy controls were included in this study. TNFSF15 gene expression and plasma levels were analyzed. TNFSF15 gene expression was compared in subgroups considering the frequency of painful crises and acute chest syndrome (ACS. RESULTS: It was found that TNFSF15 gene expression was significantly higher in patients with SCD than the controls (p=0.001, whereas there was no significant difference between the patients with SCD and the control groups considering plasma levels of TNFSF15. TNFSF15 gene expression was also significantly higher in SCD patients with ACS (p=0.008. CONCLUSION: These findings suggest that TNFSF15 may have a role in the pathogenesis of SCD presenting with ACS. Further studies on larger groups are needed to determine the function of TNFSF15 in SCD patients with ACS and pulmonary hypertension. Analysis of TNFSF15 expression may also serve as a promising approach in ACS therapy.

  13. Effect of interleukin-1 and tumor necrosis factor/cachectin on glucose turnover in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Flores, E.A.; Istfan, N.; Pomposelli, J.J.; Blackburn, G.L.; Bistrian, B.R. (Harvard Medical School, Boston, MA (USA))

    1990-07-01

    We studied the effect of recombinant human interleukin-1 beta (IL-1) and recombinant human tumor necrosis factor alpha/cachectin (TNF) on glucose kinetics in healthy rats by means of a primed constant infusion of D-(6-3H)glucose and D-(U-{sup 14}C)glucose. During the isotope (6-hour) and monokine (4-hour) infusion, plasma levels of glucagon and insulin were determined and correlated with changes in glucose metabolism. The rates of glucose appearance (Ra) and disappearance (Rd) were elevated only with IL-1 and were associated with an increase in glucagon and a concomitant decrease in the ratio of insulin to glucagon. Plasma glucose concentration was increased early after IL-1 administration and coincided with the peak in the Ra. The augmentation of the metabolic clearance rate (MCR) and percent of flux oxidized by IL-1 suggest that this monokine induces the utilization of glucose as a substrate. TNF administration failed to modify the Ra or Rd, percent of flux oxidized, or MCR. TNF-treated rats increased the percent of glucose recycling, but not the total rate of glucose production. The results of this experiment suggest that endogenous macrophage products participate in the diverse alterations of carbohydrate metabolism seen during injury and/or infection.

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

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The levels of lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression in culture of peripheral blood mononuclear cells (PBMC) and the plasma levels of IL-6 and TNF-α in the patients with obstructive sleep apnea syndrome (OSAS) were measured and the relationship between OSAS and IL-6 or TNF-α expression studied. Both IL-6 and TNF-α were detected by using ELISA in 22 patients with OSAS and 16 normal controls. The levels of LPS-induced IL-6 (787.82±151.97 pg/ml) and TNF-α (4165.45±1501.43 pg/ml) expression in the supernatant of the culture of PBMC and plasma level of IL-6 (50.67±4.70 pg/ml) and TNF-α (299.09±43.57 pg/ml) in the patients with OSAS were significantly higher than those in the normal controls (in the supernatant of the culture of PBMC: 562.69±197.54 pg/ml and 1596.25±403.08 pg/ml respectively; in the plasma: 12.69±2.75 pg/ml and 101.88±21.27 pg/ml respectively). There were significantly positive correlation between the levels of IL-6 and TNF-α and the percentage of time of apnea and hyponea, as well as the percentage of time spending at SaO2 below 90 % in the total sleep time. It was concluded that LPS-induced IL-6 and TNF-α levels as well as plasma IL-6 and TNF-α levels in the patients with OSAS were up-regulated, which may be associated with the pathogenesis of OSAS.

  15. Influence of tumor necrosis factor α in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    von der Schulenburg, Johann-Matthias

    2005-12-01

    Full Text Available Objective: Rheumatoid arthritis (RA is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor α (TNF-α have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-α. Etanercept is a soluble human TNF-α receptor. The report assesses the efficacy of TNF-α-antagonists to down-regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. Methods: A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. Results: Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and

  16. Influence of tumor necrosis factor α in rheumatoid arthritis

    Science.gov (United States)

    Kulp, Werner; Corzillus, Michael; Greiner, Wolfgang; Pientka, Ludger; Siebert, Uwe; von der Schulenburg, Johann-Matthias; Wasem, Jürgen

    2005-01-01

    Objective Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor α (TNF-α) have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-α. Etanercept is a soluble human TNF-α receptor. The report assesses the efficacy of TNF-α-antagonists to down-regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. Methods A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. Results Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and practice guidelines

  17. Phillyrin, a natural lignan, attenuates tumor necrosis factor α-mediated insulin resistance and lipolytic acceleration in 3T3-L1 adipocytes.

    Science.gov (United States)

    Kong, Poren; Zhang, Linlin; Guo, Yuyu; Lu, Yingli; Lin, Dongping

    2014-07-01

    In obese adipose tissue, tumor necrosis factor-α secreted from macrophages plays an important role in the adipocyte dysfunctions, including insulin resistance, lipolytic acceleration, and changes of adipokines, which promote the development of obesity-related complications. Phillyrin, an active ingredient found in many medicinal plants and certain functional foods, elicits anti-obesity and anti-inflammatory properties in vivo. The aim of the current study was to investigate the role of phillyrin in preventing tumor necrosis factor α-induced insulin resistance or lipolytic acceleration in 3T3-L1 adipocytes. Our results showed that phillyrin partially restored insulin-stimulated 2-DOG uptake, which was reduced by tumor necrosis factor-α, with concomitant restoration in serine phosphorylation of insulin receptor substrate-1 and insulin-stimulated Glut4 translocation to plasma membrane. Phillyrin also dose-dependently prevented tumor necrosis factor α-stimulated adipocyte lipolysis with preserved downregulation of perilipin. The mitogen-activated protein kinases and I kappaB kinase activation was promoted in tumor necrosis factor α-stimulated adipocytes, but pretreatment with 40 µM phillyrin inhibited the phosphorylation of extracellular signal-regulated kinases1/2, stress-activated protein kinase/Jun N-terminal kinase and I kappaB kinase (padipocytes and RAW 264.7 macrophages, the enhanced productions of tumor necrosis factor-α and free fatty acids in the medium were significantly reduced by phillyrin (padipocyte dysfunctions induced by tumor necrosis factor-α through suppression of the activation of I kappaB kinase and N-terminal kinase. Phillyrin may have the potential to ameliorate the inflammatory changes and insulin resistance in obese adipose tissue. Georg Thieme Verlag KG Stuttgart · New York.

  18. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

    OpenAIRE

    Yamada, Yasuhiro; Kirillova, Irina; Peschon, Jacques J.; Fausto, Nelson

    1997-01-01

    The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-κB and STAT3 transcription factors shortly after...

  19. MRI Brain Tumor Segmentation and Necrosis Detection Using Adaptive Sobolev Snakes

    Science.gov (United States)

    Nakhmani, Arie; Kikinis, Ron; Tannenbaum, Allen

    2014-01-01

    Brain tumor segmentation in brain MRI volumes is used in neurosurgical planning and illness staging. It is important to explore the tumor shape and necrosis regions at different points of time to evaluate the disease progression. We propose an algorithm for semi-automatic tumor segmentation and necrosis detection. Our algorithm consists of three parts: conversion of MRI volume to a probability space based on the on-line learned model, tumor probability density estimation, and adaptive segmentation in the probability space. We use manually selected acceptance and rejection classes on a single MRI slice to learn the background and foreground statistical models. Then, we propagate this model to all MRI slices to compute the most probable regions of the tumor. Anisotropic 3D diffusion is used to estimate the probability density. Finally, the estimated density is segmented by the Sobolev active contour (snake) algorithm to select smoothed regions of the maximum tumor probability. The segmentation approach is robust to noise and not very sensitive to the manual initialization in the volumes tested. Also, it is appropriate for low contrast imagery. The irregular necrosis regions are detected by using the outliers of the probability distribution inside the segmented region. The necrosis regions of small width are removed due to a high probability of noisy measurements. The MRI volume segmentation results obtained by our algorithm are very similar to expert manual segmentation. PMID:25302005

  20. Extended postinterventional tumor necrosis-implication for outcome in liver transplant patients with advanced HCC.

    Directory of Open Access Journals (Sweden)

    Arno Kornberg

    Full Text Available BACKGROUND: Locoregional interventional bridging therapy (IBT is an accepted neoadjuvant approach in liver transplant candidates with hepatocellular carcinoma (HCC. However, the prognostic value of IBT in patients with advanced HCC is still undefined. AIM: The aim of this trial was to evaluate the impact of postinterventional tumor necrosis on recurrence-free long-term survival after liver transplantation (LT in patients with HCC, especially focusing on those exceeding the Milan criteria on pretransplant radiographic imaging. PATIENTS AND METHODS: A total of 93 consecutive liver transplant candidates with HCC were included in this trial. In 36 patients, tumors were clinically staged beyond Milan criteria prior LT. Fifty-nine patients underwent IBT by transarterial chemoembolization or radiofrequency ablation pretransplantation. Postinterventional tumor necrosis rate as assessed at liver explant pathology was correlated with outcome post-LT. RESULTS: There was no significant difference in 5-year tumor-free survival rate between the IBT- and the non-IBT subpopulation (78% versus 68%, P=0.25. However, tumor response following IBT (≥ 50% tumor necrosis rate at explant pathology resulted in a significantly better outcome 5 years post-LT (96% than tumor non-response to IBT (<50% tumor necrosis rate at explant pathology; 21%; P<0.001. Five-year recurrence-free survival rate was 80% in Milan Out patients with extended post-IBT tumor necrosis versus 0% in Milan Out patients without tumor response to IBT (P<0.001. None of macromorphological HCC features, but only the absence of increased (18F-fluoro-deoxy-glucose ((18FDG uptake on pretransplant positron emission tomography (PET was identified as independent predictor of postinterventional tumor response (P<0.001. CONCLUSION: Our results implicate that extended postinterventional tumor necrosis promotes recurrence-free long-term survival in patients with HCC beyond standard criteria. Pretransplant PET

  1. Prediction of mutant activity and its application in molecular design of tumor necrosis factor-a

    Institute of Scientific and Technical Information of China (English)

    唐卫东; 奚涛; 王波; 郭冬林; 徐贤秀; 朱德煦

    1997-01-01

    Two models for prediction of the activity and stability of site-directed mutagenesis on tumor necrosis factor-α are established. The models are based on straightforward structural considerations, which do not require the elaboration of site-directed mutagenesis on the protein core and the hydrophobic surface area by analyzing the properties of the mutated amino acid residues. The reliabilities of the models have been tested by analyzing the mutants of tumor necrosis factor-α (TNF-α) whose two leucine residues (L29, L157) were mutated. Based on these models, a TNF-α mutant with high activity was created by molecular design.

  2. Tumor necrosis factor-alpha induced enhancement of cryosurgery

    Science.gov (United States)

    Goel, Raghav; Paciotti, Guilio F.; Bischof, John C.

    2008-02-01

    Local recurrence of cancer after cryosurgery is related to the inability to monitor and predict destruction of cancer (temperatures > -40°C) within an iceball. We previously reported that a cytokine adjuvant TNF-α could be used to achieve complete cancer destruction at the periphery of an iceball (0 to -40°C). This study is a further development of that work in which cryosurgery was performed using cryoprobes operating at temperatures > -40°C. LNCaP Pro 5 tumor grown in a dorsal skin fold chamber (DSFC) was frozen at -6°C after TNF-α incubation for 4 or 24 hours. Tumors grown in the hind limb were frozen with a probe tip temperature of -40°C, 4 or 24 hours after systemic injection with TNF-α. Both cryosurgery alone or TNF-α treatment alone caused only a minimal damage to the tumor tissue at the conditions used in the study. The combination of TNF-α and cryosurgery produced a significant damage to the tumor tissue in both the DSFC and the hind limb model system. This augmentation in cryoinjury was found to be time-dependent with 4-hour time period between the two treatments being more effective than 24-hour. These results suggests the possibility of cryotreatment at temperatures > -40°C with the administration of TNF-α.

  3. miR-29a suppresses MCF-7 cell growth by downregulating tumor necrosis factor receptor 1.

    Science.gov (United States)

    Zhao, Yiling; Yang, Fenghua; Li, Wenyuan; Xu, Chunyan; Li, Li; Chen, Lifei; Liu, Yancui; Sun, Ping

    2017-02-01

    Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to

  4. Tumor necrosis factor (TNF)-alpha, soluble TNF receptors and endometrial cancer risk : the EPIC study

    NARCIS (Netherlands)

    Dossus, Laure; Becker, Susen; Rinaldi, Sabina; Lukanova, Annekatrin; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Chabbert-Buffet, Nathalie; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise; Teucher, Birgit; Chang-Claude, Jenny; Pischon, Tobias; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vasiliki; Valanou, Elisavet; Palli, Domenico; Sieri, Sabina; Tumino, Rosario; Sacerdote, Carlotta; Galasso, Rocco; Redondo, Maria-Luisa; Bonet Bonet, Catalina; Molina-Montes, Esther; Altzibar, Jone M.; Chirlaque, Maria-Dolores; Ardanaz, Eva; Bueno-de-Mesquita, H. Bas; van Duijnhoven, Franzel J. B.; Peeters, Petra H. M.; Onland-Moret, N. Charlotte; Lundin, Eva; Idahl, Annika; Khaw, Kay-Tee; Wareham, Nicholas; Allen, Naomi; Romieu, Isabelle; Fedirko, Veronika; Hainaut, Pierre; Romaguera, Dora; Norat, Teresa; Riboli, Elio; Kaaks, Rudolf

    2011-01-01

    Chronic inflammation has been hypothesized to play a role in endometrial cancer development. Tumor necrosis factor-alpha (TNF-alpha), one of the major pro-inflammatory cytokines, has also been implicated in endometrial physiology. We conducted a case-control study nested within the European prospect

  5. Association of tumor necrosis factor polymorphisms with susceptibility to ulcerative colitis in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    曹倩

    2006-01-01

    Objective To investigate the association between tumor necrosis factor(TNF) promoter polymorphisms and susceptibility to ulcerative colitis (UC) in the Chinese Han population. Methods Blood samples from 110 unrelated UC patients and 292 healthy controls from Zhejiang Province, Eastern China were studied. Genotyping for 6 common TNF promoter polymorphisms (TNF-

  6. Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells

    NARCIS (Netherlands)

    Endres, S; Sinha, B; Fülle, H J

    1994-01-01

    Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nu

  7. Interleukin-10 and soluble tumor necrosis factor receptors in cerebrospinal fluid of children with bacterial meningitis

    NARCIS (Netherlands)

    Kornelisse, R.F.; Savelkoul, H.F.J.; Mulder, P.H.G.; Suur, M.H.; Straaten, van der P.J.C.; Heijden, van der A.J.; Sukhai, R.N.; Hählen, K.; Neijens, H.J.; Groot, de R.

    1996-01-01

    The antiinflammatory mediators interleukin (IL)-10 and soluble tumor necrosis factor (TNF) receptors p55 (sTNFR-55) and sTNFR-75 in cerebrospinal fluid (CSF) from 37 children with bacterial meningitis were studied. CSF concentrations of IL-10, sTNFR-55, and sTNFR-75 and of the proinflammatory cytoki

  8. 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 molecules

  9. Structural Biology of Tumor Necrosis Factor Demonstrated for Undergraduates Instruction by Computer Simulation

    Science.gov (United States)

    Roy, Urmi

    2016-01-01

    This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The…

  10. T cells activate the tumor necrosis factor-alpha system during hemodialysis, resulting in tachyphylaxis

    NARCIS (Netherlands)

    van Riemsdijk, I C; Baan, C C; Loonen, E H; Knoop, C J; Navarro Betonico, G; Niesters, H G; Zietse, R; Weimar, W

    2001-01-01

    BACKGROUND: The immunosuppressive state of hemodialysis (HD) patients is accompanied by activation of antigen-presenting cell-derived cytokines, for example, tumor necrosis factor-alpha (TNF-alpha), which are required for T-cell activation. To test whether an activated TNF-alpha system results in im

  11. Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways

    NARCIS (Netherlands)

    Langen, R.C.J.; Schols, A.M.W.J.; Kelders, M.C.J.M.; van der Velden, A.L.J.; Wouters, E.F.M.; Janssen, Y.M.W.

    2002-01-01

    Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways. Langen RC, Schols AM, Kelders MC, Van Der Velden JL, Wouters EF, Janssen-Heininger YM. Department of Pulmonology, Maastricht University, The Netherlands. Muscle wasting accompanies diseases that are as

  12. 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 in

  13. Study on the association between tumor necrosis factor α gene polymorphism and systemic lupus erythematosus.

    Institute of Scientific and Technical Information of China (English)

    王敏

    1999-01-01

    Objective: To examine whether polymorphism within the tumor necrosis factor α(TNFα) gene is associated with the susceptibility and clinic manifestations to systemic lupus erythe matosus (SLE) in the patients of Han ethnic group collected from the Northern China. Methods: TNF1 and TNF2 subtypes

  14. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor

    DEFF Research Database (Denmark)

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

    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 infa...

  15. 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...

  16. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

    DEFF Research Database (Denmark)

    El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar

    2013-01-01

    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

  17. 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.......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....

  18. Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor.

    OpenAIRE

    Lantz, M.; Gullberg, U; Nilsson, E; OLSSON, I.

    1990-01-01

    Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammatory responses. A cysteine-rich, highly glycosylated 30-kD TNF-binding protein (TNF-BP) purified from urine may have a role in regulation because it protects in vitro against the biological effects of TNF. The cytotoxic effect of TNF on the fibrosarcoma cell line WEHI 164 was inhibited by 50% at a 10-fold excess of TNF-BP. The binding of TNF to the receptor was partially reversed after the addition of TNF-BP. Results from biosyn...

  19. Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

    Directory of Open Access Journals (Sweden)

    Ayesha Fatima

    2015-01-01

    Full Text Available Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ and the Nuclear factor κB (NF-κB component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis.

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

    Science.gov (United States)

    Brock, C; Brock, B; Aziz, Q; Møller, H J; Pfeiffer Jensen, M; Drewes, A M; Farmer, A D

    2016-12-12

    The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-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 warrants further evaluation in larger controlled studies.

  1. Carbohydrate plasma expanders for passive tumor targeting

    DEFF Research Database (Denmark)

    Hoffmann, Stefan; Caysa, Henrike; Kuntsche, Judith

    2013-01-01

    The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include...

  2. Time courses of PIVKA-II and AFP levels after hepatic artery embolization and hepatic artery infusion against hepatocellular carcinoma: relation between the time course and tumor necrosis.

    Science.gov (United States)

    Kishi, K; Sonomura, T; Mitsuzane, K; Nishida, N; Kimura, M; Satoh, M; Yamada, R; Kodama, N; Kinoshita, M; Tanaka, H

    1992-01-01

    We examined 35 untreated patients with unresectable hepatocellular carcinoma who exhibited positivity for both plasma PIVKA-II and serum AFP, and studied the weekly course of these markers from the pre-TAE or -HAI period to the third week of treatment. We correlated changes in these markers with the tumor necrosis rate and the time course on X-ray CT images. One week after TAE, the tumor necrosis rate and the time course of PIVKA-II showed a significant correlation (r = 0.7), while the correlation was between the time course of AFP and the tumor necrosis rate was insignificant (r = 0.2). At two and three weeks after TAE, both the time course of AFP and PIVKA-II showed significant correlations with the tumor necrosis rate. In 16 patients with tumor necrosis rates of not less than 90%, the mean of the actual half-life (AHL) of PIVKA-II was 3.2 days, the shortest was 1.83 days, and 75% of all AHLs clustered from two days to four days, while the mean and shortest AHLs of AFP were six days and 2.98 days, respectively, exhibiting a broader distribution. On the other hand, in three out of the nine cases of hepatocellular carcinoma complicated with portal tumor thrombi, PIVKA-II increased after HAI in spite of a reduction in tumor size. It was suggested that the PIVKA-II level requires careful interpretation in cases of portal vein obstruction after intensive hepatic arterial infusion of anticancer agents.

  3. Naringin Inhibits Tumor Growth And Reduces Interleukin-6 And Tumor Necrosis Factor α Levels In Rats With Walker 256 Carcinosarcoma

    OpenAIRE

    Camargo C.A.; Gomes-Marcondes M.C.C.; Wutzki N.C.; Aoyama H.

    2012-01-01

    The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus. Patients with cancer generally present features of malnutrition and cachexia. Levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are raised in patients with cancer. This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma (W256). Rats were treated intraperitoneally with different doses o...

  4. 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...... 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...... by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  5. 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.

  6. Cytomegalovirus colitis in a patient with Behcet's disease receiving tumor necrosis factor alpha inhibitory treatment

    Institute of Scientific and Technical Information of China (English)

    Ismail Sari; Merih Birlik; Can Gonen; Server Akar; Duygu Gurel; Fatos Onen; Nurullah Akkoc

    2008-01-01

    Anti-tumor necrosis factor alpha (TNF-α) inhibitors are effective in the treatment of various inflammatory rheumatic conditions. Increased risks of serious infections are the major issues concerning the long-term safety of these agents. We present a case of a young male Behcet's patient whose disease was complicated by cytomegalovirus (CMV) colitis. Colitis started 10 d after the third Infliximab dose and responded to the cessation of TNF blocking treatment and administration of ganciclovir. Tumor necrosis factor alpha and interferon gamma act at several levels in combating viral infections.CMV infections should be kept in mind and included in the differential diagnosis of severe gastrointestinal symptoms in patients receiving anti-TNF agents.

  7. 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

    2016-11-25

    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.

  8. INTERLEUKIN-6, INTERLEUKIN-8 AND TUMOR NECROSIS FACTOR-α EXPRESSION IN ULCERATIVE COLITIS

    Institute of Scientific and Technical Information of China (English)

    李琪佳; 宫恩聪; 刘叔平; 鄂文

    2001-01-01

    Objectve To study the new insight into the pathogenesis of ulcerative colitis. Methods Interleukin-6 (IL-6), Interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) mRNA expression were assessed in the intestinal mucosa of active (n=32) and inactive (n=18) phase using in situ hybridization. Immunohistochemistry for different leukocyte subsets was performed in biopsy specimens of the intestinal mucosa from 50 patients with ulcerative colitis and 5 healthy controls.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Endothelial cells undergo morphological, biomechanical, and dynamic changes in response to tumor necrosis factor-α

    OpenAIRE

    Stroka, Kimberly M.; Vaitkus, Janina A.; Aranda-Espinoza, Helim

    2012-01-01

    The immune response triggers a complicated sequence of events, one of which is release of the cytokine tumor necrosis factor-α (TNF-α) from stromal cells such as monocytes and macrophages. In this work we explored the biophysical effects of TNF-α on endothelial cells (ECs), including changes in cell morphology, biomechanics, migration, and cytoskeletal dynamics. We found that TNF-α induces a wide distribution of cell area and aspect ratio, with these properties increasing on average during tr...

  11. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1

    OpenAIRE

    1986-01-01

    Tumor necrosis factor/cachectin (TNF) has been implicated as a mediator of the host response in sepsis and neoplasia. Recent work has shown that TNF can modulate endothelial cell hemostatic properties, suggesting that endothelium is a target tissue for TNF. This led us to examine whether endothelial cells have specific binding sites for TNF and augment the biological response to TNF by elaborating the inflammatory mediator, IL-1. Incubation of 125I-recombinant human TNF with confluent, cultur...

  12. Roles of tumor necrosis factor alpha on sperm acrosin activity and acrosome reaction

    Institute of Scientific and Technical Information of China (English)

    Shu-LingBian; Guo-YiLiu; Hai-XiaWen; Shu-ZhenWang; JiangNi; WeiZhang; HuiSi

    2004-01-01

    Aim: To study the roles of tumor necrosis factor alpha (TNF-a)on the sperm acrosin activity and acrosome reaction. Methods:The sperm acrosin activity was tested by the method of BAEE/ADH Unity and the acrosome reaction by the Triple-stain technique. Results: TNF-a decreased the sperm acrosin activityand acrosome reaction (P<0.01, P<0.01, respectively);

  13. TUMOR NECROSIS FACTOR-α INHIBITORS IN THE TREATMENT OF AXIAL SPONDYLOARTHRITIS, INCLUDING ANKYLOSING SPONDYLITIS

    Directory of Open Access Journals (Sweden)

    S. A. Lapshina

    2016-01-01

    Full Text Available The paper provides guidelines for the use of tumor necrosis factor-α  (TNF-α inhibitors in the treatment of patients with axial spondyloarthritis  (axSpA, including ankylosing spondylitis. It gives data on the efficacy of TNF-α inhibitors in patients with non-radiographic axSpA. By using international and Russian guidelines, the authors lay down indications for this therapy and criteria for evaluation of its efficiency and safety.

  14. Tumor Necrosis Factor and Lymphotoxin-α Polymorphisms and Severe Malaria in African Populations

    OpenAIRE

    Taane G Clark; Diakite, Mahamadou; Auburn, Sarah; Campino, Susana; Fry, Andrew E.; Green, Angela; Richardson, Anna; Small, Kerrin; Teo, Yik Y; Wilson, Jonathan; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Griffiths, Michael J.; Peshu, Norbert

    2009-01-01

    The tumor necrosis factor gene (TNF) and lymphotoxin-α gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving > 10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF −238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were ...

  15. Anti-Tumor Necrosis Factor Alpha for Retinal Diseases: Current Knowledge and Future Concepts

    OpenAIRE

    Alireza Mirshahi; René Hoehn; Katrin Lorenz; Christina Kramann; Holger Baatz

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers ar...

  16. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

    OpenAIRE

    2007-01-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune...

  17. Augmentation of the effect of doxorubicin with low-dose tumor necrosis factor in experimental liver metastasis.

    Science.gov (United States)

    Bloom, N D; Norbergs, D A; Sherman, B; Sadjadi, M; Ramaswamy, G; Jacobs, R; Ackerman, N

    1990-06-01

    The antitumor activity of recombinant human tumor necrosis factor was studied in vivo as a single agent and in combination with a conventional chemotherapeutic agent. Dosages of tumor necrosis factor of 100 micrograms, 50 micrograms, and 25 micrograms were injected intraportally in Sprague-Dawley rats containing hepatic implants of Walker carcinosarcoma. An effect on the tumor was seen but was associated with a significant acute mortality. Lower dosages of tumor necrosis factor, 10 micrograms, 5 micrograms, and 1 microgram, administered with 10 mg/kg of doxorubicin (Adriamycin) significantly enhanced the antitumor effect of doxorubicin without an acute mortality. This suggests that lower dosages of tumor necrosis factor with conventional chemotherapy may augment the latter's effect without any added toxicity.

  18. Immunological effects of a tumor necrosis factor alpha-armed oncolytic adenovirus.

    Science.gov (United States)

    Hirvinen, Mari; Rajecki, Maria; Kapanen, Mika; Parviainen, Suvi; Rouvinen-Lagerström, Noora; Diaconu, Iulia; Nokisalmi, Petri; Tenhunen, Mikko; Hemminki, Akseli; Cerullo, Vincenzo

    2015-03-01

    For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.

  19. 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...

  20. 儿童睡眠呼吸暂停与血浆血管内皮生长因子和肿瘤坏死因子α的相关性研究%Relationship between plasma vascular endothelial growth factor and tumor necrosis factor-alpha and obstructive sleep apnea hypopnea syndrome in children

    Institute of Scientific and Technical Information of China (English)

    李健; 李闯; 柴丽萍; 龚未池

    2014-01-01

    Objective To investigate the relation of plasma vascular endothelial growth factor (VEGF) and tumor necrosis factor-α(TNF-α) with obstructive sleep apnea-hypopnea syndrome(OSAHS) in children.Methods Eighty children were recruited from October 2008 to March 2009,including 60 children with snoring and 20 healthy children without snoring as control.Plasma VEGF or TNF-α concentration was measured by enzyme-linked immunosorbent assay (ELISA) respectively.Sixty children with snoring underwent an overnight polysomnography test their PSG data,including whole night mean saturation (MSaO2),lowest oxygen saturation (LSaO2),desatuation cumulate time/total sleep time (DCT/TST),oxygen desaturation index 3 (ODI3),apnea-hypopnea index (AHI),obstructive apnea index (OAI),were collected and analysed.SPSS 13.0 software was used to analyze the data.Results The levels of plasma VEGF and TNF-α in children with OSAHS (540.45 pg/ml and 311.94 pg/ml) were higher than those in children with snoring alone (234.45 pg/ml and 97.55 pg/ml) or those in healthy children (259.80 pg/ml and 120.70 pg/ml),with statistically significant differences (HC value:14.176 and 15.571,P < 0.05,respectively),but with no statistical difference between children with snoring alone and healthy children (P > 0.05).The differences in plasma VEGF or TNF-α levels between children with moderate and severe hypoxemia and children with mild hypoxemia were not statistically significant (P > 0.05).Spearman rank correlation analysis showed no significant correlation between plasma level of VEGF or TNF-α and LSaO2,MSaO2,ODI3,DCT/TST,OAI,AHI or BMI (r values were <0.5,P>O.05).Conclusion Plasma levels of VEGF and TNF-α increase in children with OSAHS.%目的 了解血浆血管内皮生长因子(vascular endothelial growth factor,VEGF)和肿瘤坏死因子α(tumor necrosis factor-alpha,TNF-α)在儿童阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患儿体内的变化,探讨OSAHS患儿血浆VEGF和TNF-α水

  1. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL.

    Science.gov (United States)

    Griffith, T S; Wiley, S R; Kubin, M Z; Sedger, L M; Maliszewski, C R; Fanger, N A

    1999-04-19

    TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-gamma or -alpha and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.

  2. Tumor necrosis factor-alpha augmented tumor response in B16BL6 melanoma-bearing mice treated with stealth liposomal doxorubicin (Doxil) correlates with altered Doxil pharmacokinetics.

    NARCIS (Netherlands)

    Brouckaert, P.; Takahashi, N.; Tiel, S.T.; Hostens, J.; Eggermont, A.M.M.; Seynhaeve, A.L.; Fiers, W.; Hagen, T.L.M. ten

    2004-01-01

    The application of tumor necrosis factor-alpha (TNF) for the treatment of solid tumors is limited by its severe, life-threatening, toxicity. Therefore, only low dosages of this cytokine can be applied systemically, which results in poor tumor response. It has been demonstrated previously that

  3. Cyberknife radiosurgery for cranial plasma cell tumor.

    Science.gov (United States)

    Alafaci, Cetty; Grasso, Giovanni; Conti, Alfredo; Caffo, Mariella; Salpietro, Francesco Maria; Tomasello, Francesco

    2014-01-01

    Cranial and intracranial involvement by myelomatous disease is relatively uncommon. Furthermore, systemic manifestations of multiple myeloma are present in the majority of these cases at the time of symptom onset. The authors report the case of a patient with serial appearance of multiple intracranial plasma cell tumor localizations as the first manifestations of a multiple myeloma. The patient was treated with CyberKnife radiosurgery for a lesion localized at the clivus and sella turcica with complete local control. With such a technique, based on high-dose conformality, the tumor was centered with an ablative dose of radiation and, at the same time, with a low dose spreading to the surrounding critical structures. The radiosensitivity of plasma cell tumors renders this treatment modality particularly advantageous for their localized manifestation. A technical description of this case is provided. To our knowledge, this is the first case of successful Cyberknife radiosurgery of multifocal intracranial plasmacytoma.

  4. Anti-tumor necrosis factor therapy inhibits lung metastasis in an osteosarcoma cell line.

    Science.gov (United States)

    Kato, Hiroaki; Wakabayashi, Hiroki; Naito, Yohei; Kato, Sho; Nakagawa, Taro; Matsumine, Akihiko; Sudo, Akihiro

    2015-01-01

    Osteosarcoma is the most common primary malignancy of bone, and patients often develop pulmonary metastases. In a previous study, tumor necrosis factor (TNF)-α treatment of human osteosarcoma cells increases their metastatic ability in an animal model. TNF-α can act as a tumor necrosis factor and also as a tumor-promoting factor. In the present study, the effect of a TNF-α inhibitor on osteosarcoma aggressiveness and pulmonary metastases was investigated in vitro and in vivo. The effect of infliximab, a TNF-α inhibitor, on a metastatic osteosarcoma 143B cell growth and motility was investigated in vitro. An orthotopic xenograft model of 143B cell growth and spontaneous metastasis in SCID mice was used to assess the in vivo effect of infliximab. Infliximab greatly reduced cell motility and pulmonary metastases in 143B cells. The mechanism of pulmonary metastasis inhibition involved decreased expression of CXC chemokine receptor 4 (CXCR4), Rho (small GTPase protein), and its effector. These results suggest a novel role for TNF-α inhibition in the reduction or prevention of pulmonary metastases of osteosarcoma in this animal model. TNF-α inhibition may become a preventive therapeutic option for the pulmonary metastases of osteosarcoma. © 2014 S. Karger AG, Basel.

  5. [Profile of use of anti tumor necrosis factor in Colombian patients].

    Science.gov (United States)

    Machado, Jorge; Moncada, Juan Carlos; Pineda, Ricardo

    2011-06-01

    Tumor necrosis factor-alpha antagonists (anti-TNFα) have shown an increasing consumption and generate a significant economic burden on health systems. The prescribing patterns of tumor necrosis factor-alpha antagonists were determined in a patient population associated with the Sistema General de Seguridad Social en Salud in Colombia. A descriptive observational study was conducted in 316 patients with respect to use of tumor necrosis factor-alpha antagonists during a treatment period from January 2008 to June 2009. The database examined contained indications of use, inclusion criteria to medication, duration of illness, co-morbidities and adverse reactions. The data were retrieved from the clinical histories. Student's t test was used for the comparison of quantitative variables, and the chi-square test was used to establish associations between categorical variables and multivariate analysis were used. Mean age was 44.613.9 years; 63.9% of participants were female. Of the 316 patients, 17.1% received monotherapy. The order of prescription drugs was as follows: adalimumab (37.3%), infliximab (37.3%) and etanercept (25.4%), all were prescribed in appropriately defined daily doses. Co-medication drugs most frequently prescribed were: disease-modifying anti-rheumatic (82.9%), NSAIDs (29.1%), omeprazole (22.5%), antihypertensives (21.2%), folic acid (19.9%) calcium plus vitamin D (9.8%), calcitriol (6.0%). 10.4% of patients had a record of some adverse drug reaction. The average cost of therapy per patient per year was US$23,464. Anti-TNFα are being used at recommended doses, particularly in rheumatoid arthritis and in combination with other anti-rheumatic drugs. The direct cost of therapy was high for the country's health system.

  6. Bilateral optic neuropathy associated with the tumor necrosis factor-alpha inhibitor golimumab.

    Science.gov (United States)

    Chang, Jessica R; Miller, Neil R

    2014-12-01

    A 62-year-old man developed bilateral blurred vision associated with bilateral optic disc swelling shortly after receiving his third dose of the tumor necrosis factor-alpha (TNF-α) inhibitor golimumab, that he took for psoriatic arthritis. An extensive assessment including magnetic resonance imaging, lumbar puncture, and serologies was negative. He was treated with systemic corticosteroids and the golimumab was stopped, after which his vision improved and his disc swelling resolved. We postulate that the bilateral, simultaneous anterior optic neuropathies in this patient were due to golimumab, representing a rare but well-documented serious adverse event associated with TNF-α inhibitors.

  7. Expression of soluble human tumor necrosis factor receptor Ⅰ in Aspergillus niger

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The cDNA of soluble human tumor necrosis factor receptorⅠ(sTNFRI) was inserted into fusion-protein expression plasmid pIGF of A. niger to construct fusion expression vector pHBC containing a KEX2 like protein processing site designed on the fusion position. Extracellular protease-deficient strain of A. niger 3.795-1-23 was transformed with pHBC. Positive clone was estimated by Southern hybridization. SDS-PAGE for protein produced by re-combinant strain showed the distinctive expression band. Western blotting indicated that the secreted protein had immunoactivity of sTNFRI.

  8. Iron-independent induction of ferritin H chain by tumor necrosis factor.

    OpenAIRE

    Miller, L L; Miller, S C; Torti, S. V.; Tsuji, Y; Torti, F M

    1991-01-01

    Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulatin...

  9. Coupling purification and on-column PEGylation of tumor necrosis factor alpha analogue.

    Science.gov (United States)

    Milunović, Tatjana; Kunstelj, Menči; Fidler, Katarina; Anderluh, Gregor; Gaberc Porekar, Vladka

    2012-11-15

    Trends in preparation of PEGylated protein drugs strive for simple, fast, and cheap processes, resulting in well-defined homogeneous products. We investigated the on-column PEGylation of tumor necrosis factor alpha (TNF-α), where purification and conjugation were performed in one step by using immobilized metal affinity chromatography (IMAC). The same quality of the PEGylated product was obtained by the on-column approach starting from either the crude Escherichia coli protein extract or the purified protein. In comparison with the PEGylation in solution, the on-column approach resulted in more homogeneous PEGylated product. The on-column PEGylation reduces the number of production steps, costs, and preparation time.

  10. High Serum Interleukin-10 and Tumor Necrosis Factor Alpha Levels in Chronic Paracoccidioidomycosis

    Science.gov (United States)

    Fornari, M. C.; Bava, A. J.; Guereño, M. T.; Berardi, V. E.; Silaf, M. R.; Negroni, R.; Diez, R. A.

    2001-01-01

    In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean ± standard error of the mean), were higher than in normal controls (n = 8): 186 ± 40 versus 40 ± 7 (P < 0.05), 203 ± 95 versus 20 ± 8 (P = 0.001), and 96.3 ± 78.57 versus 1.19 ± 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls. PMID:11527826

  11. Fármacos que inhiben el factor de necrosis tumoral α y embarazo

    OpenAIRE

    Cristian Simon, Petru; Vallano Ferraz, Antonio

    2013-01-01

    Pregunta: ?Es segura la administración de los fármacos que inhiben el factor de necrosis tumoral a (TNF-a) durante el embarazo? Respuesta: En los últimos años se han desarrollado medicamentos que inhiben el TNF-a, porque esta citocina tiene un efecto inflamatorio que condiciona el proceso patológico de diversas enfermedades autoinmunitarias sistémicas, como artritis reumatoide, psoriasis, enfermedades inflamatorias intestinales y otras. Actualmente existen en el mercado farmacéutico 5 fármaco...

  12. Neutrophil Recruitment by Tumor Necrosis Factor from Mast Cells in Immune Complex Peritonitis

    Science.gov (United States)

    Zhang, Yan; Ramos, Bernard F.; Jakschik, Barbara A.

    1992-12-01

    During generalized immune complex-induced inflammation of the peritoneal cavity, two peaks of tumor necrosis factor (TNF) were observed in the peritoneal exudate of normal mice. In mast cell-deficient mice, the first peak was undetected, and the second peak of TNF and neutrophil influx were significantly reduced. Antibody to TNF significantly inhibited neutrophil infiltration in normal but not in mast cell-deficient mice. Mast cell repletion of the latter normalized TNF, neutrophil mobilization, and the effect of the antibody to TNF. Thus, in vivo, mast cells produce the TNF that augments neutrophil emigration.

  13. Tumor Necrosis Factor and the Pathogenesis of Pichinde Virus Infection in Guinea Pigs

    OpenAIRE

    Aronson, Judith F.; Herzog, Norbert K.; Jerrells, Thomas R.

    1995-01-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage–adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. ...

  14. Fármacos que inhiben el factor de necrosis tumoral α y embarazo

    OpenAIRE

    Cristian Simon, Petru; Vallano Ferraz, Antonio

    2013-01-01

    Pregunta: ?Es segura la administración de los fármacos que inhiben el factor de necrosis tumoral a (TNF-a) durante el embarazo? Respuesta: En los últimos años se han desarrollado medicamentos que inhiben el TNF-a, porque esta citocina tiene un efecto inflamatorio que condiciona el proceso patológico de diversas enfermedades autoinmunitarias sistémicas, como artritis reumatoide, psoriasis, enfermedades inflamatorias intestinales y otras. Actualmente existen en el mercado farmacéutico 5 fármaco...

  15. 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.

  16. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    OpenAIRE

    1992-01-01

    The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell- associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on...

  17. Factor de necrosis tumoral alfa en una población infanto-juvenil con sobrepeso

    OpenAIRE

    Teresita del R. Carrizo; Elba I. Díaz; María S. Velarde; María M. Prado; María C. Bazán; Abregú, Adela V.

    2013-01-01

    El sobrepeso infantil está asociado a sobrepeso/obesidad en la edad adulta. El tejido adiposo en obesos produce una cantidad incrementada de citoquinas proinflamatorias como el factor de necrosis tumoral alfa (TNF-a), ejerciendo un efecto deletéreo sobre la función vascular. El objetivo de este trabajo fue evaluar niveles de TNF-a en una población infantojuvenil con sobrepeso y su relación con otras variables. Se estudiaron 30 niños con sobrepeso (12 varones) de edades entre 8-13 años, se mid...

  18. Construction of novel tumor necrosis factor-alpha mutants with reduced toxicity and higher cytotoxicity on human tumor cells

    Institute of Scientific and Technical Information of China (English)

    LIU; Hui; (刘; 惠); LU; Fang; (卢; 芳); CHEN; Jianjun; (陈建军); REN; Hongyu; (任红玉); CHEN; Changqing(陈常庆)

    2003-01-01

    Two tumor necrosis factor-( mutants MT1 (32Trp157Phe) and MT2 (2Lys30Ser- 32Trp157Phe) were constructed by site-directed mutagenesis. These mutants were soluble and over-expressed in E. coli. The purity of purified mutants was above 95% by serial chromatography. The results of Western blot indicated that these mutants could be cross-reactive with monoclonal antibody against native hTNF-α. Compared to parent hTNF-α, the cytotoxicity of these mutants on murine fibrosarcoma L929 cell lines reduced 4-5 orders of magnitude but was equivalent to that of native hTNF-α on human tumor cell lines. The LD50 of mutant MT1 was reduced to 0.34% of wild type and the dose of MT2 that resulted in 30% death of mice reduced to less than 1/700 that of parent hTNF-α.

  19. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gissel, Hanne; Hojman, Pernille;

    2012-01-01

    Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill...... in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP......, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment...

  20. Detection of circulant tumor necrosis factor-alpha , soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever

    Directory of Open Access Journals (Sweden)

    Elzinandes LA Braga

    2001-02-01

    Full Text Available Pro-inflammatory cytokines are believed to play an important role in the pathogenesis of dengue infection. This study reports cytokine levels in a total of 54 patients examined in Recife, State of Pernambuco, Brazil. Five out of eight patients who had hemorrhagic manifestations presented tumor necrosis factor-alpha (TNF-alpha levels in sera which were statistically higher than those recorded for controls. In contrast, only one out of 16 patients with mild manifestations had elevated TNF-alpha levels. The levels of interleukin-6 (IL, IL-1beta tested in 24 samples and IL-12 in 30 samples were not significantly increased. Interferon-g was present in 10 out of 30 patients with dengue. The data support the concept that the increased level of TNF-alpha is related to the severity of the disease. Soluble TNF receptor p75 was found in most patients but it is unlikely to be related to severity since it was found with an equivalent frequency and levels in 15 patients with dengue fever and another 15 with dengue hemorrhagic fever.

  1. Tumor necrosis factor and the pathogenesis of Pichinde virus infection in guinea pigs.

    Science.gov (United States)

    Aronson, J F; Herzog, N K; Jerrells, T R

    1995-03-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage-adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. Tumor necrosis factor was found in the spleens of adPIC- and PIC3739-infected animals in week 1 of infection; TNF alpha mRNA levels in spleens and livers of adPIC infected animals increased and remained high throughout infection, whereas PIC3739-infected organs showed down regulation of TNF alpha mRNA late in infection. Peritoneal macrophages explanted from adPIC-infected animals showed enhanced lipopolysaccharide-inducible TNF production. Altered regulation of TNF production may play a role in the pathogenesis of guinea pig arenavirus disease.

  2. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    Science.gov (United States)

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.

  3. NANOCOMPOSITE COMPLEX EMAP II INFLUENCE ON TUMOR NECROSIS FACTOR AND INTERFERON

    Directory of Open Access Journals (Sweden)

    L. A. Kolomiets-Babenko

    2016-10-01

    Full Text Available The goal of the research was to determine the ability of new nanocomposite preparation EMAP II (endothelial monocyte activating poplypeptide II to affect the expression of the tumor-necrosis factor and interferon in vitro. In the experiments, the transformed cell line L929 cells was used. The induced interferon levels were determined in samples of culture medium by the microtitration method in the L929 cell culture against test virus vesicular stomatitus VSV. Toxicity of the substance was assessed by its maximum tolerated dose. The amount of endotoxins in nanocomposite preparation EMAP II was measured using gel-clot test. The range of concentrations of EMAP II causing the production of tumor necrosis factor was determined. The concentration of lipopolysaccharides in the tested nanocomposite preparation was less then 0.5 IEU/kg. New nanocomposite preparation EMAP II has the ability to induce TNF-α production at rather low concentration 1.56–25.00 μg/ml (82.49–1370.00 mol х 10–12. The interferon production under the influence of nanocomposite preparation EMAP II was not found. The results support the application of the target nanocomposite reparation EMAP II for cancer treatment.

  4. The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor-related apoptosis-inducing ligand.

    Science.gov (United States)

    Horinaka, Mano; Yoshida, Tatsushi; Shiraishi, Takumi; Nakata, Susumu; Wakada, Miki; Sakai, Toshiyuki

    2006-04-01

    Dietary flavonoid apigenin is expected to have preventive and therapeutic potential against malignant tumors. In this report, we show for the first time that apigenin markedly induces the expression of death receptor 5 (DR5) and synergistically acts with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in malignant tumor cells. TRAIL is a promising candidate for cancer therapeutics due to its ability to selectively induce apoptosis in cancer cells. The combined use of apigenin and TRAIL at suboptimal concentrations induces Bcl-2-interacting domain cleavage and the activation of caspases-8, -10, -9, and -3. Furthermore, human recombinant DR5/Fc chimera protein and caspase inhibitors dramatically inhibit apoptosis induced by the combination of apigenin and TRAIL. On the other hand, apigenin-mediated induction of DR5 expression is not observed in normal human peripheral blood mononuclear cells. Moreover, apigenin does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis. These results suggest that this combined treatment with apigenin and TRAIL might be promising as a new therapy against malignant tumors.

  5. Carbohydrate plasma expanders for passive tumor targeting

    DEFF Research Database (Denmark)

    Hoffmann, Stefan; Caysa, Henrike; Kuntsche, Judith

    2013-01-01

    The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include...... inexpensive synthesis, constant availability, a good safety profile, biodegradability and the long clinical use as plasma expanders. Three polymers have been tested for cytotoxicity and cytokine activation in cell cultures and conjugated with a near-infrared fluorescent dye: hydroxyethyl starches (HES 200 k......Da and HES 450 kDa) and dextran (DEX 500 kDa). Particle size and molecular weight distribution were determined by asymmetric flow field-flow fractionation (AF4). The biodistribution was investigated non-invasively in nude mice using multispectral optical imaging. The most promising polymer conjugate...

  6. Erythropoietin Levels Increase during Cerebral Malaria and Correlate with Heme, Interleukin-10 and Tumor Necrosis Factor-Alpha in India.

    Science.gov (United States)

    Dalko, Esther; Tchitchek, Nicolas; Pays, Laurent; Herbert, Fabien; Cazenave, Pierre-André; Ravindran, Balachandran; Sharma, Shobhona; Nataf, Serge; Das, Bidyut; Pied, Sylviane

    2016-01-01

    Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman's rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population.

  7. Effects of dexmedetomidine on plasma concentrations of tumor necrosis factor-α and interleukin-6 in patients undergoing radical esophagectomy with one-lung ventilation%右美托咪定对食管癌根治术单肺通气患者肿瘤坏死因子-α和白细胞介素-6的影响

    Institute of Scientific and Technical Information of China (English)

    付琦; 庞志路; 韩雪萍

    2012-01-01

    目的 观察右美托咪定对食管癌根治术单肺通气患者血浆肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6水平的影响.方法 60例拟行食管癌根治术的患者,随机分为D1组、D2组和C组,每组20例.D1组麻醉诱导前0.6μg/kg静脉泵注右美托咪定;D2组麻醉诱导后以0.3μg/(kg·h)静脉泵注右美托咪定;C组为对照组.分别测定麻醉诱导前20 min(T0),气管插管后10 min(T1),单肺通气30 min(T2),单肺通气90 min(T3)及再次双肺通气后10 min(T4)5个时间点血浆中TNF-α和IL-6浓度.结果 3组患者血浆TNF-α水平在T3、T4时点较T0高(P <0.05);D1组和D2组在T3(10.5±2.5,11.1 ±2.6)、T4(11.2±2.4,11.8±2.7)时点较C组增高(P<0.05).3组患者血浆IL-6水平在T4时点较T0高(P <0.05);D1组和D2组在T4时点(23.2±3.3,23.9±3.2)较C组增高(P<0.05).结论 术前静脉泵注0.6 μg/kg及术中持续以0.3μg,/(kg·h)静脉泵注右美托咪定均能抑制食管癌根治术单肺通气患者血浆中TNF-α和IL-6水平升高.%Objective To observe the changes in plasma concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in patients undergoing radical esophagectomy during one-lung ventilation.Methods Sixty patients undergoing open radical esophagectomy were randomly divided into three groups:group D1 was given dexmedetomidine intravenously at 0.6 μg/kg 20 min before induction of anesthesia; group D2 was given dexmedetomidine intravenously at 0.3 μg/(kg· h) after induction of anesthesia; group C served as control group.The plasma concentrations of TNF-α and IL-6 were measured by using enzyme linked immunosorbent assay (ELISA) at 20 min betore anesthesia induction (T0),10 min after tracheal intubation (T1),30 min after one-lung ventilation (T2),90 min after one-lung ventilation (T3) and 10 min after resuming two-lung ventilation (T4).Results As compared with T0,plasma TNF-α concentration was increased critically at T3 and T4 in three groups.Plasma TNF

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

    Institute of Scientific and Technical Information of China (English)

    LIUXing; ZHANGXiangfu; ZHENGZhiweng; LUHuishan; WUXinyuan; HUANGChangmin; WANGChuan; GUANGuoxian

    2005-01-01

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

  9. Use of the tumor necrosis factor-blockers for Crohn's disease

    Institute of Scientific and Technical Information of China (English)

    Alan BR Thomson; Milli Gupta; Hugh J Freeman

    2012-01-01

    The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn's disease study thirty years ago.The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses.In general,it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1)for persons with moderately-severe Crohn's disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids.Once TNFBs have been introduced and the patient is responsive,therapy given by the IV and SC rate must be continued.It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy,and when or if TNFB may be weaned and discontinued.The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient's illness needs to be confirmed.The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB,and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic.Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high,the ultimate application of use of TNFBs will likely be established by cost/benefit studies.

  10. Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

    NARCIS (Netherlands)

    T.E. Lans; T.L.M. ten Hagen (Timo); R. van Horssen (Remco); P.C. Wu; S.T. van Tiel (Sandra); S.K. Libutti; H.R. Alexander; A.M.M. Eggermont (Alexander)

    2002-01-01

    textabstractBACKGROUND: Experiments with tumor necrosis factor alpha (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the

  11. Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease.

    Science.gov (United States)

    Hagel, A F; de Rossi, T; Konturek, P C; Albrecht, H; Walker, S; Hahn, E G; Raithel, M

    2015-08-01

    Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-α) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-α levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P ≤ 0.04). Plasma TNF-α levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-α values, but not the type of treatment. We concluded that in contrast to TNF-α, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-α secreted from mast cells in the plasma in patients with IBD is less important.

  12. Tumor necrosis factor alpha affect hydrocortisone expression in mice adrenal cortex cells mainly through tumor necrosis factor alpha-receptor 1

    Institute of Scientific and Technical Information of China (English)

    XIA Hai-ming; FANG Yuan; HUANG Pei-lin

    2011-01-01

    Background Tumor necrosis factor alpha (TNF-α) is important in promoting relative adrenal insufficiency (RAI) due to systemic inflammatory response syndrome (SIRS).We identified the TNF-α receptor involved in the inhibition of adrenal corticotrophin (ACTH)-stimulated hydrocortisone release by studying the expression of TNF-α receptors in adrenal cortex Y1 cells and the effect of downregulating TNF receptors on ACTH-stimulated hydrocortisone release.Methods We used real-time PCR and immunocytochemistry to evaluate the expression of TNF receptors on Y1 cells.TNF-receptor 1 (TNF-R1) DNA fragments corresponding to the short hairpin RNA (shRNA)-sequences were synthesized and cloned into pcDNATM 6.2-GW/EmGFP expression vector.Knockdown efficiency of TNF-R1 expression was evaluated in miRNA transfected and mock-miRNA transfected Y1 cells by quantitative real-time PCR (Q-PCR).Hydrocortisone expression levels were determined in TNF-R1-knockdown and control Y1 cells treated with TNF-α and ACTH.Results Mouse adrenal cortex Y1 cells were positive for type I TNF-R1,but not type Ⅱ TNF-receptor (TNF-R2).Blocking TNF-R1 expression resulted in loss of TNF-α-mediated inhibition of ACTH-stimulated hydrocortisone expression,suggesting a role for the TNF-R1 related signaling pathway in ACTH-stimulated hydrocortisone synthesis.Conclusion The inhibitory effect of TNF-α on ACTH-stimulated hydrocortisone synthesis was mediated via TNF-R1 in adrenal cortex.

  13. Influence of ?S-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Marília Rocha Laurentino

    2014-04-01

    Full Text Available Background: Sickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown. Objective: The aim of this study was to investigate the association of tumor necrosis factor-alpha levels with β-globin haplotypes and the use of hydroxyurea. Methods: A cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceará, Brazil. A group of 26 healthy individuals was used as control. βS-haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor-alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann-Whitney tests. Statistical significance was established for p-values < 0.05 for all analyses. Results: The mean age of the participants was 35.48 years. Patients with sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values < 0.0001. Tumor necrosis factor-alpha levels were lower in sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249. Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021. Conclusion: In summary, βS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many

  14. Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis.

    Science.gov (United States)

    Matsumoto, Isao; Inoue, Asuka; Takai, Chinatsu; Umeda, Naoto; Tanaka, Yuki; Kurashima, Yuko; Sumida, Takayuki

    2014-07-01

    Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans.

  15. Structural requirements for inducible shedding of the p55 tumor necrosis factor receptor

    DEFF Research Database (Denmark)

    Brakebusch, C; Varfolomeev, E E; Batkin, M

    1994-01-01

    Induced shedding of the p55 tumor necrosis factor receptor (p55-R) was previously shown to be independent of the amino acid sequence properties of the intracellular domain of this receptor. We now find it also independent of the sequence properties of the transmembrane domain and of the cysteine......-rich region that constitutes most of the extracellular domain of the receptor. The shedding is shown to depend solely on the sequence properties of a small region within the spacer that links the cysteine-rich region in the extracellular domain to the transmembrane domain. Detailed tests of effects......, however, by some mutations that seem to change the conformation of the spacer region. These findings suggest that a short amino acid sequence in the p55-R is essential and sufficient for its shedding and that the shedding is mediated either by a protease with limited sequence specificity or by several...

  16. Unusual location of tuberculosis in the course of tumor necrosis factor α inhibitor therapy.

    Science.gov (United States)

    Bielewicz-Zielińska, Agnieszka; Brzezicki, Jan; Rymko, Marcin; Jeka, Sławomir

    2015-01-01

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex mycobacteria. Extrapulmonary tuberculosis usually develops more than two years after infection or many years later. Factors favoring onset of the disease are malnutrition, older age, renal failure, diabetes, cancer, immunosuppression and biological treatment, e.g. tumor necrosis factor α (TNF-α) inhibitors. The paper presents a case of a 56-year-old patient with ankylosing spondylitis treated with infliximab, diagnosed with tuberculosis of the spleen. The unusual location and uncharacteristic symptoms created a lot of diagnostic difficulties, particularly as during qualification for biological treatment tests are performed to exclude infection with Mycobacterium tuberculosis. Pharmacological treatment of tuberculosis is typical, but in the case of tuberculosis of the spleen, splenectomy also is a method of treatment. The decision was made to implement pharmacological treatment, which proved to be effective, so the patient avoided surgery.

  17. Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis

    Science.gov (United States)

    Noor, Zannatun; Watanabe, Koji; Abhyankar, Mayuresh M.; Burgess, Stacey L.; Buonomo, Erica L.

    2017-01-01

    ABSTRACT The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α) production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25) is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α. PMID:28246365

  18. Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis

    Institute of Scientific and Technical Information of China (English)

    Gulseren Seven; Adel Assaad; Thomas Biehl; Richard A Kozarek

    2012-01-01

    Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain,weight loss associated with diarrhea,and multiple inflammatory ulcerations and strictures of the small bowel.Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo.Increased levels of tumor necrosis factor-alpha (TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder.No specific therapy has been shown to change the course of ulcerative jejunoileitis.We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies,including high dose corticosteroids and cyclosporine.The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody,infliximab (Remicade(R)).

  19. Formation of Ion-Permeable Channels by Tumor Necrosis Factor-α

    Science.gov (United States)

    Kagan, Bruce L.; Baldwin, Rae Lynn; Munoz, David; Wisnieski, Bernadine J.

    1992-03-01

    Tumor necrosis factor-α (TNF, cachectin), a protein secreted by activated macrophages, participates in inflammatory responses and in infectious and neoplastic disease states. The mechanisms by which TNF exerts cytotoxic, hormonal, and other specific effects are obscure. Structural studies of the TNF trimer have revealed a central pore-like region. Although several amino acid side chains appear to preclude an open channel, the ability of TNF to insert into lipid vesicles raised the possibility that opening might occur in a bilayer milieu. Acidification of TNF promoted conformational changes concordant with increased surface hydrophobicity and membrane insertion. Furthermore, TNF formed pH-dependent, voltage-dependent, ion-permeable channels in planar lipid bilayer membranes and increased the sodium permeability of human U937 histiocytic lymphoma cells. Thus, some of the physiological effects of TNF may be elicited through its intrinsic ion channel-forming activity.

  20. Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis.

    Science.gov (United States)

    Atzeni, Fabiola; Costa, Luisa; Caso, Francesco; Scarpa, Raffaele; Sarzi-Puttini, Piercarlo

    2015-11-01

    Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents.

  1. New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol.

    Science.gov (United States)

    Cauli, Alberto; Piga, Matteo; Lubrano, Ennio; Marchesoni, Antonio; Floris, Alberto; Mathieu, Alessandro

    2015-11-01

    The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-α (TNF-α) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-α activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.

  2. Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis

    Directory of Open Access Journals (Sweden)

    Zannatun Noor

    2017-02-01

    Full Text Available The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25 is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α.

  3. Type I pityriasis rubra pilaris: upregulation of tumor necrosis factor alpha and response to adalimumab therapy.

    Science.gov (United States)

    Zhang, Yao-Hua; Zhou, Youwen; Ball, Nigel; Su, Ming-Wan; Xu, Jin-Hua; Zheng, Zhi-Zhong

    2010-01-01

    pityriasis rubra pilaris (PRP) has unknown etiology and is often refractory to conventional therapies. to document a PRP patient's response to adalimumab therapy and to highlight the potential role of tumor necrosis factor (TNF) in the development of PRP skin lesions. a patient received adalimumab therapy at standard dosing intervals. In addition, the messenger ribonucleic acid (mRNA) of TNF in the lesional and perilesional normal skin was quantified in two patients with PRP. the patient responded to adalimumab therapy and achieved clinical remission by 4 months. There was a significant elevation of TNF mRNA in the lesional skin of PRP. TNF upregulation is detected in PRP lesional skin, consistent with the observed clinical efficacy of TNF blockade for the treatment of PRP.

  4. Mechanism of inhibition of HSV-1 replication by tumor necrosis factor and interferon gamma.

    Science.gov (United States)

    Feduchi, E; Carrasco, L

    1991-02-01

    Tumor necrosis factor (TNF) synergizes with interferon (IFN gamma) in the blockade of HSV-1 replication. Antibodies against IFN beta block this synergism, implying a role of IFN beta in the antiviral activity of TNF plus IFN gamma. IFN beta 1 added exogenously to Hep-2 cells shows antiviral activity against HSV-1 only at high concentrations, whereas IFN beta 2 (also known as IL-6) alone has no effect on the replication of VSV or HSV-1 even when 1,000 U/ml are present. Our results are in accordance with the idea that TNF induces IFN beta 1 and that both cytokines must be present in the culture medium to synergize with IFN gamma in order to inhibit HSV-1 replication.

  5. Tumor Necrosis Factor and Lymphotoxin-α Polymorphisms and Severe Malaria in African Populations

    Science.gov (United States)

    Clark, Taane G.; Diakite, Mahamadou; Auburn, Sarah; Campino, Susana; Fry, Andrew E.; Green, Angela; Richardson, Anna; Small, Kerrin; Teo, Yik Y.; Wilson, Jonathan; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Griffiths, Michael J.; Peshu, Norbert; Williams, Thomas N.; Marsh, Kevin; Molyneux, Malcolm E.; Taylor, Terrie E.; Rockett, Kirk A.; Kwiatkowski, Dominic P.

    2009-01-01

    The tumor necrosis factor gene (TNF) and lymphotoxin-α gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving > 10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF −238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. PMID:19281305

  6. 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...... differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy...... is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF...

  7. Protective effects of tumor necrosis factor antibody and ulinastatin on liver ischemic reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Ling Yang; Ji-Peng Li; Xiao-Ping Xu; Ke-Feng Dou; Shu-Qiang Yue; Kai-Zong Li

    2004-01-01

    AIM: To study the protective effects of tumor necrosis factor α(TNFα) antibody and ulinastatin on liver ischemic reperfusion in rats.METHODS: One hundred and twenty male SD rats were randomly divided into four groups: normal control group,ischemic group, TNFα antibody group and TNFα antibody + ulinastatin group. The animals were killed at 0, 3, 6, 9,12 h after ischemia for 60 min and followed by reperfusion.Serum alanine aminotransferase (ALT), malondialdehyde (MDA) and liver histopathology were observed.RESULTS: After ischemic reperfusion, the serum ALT and MDA were remarkably increased, and the hepatic congestion was obvious. Treatment of TNFα antibody and ulinastatin could significantly decrease serum ALT and MDA levels,and relieve hepatic congestion.CONCLUSION: Ulinastatin and TNFα antibody can suppress the inflammatory reaction induced by hepatic ischemic reperfusion, and have protective effects on rat hepatic ischemic reperfusion injury.

  8. Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Yan-Ling Yang; Ji-Peng Li; Kai-Zong Li; Ke-Feng Dou

    2004-01-01

    AIM: To study the protective effects of tumor necrosis factor á (TNFα) antibody on pancreatic encephalopathy in rats.METHODS:One hundred and twenty SD rats were randomly divided into normal control group,acute necrotizing pancreatitis group and TNFα antibody treated group.Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct.Serum TNFα was detected and animals were killed 12 h after drug administration.Changes in content of brain water,MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS:In TNFα antibody treated group,serum TNFálevel was decreased.Content of brain water,MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05).CONCLUSION:TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

  9. The Tumor Necrosis Factor Superfamily of Cytokines in the Inflammatory Myopathies: Potential Targets for Therapy

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2012-01-01

    Full Text Available The idiopathic inflammatory myopathies (IM represent a heterogeneous group of autoimmune diseases, of which dermatomyositis (DM, polymyositis (PM, and sporadic inclusion body myositis (IBM are the most common. The crucial role played by tumor necrosis factor alpha (TNFα in the IM has long been recognized. However, so far, 18 other members of the TNF superfamily have been characterized, and many of these have not yet received the attention they deserve. In this paper, we summarize current findings for all TNF cytokines in IM, pinpointing what we know already and where current knowledge fails. For each TNF family member, possibilities for treating inflammatory diseases in general and the IM in particular are explored.

  10. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

    Science.gov (United States)

    Ott, Lee W.; Resing, Katheryn A.; Sizemore, Alecia W.; Heyen, Joshua W.; Cocklin, Ross R.; Pedrick, Nathan M.; Woods, H. Cary; Chen, Jake Y.; Goebl, Mark G.; Witzmann, Frank A.; Harrington, Maureen A.

    2010-01-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFα and IL-1 regulate different processes. A large-scale proteomic analysis of TNFα- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFα and IL-1. When combined with genomic studies, our results indicate that TNFα, but not IL-1, mediates cell cycle arrest. PMID:17503796

  11. Tumor Necrosis Factor-alpha- and interleukin-1-induced cellular responses: coupling proteomic and genomic information.

    Science.gov (United States)

    Ott, Lee W; Resing, Katheryn A; Sizemore, Alecia W; Heyen, Joshua W; Cocklin, Ross R; Pedrick, Nathan M; Woods, H Cary; Chen, Jake Y; Goebl, Mark G; Witzmann, Frank A; Harrington, Maureen A

    2007-06-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFalpha) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFalpha- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFalpha and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFalpha and IL-1 regulate different processes. A large-scale proteomic analysis of TNFalpha- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFalpha and IL-1. When combined with genomic studies, our results indicate that TNFalpha, but not IL-1, mediates cell cycle arrest.

  12. 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

    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...... as confounders. CONCLUSION: TNF-alpha was an independent prognostic marker for mortality in persons aged 100 years, suggesting that it has specific biological effects and is a marker of frailty in the very elderly.......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...

  13. [Tumor necrosis factor alfa in cardiovascular diseases: molecular biology and genetics].

    Science.gov (United States)

    Fragoso Lona, José Manuel; Sierra Martínez, Mónica; Vargas Alarcón, Gilberto; Barrios Rodas, Angélica; Ramírez Bello, Julián

    2013-01-01

    Cardiovascular diseases are a major public health problem globally. In 1997, cardiovascular disease caused 41% of deaths in the United States. It has been reported that about 60 million people in the United States have some form of cardiovascular disease. These entities are chronic conditions initiated by a dysregulation of the immune response. One gene and its protein product -tumor necrosis factor a (TNF-α)- a powerful pleiotropic cytokine with multiple cellular functions, plays a role in the inflammation, initiation, development, susceptibility, severity, and response to treatment, etc. of coronary artery disease (CAD). The focus of the present review is to summarize recent evidence showing the biological role of TNF-α in the initiation and progression of endothelial dysfunction and complications of atherosclerosis, and as a genetic variation of TNF-α confer susceptibility, severity, and treatment response in CAD: ST-segment elevation myocardial infarction and non-ST segment elevation myocardial infarction, unstable angina, and coronary restenosis.

  14. Interferon and tumor necrosis factor as humoral mechanisms coupling hematopoietic activity to inflammation and injury.

    Science.gov (United States)

    Askenasy, Nadir

    2015-01-01

    Enhanced hematopoiesis accompanies systemic responses to injury and infection. Tumor necrosis factor (TNF) produced by injured cells and interferons (IFNs) secreted by inflammatory cells is a co-product of the process of clearance of debris and removal of still viable but dysfunctional cells. Concomitantly, these cytokines induce hematopoietic stem and progenitor cell (HSPC) activity as an intrinsic component of the systemic response. The proposed scenario includes induction of HSPC activity by type I (IFNα/β) and II (IFNγ) receptors within the quiescent bone marrow niches rendering progenitors responsive to additional signals. TNFα converges as a non-selective stimulant of HSPC activity and both cytokines synergize with other growth factors in promoting differentiation. These physiological signaling pathways of stress hematopoiesis occur quite frequent and do not cause HSPC extinction. The proposed role of IFNs and TNFs in stress hematopoiesis commends revision of their alleged involvement in bone marrow failure syndromes.

  15. Biodentine Reduces Tumor Necrosis Factor Alpha-induced TRPA1 Expression in Odontoblastlike Cells.

    Science.gov (United States)

    El Karim, Ikhlas A; McCrudden, Maelíosa T C; McGahon, Mary K; Curtis, Tim M; Jeanneau, Charlotte; Giraud, Thomas; Irwin, Chris R; Linden, Gerard J; Lundy, Fionnuala T; About, Imad

    2016-04-01

    The transient receptor potential (TRP) ion channels have emerged as important cellular sensors in both neuronal and non-neuronal cells, with TRPA1 playing a central role in nociception and neurogenic inflammation. The functionality of TRP channels has been shown to be modulated by inflammatory cytokines. The aim of this study was to investigate the effect of inflammation on odontoblast TRPA1 expression and to determine the effect of Biodentine (Septodent, Paris, France) on inflammatory-induced TRPA1 expression. Immunohistochemistry was used to study TRPA1 expression in pulp tissue from healthy and carious human teeth. Pulp cells were differentiated to odontoblastlike cells in the presence of 2 mmol/L beta-glycerophosphate, and these cells were used in quantitative polymerase chain reaction, Western blotting, calcium imaging, and patch clamp studies. Immunofluorescent staining revealed TRPA1 expression in odontoblast cell bodies and odontoblast processes, which was more intense in carious versus healthy teeth. TRPA1 gene expression was induced in cultured odontoblastlike cells by tumor necrosis factor alpha, and this expression was significantly reduced in the presence of Biodentine. The functionality of the TRPA1 channel was shown by calcium microfluorimetry and patch clamp recording, and our results showed a significant reduction in tumor necrosis factor alpha-induced TRPA1 responses after Biodentine treatment. In conclusion, this study showed TRPA1 to be modulated by caries-induced inflammation and that Biodentine reduced TRPA1 expression and functional responses. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  16. Differentiation between Treatment-Induced Necrosis and Recurrent Tumors in Patients with Metastatic Brain Tumors: Comparison among (11)C-Methionine-PET, FDG-PET, MR Permeability Imaging, and MRI-ADC-Preliminary Results.

    Science.gov (United States)

    Tomura, N; Kokubun, M; Saginoya, T; Mizuno, Y; Kikuchi, Y

    2017-08-01

    In patients with metastatic brain tumors after gamma knife radiosurgery, the superiority of PET using (11)C-methionine for differentiating radiation necrosis and recurrent tumors has been accepted. To evaluate the feasibility of MR permeability imaging, it was compared with PET using (11)C-methionine, FDG-PET, and DWI for differentiating radiation necrosis from recurrent tumors. The study analyzed 18 lesions from 15 patients with metastatic brain tumors who underwent gamma knife radiosurgery. Ten lesions were identified as recurrent tumors by an operation. In MR permeability imaging, the transfer constant between intra- and extravascular extracellular spaces (/minute), extravascular extracellular space, the transfer constant from the extravascular extracellular space to plasma (/minute), the initial area under the signal intensity-time curve, contrast-enhancement ratio, bolus arrival time (seconds), maximum slope of increase (millimole/second), and fractional plasma volume were calculated. ADC was also acquired. On both PET using (11)C-methionine and FDG-PET, the ratio of the maximum standard uptake value of the lesion divided by the maximum standard uptake value of the symmetric site in the contralateral cerebral hemisphere was measured ((11)C-methionine ratio and FDG ratio, respectively). The receiver operating characteristic curve was used for analysis. The area under the receiver operating characteristic curve for differentiating radiation necrosis from recurrent tumors was the best for the (11)C-methionine ratio (0.90) followed by the contrast-enhancement ratio (0.81), maximum slope of increase (millimole/second) (0.80), the initial area under the signal intensity-time curve (0.78), fractional plasma volume (0.76), bolus arrival time (seconds) (0.76), the transfer constant between intra- and extravascular extracellular spaces (/minute) (0.74), extravascular extracellular space (0.68), minimum ADC (0.60), the transfer constant from the extravascular

  17. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α in Major Depressive Disorder: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Ke Ma

    2016-05-01

    Full Text Available Major depressive disorder (MDD is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α, play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  18. Tumor necrosis factor (TNF) is induced in mice by Candida albicans: role of TNF in fibrinogen increase.

    Science.gov (United States)

    Riipi, L; Carlson, E

    1990-09-01

    One intraperitoneal dose of Candida albicans (10(8) CFU) caused a chronic (longer than 2 months), significant elevation of plasma fibrinogen levels (Clauss method) in mice of strain C3H/HeN. Even a small dose (10(6) CFU) resulted in a significant increase in fibrinogen level for 5 days following injection, whereas other blood parameters (leukocytes, erythrocytes, platelets, hematocrit, hemoglobin, blood urea nitrogen, aspartate aminotransferase, albumin, alkaline phosphatase, antithrombin III, glucose, calcium, and total protein) measured by standard methods were normal. Blood taken during this period was negative for C. albicans. The role of tumor necrosis factor (TNF) in C. albicans infections was investigated by measuring the fibrinogen response after the administration of C. albicans or recombinant mouse TNF-alpha. Both challenges resulted in an elevated fibrinogen level. When polyclonal antibodies to mouse TNF-alpha were given prior to challenge with C. albicans or mouse TNF-alpha, the fibrinogen increase was significantly inhibited. C. albicans injections were found to significantly elevate endogenous TNF levels in mice (enzyme-linked immunosorbent assay). It was concluded that C. albicans induces TNF in the mouse. Furthermore, these data give evidence which supports a relationship between TNF and the fibrinogen increase induced by C. albicans.

  19. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review.

    Science.gov (United States)

    Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

    2016-05-14

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  20. Curcumin attenuates lipolysis stimulated by tumor necrosis factor-α or isoproterenol in 3T3-L1 adipocytes.

    Science.gov (United States)

    Xie, Xiao-yun; Kong, Po-Ren; Wu, Jin-feng; Li, Ying; Li, Yan-xiang

    2012-12-15

    Curcumin, an active component derived from dietary spice turmeric (Curcuma longa), has been demonstrated antihyperglycemic, antiinflammatory and hypocholesterolemic activities in obesity and diabetes. These effects are associated with decreased level of circulating free fatty acids (FFA), however the mechanism has not yet been elucidated. The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-α (TNFα) stimulates chronic lipolysis in obesity and type 2 diabetes. In this study, we examined the role of curcumin in inhibiting lipolytic action upon various stimulations in 3T3-L1 adipocytes. Glycerol release from TNFα or isoproterenol-stimulated 3T3-L1 adipocytes in the absence or presence of curcumin was determined using a colorimetric assay (GPO-Trinder). Western blotting was used to investigate the TNFα-induced phosphorylation of MAPK and perilipin expression. Fatcake and cytosolic fractions were prepared to examine the isoproterenol-stimulated hormone-sensitive lipase translocation. Treatment with curcumin attenuated TNFα-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and reversing the downregulation of perilipin protein in TNFα-stimulated adipocytes (plipolysis response to TNFα and catecholamines. The antilipolytic effect could be a cellular basis for curcumin decreasing plasma FFA levels and improving insulin sensitivity. Copyright © 2012 Elsevier GmbH. All rights reserved.

  1. Tumor necrosis factor-α predicts response to cardiac resynchronization therapy in patients with chronic heart failure.

    Science.gov (United States)

    Rordorf, Roberto; Savastano, Simone; Sanzo, Antonio; Spazzolini, Carla; De Amici, Mara; Camporotondo, Rita; Ghio, Stefano; Vicentini, Alessandro; Petracci, Barbara; De Regibus, Valentina; Taravelli, Erika; Landolina, Maurizio; Schwartz, Peter J

    2014-01-01

    Pro-inflammatory cytokines contribute to the pathophysiology of heart failure (HF) and are up-regulated in affected patients. We investigated whether pro-inflammatory cytokines might predict the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 were assessed in 91 patients before CRT. Response to CRT was defined as a decrease ≥15% in left ventricular end-systolic volume (LVESV) at 6 months. Baseline TNF-α did correlate with LVESV reduction (P=0.001) after CRT. The subject group was divided according to tertiles of TNF-α. From the lower to the upper tertile LVESV (-31±28%, -17±17%, -9±22%) and LV end-diastolic volume (-23±25%, -14±16%, -4±18%) were progressively less reduced after CRT (P<0.001). The proportion of responders to CRT was 70%, 42% and 33%, according to the lower, intermediate and upper tertile of TNF-α distribution (P=0.01). Serious cardiac events (cardiac death, HF hospitalization or urgent heart transplantation) occurred in 63% of patients in the upper tertile vs. 32% and 17% in the intermediate and lower tertiles, respectively, during a median follow-up of 47 months (P<0.001). Circulating TNF-α predicts the degree of LV reverse remodeling after CRT and may contribute to the early identification of those patients at higher risk of events after device implantation.

  2. Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

    OpenAIRE

    Molinsky, J.; Klánová, M.; Koc, M; Beranová, L. (Lenka); Anděra, L. (Ladislav); Ludvíková, Z.; Bohmova, M.; Gasova, Z.; Strnad, M.; Ivánek, R. (Robert); Trněný, M.; Nečas, E.; Živný, J.; Klener, P.

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced en...

  3. Evaluation of dynamic contrast-enhanced T1-weighted perfusion MRI in the differentiation of tumor recurrence from radiation necrosis

    DEFF Research Database (Denmark)

    Larsen, Anne Vibeke Andrée; Simonsen, Helle J; Law, Ian

    2013-01-01

    INTRODUCTION: To investigate if perfusion measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to differentiate radiation necrosis from tumor recurrence in patients with high-grade glioma. METHODS: The study was approved by the institutional review board...... and informed consent was obtained from all subjects. 19 patients were recruited following surgery and radiation therapy for glioma. Patients had contrast enhancing lesions, which during the standard MRI examination could not be exclusively determined as recurrence or radiation necrosis. DCE-MRI was used......-MRI may predict the status of contrast enhancing lesions and give results very similar to FDG-PET with regards to differentiation between tumor recurrence and radiation necrosis....

  4. Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mukaida, Naofumi, E-mail: naofumim@kenroku.kanazawa-u.ac.jp; Sasakki, So-ichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Popivanova, Boryana K. [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Present Address, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2011-06-27

    The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice.

  5. Eupatilin protects against tumor necrosis factor-α-mediated inflammation inhuman umbilical vein endothelial cells.

    Science.gov (United States)

    Yu, Kai; Li, Xi-Ming; Xu, Xiao-Lei; Zhang, Ru-Yan; Cong, Hong-Liang

    2015-01-01

    Inflammatory responses in the blood vessel play a pivotal role in the pathogenesis of atherosclerosis. Eupatilin, a flavone derived from Artemisia princepsPampanini, has various pharmacological activities, including antioxidant, anti-tumor, and anti-inflammatory capacities. However, there has been no research examining the function of eupatilin on vascular inflammation. Therefore, the aim of this study was to investigate the effects of eupatilin on tumor necrosis factor (TNF)-α-induced human umbilical vein endothelial cells (HUVECs) activation and the underlying molecular mechanisms. Our findings showed that eupatilin reduced U937 cells adhesion to TNF-α-stimulated HUVECs and attenuated TNF-α-induced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HUVECs, as well as the production of intracellular reactive oxygen species (ROS). Moreover, eupatilininhibits TNF-α-induced phosphorylation of NF-kB p65 and MAPKs in HUVECs. Taken together, the results of the present study suggest that eupatilin inhibited inflammatory reaction through suppressing the ROS/MAPK-NF-ĸB pathway in HUVECs. Thus, eupatilin is proposed as an effective new anti-inflammatory agent to suppress vascular inflammation, and further prevent atherosclerosis.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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 {sup 51}Cr- and {sup 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{sub 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.

  8. Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Eisenhut, T; Sinha, B; Gröttrup-Wolfers, E; Semmler, J; Siess, W; Endres, S

    1993-01-01

    Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of

  9. Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids

    NARCIS (Netherlands)

    Sinha, B; Semmler, J; Eisenhut, T; Eigler, A; Endres, S

    1995-01-01

    We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cA

  10. 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...

  11. 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 produ

  12. Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Eisenhut, T; Sinha, B; Gröttrup-Wolfers, E; Semmler, J; Siess, W; Endres, S

    1993-01-01

    Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of inte

  13. Differential sensitivity of hormone-responsive and unresponsive human prostate cancer cells (LNCaP) to tumor necrosis factor

    NARCIS (Netherlands)

    X. Zhao (X.); G.J. van Steenbrugge (Gert Jan); F.H. Schröder (Fritz)

    1992-01-01

    textabstractTwo sublines, the hormone-sensitive LNCaP-FGC and the insensitive LNCaP-r (resistant) carcinoma cell lines, originating from the parental human prostatic carcinoma cell line LNCaP were tested for sensitivity to human tumor necrosis factor-α (TNF) using the MTT assay. Irrespective of the

  14. 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 ...

  15. Tumor Necrosis Factor-alpha Inhibitor Etanercept Does Not Alter Methotrexate-induced Gastrointestinal Mucositis in Rats

    NARCIS (Netherlands)

    Kuiken, Nicoline S S; Rings, Edmond H H M; Alffenaar, Jan-Willem C; Havinga, Rick; Jurdzinski, Angelika; Groen, Albert K; Tissing, Wim J E

    2016-01-01

    OBJECTIVES: Gastrointestinal (GI) mucositis is a severe side effect of chemotherapy and radiotherapy. Pro-inflammatory cytokines are thought to play an important role in the pathophysiology of GI mucositis. We aimed to determine the effect of the Tumor Necrosis Factor-alpha (TNF-α) inhibitor Etanerc

  16. Tumor Necrosis Factor-alpha Stimulates the Overproduction of Intestinal Apolipoprotein B48-containing Very Low Density Lipoproproteins

    Science.gov (United States)

    Tumor necrosis factor-alpha(a)(TNFa), a proinflammatory cytokine, is involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. TNFa enhanced postprandial apoB48-VLDL1 overproduction by about 89% compared with the control after 90 min olive oil loading; TNFa did not si...

  17. Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases From a Single Institution.

    Science.gov (United States)

    Khor, Li-Yan; Dhakal, Hari P; Jia, Xuefei; Reynolds, Jordan P; McKenney, Jesse K; Rini, Brian I; Magi-Galluzzi, Cristina; Przybycin, Christopher G

    2016-09-01

    Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (PISUP grade could be further prognostically

  18. Analysis of Tumor Necrosis Factor Function Using the Resonant Recognition Model.

    Science.gov (United States)

    Cosic, Irena; Cosic, Drasko; Lazar, Katarina

    2016-06-01

    The tumor necrosis factor (TNF) is a complex protein that plays a very important role in a number of biological functions including apoptotic cell death, tumor regression, cachexia, inflammation inhibition of tumorigenesis and viral replication. Its most interesting function is that it is an inhibitor of tumorigenesis and inductor of apoptosis. Thus, the TNF could be a good candidate for cancer therapy. However, the TNF has also inflammatory and toxic effects. Therefore, it would be very important to understand complex functions of the TNF and consequently be able to predict mutations or even design the new TNF-related proteins that will have only a tumor inhibition function, but not other side effects. This can be achieved by applying the resonant recognition model (RRM), a unique computational model of analysing macromolecular sequences of proteins, DNA and RNA. The RRM is based on finding that certain periodicities in distribution of free electron energies along protein, DNA and RNA are strongly correlated to the biological function of these macromolecules. Thus, based on these findings, the RRM has capabilities of protein function identification, prediction of bioactive amino acids and protein design with desired biological function. Using the RRM, we separate different functions of TNF as different periodicities (frequencies) within the distribution of free energy electrons along TNF protein. Interestingly, these characteristic TNF frequencies are related to previously identified characteristics of proto-oncogene and oncogene proteins describing TNF involvement in oncogenesis. Consequently, we identify the key amino acids related to the crucial TNF function, i.e. receptor recognition. We have also designed the peptide which will have the ability to recognise the receptor without side effects.

  19. 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....

  20. Tumor necrosis factor alpha and alpha-1 antitrypsin gene variants in Serbian pediatric arterial ischemic stroke patients

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    Đorđević Valentina

    2013-01-01

    Full Text Available The etiology of arterial ischemic stroke (AIS in children is complex, and different from that in adults. Although rare, stroke in children is an important cause of mortality and morbidity. There is increasing evidence that genetic factors, including inflammation mediators, have a role in occurrence and outcome of stroke. We have chosen to assess the role of polymorphism -308G/A in the promoter of tumor necrosis factor α (TNFα gene and S and Z mutations in alpha 1-antitrypsin (AAT gene in the etiology of stroke in children. TNFα polymorphism affects plasma levels of this proinflamatory cytokine, and this could contribute to stroke pathology. It has been shown that increased AAT concentration may present a risk for AIS in children. Since S and Z mutations in AAT gene reduce its levels in plasma they could have a protective role in pediatric stroke. In this study twenty six children with AIS and 100 unrelated individuals from Serbian general population were investigated by PCR/RFLP for these gene variations. No statistically significant difference was observed between patients and general population in distribution of genotypes for -308G/A TNFα polymorphism, so its contributory role in the etiology of stroke was not evident in our group of patients. None of the tested AAT gene mutations were found in patients, which is in concordance with the proposed protective role of deficient AAT variants. AIS is a multifactorial disease, with many genes having a modest role in its pathophysiology, so further analyses of their combined effect are needed to elucidate genetic risk factors in the etiology and outcome of stroke in pediatric patients.

  1. Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy

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    Choon Hee Chung

    2015-02-01

    Full Text Available Background/Aims: Tumor necrosis factor (TNF-α is believed to play a role in diabetic kidney disease. This study explores the specific effects of TNF-α with regard to nephropathy-relevant parameters in the podocyte. Methods: Cultured mouse podocytes were treated with recombinant TNF-α and assayed for production of monocyte chemoattractant protein-1 (MCP-1 by enzyme-linked immunosorbent assay (ELISA. TNF-α signaling of MCP-1 was elucidated by antibodies against TNF receptor (TNFR 1 or TNFR2 or inhibitors of nuclear factor-kappaB (NF-κB, phosphatidylinositol 3-kinase (PI3K or Akt. In vivo studies were done on male db/m and type 2 diabetic db/db mice. Levels of TNF-α and MCP-1 were measured by RT-qPCR and ELISA in the urine, kidney and plasma of the two cohorts and correlated with albuminuria. Results: Podocytes treated with TNF-α showed a robust increase (∼900% in the secretion of MCP-1, induced in a dose- and time-dependent manner. Signaling of MCP-1 expression occurred through TNFR2, which was inducible by TNF-α ligand, but did not depend on TNFR1. TNF-α then proceeded via the NF-κB and the PI3K/Akt systems, based on the effectiveness of the inhibitors of those pathways. For in vivo relevance to diabetic kidney disease, TNF-α and MCP-1 levels were found to be elevated in the urine of db/db mice but not in the plasma. Conclusion: TNF-α potently stimulates podocytes to produce MCP-1, utilizing the TNFR2 receptor and the NF-κB and PI3K/Akt pathways. Both TNF-α and MCP-1 levels were increased in the urine of diabetic db/db mice, correlating with the severity of diabetic albuminuria.

  2. 胶原性关节炎大鼠血浆肿瘤坏死因子α和滑膜血管内皮生长因子表达的相关性%Correlation between plasma contents of tumor necrosis factor-alpha and expressions of vascular endothelium growth factor of synovium in collagen-induced arthritis rats

    Institute of Scientific and Technical Information of China (English)

    熊新贵; 梁清华; 陈疆; 李春燕; 何金华; 李霞玲; 张花先; 刘小春

    2006-01-01

    积分的关系,与血浆肿瘤坏死因子α含量及滑膜血管内皮生长因子表达的关系,胶原性关节炎大鼠血浆肿瘤坏死因子α与滑膜血管内皮生长因子表达相关分析.结果:纳入动物40只,均进入结果分析.随着胶原性关节炎发病时间的延长,滑膜新生血管逐渐增多、滑膜增厚、关节炎指数积分逐渐增加、肿瘤坏死因子α含量和血管内皮生长因子水平也随之升高;其关节炎指数积分与血管内皮生长因子表达水平呈正相关(r=0.535,P<0.05),与肿瘤坏死因子α含量虽有相关增高趋势,但差异无显著性(r=0.371,P>0.05).血浆肿瘤坏死因子α含量与血管内皮生长因子表达水平呈显著正相关(r=0.893,P<0.01).结论:肿瘤坏死因子α与血管内皮生长因子在类风湿关节炎炎症反应,滑膜新生血管形成的细胞因子网络中起重要作用,二者相互可能具有影响,相互促进,充当恶性网络循环的调控作用;是介导类风湿关节炎发生和发展以及骨质侵蚀、致残的众多因子中的关键因子.%BACKGROUND: Pathological change of synovium in rheumatoid arthritis (RA) has the characteristic of tumor-like growth, it appears thickening of the synovium tissue and the formatiom of pannus, which generate periarticular erosion and destruction. Multiplicate cell factors and growth factors participate in the development course of tumor-like lesion of synovium, and the tumor necrosis factor-α(TNF-α) and vascular endothelial growth factor(VEGF)play important roles in the development of RA and the formation of pannus.OBJECTIVE: To observe the contents of plasma TNF-α of collagen-induced arthritis and the expression change of VEGF of synovium at different time point, and investigate the effect and correlation of TNF-α and VEGF in the pathogenesis of RA.DESIGN: Randomized grouping experiment taking animals as subjects.SETTING: Institute integrated traditional and western medicine of Xiangya

  3. Tumor Necrosis Factor-α sebagai Prediktor Terjadinya Anemia pada Ibu Hamil di Wilayah Endemis Malaria

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    Rostika Flora

    2015-04-01

    Full Text Available Ibu hamil yang berada di daerah endemis malaria sangat rentan terhadap infeksi malaria selama kehamilan. Gejala malaria pada kelompok ini sering asimptomatik atau bahkan tidak terdeteksi sama sekali karena adanya efek imunitas protektif melalui infeksi yang berulang. Adanya peningkatan kadar tumor necrosis factor-alpha (TNF-α dapat dijadikan indikator terjadinya infeksi malaria. TNF-α berperan penting dalam respons imun pada malaria akut yang menghambat terjadinya eritropoesis. Penelitian ini bertujuan untuk mengetahui hubungan antara kadar TNF-α dengan kejadian anemia pada ibu hamil didaerah endemik malaria vivax. Penelitian ini menggunakan desain potong lintang, dilakukan pada bulan Januari - Februari 2014 di lima wilayah kerja puskesmas Kota Bengkulu. Sampel penelitian adalah ibu hamil di daerah endemis malaria vivax yang diambil secara accidental sampling. Dilakukan pengambilan darah untuk pemeriksaan mikroskopis malaria, kadar TNF-α dan kadar hemoglobin (Hb. Hasil penelitian menunjukkan seluruh ibu hamil memiliki riwayat pernah terinfeksi malaria vivax, walaupun hasil pemeriksaan slide negatif. Terjadi peningkatan kadar TNF- α dengan rerata 6,90 ± 2,48 pg/mL dan penurunan kadar Hb dengan rerata 9,75 ± 0,88 g%. Uji korelasi Spearman didapatkan korelasi negatif yang kuat (r = -0,734 dan bermakna (nilai p < 0,05 antara Kadar TNF-α dengan kadar Hb. Terdapat hubungan yang bermakna antara kadar TNF-α dengan kejadian anemia. Tumor Necrosis Factor-α as Predictor of Anemia Occurrence among Pregnant Mothers in Malaria-Endemic Areas Pregnant mothers living in malaria - endemic area are very susceptible to malaria infection during pregnancy. Malaria symptoms in this group are often asymptomatic or even not detected at all due to protective immunity effect through repeated infections. Any elevation of tumor necrosis factor-alpha (TNF-α level can be used as indicator of malaria infection. TNF-α takes an important role in immune response on

  4. 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...

  5. 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...

  6. 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

  7. Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease

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    Fiona E McAlpine

    2008-11-01

    Full Text Available Fiona E McAlpine, Malú G TanseyAbstract: Alzheimer’s disease (AD is a progressive neurodegenerative disorder that affects nearly one in two individuals over 90 years of age. Its neuropathological hallmarks are accumulation of extraneuronal plaques of amyloid-beta (Aβ, the presence of neurofibrillary tangles formed by aberrantly hyperphosphorylated tau, progressive synaptic loss, and neurodegeneration which eventually results in decline of memory and cognitive faculties. Although the etiology of sporadic AD in humans is unknown, mutations in amyloid precursor protein or components of its processing machinery (β-secretase and γ-secretase result in overproduction of Aβ1–40 and 1–42 peptides and are sufficient to cause disease. In this review, we highlight the experimental and clinical evidence that suggests a close association between neuroinflammation and AD pathogenesis. Overproduction of inflammatory mediators in the brain occurs when microglia, which are often found in close physical association with amyloid plaques in AD brains, become chronically activated. It has been proposed that elevated levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF, may inhibit phagocytosis of Aβ in AD brains thereby hindering efficient plaque removal by resident microglia. In support of this idea, the bacterial endotoxin lipopolysaccharide, a potent trigger of inflammation that elicits production of TNF and many other cytokines, can accelerate the appearance and severity of AD pathology in several animal models of AD. We review the evidence implicating TNF signaling in AD pathology and discuss how TNF-dependent processes may contribute to cognitive dysfunction and accelerated progression of AD. We conclude by reviewing the observations that provide compelling rationale to investigate the extent to which new therapeutic approaches that selectively target the TNF pathway modify progression of neuropathology in pre-clinical models

  8. Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis

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    Martínez-Santana V

    2013-07-01

    Full Text Available Virginia Martínez-Santana,1 E González-Sarmiento,2 MA Calleja-Hernández,3 T Sánchez-Sánchez1 1Pharmacy Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 2Internal Medicine Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 3Pharmacy Department, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain Background: Persistence of anti-tumor necrosis factor (TNF therapy in rheumatoid arthritis (RA is an overall marker of treatment success. Objective: To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. Design: An observational, descriptive, longitudinal, retrospective study. Setting: The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. Patients: RA patients treated with anti-TNF therapy between January 2011 and January 2012. Measurements: Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations for quantitative variables and frequency distribution for qualitative variables. Kaplan–Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. Results: In total, 126 treatment series with infliximab (n = 53, etanercept (n = 51 or adalimumab (n = 22 were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. Limitation: The small sample size. Conclusion: The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with

  9. Tumor necrosis factor receptor-associated protein 1 improves hypoxia-impaired energy production in cardiomyocytes through increasing activity of cytochrome c oxidase subunit II.

    Science.gov (United States)

    Xiang, Fei; Ma, Si-Yuan; Zhang, Dong-Xia; Zhang, Qiong; Huang, Yue-Sheng

    2016-10-01

    Tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes against hypoxia, but the underlying mechanisms are not completely understood. In the present study, we used gain- and loss-of-function approaches to explore the effects of tumor necrosis factor receptor-associated protein 1 and cytochrome c oxidase subunit II on energy production in hypoxic cardiomyocytes. Hypoxia repressed ATP production in cultured cardiomyocytes, whereas overexpression of tumor necrosis factor receptor-associated protein 1 significantly improved ATP production. Conversely, knockdown of tumor necrosis factor receptor-associated protein 1 facilitated the hypoxia-induced decrease in ATP synthesis. Further investigation revealed that tumor necrosis factor receptor-associated protein 1 induced the expression and activity of cytochrome c oxidase subunit II, a component of cytochrome c oxidase that is important in mitochondrial respiratory chain function. Moreover, lentiviral-mediated overexpression of cytochrome c oxidase subunit II antagonized the decrease in ATP synthesis caused by knockdown of tumor necrosis factor receptor-associated protein 1, whereas knockdown of cytochrome c oxidase subunit II attenuated the increase in ATP synthesis caused by overexpression of tumor necrosis factor receptor-associated protein 1. In addition, inhibition of cytochrome c oxidase subunit II by a specific inhibitor sodium azide suppressed the ATP sy nthesis induced by overexpressed tumor necrosis factor receptor-associated protein 1. Hence, tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes from hypoxia at least partly via potentiation of energy generation, and cytochrome c oxidase subunit II is one of the downstream effectors that mediates the tumor necrosis factor receptor-associated protein 1-mediated energy generation program.

  10. Factor de necrosis tumoral alfa en pacientes con preeclampsia a término y pretérmino

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    Eduardo Reyna Villasmil

    2012-07-01

    Full Text Available El objetivo de la investigación fue identificar y comparar las concentraciones de factor de necrosis tumoral alfa en pacientes con preeclampsia a término y pre-término. Se seleccionó un total de 50 pacientes. Se incluyeron a 20 pacientes preeclámpticas pre-término (grupo A y 30 preeclámpticas a término (grupo B. Las muestras de sangre para la determinación de factor de necrosis tumoral alfa se recolectaron en todas las pacientes antes del parto e inmediatamente después del diagnóstico de preeclampsia. No se encontraron diferencias significativas con relación a la edad materna e Índice de masa corporal al momento de la toma de la muestra. Se observaron diferencias estadísticamente significativas entre los grupos con respecto a la edad gestacional (p < 0,0001. El valor promedio de la presión arterial sistólica en el grupo A fue de 149,4 ± 11,3 mmHg mientras que en las pacientes del grupo B fue de 148,1 ± 12,3 mmHg (p = 0,7071 y el valor promedio de presión arterial diastólica en el grupo A fue de 103,8 ± 8,6 mmHg y en el grupo B fue de 102,7 ± 7,9 mmHg (p = 0,6436. Las concentraciones de factor de necrosis tumoral alfa fueron similares en el grupo de preeclámpticas pre-término (98,2 ± 45,1 pg/mL comparado con el grupo de preeclámpticas a término (96,6 ± 48,7 pg/mL; p = 0,9072. Al realizar la correlación entre los valores de factor de necrosis tumoral alfa con los valores de presión arterial se observó que no existía correlación con la presión arterial sistólica (r = 0,129; p = 0,374 ni con la de presión arterial diastólica (r = 0,158, p = 0,273. Se concluye que las concentraciones sanguíneas del factor de necrosis tumoral alfa resultaron similares en las pacientes preeclámpticas con embarazo pretérmino y a término. La correlación de las concentraciones de factor de necrosis tumoral alfa con los valores de presión arterial sistólica y diastólica resultó no significativa. Palabras clave:Factor de

  11. Tumor necrosis factor-α modifies the effects of Shiga toxin on glial cells.

    Science.gov (United States)

    Leu, Hue; Sugimoto, Naotoshi; Shimizu, Masaki; Toma, Tomoko; Wada, Taizo; Ohta, Kunio; Yachie, Akihiro

    2016-09-01

    Shiga toxin (STX) is one of the main factors inducing hemorrhagic colitis and hemolytic-uremic syndrome (HUS) in infections with STX-producing Escherichia coli (STEC). Approximately 62% of patients with HUS showed symptoms of encephalopathy in the 2011 Japanese outbreak of STEC infections. At that time, we reported elevated serum concentrations of tumor necrosis factor (TNF)-α in patients with acute encephalopathy during the HUS phase. In the current study, we investigated whether TNF-α augments the effects of STX in glial cell lines and primary glial cells. We found that TNF-α alone or STX in combination with TNF-α activates nuclear factor-κB (NF-κB) signaling and inhibits growth of glial cells. The magnitude of the NF-κB activation and the inhibition of cell growth by the STX and TNF-α combination was greater than that obtained with TNF-α alone or STX alone. Thus, this in vitro study reveals the role of TNF-α in glial cells during STEC infections. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Leukotriene B4 and tumor necrosis factor release from leukocytes: effect of peritoneal dialysate.

    Science.gov (United States)

    Jörres, A; Jörres, D; Gahl, G M; Kessel, M; Müller, C; Köttgen, E; Serke, S; Schulz, E; Mahiout, A

    1991-01-01

    The effect of peritoneal dialysate on the capacity of peripheral blood polymorphonuclear (PMNL) and mononuclear leukocytes (MNC) to release leukotriene B4 (LTB4) and tumor necrosis factor alpha (TNF alpha) was investigated in vitro. Following density gradient separation, aliquots of 5 x 10(6) PMNL or MNC were incubated in peritoneal dialysis fluid containing 1.5% glucose or Hanks' buffer (= control) for 1-2 h at 37 degrees C. TNF alpha and LTB4 production was stimulated with Escherichia coli lipopolysaccharide (LPS) and calcium ionophore A23187, respectively. MNC incubated in buffer and LPS produced (mean +/- SD) 1,006 +/- 522 pg TNF alpha/5 x 10(6) cells; no significant amounts of TNF alpha were detectable in the presence of dialysate. An inhibition of TNF alpha release was also observed in MNC exposed to bicarbonate-buffered dialysates (pH 7.40) and 4.25% and 1.5% glucose solution with physiologic osmolality. Incubation of PMNL in Hanks' buffer followed by A23187 stimulation led to production of 29.1 +/- 19.2 ng LTB4/5 x 10(6) cells, whereas glucose-incubated cells were refractory to ionophore stimulation (less than 0.1 ng LTB4/5 x 10(6) cells). The failure of dialysate-exposed leukocytes to release inflammatory mediators in response to adequate stimuli may contribute to the impairment of cellular host defense in the setting of continuous ambulatory peritoneal dialysis.

  13. 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

  14. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

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    Mark Bounthavong

    2014-05-01

    Full Text Available Introduction. Anti-tumor necrosis factor (TNF agents are effective for several immunologic conditions (rheumatoid arthritis (RA, Crohn’s disease (CD, and psoriasis. The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review.Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events.Results. A majority of patients were prescribed anti-TNF agents for CD (27% and RA (24%. Patients were initiated on etanercept (41%, adalimumab (40%, and infliximab (18% between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab.Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population.

  15. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population.

    Science.gov (United States)

    Bounthavong, Mark; Madkour, Nermeen; Kazerooni, Rashid

    2014-01-01

    Introduction. Anti-tumor necrosis factor (TNF) agents are effective for several immunologic conditions (rheumatoid arthritis (RA), Crohn's disease (CD), and psoriasis). The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review. Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events. Results. A majority of patients were prescribed anti-TNF agents for CD (27%) and RA (24%). Patients were initiated on etanercept (41%), adalimumab (40%), and infliximab (18%) between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab. Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population.

  16. Golimumab and certolizumab: The two new anti-tumor necrosis factor kids on the block

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    Mittal Mohit

    2010-01-01

    Full Text Available Anti-tumor necrosis factor (anti-TNF agents have revolutionized treatment of psoriasis and many other inflammatory diseases of autoimmune origin. They have considerable advantages over the existing immunomodulators. Anti-TNF agents are designed to target a very specific component of the immune-mediated inflammatory cascades. Thus, they have lower risks of systemic side-effects. In a brief period of 10 years, a growing number of biological therapies are entering the clinical arena while many more biologicals remain on the horizon. With time, the long-term side-effects and efficacies of these individual agents will become clearer and help to determine which ones are the most suitable for long-term care. Golimumab (a human monoclonal anti-TNF-α antibody and Certolizumab (a PEGylated Fab fragment of humanized monoclonal TNF-α antibody are the two latest additions to the anti-TNF regimen. Here, we are providing a brief description about these two drugs and their uses.

  17. Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.

    Science.gov (United States)

    McGuire, S O; Ling, Z D; Lipton, J W; Sortwell, C E; Collier, T J; Carvey, P M

    2001-06-01

    Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNFalpha-induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNFalpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNFalpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNFalpha-treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNFalpha-induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNFalpha receptor 1 (p55, R1) and TNFalpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNFalpha treatment. These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD.

  18. Mutational Analysis of Region-cytotoxicity Relationship in Human Transmembrane Tumor Necrosis Factor-alpha

    Institute of Scientific and Technical Information of China (English)

    ZHENGFang; GONGFeili; LIZhuoya; JIANGXiaodan; XIONGPing; FENGWei; XUYong

    2002-01-01

    Objective:To determine the region of human transmembrane tumor necrosis factor-alpha (TM-TNFa), essential for cytotoxic activity a-gainst human breast cancer cell line MCF-7. Methods:Single amino-acid-substituted TM-TNFα mutant proteins (muteins) were produced by in vitro transcription linked translation techniques. The cDNA of TM-TNFα was site-directed mutagenized by recombinant PCR. Results:13 single amino-acid substituted TM-TNFα muteins were generated and assayed for cytotoxic activity. The cytotoxic activities of TM-TNFα muteins, eg, TM-TNFα-71/Lys, -28/Phe and 117/Leu were significantly decreased (P<0.01) compared to that of parent TM-TNFα, 143/Tyr decreased 4-folds, and-17/Thr,-39/Ser,ll9/His,35/Gly,95/Cys and 147/Phe decreased 1.5-2.5-folds, respectively. However, the cytotoxic activities of TM-TNFα-8/Arg, 31/Gly and 87/Phe showed no significant change. Conclusion:These results indicate that the regions associated with cytotoxic-activity of TM-TNFα are different with that of secretory TNF-lpha (S-TNFα). The inner cell region and transmembrane region of TM-TNFα are related to the cytotoxic activity of TM-TNFα.

  19. 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.

  20. Tumor necrosis factor alpha gene polymorphism in Serbian patients with sarcoidosis

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    Rađenović-Petković Tatjana

    2013-01-01

    Full Text Available Introduction. Sarcoidosis is a multisystemic disease of unknown etiology. Genetic factors play a considerable role in the onset of the disease. Tumor necrosis factor alpha (TNF-α is a proinflammatory cytokine which plays an important role in the pathogenesis of the disease and the formation of granuloma by regulating cellular proliferation and apoptosis. Objective. The aim of this study was to investigate the role of TNF-α-308 G/A polymorphism in the development of sarcoidosis and to evaluate the association between the aforementioned type of polymorphism and the clinical course of the disease. Methods. Seventy patients with sarcoidosis and 50 healthy volunteers were genotyped for the TNF-α-308G/A polymorphism. Polymorphism variants were examined by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism on the DNA isolated from blood leukocytes. Results. There were no significant differences in TNF-α-308A allele frequency distribution between sarcoidosis patients and the control group, but the TNF-α-308A allele was observed significantly more frequently in the sarcoidosis patients with Löfgren’s syndrome when compared with non-Löfgren’s patients. Conclusion. We have found that the TNF-α-308A variant is associated with Löfgren’s syndrome in Serbian patients with sarcoidosis.

  1. Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

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    Loft Steffen

    2006-02-01

    Full Text Available Abstract Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs. Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6 and the chemokines, monocyte chemoattractant protein (Mcp-1, macrophage inflammatory protein-2 (Mip-2 and keratinocyte derived chemokine (Kc in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1.

  2. Tumor Necrosis Factor-α as a Diagnostic Marker for Neonatal Sepsis: A Meta-Analysis

    Science.gov (United States)

    Lv, Bokun; Huang, Jie; Yuan, Haining; Yan, Wenying

    2014-01-01

    Neonatal sepsis (NS) is an important cause of mortality in newborns and life-threatening disorder in infants. The meta-analysis was performed to investigate the diagnosis value of tumor necrosis factor-α (TNF-α) test in NS. Our collectible studies were searched from PUBMED, EMBASE, and the Cochrane Library between March 1994 and August 2013. Accordingly, 347 studies were collected totally, in which 15 articles and 23 trials were selected to study the NS in our meta-analysis. The TNF-α test showed moderate accuracy of the diagnosis of NS both in early-onset neonatal sepsis (sensitivity = 0.66, specificity = 0.76, Q∗ = 0.74) and in late-onset neonatal sepsis (sensitivity = 0.68, specificity = 0.89, Q∗ = 0.87). We also found the northern hemisphere group in the test has higher sensitivity (0.84) and specificity (0.83). A diagnostic OR analysis found that the study population may be the major reason for the heterogeneity. Accordingly, we suggest that TNF-α is also a valuable marker in the diagnosis of NS. PMID:24672322

  3. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Madonna, Rosalinda [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Shelat, Harnath; Xue, Qun; Willerson, James T. [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States); De Caterina, Raffaele [Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Geng, Yong-Jian, E-mail: yong-jian.geng@uth.tmc.edu [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States)

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  4. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells.

    Science.gov (United States)

    Soeda, S; Ochiai, T; Paopong, L; Tanaka, H; Shoyama, Y; Shimeno, H

    2001-11-01

    Crocus sativus L. is used in Chinese traditional medicine to treat some disorders of the central nervous system. Crocin is an ethanol-extractable component of Crocus sativus L.; it is reported to prevent ethanol-induced impairment of learning and memory in mice. In this study, we demonstrate that crocin suppresses the effect of tumor necrosis factor (TNF)-alpha on neuronally differentiated PC-12 cells. PC-12 cells dead from exposure to TNF-alpha show apoptotic morphological changes and DNA fragmentation. These hallmark features of cell death did not appear in cells treated in the co-presence of 10 microM crocin. Moreover, crocin suppressed the TNF-alpha-induced expression of Bcl-Xs and LICE mRNAs and simultaneously restored the cytokine-induced reduction of Bcl-X(L) mRNA expression. The modulating effects of crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-alpha-induced release of cytochrome c from the mitochondria. Crocin also blocked the cytochrome c-induced activation of caspase-3. To learn how crocin exhibits these anti-apoptotic actions in PC-12 cells, we tested the effect of crocin on PC-12 cell death induced by daunorubicin. We found that crocin inhibited the effect of daunorubicin as well. Our findings suggest that crocin inhibits neuronal cell death induced by both internal and external apoptotic stimuli.

  5. Expression of tumor necrosis factor-alpha converting enzyme in liver regeneration after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Xian-Ming Lin; Ying-Bin Liu; Fan Zhou; Yu-Lian Wu; Li Chen; He-Qing Fang

    2008-01-01

    AIM:To study the expression of tumor necrosis factor-alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo.METHODS:Male SD rats underwent 70% partial hepatec-tomy.The remaining liver and spleen tissue samples were collected at indicated time points after hepatectomy.TACE expression was investigated by Western blotting,immunohistochemistry,and serial section immunostaining.RESULTS:Expression of TACE in liver and spleen tissues after partial hepatectomy was a time-dependent alteration,reaching a maximal level between 24 and 48 h and remaining elevated for more than 168 h.TACE protein was localized to mononuclear cells (MNC),which infiltrated the liver from the spleen after hepatectomy.The kinetics of TACE expression was in accordance with the number of TACE-staining MNCs and synchronized with those of transforming growth factor-α(TGFα).In addition,TACE-staining MNC partially overlapped with CD3+ T lymphocytes.CONCLUSION:TACE may be involved in liver regenera-tion by pathway mediated with TGFα-EGFR in the cell-cycle progressive phase in vivo.TACE production and effect by paracrine may be a pathway of involvement in liver regeneration for the activated CD3+ T lymphocytes.

  6. 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

  7. Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis.

    Science.gov (United States)

    Noor, Zannatun; Watanabe, Koji; Abhyankar, Mayuresh M; Burgess, Stacey L; Buonomo, Erica L; Cowardin, Carrie A; Petri, William A

    2017-02-28

    The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α) production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25) is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α.IMPORTANCE The intestinal epithelial barrier is important for protection from intestinal amebiasis. We discovered that the intestinal epithelial cytokine IL-25 was suppressed during amebic colitis in humans and that protection could be restored in the mouse model by IL-25 administration. IL-25 acted via eosinophils and suppressed TNF-α. This work illustrates a previously unrecognized pathway of innate mucosal immune response. Copyright © 2017 Noor et al.

  8. 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.

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

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    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.

  10. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    DEFF Research Database (Denmark)

    Aderka, D; Engelmann, H; Maor, Y;

    1992-01-01

    activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on prolonged treatment with this cytokine are augmented, reflecting an attenuation by the sTNF-Rs of spontaneous......The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell-associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF...... TNF activity decay. Evidence that this stabilization of TNF activity by the sTNF-Rs follows from stabilization of TNF structure within the complexes that TNF forms with the sTNF-Rs is presented here, suggesting that the sTNF-Rs can affect TNF activity not only by interfering with its binding to cells...

  11. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor.

    Science.gov (United States)

    Abbas, Sabiha; Zhang, Yan-Hong; Clohisy, John C; Abu-Amer, Yousef

    2003-04-01

    Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine with a profound role in many skeletal diseases. The cytokine has been described as a mediator of bone loss in osteolysis and other inflammatory bone diseases. In addition to its known bone resorptive action, TNF reduces bone formation by inhibiting osteoblast differentiation. Using primary and transformed osteoblastic cells, we first document that TNF inhibits expression of alkaline phosphatase and matrix deposition, both considered markers of osteoblast differentiation. The effects are dose- and time-dependent. Core-binding factor A1 (cbfa1) is a transcription factor critical for osteoblast differentiation, and we show here that it is activated by the osteoblast differentiation agent, beta-glycerophosphate. Therefore, we investigated whether the inhibitory effects of TNF were associated with altered activity of this transcription factor. Using retardation assays, we show that TNF significantly inhibits cbfal activation by beta-glycerophosphate, manifested by reduced DNA-binding activity. Next, we turned to determine the signaling pathway by which TNF inhibits osteoblast differentiation. Utilizing animals lacking individual TNF receptors, we document that TNFr1 is required for transmitting the cytokine's inhibitory effect. In the absence of this receptor, TNF failed to impact all osteoblast differentiation markers tested. In summary, TNF blocks expression of osteoblast differentiation markers and inhibits beta-glycerophosphate-induced activation of the osteoblast differentiation factor cbfa1. Importantly, these effects are mediated via a mechanism requiring the TNF type-1 receptor.

  12. 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.

  13. Synergism between human tumor necrosis factor and human interferon-alpha: effects on cells in culture.

    Science.gov (United States)

    Orita, K; Ando, S; Kurimoto, M

    1987-08-01

    The cytostatic and cytotoxic effects of highly purified natural human tumor necrosis factor (HuTNF-alpha) and natural human interferon-alpha (HuIFN-alpha) on 23 cell lines were studied in vitro. Natural HuTNF-alpha showed cytostatic and cytotoxic effects on PC-9, KHG-2, HT-1197, KG-1 and L-929 cells, and HuIFN-alpha showed both effects on KHG-2 and Daudi cells. A mixture of HuTNF-alpha and HuIFN-alpha (1:1, by unit) showed cytostatic and cytotoxic effects on HuTNF-alpha- or HuIFN-alpha-resistant cell lines such as KB, KATO-III, HEp-2, P-4788, as well as on HuTNF-alpha- or HuIFN-alpha-susceptible cells. Thus, the combined preparation of HuTNF-alpha and HuIFN-alpha expanded the spectrum of sensitive cells. The dosage of the mixed preparation required to produce 50% inhibition of cell growth was less than 20% of that of HuTNF-alpha or HuIFN-alpha alone. These results indicate that the cytostatic and cytotoxic effects of HuTNF-alpha and HuIFN-alpha are synergistically enhanced when they are administered together.

  14. Synergism between human tumor necrosis factor and human interferon-alpha: effects on cells in culture.

    Directory of Open Access Journals (Sweden)

    Orita,Kunzo

    1987-08-01

    Full Text Available The cytostatic and cytotoxic effects of highly purified natural human tumor necrosis factor (HuTNF-alpha and natural human interferon-alpha (HuIFN-alpha on 23 cell lines were studied in vitro. Natural HuTNF-alpha showed cytostatic and cytotoxic effects on PC-9, KHG-2, HT-1197, KG-1 and L-929 cells, and HuIFN-alpha showed both effects on KHG-2 and Daudi cells. A mixture of HuTNF-alpha and HuIFN-alpha (1:1, by unit showed cytostatic and cytotoxic effects on HuTNF-alpha- or HuIFN-alpha-resistant cell lines such as KB, KATO-III, HEp-2, P-4788, as well as on HuTNF-alpha- or HuIFN-alpha-susceptible cells. Thus, the combined preparation of HuTNF-alpha and HuIFN-alpha expanded the spectrum of sensitive cells. The dosage of the mixed preparation required to produce 50% inhibition of cell growth was less than 20% of that of HuTNF-alpha or HuIFN-alpha alone. These results indicate that the cytostatic and cytotoxic effects of HuTNF-alpha and HuIFN-alpha are synergistically enhanced when they are administered together.

  15. Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

    Science.gov (United States)

    Huie, J. Russell; Baumbauer, Kyle M.; Lee, Kuan H.; Bresnahan, Jacqueline C.; Beattie, Michael S.; Ferguson, Adam R.; Grau, James W.

    2012-01-01

    Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury. PMID:22745823

  16. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats.

    Directory of Open Access Journals (Sweden)

    Diana M Sama

    Full Text Available The role of tumor necrosis factor α (TNF in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1 are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2 in aged (22 months but not young adult (6 months Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+ channel (VSCC activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.

  17. Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL☆

    Science.gov (United States)

    Osório, Catarina; Chacón, Pedro J.; White, Matthew; Kisiswa, Lilian; Wyatt, Sean; Rodríguez-Tébar, Alfredo; Davies, Alun M.

    2014-01-01

    APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signaling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3β and the expression of a constitutively active form of GSK-3β. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3β signaling. PMID:24444792

  18. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists.

    Science.gov (United States)

    Bendtzen, Klaus

    2013-04-01

    With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies.

  19. Tumor necrosis factor-α gene polymorphisms in FMF and their association with amyloidosis.

    Science.gov (United States)

    Bonyadi, Mortaza; Bahrami, Salahadin; Jahanafrooz, Zohreh; Dastgiri, Saeed

    2012-11-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by periodic provocative attacks of fever with peritonitis, pleuritis, arthritis, or eriseplemya. Tumor necrosis factor-α (TNF-α) plays an important role in the regulation of the immune response as a part of the cytokine network, including activation of macrophages and apoptosis. We investigated the possible association of TNF-α promoter -1031T/C and -308G/A polymorphisms in 86 FMF patients carrying M694 V homozygous mutation and 100 matched healthy controls both from Iranian Azeri Turks. Our data showed that patients with TNF-α -308 GG are more susceptible to the development of amyloidosis and arthritis (P value <.05). These data also showed that the frequency of TNF-α -308 A allele is considerably low among patients with amyloidosis, and it may have protective role among them (odds ratio [OR] = 0.083, χ(2) = 5.46, P value = .003). Further evaluation of this polymorphism may be important and need further studies.

  20. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease.

    Science.gov (United States)

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-06-01

    Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy.

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

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    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.

  2. 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

    2006-04-11

    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.

  3. 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.

  4. Inflammatory myofibroblastic tumor of the maxillary sinus related with pulp necrosis of maxillary teeth: case report.

    Science.gov (United States)

    Kim, Sin-Young; Yang, Sung-Eun

    2011-11-01

    Inflammatory myofibroblastic tumor (IMT) is a benign lesion composed of myofibroblasts accompanied by varying numbers of inflammatory cells. Various pathogenetic factors have been proposed, but the etiology of most IMTs remains unknown. This article presents a case of IMT occurring in the left maxillary sinus. A 24-year-old man complained of throbbing pain in the maxillary left molars and swelling of the left cheek. His maxillary left second molar was diagnosed as pulp necrosis and root canal treatment performed. After that, his symptoms continued and he was referred to the Department of Otolaryngology. Computerized tomography disclosed compact soft tissue masses in the left maxillary sinus with obstruction of maxillary ostium. Under general anesthesia, the lesions were fully excised. Histopathologically, the lesions were composed of plump or spindled myofibroblasts. Cells were immunoreactive for smooth muscle actin and β-catenin, and were negative for ALK1, CD34, and EMA. The diagnosis was IMT of left maxillary sinus. Although it is very rare, IMT should be included as a differential diagnosis in patients with compact masses in maxillary sinus. Copyright © 2011 Mosby, Inc. All rights reserved.

  5. Intravenous immunoglobulin reduces serum tumor necrosis factor a in patients with Guillain-Barre Syndrome

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    Reuben S

    2003-10-01

    Full Text Available Background: Tumor necrosis factor a TNF-alpha has a possible role in the pathogenesis of the Guillain-Barre' syndrome (GBS. Aims: To study the effect of intravenous immunoglobulin (IVIg on serum TNF-alpha concentrations in patients with GBS. Material and Methods: The effect of IVIg on TNF-alpha was evaluated in 36 patients with GBS. Serum TNF-alpha concentration was measured by enzyme-linked immunosorbent assay (ELISA. The sera of 22 (61% patients with GBS showed elevated concentrations of TNF-alpha (35-182 pg/ml and these sera were individually incubated in vitro with IVIg (0.25mg/ml at 37°C for 24 hours. Results: The serum TNF-alpha concentrations in the 22 GBS patients with elevated levels showed a steady decline (60.34—19.78 pg/ml following incubation with IVIg. These 22 patients also received IVIg therapy, and serum TNF-alpha concentrations showed a significant decline (65.5—9.75 pg/ml at the end of the therapy. At the time of discharge from the hospital, there was a positive correlation between neurological recovery and decline in TNF-alpha concentrations in these 22 GBS patients. Conclusions: The results of this study indicate that elevated levels of TNF-alpha occur in a proportion of patients with GBS and in these patients elevated serum TNF-alpha levels decline with IVIg therapy.

  6. Anti-Tumor Necrosis Factor Alpha for Retinal Diseases: Current Knowledge and Future Concepts

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    Alireza Mirshahi

    2012-01-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

  7. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts.

    Science.gov (United States)

    Mirshahi, Alireza; Hoehn, René; Lorenz, Katrin; Kramann, Christina; Baatz, Holger

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

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

    Institute of Scientific and Technical Information of China (English)

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

    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. Eightyeight and forty-six genes were found to be up- or downregulated 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 RTPCR. 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.

  9. Effect of tumor necrosis factor-α inhibitors on ambulatory 24-h blood pressure.

    Science.gov (United States)

    Grossman, Chagai; Bornstein, Gil; Leibowitz, Avshalom; Ben-Zvi, Ilan; Grossman, Ehud

    2017-02-01

    Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used in inflammatory rheumatic diseases (IRD). The risk of cardiovascular disease is elevated in patients with IRD and TNF-α inhibitors reduce this risk. We assessed whether the beneficial effect of TNF-α inhibitors on cardiovascular risk is mediated by blood pressure reduction. We measured blood pressure levels with 24-h ambulatory blood pressure measurements device in patients with IRD before and 3 months after treatment with TNF-α inhibitors. The study population consisted of 15 subjects (6 men; mean age 45.9 ± 14.1 years). Most patients had either rheumatoid arthritis or psoriatic arthritis and adalimumab was the most common TNF-α inhibitor used. Mean 24-h systolic and diastolic blood pressure levels remained the same after treatment (121 ± 12/66 ± 7 before and 123 ± 11/67 ± 10 mm Hg after; p = 0.88 and 0.66, respectively). The study demonstrates that TNF-α inhibitors have no effect on blood pressure levels.

  10. Effects of Panax ginseng on Tumor Necrosis Factor-α-Mediated Inflammation: A Mini-Review

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    Davy CW Lee

    2011-03-01

    Full Text Available Panax ginseng is one of the most commonly used Chinese medicines in China, Asia and Western countries. The beneficial effects of ginseng have been attributed to the biological activities of its constituents, the ginsenosides. In this review, we summarize recent publications on the anti-inflammatory effects of ginseng extracts and ginsenosides on cellular responses triggered by different inducers including endotoxin, tumor necrosis factor-alpha (TNF-α, interferon-gamma and other stimuli. Proinflammatory cytokines, chemokines, adhesion molecules and mediators of inflammation including inducible nitric oxide synthase, cyclooxygenase-2 and nitric oxide orchestrate the inflammatory response. Ginseng extracts and ginsenosides including Rb1, Rd, Rg1, Rg3, Rh1, Rh2, Rh3 and Rp1 have been reported to have anti-inflammatory properties in different studies related to inflammation. Ginsenosides inhibit different inducers-activated signaling protein kinases and transcription factor nuclear factor-kappaB leading to decreases in the production of cytokines and mediators of inflammation. The therapeutic potential of ginseng on TNF-α-mediated inflammatory diseases is also discussed. Taken together, this summary provides evidences for the anti-inflammatory effects of ginseng extracts and ginsenosides as well as the underlying mechanisms of their effects on inflammatory diseases.

  11. 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.

  12. 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.

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

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    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.

  14. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease.

    Science.gov (United States)

    Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian J; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; Heimke-Brinck, Ralph; Reuter, Eva; Dörje, Frank; Rau, Tilman T; Uter, Wolfgang; Wang, Thomas D; Kiesslich, Ralf; Vieth, Michael; Hannappel, Ewald; Neurath, Markus F

    2014-03-01

    As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.

  15. Tumor necrosis in osteosarcoma: inclusion of the point of greatest metabolic activity from F-18 FDG PET/CT in the histopathologic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Costelloe, Colleen M.; Fitzgerald, Nancy E.; Madewell, John E.; Marom, Edith M. [The University of Texas M. D. Anderson Cancer Center, Division of Diagnostic Imaging, Department of Radiology, Houston, TX (United States); Raymond, A.K. [The University of Texas M. D. Anderson Cancer Center, Department of Pathology, Houston, TX (United States); Mawlawi, Osama R. [The University of Texas M. D. Anderson Cancer Center, Division of Diagnostic, Department of Imaging Physics, Houston, TX (United States); Nunez, Rodolfo F. [The University of Texas M. D. Anderson Cancer Center, Division of Diagnostic Imaging, Department of Nuclear Medicine, Houston, TX (United States); Harrell, Robyn K.; Bassett, Roland L. [The University of Texas M. D. Anderson Cancer Center, Department of Biostatistics, Houston (United States)

    2010-02-15

    To determine if the location of the point of maximum standardized uptake value (SUVmax) being included in or not included in the histopathologic slab section corresponded to tumor necrosis or survival. Twenty-nine osteosarcoma patients underwent post-chemotherapy [fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography-computed tomography (PET/CT) prior to resection. PET/CT images were correlated with slab-section location as determined by photographs or knowledge of specimen processing. The location of the point of SUVmax was then assigned as being 'in' or 'out' of the slab section. Cox's proportional hazard regression was used to evaluate relationships between the location and value of SUVmax and survival. Logistic regression was employed to evaluate tumor necrosis. No correlation was found between the SUVmax location and survival or tumor necrosis. High SUVmax correlated to poor survival. High SUVmax value correlated to poor survival. Minimal viable tumor (> 10%) following chemotherapy is a known indicator of poor survival. No correlation was found between the location of SUVmax and survival or tumor necrosis. Therefore, the SUVmax value either does not correspond to a sufficient number of tumor cells to influence tumor necrosis measurement or it was included in the out-of-slab samples that were directed to viable-appearing areas of the gross specimen. Since high SUVmax has been previously found to correspond to poor tumor necrosis, and tumor necrosis is simply an estimate of the amount of viable tumor, SUVmax likely represents many viable tumor cells. Therefore, when not in the slab section, SUVmax was likely included in the tumor necrosis measurement through directed sampling, validating our current method of osteosarcoma specimen analysis. (orig.)

  16. 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

  17. Influence of noninvasive ventilator in the treatment of plasma C-reactive protein , endothelin-1 and tumor necrosis factor-α in patients with obstructive sleep apneahypopnea syndrome%无创呼吸机治疗对OSAHS患者血清C反应蛋白、内皮素-1及肿瘤坏死因子-α水平的影响

    Institute of Scientific and Technical Information of China (English)

    孟庆华; 李承红; 江城; 孔彬; 冯琼

    2015-01-01

    Objective To investigate the effect of noninvasive ventilator therapy on serum C-reactive protein (CRP), endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) levels in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and its clinical significance. Methods One hundred cases of moder-ate and severe OSAHS patients were selected by the method of parallel opening. All of the patients were given health education requirement , quitting smoking and wine , low fat diet and exercise to lose weight and other con-ventional treatment. The patients were randomly divided into the treatment group of 42 cases with noninvasive ventilator treatment , 44 cases treated with conventional treatment , to observe the changes of serum CRP , ET-1 and TNF-α levels and PSG parameters after 12 weeks in two groups. Results Apnea hypopnea index (AHI), oxygen desaturation index (ODI), the lowest oxygen saturation (LSpO2), and the average oxygen saturation MSpO2 in OSAHS patients were significantly improved after treatment (P < 0.01), but the degree of improvement in the two groups after treatment was significantly higher than the control group (P < 0.01). Plasma CRP, ET-1 and TNF-α levels in the two groups after treatment were lower than before treatment (P < 0.05 or P < 0.01), but the treatment group was significantly higher than that of the control group ( P < 0 . 05 or P < 0 . 01 ) . Conclusion Noninvasive ventilator therapy in improving the OSAHS monitoring data of patients with PSG can effectively reduce the serum CRP, TNF-α, ET-1 level, reduce the body′s inflammatory reaction.%目的:探讨无创呼吸机治疗对阻塞性睡眠呼吸暂停低通气综合征( OSAHS )患者血清 C 反应蛋白( CRP )、内皮素-1 ( ET-1 )、肿瘤坏死因子-α( TNF-α)水平的影响及临床意义. 方法:采用平行开放的方法选取中重度 OSAHS 患者 100 例,均予以健康宣教,要求戒烟酒、低脂饮食和运动减肥等常规治疗;随机分为治疗组42

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

    Institute of Scientific and Technical Information of China (English)

    王卫; 黄唯佳; 陈寿权; 李章平; 王万铁; 王明山

    2004-01-01

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

  19. Daily injection of tumor necrosis factor-{alpha} increases hepatic triglycerides and alters transcript abundance of metabolic genes in lactating dairy cattle.

    Science.gov (United States)

    Bradford, Barry J; Mamedova, Laman K; Minton, J Ernest; Drouillard, James S; Johnson, Bradley J

    2009-08-01

    To determine whether inflammation can induce bovine fatty liver, we administered recombinant bovine tumor necrosis factor-alpha (rbTNF) to late-lactation Holstein cows. Cows (n = 5/treatment) were blocked by feed intake and parity and randomly assigned within block to control (CON; saline), rbTNF at 2 microg/(kg.d), or pair-fed control (saline, intake matched) treatments. Treatments were administered once daily by subcutaneous injection for 7 d. Plasma samples were collected daily for analysis of glucose and FFA and a liver biopsy was collected on d 7 for triglyceride (TG) and quantitative RT-PCR analyses. Data were analyzed using treatment contrasts to assess effects of tumor necrosis factor-alpha (TNFalpha) and decreased feed intake. By d 7, feed intake of both rbTNF and pair-fed cows was approximately 15% less than CON (P carnitine palmitoyltransferase 1 transcript abundance tended to be lower (P = 0.09) and transcript abundance of fatty acid translocase and 1-acyl-glycerol-3-phosphate acyltransferase was higher (both P < 0.05) after rbTNF treatment, consistent with increased FFA uptake and storage as TG. Transcript abundance of glucose-6-phosphatase (P < 0.05) and phosphoenolpyruvate carboxykinase 1 (P = 0.09), genes important for gluconeogenesis, was lower for rbTNF-treated cows. These findings indicate that TNFalpha promotes liver TG accumulation and suggest that inflammatory pathways may also be responsible for decreased glucose production in cows with fatty liver.

  20. Expression of tumor necrosis factor related apoptosis inducing ligand receptor in glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Dongling Gao; Zhongwei Zhao; Hongxin Zhang; Lan Zhang; Kuisheng Chen; Yunhan Zhang

    2008-01-01

    BACKGROUND: Receptors for tumor necrosis factor related apoptosis inducing ligand (TRAIL) include death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2. Activation of death receptor 4 and 5 selectively kills tumor cells.OBJECTIVE: To detect TRAIL receptor expression in glioblastoma by immunohistochemistry and RT-PCR and to compare this expression to that in normal brain tissue.DESIGN: Observational analysis.SETTING: Department of Pathology, the First Affiliated Hospital of Zhengzhou University; Henan Tumor Pathology Key Laboratory.PARTICIPANTS: Twenty-five patients (17 males and 8 females) who received glioblastoma resection were selected from the Fifth Affiliated Hospital of Zhengzhou University, between September 2003 to June 2004. All glioblastoma samples were diagnosed pathologically. Twenty patients (12 males and 8 females) with craniocerebral injury who received normal brain tissue resection were selected in the same time period. There were no significant differences in sex and age between glioblastoma patients or between craniocerebral injury patients (P>0.05). All patients and appropriate relatives provided informed consent, and this study was approved by the local research ethics committee.METHODS: Polyclonal antibody against TRAIL receptors and an immunohistochemical kit (batch number: 200502) were purchased from Boster Company, Wuhan. Immunohistochemistry: Expression of death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2 were observed in both glioblastoma and normal brain tissue. The experiment was performed according to the kit instructions, and positive staining was brown-yellow. Assessment: There were no positive signals (-); weakly positive signals, positive cells75% (++++). Evaluation: Expression levels of TRAIL receptors were estimated in both normal brain tissue and glioblastoma. Expression of decoy receptor 1 and decoy receptor 2 mRNA in glioblastoma were detected by reverse transcription polymerase

  1. Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide induced peritonitis

    Institute of Scientific and Technical Information of China (English)

    LIU Zhi-hai; MA Yue-feng; WU Jun-song; GAN Jian-xin; XU Shao-wen; JIANG Guan-yu

    2010-01-01

    Background The nervous system, through the vagus nerve and its neurotransmitter acetylcholine, can down-regulate the systemic inflammation in vivo, and recently, a role of brain cholinergic mechanisms in activating this cholinergic anti-inflammatory pathway has been indicated. Galanthamine is a cholinesterase inhibitor and one of the centrally acting cholinergic agents available in clinic. This study aimed to evaluate the effect of galanthamine on circulating tumor necrosis factor alpha (TNF-α) in rats with lipopolysaccharide-induced peritonitis and the possible role of the vagus nerve in the action of galanthamine.Methods Rat models of lipopolysaccharide-induced peritonitis and bilateral cervical vagotomy were produced. In the experiment 1, the rats were randomly divided into control group, peritonitis group, and peritonitis groups treated with three dosages of galanthamine. In the experiment 2, the rats were randomly divided into sham group, sham plus peritonitis group, sham plus peritonitis group treated with galanthamine, vagotomy plus peritonitis group, and vagotomy plus peritonitis group treated with galanthamine. The levels of plasma TNF-α were determined in every group. Results The level of circulating TNF-α was significantly increased in rats after intraperitoneal injection of endotoxin. Galanthamine treatment decreased the level of circulating TNF-α in rats with lipopolysaccharide-induced peritonitis, and there was significant difference compared with rats with lipopolysaccharide-induced peritonitis without treatment. The 3 mg/kg dosage of galanthamine had the most significant inhibition on circulating TNF-α level at all the three tested doses. Galanthamine obviously decreased the TNF-α level in rats with lipopolysaccharide-induced peritonitis with sham operation, but could not decrease the TNF-α level in rats with lipopolysaccharide-induced peritonitis with vagotomy. Conclusion Cholinesterase inhibitor galanthamine has an inhibitory effect on TNF

  2. Different presentations in patients with tumor necrosis factor receptor-associated periodic syndrome mutations: report of two cases.

    Science.gov (United States)

    Celebi-Tayfur, Aslı; Bilginer, Yelda; Finetti, Martina; Gattorno, Marco; Ozen, Seza

    2013-01-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-α. It is characterized by recurrent prolonged episodes of fever accompanied by abdominal pain, pleuritis, migratory skin rashes, fasciitis, headache, conjunctivitis, and periorbital edema. We report two children, one with a severe mutation in the TNFRSF1A gene causing the typical phenotype. The second patient had a homozygous R92Q-type mutation and displayed a periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome-like phenotype. In the eastern Mediterranean region, TRAPS is probably underdiagnosed because of the overwhelming frequency of familial Mediterranean fever (FMF). However, TRAPS should be sought for in patients with atypical symptoms for FMF.

  3. 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 of the pancr......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...... in INSr3#2 cells and in primary rat islets. Furthermore, SOCS-3 repressed TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum...

  4. TUMOR NECROSIS FACTOR-α INCREASES BDNF EXPRESSION IN TRIGEMINAL GANGLION NEURONS IN AN ACTIVITY-DEPENDENT MANNER

    OpenAIRE

    2011-01-01

    Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic ...

  5. Tumor necrosis factor α sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine

    OpenAIRE

    2010-01-01

    Abstract Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor α (TNFα), is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord has been shown to play an important role in neuropathic and inflam...

  6. Production of tumor necrosis factors alpha and beta by human mononuclear leukocytes stimulated with mitogens, bacteria, and malarial parasites.

    OpenAIRE

    Ferrante, A; Staugas, R E; Rowan-Kelly, B; Bresatz, S; Kumaratilake, L M; Rzepczyk, C M; Adolf, G R

    1990-01-01

    Tumor necrosis factors alpha and beta (TNF-alpha and TNF-beta) are multifaceted polypeptide cytokines which may mediate some of the significant changes in cellular homeostasis which accompany the invasion of the mammalian host by viruses, bacteria, and parasites. Although it is well established that bacterial lipopolysaccharide is a potent inducer of TNF-alpha, there is still very little known of the types of agents which can trigger the production of TNFs in mononuclear leukocytes. Using an ...

  7. Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Loza Matthew J

    2012-02-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease (COPD is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation. Methods Serum samples (n = 234 from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160 and 2 healthy control cohorts (n = 50; n = 109. Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay. Results Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile. Conclusions A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear. Trial Registration Clinical

  8. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    OpenAIRE

    Ramesh Vijay; Nair Deepti; Zhang Shelley X L; Hakim Fahed; Kaushal Navita; Kayali Foaz; Wang Yang; Li Richard C; Carreras Alba; Gozal David

    2012-01-01

    Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who...

  9. Texture descriptors to distinguish radiation necrosis from recurrent brain tumors on multi-parametric MRI

    Science.gov (United States)

    Tiwari, Pallavi; Prasanna, Prateek; Rogers, Lisa; Wolansky, Leo; Badve, Chaitra; Sloan, Andrew; Cohen, Mark; Madabhushi, Anant

    2014-03-01

    Di erentiating radiation necrosis (a radiation induced treatment e ect) from recurrent brain tumors (rBT) is currently one of the most clinically challenging problems in care and management of brain tumor (BT) patients. Both radiation necrosis (RN), and rBT exhibit similar morphological appearance on standard MRI making non-invasive diagnosis extremely challenging for clinicians, with surgical intervention being the only course for obtaining de nitive ground truth". Recent studies have reported that the underlying biological pathways de n- ing RN and rBT are fundamentally di erent. This strongly suggests that there might be phenotypic di erences and hence cues on multi-parametric MRI, that can distinguish between the two pathologies. One challenge is that these di erences, if they exist, might be too subtle to distinguish by the human observer. In this work, we explore the utility of computer extracted texture descriptors on multi-parametric MRI (MP-MRI) to provide alternate representations of MRI that may be capable of accentuating subtle micro-architectural di erences between RN and rBT for primary and metastatic (MET) BT patients. We further explore the utility of texture descriptors in identifying the MRI protocol (from amongst T1-w, T2-w and FLAIR) that best distinguishes RN and rBT across two independent cohorts of primary and MET patients. A set of 119 texture descriptors (co-occurrence matrix homogeneity, neighboring gray-level dependence matrix, multi-scale Gaussian derivatives, Law features, and histogram of gradient orientations (HoG)) for modeling di erent macro and micro-scale morphologic changes within the treated lesion area for each MRI protocol were extracted. Principal component analysis based variable importance projection (PCA-VIP), a feature selection method previously developed in our group, was employed to identify the importance of every texture descriptor in distinguishing RN and rBT on MP-MRI. PCA-VIP employs regression analysis to provide

  10. Serum tumor necrosis factor and interleukin 1 in leprosy and during lepra reactions.

    Science.gov (United States)

    Parida, S K; Grau, G E; Zaheer, S A; Mukherjee, R

    1992-04-01

    Tumor necrosis factor--alpha (TNF), one of the mediators of septic shock, has a role in the immunopathological complications of several infections. However, its role in leprosy is yet unclear. In this study, serum TNF and IL-1 levels in 64 patients spread over the spectrum of leprosy [lepromatous leprosy (LL), 30; borderline lepromatous, 12; borderline borderline, 8; and borderline tuberculoid-tuberculoid leprosy, 14] were measured at the time of admission. Elevated levels of TNF ranging from 15 to 4500 pg/ml were detected in lepromatous leprosy cases (399 +/- 189) and low levels ranging from 15 to 160 pg/ml were detected in the tuberculoid form of leprosy. Patients undergoing type 1 and type 2 lepra reactions also exhibited high TNF levels of 15-2100 pg/ml. Of the 14 clinically healthy individuals studied, 3 showed TNF levels of 15, 50, and 58 pg/ml. Interleukin 1-beta (IL-1) levels were found to be significantly higher in LL cases (70-5000 pg/ml) (328 +/- 184) in comparison to other groups or normal controls (9 +/- 3). The coefficient of correlation between TNF and IL-1 levels was statistically significant in LL and reaction cases (r = 0.96, P less than 0.001). These patients were followed up as outpatients for a period of 1 year. It was observed that 4 out of 8 patients with TNF levels greater than 100 pg/ml went into lepra reactions between 2 and 6 months after entry into the study, whereas only 5 out of 56 with less than 100 pg/ml went into mild lepra reactions (chi 2 = 9.7, P less than 0.01). Determination of TNF and IL-1 levels thus seems to have a prognostic significance in terms of lepra reaction in patients.

  11. Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection

    Directory of Open Access Journals (Sweden)

    Cacilda Tezelli Junqueira Padovani

    2013-06-01

    Full Text Available Introduction The progression of human papillomavirus (HPV infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. Methods We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. Results We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8% was predominant in samples with ≥1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL samples (p = 0.16. CD25 was present in great quantities in all samples. Conclusions The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker.

  12. Tumor necrosis factor inhibitors block apoptosis of human epithelial cells of the salivary glands.

    Science.gov (United States)

    Sisto, Margherita; D'Amore, Massimo; Caprio, Simone; Mitolo, Vincenzo; Scagliusi, Pasquale; Lisi, Sabrina

    2009-08-01

    Inhibition of tumor necrosis factor-alpha (TNF-alpha) in organ-specific autoimmune disease is proving efficacious for a large number of patients. A wide array of biological agents has been designed to inhibit TNF-alpha, such as adalimumab (fully humanized) and etanercept (soluble TNF-alpha receptor fusion constructs p75 subunit). Recently, we suggested that anti-Ro and anti-La autoantibodies (Abs) isolated from patients with Sjögren's syndrome, an autoimmune rheumatic disease, are able to trigger cell death through extrinsic apoptotic mechanisms in human salivary gland epithelial cells (SGEC). We analyzed if primary human SGEC cultures, established from biopsy of labial minor salivary glands, are able to produce TNF-alpha, an inductor of the extrinsic apoptotic pathway, when treated with anti-Ro autoantibodies. A comparative study was performed to test the efficacy of adalimumab and etanercept to block TNF-alpha-mediated apoptosis. ELISA assay and RT-PCR were employed to visualize TNF-alpha production, and apoptosis was evaluated by DNA ladder and flow cytometry. We found that cell treatment with anti-Ro autoantibodies determines TNF-alpha production that reaches a maximum at 16 h and is decreased (P < 0.05) at 24 and 48 h. Adalimumab seems to be more efficacious than etanercept in blocking TNF-alpha-mediated apoptosis. The YOPRO-1 (+) and propidium iodide (-) method revealed 60% of apoptotic cells after 24 h of incubation with anti-Ro compared with 15% of apoptotic cells treated with anti-Ro plus adalimumab and 25% of apoptotic cells treated with anti-Ro plus etanercept. The antiapoptotic effect of adalimumab and etanercept was supported by inhibition of DNA laddering induced by anti-Ro Abs. These data validate the therapeutic efficacy of the anti-TNF reagents in the treatment of autoimmune disorders.

  13. 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

  14. Dynamic equilibrium unfolding pathway of human tumor necrosis factor-alpha induced by guanidine hydrochloride.

    Science.gov (United States)

    Kim, Y R; Hahn, J S; Hong, H; Jeong, W; Song, N W; Shin, H C; Kim, D

    1999-01-11

    The dynamic equilibrium unfolding pathway of human tumor necrosis factor-alpha (TNF-alpha) during denaturation at different guanidine hydrochloride (GdnHCl) concentrations (0-4.2 M) was investigated by steady-state fluorescence spectroscopy, potassium iodide (KI) fluorescence quenching, far-UV circular dichroism (CD), picosecond time-resolved fluorescence lifetime, and anisotropy decay measurements. We utilized the intrinsic fluorescence of Trp-28 and Trp-114 to characterize the conformational changes involved in the equilibrium unfolding pathway. The detailed unfolding pathway under equilibrium conditions was discussed with respect to motional dynamics and partially folded structures. At 0-0.9 M [GdnHCl], the rotational correlation times of 22-25 ns were obtained from fluorescence anisotropy decay measurements and assigned to those of trimeric states by hydrodynamic calculation. In this range, the solvent accessibility of Trp residues increased with increasing [GdnHCl], suggesting the slight expansion of the trimeric structure. At 1.2-2.1 M [GdnHCl], the enhanced solvent accessibility and the rotational degree of freedom of Trp residues were observed, implying the loosening of the internal structure. In this [GdnHCl] region, TNF-alpha was thought to be in soluble aggregates having distinct conformational characteristics from a native (N) or fully unfolded state (U). At 4.2 M [GdnHCl], TNF-alpha unfolded to a U-state. From these results, the equilibrium unfolding pathway of TNF-alpha, trimeric and all beta-sheet protein, could not be viewed from the simple two state model (N-->U).

  15. 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.

  16. Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

    Science.gov (United States)

    Lei, Xu-Dan; Sun, Yan; Cai, Shi-Jiao; Fang, Yang-Wu; Cui, Jian-Lin; Li, Yu-Hao

    2016-01-01

    AIM To investigate the role of tumor necrosis factor-alpha (TNF-α) in zebrafish retinal development and myelination. METHODS Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one- to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in situ hybridization using a hepatocyte-specific mRNA probe ceruloplasmin (cp), and co-injection of TNF-α MO and TNF-α mRNA. An atonal homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zpr1, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp) was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-α morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post-fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION TNF-α is not an essential regulator for retinal neurogenesis and optic myelination. PMID:27366683

  17. Wnt3a regulates tumor necrosis factor-α-stimulated interleukin-6 release in osteoblasts.

    Science.gov (United States)

    Natsume, Hideo; Tokuda, Haruhiko; Adachi, Seiji; Matsushima-Nishiwaki, Rie; Kato, Kenji; Minamitani, Chiho; Otsuka, Takanobu; Kozawa, Osamu

    2011-01-01

    It is recognized that Wnt pathways regulate bone metabolism. We have previously shown that tumor necrosis factor-α (TNF-α) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase)/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of Wnt3a on TNF-α-stimulated IL-6 synthesis in these cells. Wnt3a, which alone did not affect the IL-6 levels, significantly suppressed the TNF-α-stimulated IL-6 release. Lithium Chloride (LiCl), which is an inhibitor of GSK3β, markedly reduced the TNF-α-stimulated IL-6 release, similar to the results with Wnt3a. The suppression by Wnt3a or LiCl was also observed in the intracellular protein levels of IL-6 elicited by TNF-α. Wnt3a failed to affect the TNF-α-induced phosphorylation of p44/p42 MAP kinase, Akt, IκB or NFκB. Either Wnt3a or LiCl failed to reduce, rather increased the IL-6 mRNA expression stimulated by TNF-α. Lactacystin, a proteasome inhibitor, and bafilomycin A1, a lysosomal protease inhibitor, significantly restored the suppressive effect of Wnt3a on TNF-α-stimulated IL-6 release. Taken together, our results strongly suggest that Wnt3a regulates IL-6 release stimulated by TNF-α at post-transcriptional level in osteoblasts.

  18. Production of tumor necrosis factor-a is increased in urinary tract infections

    Directory of Open Access Journals (Sweden)

    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.

  19. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

    Science.gov (United States)

    Shealy, David J; Cai, Ann; Staquet, Kim; Baker, Audrey; Lacy, Eilyn R; Johns, Laura; Vafa, Omid; Gunn, George; Tam, Susan; Sague, Sarah; Wang, Dana; Brigham-Burke, Mike; Dalmonte, Paul; Emmell, Eva; Pikounis, Bill; Bugelski, Peter J; Zhou, Honghui; Scallon, Bernard J; Giles-Komar, Jill

    2010-01-01

    We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.

  20. Glasgow coma score and tumor necrosis factor α as predictive criteria for initial poor graft function.

    Science.gov (United States)

    Novelli, G; Morabito, V; Lai, Q; Levi Sandri, G B; Melandro, F; Pugliese, F; Novelli, S; Rossi, M; Berloco, P B

    2012-09-01

    Initial poor graft function (IPGF) is a major factor influencing the clinical outcome after liver transplantation (LT), but there is no reliable method to assess and predict graft dysfunction. To help clinicians determine prognosis in the early postoperative period, individual parameters and complex scoring systems have been suggested, but most of them are inaccurate because of the multifactorial nature of transplantation courses. Therefore, the aim of our study was to retrospectively evaluate predictive criteria for retransplantation. Forty-two patients were enrolled in this study: 18 who experienced primary non-function (PNF) and 24 with delayed graft function (DGF). All of the patients were treated with the Molecular Adsorbent Recirculating System (MARS). They were into 3 subgroups: patients who survived without LT (n = 20; 47.7%); patients who underwent LT (n = 16; 37%), and patients who died before transplantation (n = 6; 14%). Stepwise multivariable logistic regression analysis was performed with the intent to find the risk factors for LT or death after MARS treatment (second analysis). Receiver operating characteristic (ROC) curves were performed on significant variables in the logistic regression model with the intent to individually predict variables for LT or death. After a stepwise multivariable logistic regression analysis enrolling all of the previously reported features only 2 variables, tumor necrosis factor (TFN)-α and Glasgow coma score (GCS) score, were statistically significant. TNF-α was an unique independent risk factor for retransplantation or death after MARS treatment (odds ratio [OR] 1.235; P = .013). Conversely, GCS score was protective against retransplantation or death (OR 0.150; P = .003). Starting from these assumptions, a predictive model was created using these 2 variables. On ROC analysis, the combined score showed an area under the curve greater than that of the 2 variables considered separately. Validating these results with a

  1. Complicated Whipple’s disease and endocarditis following tumor necrosis factor inhibitors

    Institute of Scientific and Technical Information of China (English)

    Thomas; Marth

    2014-01-01

    AIM: To test whether treatment with tumor necrosis factor inhibitors(TNFI) is associated with complications of Tropheryma whipplei(T. whipplei) infection. METHODS: Because unexplained arthritis is often the first Whipple’s disease(WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy(group Ⅰ, n = 41) with patients not receiving TNFI therapy(group Ⅱ, n = 61). Patients from large reviews served as controls(group Ⅲ, n = 1059).RESULTS: The rate of endocarditis in patient group Ⅰ was significantly higher than in patient group Ⅱ(12.2% in group Ⅰ vs 1.6% in group Ⅱ, P < 0.05), and group Ⅲ(12.2% in group Ⅰ vs 0.16% in group Ⅲ, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group Ⅰ as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group Ⅰ. WD istypically diagnosed with duodenal biopsy and periodic acid Schiff(PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results(diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction(PCR) for T. whipplei was more accurate than PAS-stainings(diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01).CONCLUSION: TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered.

  2. Aspirin inhibits tumor necrosis factor-α-stimulated fractalkine expression in human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    JIANG De-qian; LIU Hong; ZHANG She-bing; ZHANG Xiao-lian

    2009-01-01

    Background Fractalkine is an important chemokine mediating local monocyte accumulation and inflammatory reactions in the vascular wall. Aspirin inhibits inflammatory cytokine expression closely related to atherosclerosis through the way independent of platelet and cyclooxygenase (COX). There has been no report about the effect of aspirin on fractalkine expression. We aimed to determine the fractalkine expression in human umbilical vein endothelial cell (HUVEC) stimulated by tumor necrosis factor (TNF)-α and the effect of aspirin intervention.Methods Six of 8 HUVEC groups received either different concentrations of aspirin (0.02, 0.2, 1.0, 5.0 mmol/L) or 40 μmol/L pyrrolidinecarbodithioc acid (PDTC) or 0.5 μmol/L NS-398. The other two groups were negative control and positive control (TNF-α-stimulated). After being incubated for 24 hours, cells of the 8 groups except the negative control one were stimulated with TNF-a (4 ng/ml) for another 24 hours. After that, the cells were collected for RNA isolation and protein extraction.Results Both mRNA and protein expressions of fractalkine in HUVEC were upregulated by 4 ng/ml TNF-α stimulation,Aspirin inhibited fractalkine expression in a dose-dependent manner at mRNA and protein levels. Nuclear factor-kappa B inhibitor, PDTC, effectively decreased the fractalkine expression. Fractalkine expression was not influenced by COX-2 selective inhibitor NS-398. COX-1 protein expression was not changed by either TNF-α stimulation or aspirin, PDTC,NS-398 intervention. Both mRNA and protein expression of COX-2 in HUVEC were upregulated by 4 ng/ml TNF-α stimulation. Aspirin decreased COX-2 expression in a dose-dependent manner at mRNA and protein levels.Conclusions TNF-α-stimulated fractalkine expression is suppressed by aspirin in a dose-dependent manner through the nuclear factor-kappa B p65 pathway.

  3. Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

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    Evanthia; Zampeli; Michalis; Gizis; Spyros; I; Siakavellas; Giorgos; Bamias

    2014-01-01

    Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.

  4. Role of tumor necrosis factor-α -308 G/A promoter polymorphism in gastric cancer

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    Amar C Bhayal

    2013-01-01

    Full Text Available Background/Aim: Gastric cancer (GC is the fourth most common cancer and the second most common cause of cancer death world-wide after lung cancer. It is a multifactorial disease with the involvement of both genetic and environmental risk factors. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in severity of outcome of the disease. Tumor necrosis factor alpha (TNF-α is a potent pro-inflammatory cytokine and acid inhibitor. A bi allelic G to A polymorphism at -308 upstream from the transcription initiation site of the promoter is associated with elevated TNF levels. The present study is aimed at evaluating the role of TNF-α-308 (G → A gene polymorphism and susceptibility to GC. Subjects and Methods: A case-control study was carried out in 114 GC patients and 229 healthy control subjects. TNF-α genotyping at position-308 (G → A was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR method followed by agarose gel electrophoresis. Results: The distribution of TNF-α genotypes at -308 (G → A were GG 28.07%, GA 66.67% and AA 5.26% in GC patients and GG 33.19%, GA 55.89% and AA 10.92% in control subjects. The frequencies of alleles G and A were 0.614 and 0.386 in GC patients and 0.611 and 0.389 in control subjects respectively. Conclusion: The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.

  5. Parents' information needs in tumor necrosis factor-α inhibitor treatment decisions.

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    Lipstein, Ellen A; Lovell, Daniel J; Denson, Lee A; Moser, David W; Saeed, Shehzad A; Dodds, Cassandra M; Britto, Maria T

    2013-03-01

    The aim of the study was to describe parents' experiences and the information used when making decisions about tumor necrosis factor-α inhibitor (TNFαi) treatment. We interviewed parents of children with Crohn disease (CD) or juvenile idiopathic arthritis who had experience deciding about TNFαi treatment. Interview questions focused on information used to make decisions and factors that influenced decision making. We used thematic analysis for all coding and analysis. Coding structure was developed by a multidisciplinary team review of the initial interviews. Two coders then coded the remaining interviews, compared coding, and resolved disagreements through discussion. Data were analyzed by thematic grouping and then compared between diseases. We interviewed 35 parents. For nearly all parents the decision about TNFαi treatment was the most challenging medical decision they had made; however, parents of children with CD experienced more stress and anxiety than did other parents. Both groups of parents sought information from multiple sources including health care providers, the Internet, and social contacts. They looked for information related to treatment effectiveness, adverse effects, and other individuals' treatment experiences. In CD, information was used to help make the decision, whereas in juvenile idiopathic arthritis it was used to confirm the decision. The decision-making experience, and associated information seeking, leaves some parents with long-lasting concerns and worry about TNFαi treatment. Providing parents with structured decision-making support may lead to more effective and efficient decision making, decreased psychosocial distress, and, ultimately, improved outcomes for their children.

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

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    Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A. (Univ. of Freiburg (Germany, F.R.))

    1990-08-01

    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.

  7. Transfection of influenza A virus nuclear export protein induces the expression of tumor necrosis factor alpha.

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    Lara-Sampablo, Alejandra; Flores-Alonso, Juan Carlos; De Jesús-Ortega, Nereyda; Santos-López, Gerardo; Vallejo-Ruiz, Verónica; Rosas-Murrieta, Nora; Reyes-Carmona, Sandra; Herrera-Camacho, Irma; Reyes-Leyva, Julio

    2014-06-24

    Influenza A virus genomic segments eight codes for non-structural 1 (NS1) protein that is involved in evasion of innate antiviral response, and nuclear export protein (NEP) that participates in the export of viral ribonucleoprotein (RNP) complexes, transcription and replication. Tumor necrosis factor alpha (TNF-α) is highly expressed during influenza virus infections and is considered an anti-infective cytokine. NS1 and NEP proteins were overexpressed and their role on TNF-α expression was evaluated. Both TNF-α mRNA and protein increased in cells transfected with NEP but not with NS1. We further investigate if NS1 or NEP regulates the activity of TNF-α promoter. In the presence of NEP the activity of TNF-α promoter increased significantly compared with the control (83.5±2.9 vs. 30.9±2.8, respectively; p=0.001). This effect decreased 15-fold when the TNF-α promoter distal region was deleted, suggesting the involvement of mitogen-activated protein kinases (MAPK) and NF-kB response elements. This was corroborated by testing the effect produced on TNF-α promoter by the treatment with Raf/MEK/ERK (U0126), NF-kB (Bay-11-7082) and PI3K (Ly294-002) cell signaling inhibitors. Treatment with U0126 and Bay-117082 reduced the activity of TNF-α promoter mediated by NEP (41.5±3.2, 70% inhibition; and 80.6±7.4, 35% inhibition, respectively) compared to mock-treated control. The results suggest a new role for NEP protein that participates in the transcriptional regulation of human TNF-α expression.

  8. Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization

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    Sabino Riestra

    Full Text Available Aims: To determine risk factors for active tuberculosis in patients with inflammatory bowel diseases. Methods: Retrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years and time of inflammatory bowel disease diagnosis (within 3 years. Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used. Results: Thirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = 0.001; hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = 0.027; and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = 0.001. The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58 months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients. Conclusions: The main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.

  9. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis.

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    Inês P Perpétuo

    Full Text Available Ankylosing Spondylitis (AS is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC in AS patients.13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed.RANKL+ circulating lymphocytes (B and T cells and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline.In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.

  10. Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B.

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    Thi A Tran

    Full Text Available Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD and inhibition of microglial activation attenuates degeneration of dopaminergic (DA neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1β, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD.

  11. Dissociative symptoms reflect levels of tumor necrosis factor alpha in patients with unipolar depression

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    Bizik G

    2014-04-01

    Full Text Available Gustav Bizik,1 Petr Bob,1 Jiri Raboch,1 Josef Pavlat,1 Jana Uhrova,2 Hana Benakova,2 Tomas Zima2 1Center for Neuropsychiatric Research of Traumatic Stress, Department of Psychiatry and UHSL, 2Department of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Abstract: Recent evidence indicates that the nature of interactions between the nervous system and immune system is important in the pathogenesis of depression. Specifically, alterations in pro-inflammatory cytokines have been related to the development of several psychological and neurobiological manifestations of depressive disorder, as well as to stress exposure. A number of findings point to tumor necrosis factor alpha (TNF-α as one of the central factors in these processes. Accordingly, in the present study, we test the hypothesis that specific influences of chronic stressors related to traumatic stress and dissociation are related to alterations in TNF-α levels. We performed psychometric measurement of depression (Beck Depression Inventory [BDI]-II, traumatic stress symptoms (Trauma Symptom Checklist [TSC]-40, and psychological and somatoform dissociation (Dissociative Experiences Scale [DES] and Somatoform Dissociation Questionnaire [SDQ]-20, respectively, and immunochemical measure of serum TNF-α in 66 inpatients with unipolar depression (mean age 43.1 ± 7.3 years. The results show that TNF-α is significantly related to DES (Spearman R=−0.42, P<0.01, SDQ-20 (Spearman R=−0.38, P<0.01, and TSC-40 (Spearman R=−0.41, P<0.01, but not to BDI-II. Results of the present study suggest that TNF-α levels are related to dissociative symptoms and stress exposure in depressed patients. Keywords: depression, dissociation, TNF-alpha, traumatic stress

  12. TUMOR NECROSIS FACTOR-ALPHA POLYMORPHISM AND SECRETION IN MYASTHENIA GRAVIS

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    Yu-zhou Guan; Li-ying Cui; Yan-feng Li; Jun-bao Zhang

    2005-01-01

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

  13. Tumor necrosis factor gene polymorphisms and endometriosis in Asians: a systematic review and meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Lyu Jiangtao; Yang Hua; Lang Jinghe; Tan Xianjie

    2014-01-01

    Background Numerous studies have described the association between polymorphisms in the tumor necrosis factor (TNF) gene and risk of endometriosis.However,the results remain controversial.Here we reviewed studies reporting the association between TNF gene polymorphisms and endometriosis risk in Asians.Methods PubMed and Embase were searched.Twelve case-control studies assessing the role of multiple TNF gene polymorphisms in endometriosis were included.If no less than two articles evaluated one variant,meta-analysis was conducted; otherwise,narrative analysis was chosen.A fixed-or random-effects model was employed according to the heterogeneity among studies.The strength of the association between TNF gene polymorphisms and endometriosis risk was assessed by odds ratios and 95% confidence intervals.Results For TNF-α-238G>A,-308G>A,-857C>T,and-863C>A,no significant associations were identified from all genetic models.For TNF-α-850T>C,results from one study showed that patients harboring the heterozygote TC were less susceptible to endometriosis than patients harboring the homozygote TT.For TNF-α-1031T>C,a mild increase in endometriosis risk was found in the Asian population.Meta-analysis from two studies found that the TNF-β +252>G polymorphism had a protective effect in Chinese individuals.Due to the limitations of the included studies,it is necessitated to perform more studies to elucidate the possible roles of TNF gene polymorphisms in the pathogenesis of endometriosis.Conclusions TNF-α-1031T>C and TNF-β +252A>G were significantly associated with the risk of endometriosis in Asian and Chinese populations,respectively.To further evaluate these associations,more large-scale,rigorously designed studies are needed.

  14. The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis

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    Feingold, K.R.; Soued, M.; Serio, M.K.; Adi, S.; Moser, A.H.; Grunfeld, C. (Univ. of California, San Francisco (USA))

    1990-06-01

    In this study, we determined the effects of tumor necrosis factor (TNF) on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection.

  15. Safety and tolerability of tumor necrosis factor-α inhibitors in psoriasis: a narrative review.

    Science.gov (United States)

    Semble, Ashley L; Davis, Scott A; Feldman, Steven R

    2014-02-01

    Tumor necrosis factor (TNF)-α inhibitors are an alternative to oral systemic therapies for psoriasis. Data regarding the safety of TNF-α inhibitors from randomized clinical trials may not fully reflect the effects on the clinic patient population receiving the therapy, but other sources of information are available. We performed a literature review to assess the safety and tolerability of the treatment of moderate-to-severe plaque psoriasis with TNF-α inhibitors. A literature search was conducted using PubMed for articles dating from January 2000 to October 2013. Randomized controlled, cohort, open-label, and observational studies were included, as well as case reports and letters to the editor. Articles found on PubMed describing the safety of anti-TNF-α therapy in psoriasis patients were included, while studies highlighting interleukin (IL)-12 and IL-23 inhibitors were excluded, as were non-English articles. In total, 58 articles were included in the review. TNF-α inhibitors exhibit both efficacy and tolerability in patients with moderate-to-severe plaque psoriasis. Adverse effects associated with these medications are not common and can be minimized with routine clinical monitoring and patient education. While the risk of severe adverse events is low, the lack of very large, long-term, randomized safety trials limits the ability to fully define the safety of these agents. TNF-α inhibitors have a good efficacy/safety ratio for use in patients with moderate-to-severe psoriasis. Serious adverse effects are not common, and common injection-site reactions are usually manageable. The benefits of TNF-α inhibitors outweigh the risks for moderate-to-severe psoriasis; however, there are potential adverse effects and the patient populations at highest risk include the elderly and those with a history of malignancy.

  16. Tumor necrosis factor-alpha and interleukin-6 in early-onset neonatal sepsis

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    Prambudi Rukmono

    2016-05-01

    Full Text Available Background Neonatal sepsis remains a major cause of mortality and morbidity in newborns. Early-onset neonatal sepsis occurs in infants under the age of 72 hours, while late-onset neonatal sepsis occurs in infants over the age of 72 hours and may be due to nosocomial infection. Diagnosing neonatal sepsis is a challenge, as its clinical symptoms are not clear. Corroborating tests include routine blood, C-reactive protein (CRP, serology, tumor necrosis factor-alpha (TNF-α, and interleukin-6 (IL-6 examinations.Objective To compare the TNF-α and IL-6 levels in patients with proven and unproven early-onset neonatal sepsis (EONSMethods This case-control study was done in the Perinatology Unit, Abdul Moeloek Hospital, Lampung. Subjects were under the age of 72 hours with risk factors and clinical symptoms of sepsis. They underwent routine blood tests and blood cultures. Infants with positive cultures were considered to have proven sepsis (26 subjects and infants with negative blood cultures were considered to have unproven sepsis (26 subjects. All subjects underwent serological examinations of TNF-α and IL-6.Results There were no differences in the basic characteristics of subjects between the two groups. Levels of TNF-α in the sepsis group were significantly higher than in the unproven group [(28.30 vs. 10.96 pg/mL, respectively (P=0.001]. Furthermore, Il-6 was significantly higher in the proven sepsis group than in the unproven sepsis group [(28.3 vs. 9.69 pg/mL, respectively (P=0.006].Conclusion Levels of TNF-alpha and IL-6 are significantly higher in infants with proven than unproven early-onset neonatal sepsis.

  17. Heavy chain transfer by tumor necrosis factor-stimulated gene 6 to the bikunin proteoglycan.

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    Lamkin, Elliott; Cheng, Georgiana; Calabro, Anthony; Hascall, Vincent C; Joo, Eun Ji; Li, Lingyun; Linhardt, Robert J; Lauer, Mark E

    2015-02-20

    We present data that hyaluronan (HA) polysaccharides, about 14-86 monosaccharides in length, are capable of accepting only a single heavy chain (HC) from inter-α-inhibitor via transfer by tumor necrosis factor-stimulated gene 6 (TSG-6) and that this transfer is irreversible. We propose that either the sulfate groups (or the sulfation pattern) at the reducing end of the chondroitin sulfate (CS) chain of bikunin, or the core protein itself, enables the bikunin proteoglycan (PG) to accept more than a single HC and permits TSG-6 to transfer these HCs from its relatively small CS chain to HA. To test these hypotheses, we investigated HC transfer to the intact CS chain of the bikunin PG, and to the free chain of bikunin. We observed that both the free CS chain and the intact bikunin PG were only able to accept a single HC from inter-α-inhibitor via transfer by TSG-6 and that HCs could be swapped from the bikunin PG and its free CS chain to HA. Furthermore, a significant portion of the bikunin PG was unable to accept a single heavy chain. We discuss explanations for these observations, including the intracellular assembly of inter-α-inhibitor. In summary, these data demonstrate that the sulfation of the CS chain of bikunin and/or its core protein promote HC transfer by TSG-6 to its relatively short CS chain, although they are insufficient to enable the CS chain of bikunin to accept more than one HC in the absence of other cofactors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

    Science.gov (United States)

    Zhang, Jiandong; Patel, Mehul B; Griffiths, Robert; Mao, Alice; Song, Young-soo; Karlovich, Norah S; Sparks, Matthew A; Jin, Huixia; Wu, Min; Lin, Eugene E; Crowley, Steven D

    2014-12-01

    Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

  19. Remission of Behcet's disease with anti-tumor necrosis factor monoclonal antibody therapy: a case report

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    Castagna Irene

    2003-08-01

    Full Text Available Abstract Background Behcet's disease (BD is a chronic relapsing multisystem inflammatory disorder with mucocutaneous, ocular, articular, vascular, gastrointestinal and central nervous system manifestations. Tumor necrosis factor (TNF-alpha is believed to play a pivotal role in BD. Therapeutic blockade of the activity of TNF has been successfully given in a short course of therapy with favorable effects in patients with BD refractory to conventional immunosuppressive drugs. We aimed to find out whether a 12-month treatment with infliximab, a chimeric monoclonal antibody to TNF-alpha, had any beneficial effect in reducing relapses of a patient with long-standing BD refractory to conventional immunosuppressive drugs. Case presentation A 54 year-old-woman with a 35-year history of BD with orogenital ulcerations, arthritis in the right knee and retinal lesions compatible with vasculitis received infliximab, 5 mg/kg by a two-hour intravenous infusion. Symptoms improved within 24 hours and eight days later the genital and oral ulcers healed as well as the arthritis in the right knee subsided. The retinal infiltrates completely resolved within 10 days. The infusions were repeated at weeks 2, 6, 14, 22 and then every 8 weeks. The patient was able to return to her domestic daily life. No exacerbation of the mucocutaneous ocular or arthritic symptoms occurred during the treatment period. Conclusions Previous studies have suggested that infliximab given in a short course of treatment is effective in inducing remission of severe mucocutaneous, gastrointestinal and ocular manifestations of BD. Our patient received a 12-month infliximab treatment showing a favorable effect on remission of BD manifestations. The long-term infliximab treatment appears as a new therapeutic option for patients with active BD who failed to respond to conventional immunosuppressive agents.

  20. Tumor necrosis factor α accelerates Hep-2 cells proliferation by suppressing TRPP2 expression.

    Science.gov (United States)

    Wu, Jing; Guo, Jizheng; Yang, Yunyun; Jiang, Feifei; Chen, Shuo; Wu, Kaile; Shen, Bing; Liu, Yehai; Du, Juan

    2017-06-29

    TRPP2, a Ca(2+)-permeable non-selective cation channel, has been shown to negatively regulate cell cycle, but the mechanism underlying this regulation is unknown. Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine extensively involved in immune system regulation, cell proliferation and cell survival. However, the effects and mechanisms for the role of TNF-α in laryngeal cancer remain unclear. Here, we demonstrated using western blot analyses and intracellular Ca(2+) concentration measurements that TNF-α treatment suppressed both TRPP2 expression and ATP-induced Ca(2+) release in a laryngeal cancer cell line (Hep-2). Knockdown of TRPP2 by a specific siRNA significantly decreased ATP-induced Ca(2+) release and abolished the effect of TNF-α on the ATP-induced Ca(2+) release. TNF-α treatment also enhanced Hep-2 cell proliferation and growth, as determined using cell counting and flow cytometry cell cycle assays. Moreover, TNF-α treatment down-regulated phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK) and phosphorylated eukaryotic translation initiation factor (p-eIF2α) expression levels, without affecting PERK and eIF2α expression levels in Hep-2 cells. We concluded that suppressing TRPP2 expression and TRPP2-mediated Ca(2+) signaling may be one mechanism underlying TNF-α-enhanced Hep-2 cell proliferation. These results offer new insights into the mechanisms of TNF-α-mediated laryngeal cancer cell proliferation, and provide evidences showing a potential role of TNF-α in the development of laryngeal cancer.

  1. 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.

  2. Exenatide Reduces Tumor Necrosis Factor-α-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction

    Institute of Scientific and Technical Information of China (English)

    Yuan-Yuan Cao; Zhang-Wei Chen; Yan-Hua Gao; Xing-Xu Wang; Jian-Ying Ma; Shu-Fu Chang; Ju-Ying Qian

    2015-01-01

    Background: Tumor necrosis factor-α (TNF-α) plays an important role in progressive contractile dysfunction in several cardiac diseases.The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species (ROS)-and mitochondria-dependent apoptosis.Glucagon-like peptide-1 (GLP-1) or its analogue exhibits protective effects on the cardiovascular system.The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-c-treated cardiomyocytes in vitro.Methods: Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention;TNF-α group, with cells incubated with TNF-c (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide;and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-α (40 ng/ml) stimulation.We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups.Results: Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h.Also, exenatide inhibited excessive ROS production and maintained MMP.Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures.Conclusion: These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis;the anti-apoptotic effects may be associated with protection of mitochondrial function.

  3. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis.

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    Marina C Oliveira

    Full Text Available Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF in this process in an acute model of antigen-induced arthritis (AIA. Immunized male BALB/c mice received an intra-articular injection of PBS (control or methylated bovine serum albumin (mBSA into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines. Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids, adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines.

  4. Predictors of Switching Anti-Tumor Necrosis Factor Therapy in Patients with Ankylosing Spondylitis.

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    Jeong-Won Lee

    Full Text Available The aim of this study was to investigate the potential predictors of switching tumor necrosis factor (TNF-α inhibitors in Korean patients with ankylosing spondylitis (AS. The patients who had been treated with TNF-α inhibitors were divided into two groups depending on whether they had switched TNF-α inhibitors. Demographic, clinical, laboratory, and treatment data at the time of initiation of TNF-α inhibitor treatment were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Of the 269 patients, 70 (23% had switched TNF-α inhibitors once; of these, 11 switched again. The median follow-up time was 52.7 months. Three- and five-year drug survival rates were 52%/48% for infliximab, 62%/42% for etanercept, and 71%/51% for adalimumab, respectively. Switchers were more likely to be prescribed disease-modifying anti-rheumatic drugs than non-switchers. A history of joint surgery and complete ankylosis of the sacroiliac joint was more frequent in switchers. Multivariate Cox's proportional hazard analysis showed that the use of adalimumab as the first TNF-α inhibitor was less likely to lead to switching and complete ankylosis of the sacroiliac joints was more likely to lead to switching. The principal reasons for switching were drug inefficacy and adverse events, but the differences in the clinical data of these two groups of switchers were not significant. In AS patients who are candidates for TNF-α inhibitor therapy, switching may improve the therapeutic outcome based on clinical information.

  5. 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

  6. Tumor necrosis factor receptors support murine hematopoietic progenitor function in the early stages of engraftment.

    Science.gov (United States)

    Pearl-Yafe, Michal; Mizrahi, Keren; Stein, Jerry; Yolcu, Esma S; Kaplan, Ofer; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2010-07-01

    Tumor necrosis factor (TNF) family receptors/ligands are important participants in hematopoietic homeostasis, in particular as essential negative expansion regulators of differentiated clones. As a prominent injury cytokine, TNF-alpha has been traditionally considered to suppress donor hematopoietic stem and progenitor cell function after transplantation. We monitored the involvement of TNF receptors (TNF-R) 1 and 2 in murine hematopoietic cell engraftment and their inter-relationship with Fas. Transplantation of lineage-negative (lin(-)) bone marrow cells (BMC) from TNF receptor-deficient mice into wild-type recipients showed defective early engraftment and loss of durable hematopoietic contribution upon recovery of host hematopoiesis. Consistently, cells deficient in TNF receptors had reduced competitive capacity as compared to wild-type progenitors. The TNF receptors were acutely upregulated in bone marrow (BM)-homed donor cells (wild-type) early after transplantation, being expressed in 60%-75% of the donor cells after 6 days. Both TNF receptors were detected in fast cycling, early differentiating progenitors, and were ubiquitously expressed in the most primitive progenitors with long-term reconstituting potential (lin(-)c-kit(+) stem cell antigen (SCA)-1(+)). BM-homed donor cells were insensitive to apoptosis induced by TNF-alpha and Fas-ligand and their combination, despite reciprocal inductive cross talk between the TNF and Fas receptors. The engraftment supporting effect of TNF-alpha is attributed to stimulation of progenitors through TNF-R1, which involves activation of the caspase cascade. This stimulatory effect was not observed for TNF-R2, and this receptor did not assume redundant stimulatory function in TNFR1-deficient cells. It is concluded that TNF-alpha plays a tropic role early after transplantation, which is essential to successful progenitor engraftment.

  7. Plasma levels of soluble tumour necrosis factor receptors are increased in coal miners with pneumoconiosis.

    Science.gov (United States)

    Schins, R P; Borm, P J

    1995-10-01

    Among other cytokines, tumour necrosis factor (TNF)-alpha is considered to play a key role in the development of mineral dust related fibrosis. Previously, we showed that ex-vivo release of TNF by peripheral blood monocytes is a marker for progression of coal workers' pneumoconiosis (CWP). Since soluble TNF receptors (sTNF-Rs) are believed to play an important regulatory role in systemic effects of TNF, we measured plasma levels of sTNF-R55 and sTNF-R75 in coal miners with (n = 28) or without (n = 76) CWP and in nonexposed controls (n = 29). sTNF-R75 levels were significantly increased in miners with CWP (2.09 +/- 0.44 ng.mL-1) versus the nonexposed controls (1.86 +/- 0.23 ng.mL-1). Neither sTNF-R55 nor sTNF-R75 were related to exposure, stage of pneumoconiosis, smoking, or (spontaneous or ex-vivo induced) monocyte TNF-release. sTNF-R55 was increased in subjects with medication (especially those using cardiovascular drugs); upon exclusion of these subjects, sTNF-R55 was found also to be significantly increased in CWP. In conclusion, bearing in mind a confounding effect of medication, soluble TNF receptors are elevated in plasma of retired miners with coal workers' pneumoconiosis. These observations further support the important role of TNF-mediated pathways in the pathogenesis of mineral dust related fibrosis.

  8. Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

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    Neil L Spector

    Full Text Available The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER in human tumors.Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally

  9. DYNAMIC EXPRESSION OF PLASMA TUMOR NECROSIS FACTOR-α、INTERLEUKIN-6 AND NUCLEAR FACTOR-κB IN ACUTE ABDOMEN PATIENTS COMBINED WITH SYSTEMIC INFLAMMATORY RESPONSE SYNDROME%急腹症伴SIRS患者血浆细胞因子TNF-α、IL-6及NF-κB的动态变化

    Institute of Scientific and Technical Information of China (English)

    朱世纯; 杜建华; 李倩

    2010-01-01

    目的 检测急腹症伴发全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)患者血浆细胞因子肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白细胞介素6(interleukin-6,IL-6)及核因子κB(nuclear factor-κB ,NF-κB)水平的动态变化,并探讨与SIRS的关系.方法 81例急腹症伴SIRS患者于入院当日(0d)及入院后1、3、7d分别采集空腹外周静脉血,用酶联免疫吸附法测定TNF-α、IL-6及NF-κB的血浆浓度,另选30例健康成年人做为对照组.分别对NF-κB活性与TNF-α及IL-6水平进行相关统计学分析.结果 81例急腹症患者血浆各时间点TNF-α、IL-6及NF-κB水平均较对照组显著增高,差异有统计学意义(P<0.05).NF-κB活性增高与TNF-α及IL-6血浆浓度增高呈明显正相关(P<0.05).结论 急腹症伴SIRS时,TNF-α、IL-6及NF-κB表达增多.TNF-α及IL-6血浆浓度与NF-κB活性呈正相关.

  10. Inhibition of tumor necrosis factor-α reduces alveolar septal cell apoptosis in passive smoking rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Cheng; CAI Shan; CHEN Ping; CHEN Jian-bo; WU Jie; WU Shang-jie; ZHOU Rui

    2008-01-01

    Background Recent studies have revealed that lung cell apoptosis plays an important role in pathogenesis of cigarette-induced chronic obstructive pulmonary disease (COPD).Tumor necrosis factor alpha(TNF-α)is one of the most important cytokines which are involved in COPD.This study aimed at investigating the jnfluence of its inhibitor,recombinant human necrosis factor-alpha receptor Ⅱ:IgG Fc fusion protein(rhTNFR:Fc)on alveolar septal cell apoptosis in passive smoking rats.Methods Forty-eight rats were randomly divided into a normal control group,a passive smoking group,an rhTNFR:Fc intervention group and a sham intervention group.The passive smoking rats were treated by exposure to cigarette smoking daily for 80 days.Afcer smoking for one month the rhTNFR:Fc Intervention group was treated with rhTNFR:Fc by subcutaneous injection,the sham intervention group injected subcutaneousIv with a neutral preparation(normal saline 0.1 ml,manicol 0.8 ml,cane sugar 0.2 mg,Tris 0.024 mg as a control.Lung function was determined and the levels of TNF-α in serum and broncho-alveolar lavage fluid(BALF)were measured with enzyme-linked immunosorbnent assay (ELISA).Lung tissue sections stained by hematoxylin and eosin(HE)were observed for study of morphological alternations.Mean linear intercept(MLI)and mean alveolar numbers(MAN)were measured and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)method was carried out to determine the percentage of positive cells and distribution of apoptotic cells.Results Increased MLI and decreased MAN were found in the passive smoking group compared with both the normal control group and the rhTNFR:Fc intervention group(P<0.05).Forced expiratory volume in 0.3 second(FEV0.3)/forced vital capacity(FVC)and peak expiratory flow(PEF)were lower in the passive smoking group than that in the normal control group(P<0.05).Compared with the sham intervention group,FEV0.3/FVC and PEF increased in the rhTNFR:Fc intervention

  11. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis: A Meta-Analysis

    National Research Council Canada - National Science Library

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-01-01

    Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different...

  12. Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Ono M

    2013-10-01

    Full Text Available Mayu Ono, Tokiko Ito, Toshiharu Kanai, Koichi Murayama, Hiroshi Koyama, Kazuma Maeno, Yasuhiro Mochizuki, Asumi Iesato, Toru Hanamura, Toshihiro Okada, Takayuki Watanabe, Ken-ichi ItoDivision of Breast and Endocrine Surgery, Department of Surgery (II, Shinshu University School of Medicine, Matsumoto, JapanAbstract: Bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration. On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. Cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient's entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual

  13. Radiofrequency ablation of malignant liver tumors: use of a volumetric necrosis-tumor ratio for local control; Radiofrequenzablation von malignen Lebertumoren: Erlaubt ein volumetrischer Nekrose-/Tumor-Quotient eine Vorhersage zur lokalen Tumorkontrolle?

    Energy Technology Data Exchange (ETDEWEB)

    Kuehl, H. [Inst. fuer Diagnostische und Interventionelle Radiologie, Universitaetsklinik Essen (Germany); Stattaus, J.; Antoch, G.; Forsting, M. [Inst. fuer Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitaetsklinik Essen (Germany); Kuehl, B. [Klinik fuer Strahlentherapie, Universitaetsklinik Essen (Germany); Boes, T. [Inst. fuer Medizinische Informatik, Biometrie und Epidemiologie, Universitaetsklinik Essen (Germany); Frilling, A. [Klinik fuer Allgemein-, Viszeral- und Transplantationschirurgie, Universitaetsklinik Essen (Germany)

    2006-12-15

    Purpose: Sufficient safety margins are essential for preventing local tumor recurrence after radiofrequency ablation RFA of malignant liver tumors. The aim was to determine the initial tumor volume, ablation necrosis volume, and the necrosis-tumor quotient in order to compare these parameters with the rate of local control during follow-up. Materials and Methods: 35 patients with 53 tumor nodules (29 colorectal metastases and 24 HCC nodules) were enrolled. RFA procedures were performed under CT guidance with intravenous conscious sedation. Tumor volumes were measured based on CT data sets and the necrosis volume was assessed using the sum-of-area method. A volumetric necrosis/tumor quotient (NTQ) was calculated for all lesions. Follow-up examinations were performed after 3, 6, and 12 months and then on a yearly basis to identify local recurrent tumors. Results: The CRC metastases and HCC nodules had a median tumor volume of 8.3 ml and 7.4 ml, respectively. The mean ablation volumes were 37.6 ml and 29.5 ml, respectively. This resulted in a median NTQ of 3.9 for metastases and 3.4 for HCC. The follow-up (mean time 18 months) revealed local tumor recurrence in 16 of 29 (55%) metastases and 10 of 24 (42%) HCC nodules. In lesions with local recurrence, the initial tumor volume was significantly greater and the NTQ was significantly smaller. A threshold value of 3.4 for NTQ has the highest predictive value for local tumor recurrence. (orig.)

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Factor de necrosis tumoral alfa en una población infanto-juvenil con sobrepeso

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    Teresita del R. Carrizo

    2013-08-01

    Full Text Available El sobrepeso infantil está asociado a sobrepeso/obesidad en la edad adulta. El tejido adiposo en obesos produce una cantidad incrementada de citoquinas proinflamatorias como el factor de necrosis tumoral alfa (TNF-a, ejerciendo un efecto deletéreo sobre la función vascular. El objetivo de este trabajo fue evaluar niveles de TNF-a en una población infantojuvenil con sobrepeso y su relación con otras variables. Se estudiaron 30 niños con sobrepeso (12 varones de edades entre 8-13 años, se midió circunferencia de cintura (CC e índice de masa corporal (IMC y fueron comparados con 20 controles de edad y sexo semejantes. Se consideró criterio de inclusión un IMC = 85 < 95 percentilo para edad y sexo. En ambos grupos se determinó: glucemia en ayunas (método glucosa oxidasa, insulina plasmática (ECLIA, fibrinógeno (Fg, método de Clauss, proteína C reactiva ultrasensible (uPCR, método inmunoturbidimétrico, TNF-a (ELISA, perfil lipídico (métodos enzimáticos, eritrosedimentación y se calculó el índice HOMA. Los datos se expresaron como mediana y rango intercuartil y con el coeficiente de Spearman se investigaron las correlaciones entre variables, considerándose significativo un p < 0.05. Los niveles de TNF-a fueron mayores en los sujetos con sobrepeso [15.4 (13.2-24.0 vs. 12.7 (11.2-14.8 pg/ml; p = 0.028]. También resultaron más elevados los valores de Fg, insulina plasmática, índice HOMA, uPCR y triglicéridos. El TNF-a se correlacionó con la CC (r = 0.654; p = 0.021. Los niveles elevados de TNF-a, uPCR y Fg encontrados confirman un estado proinflamatorio asociado a obesidad abdominal en la población estudiada.

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

    Directory of Open Access Journals (Sweden)

    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

  17. Impact of obesity on the response to tumor necrosis factor inhibitors in axial spondyloarthritis.

    Science.gov (United States)

    Micheroli, Raphael; Hebeisen, Monika; Wildi, Lukas M; Exer, Pascale; Tamborrini, Giorgio; Bernhard, Jürg; Möller, Burkhard; Zufferey, Pascal; Nissen, Michael J; Scherer, Almut; Ciurea, Adrian

    2017-07-19

    Few studies have investigated the impact of obesity on the response to tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). The aim of our study was to investigate the impact of different body mass index (BMI) categories on TNFi response in a large cohort of patients with axSpA. Patients with axSpA within the Swiss Clinical Quality Management (SCQM) program were included in the current study if they fulfilled the Assessment in Spondyloarthritis International Society (ASAS) criteria for axSpA, started a first TNFi after recruitment, and had available BMI data as well as a baseline and follow-up visit at 1 year (±6 months). Patients were categorized according to BMI: normal (BMI 18.5 to 30). We evaluated the proportion of patients achieving the 40% improvement in ASAS criteria (ASAS40), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered nonresponders. We controlled for age, sex, HLA-B27, axSpA type, BASDAI, BASMI, elevated C-reactive protein (CRP), current smoking, enthesitis, physical exercise, and co-medication with disease-modifying antirheumatic drugs, as well as with nonsteroidal anti-inflammatory drugs in multiple adjusted logistic regression analyses. A total of 624 axSpA patients starting a first TNFi were considered in the current study (332 patients of normal weight, 204 patients with overweight, and 88 obese patients). Obese individuals were older, had higher BASDAI levels, and had a more important impairment of physical function in comparison to patients of normal weight, while ASDAS and CRP levels were comparable between the three BMI groups. An ASAS40 response was reached by 44%, 34%, and 29% of patients of normal weight, overweight, and obesity, respectively (overall p = 0.02). Significantly lower odds ratios (ORs) for achieving ASAS40 response were found in adjusted analyses in obese patients versus

  18. Expression of matrix metalloproteinase-1 and tumor necrosis factor-α in ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To examine the expression of matrix metallo-proteinase-1 (MMP-1) and tumor necrosis factor-α (TNF-α) in the colon mucosa of patients with ulcerative colitis (UC).METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to examine the expression of MMP-1 and TNF-α at both mRNA and protein levels in the colon mucosa of patients with UC. Correlation between MMP-1 and TNF-α and their correlation with the severity of the disease were also analyzed statistically.RESULTS: The expression of MMP-1 and TNF-α in the ulcerated and inflamed colon mucosa of patients with UC was significantly higher than that in the non-inflamed mucosa of normal controls at both mRNA and protein levels. Furthermore, the expression of MMP-1 and TNF-α in the ulcerated area was significantly higher than that in the inflamed area of patients with UC (0.9797 ± 0.1433 vs 0.6746 ± 0.0373, 0.8669 ± 0.0746 vs 0.5227 ± 0.0435, P < 0.05). There was no statistically significant difference in the non-inflamed area of normal controls. There was a significant correlation between MMP-1 and TNF-α expression (0.9797 ± 0.1433 vs 0.8669 ± 0.0746, P < 0.05), the correlating factor was 0.877. MMP-1 and TNF-α showed a significant correlation with the severity of the disease (0.0915 ± 0.0044 vs 0.0749 ± 0.0032 , 0.0932 ± 0.0019 vs 0.0724 ± 0.0043, P < 0.05), their correlating factors were 0.942 and 0.890, respectively.CONCLUSION: Excessively expressed MMP-1 directly damages the colon mucosa by degrading extracellular matrix (ECM) in patients with UC. While damaging colon mucosa, excessively expressed TNF-α stimulates MMPs secreting cells to produce more MMP-1 and aggravates the mucosa damage. MMP-1 promotes secretion of TNF-a in a positive feedback manner to cause further injury in the colon mucosa. MMP-1 and TNF-α correlate well with the severity of the disease, and therefore, can be used clinically as biological markers to judge the severity of UC.

  19. Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma

    Science.gov (United States)

    Xiao, Qi; Fu, BiQi; Chen, Ping; Liu, Zhong Zhong; Wang, Wei; Ye, QiFa

    2016-01-01

    Abstract Background: To assess the association between tumor necrosis factor-alpha (TNF-α) G308A, G238A and C863T polymorphisms and hepatitis B virus related hepatocellular carcinoma (HBV-HCC) susceptibility. Methods: We interrogated the databases of Pubmed, Sciencedirect and Viley online library up to March 8, 2016. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated in a fixed-effects model or a random-effects model when appropriate. Results: In total, 12 case–control studies which containing 1580 HBV-HCC cases, 2033 HBV carrier controls, 395 HBV spontaneously recovered (SR) controls and 1116 healthy controls were included. Compared with GG genotype, the genotypes GA/AA of G308A were associated with a significantly increased HBV-HCC risk when the controls were all healthy individuals (AA vs. GG, OR 2.483, 95%CI 1.243 to 4.959; GA vs. GG, OR 1.383, 95%CI 1.028 to 1.860; GA/AA vs. GG, OR 1.381, 95%CI 1.048 to 1.820). Meanwhile, only the AA vs. GG model of G238A and HBV-HCC showed a statistic significance when the controls were healthy individuals (OR 4.776, 95%CI 1.280 to 17.819). CT genotype of TNF-α C863T could increase HBV-HCC risk whenever the controls were healthy individuals, HBV carriers or HBV recovers. Conclusion: This meta-analysis shows that AA genotype in TNF-α G308A and TNF-α G238A and CT genotype in TNF-α C863T may increase HBV-HCC risk. Therefore, HBV infection seemed to be a more important factor for tumorigenesis of HCC than genetic predisposition in G308A of TNF-α, and interaction between TNF-α C863T polymorphisms and HBV infection might be associated with increased HCC risk. PMID:27977601

  20. Impact of genetic variation of tumor necrosis factor-α on gestational hypertension

    Institute of Scientific and Technical Information of China (English)

    CHEN You-peng; Thiemo Pfab; Torsten Slowinski; Claus-Michael Richter; Michael Godes; Berthold Hocher

    2006-01-01

    Background The mechanisms responsible for the pathogeneses of gestational hypertension and preeclampsia are unclear. Tumor necrosis factor-α (TNF-α) is a pro-inflammatory Th1-type cytokine. TNFA gene is located in the human leukocyte antigen (HLA) class III region of the major histocompatibility complex (MHC) on chromosome 6. The high TNF-α mRNA expression may be associated with the TNF2 (A) allele, which is the polymorphism of TNF-α at position -308 in promoter region. This study assessed whether the TNF2 (A) allele at position -308 plays a role in the alteration of blood pressure (BP) and urinary protein excretion during pregnancy.Methods The original prospective cohort study comprised 1623 pregnant women from January 2000 to October 2001. The G/A polymorphism was done by restriction fragment length polymorphism (RFLP) analysis with Nco I enzyme.Results The distributions of the G/A polymorphism of TNF-α in the promoter region at position -308 were wild-type 72.4% and variant 27.6%, respectively. The frequency of TNF2 (A) allele was approximately 0.15 for Caucasian pregnant women in the study. It was not significantly different in the distributions of genotypes and G/A allele frequencies among the three groups of pregnant women with gestational hypertension, preexisting hypertension and normal blood pressure (P>0.05). The maternal blood pressure in the third trimester was significantly higher in the group of women possessing the TNF2 (A) allele compared to homozygous for the TNF1 (G) allele (systolic BP, P<0.01 and diastolic BP, P<0.05). The elevated blood pressure in the TNF2 (A)group was accompanied by higher urinary protein excretion in the third trimester (P<0.05). The blood pressure and urinary protein excretion did not change apparently between the two groups in the first and second trimesters (P>0.05).Conclusions Maternal TNF2 (A) allele of TNF-α promoter region at position -308 could play a role in the alteration of blood pressures and

  1. Anti-tumor necrosis factor-alpha therapy and periodontal parameters in patients with rheumatoid arthritis.

    Science.gov (United States)

    Mayer, Yaniv; Balbir-Gurman, Alexandra; Machtei, Eli E

    2009-09-01

    The aim of this study was to evaluate the influence of anti-tumor necrosis factor-alpha (TNF-alpha) therapy on the clinical and immunologic parameters of the periodontium. Ten patients with rheumatoid arthritis (RA) who routinely received infusions of infliximab, 200 mg (RA+), 10 patients with RA without anti-TNF-alpha therapy (RA-), and 10 healthy controls (C) were included. Clinical parameters, including the plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (AL), and bleeding on probing (BOP), were assessed, and total gingival crevicular fluid (GCF) TNF-alpha level was determined using enzyme-linked immunosorbent assay. Analysis of variance with Scheffe modification and the Pearson correlation test were used for statistical analysis. The ages of the patients ranged from 22 to 76 years (mean, 50.73 +/- 9.1 years). The mean PI was similar among the groups. However, mean inflammatory parameters in the three groups varied significantly; GI was greater in the RA- group compared to RA+ and C groups (P = 0.0042). The RA+ group exhibited less BOP than RA- and C groups (21.1% +/- 3.0%, 45.9% +/- 6.2%, and 39.1% +/- 7.2%, respectively; P = 0.0146). The mean PD in the RA+ group was shallower than in RA- and C groups (3.22 +/- 0.13 mm, 3.85 +/- 0.22 mm, and 3.77 +/- 0.20 mm, respectively; P = 0.055). Clinical AL in the RA+ group was lower than in RA- and C groups (3.68 +/- 0.11 mm, 4.52 +/- 0.26 mm, and 4.35 +/- 0.24 mm, respectively; P = 0.0273). TNF-alpha levels in the GCF of the RA+ group were the lowest compared to RA- and C groups (0.663, 1.23, and 0.949 ng/site, respectively; P = 0.0401). A significant positive correlation was found between TNF-alpha levels in the GCF and clinical AL (r = 0.448; P = 0.0283). Patients with RA receiving anti-TNF-alpha medication had lower periodontal indices and GCF TNF-alpha levels. Thus, suppression of proinflammatory cytokines might prove beneficial in suppressing periodontal diseases.

  2. Persistent periodontal disease hampers anti-tumor necrosis factor treatment response in rheumatoid arthritis.

    Science.gov (United States)

    Savioli, Cynthia; Ribeiro, Ana Cristina M; Fabri, Gisele Maria Campos; Calich, Ana Luisa; Carvalho, Jozélio; Silva, Clovis A; Viana, Vilma S T; Bonfá, Eloísa; Siqueira, José Tadeu T

    2012-06-01

    This study aimed to evaluate prospectively the influence and the evolution of periodontal disease (PD) in rheumatoid arthritis (RA) patients submitted to anti-tumor necrosis factor (TNF) therapy. Eighteen patients with RA (according to the American College of Rheumatology criteria) were assessed for PD before (BL) and after 6 months (6M) of anti-TNF treatment: 15 infliximab, 2 adalimumab, and 1 etanercept. Periodontal assessment included plaque and gingival bleeding indices, probing pocket depth, cementoenamel junction, and clinical attachment level. Rheumatologic evaluation was performed blinded to the dentist's assessment: demographic data, clinical manifestations, and disease activity (Disease Activity Score using 28 joints [DAS28], erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]). The median age and disease duration of patients with RA were 50 years (25-71 y) and 94% were female. Periodontal disease was diagnosed in 8 patients (44.4%). Comparing BL to 6M, periodontal parameters in the entire group remained stable (P > 0.05) throughout the study (plaque and gingival bleeding indices, probing pocket depth, cementoenamel junction, and clinical attachment level), whereas an improvement in most analyzed RA parameters was observed in the same period: DAS28 (5.5 vs. 3.9, P = 0.02), ESR (21 vs. 12.5 mm/first hour, P = 0.07), and CRP (7.8 vs. 2.8 mg/dL, P = 0.25). Further analysis revealed that this improvement was restricted to the group of patients without PD (DAS28 [5.5 vs. 3.6, P = 0.04], ESR [23.0 vs. 11.5 mm/first hour, P = 0.008], and CRP [7.4 vs. 2.1, P = 0.01]). In contrast, patients with PD had lack of response, with no significant differences in disease activity parameters between BL and 6M: DAS28 (5.2 vs. 4.4, P = 0.11), ESR (17.0 vs. 21.0, P = 0.56), and CRP (9.0 vs. 8.8, P = 0.55). This study supports the notion that PD may affect TNF blocker efficacy in patients with RA. The possibility that a sustained gingival inflammatory state may

  3. Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease

    Science.gov (United States)

    Al-Meghaiseeb, Ebtissam Saleh; Al-Robayan, Abdulrahman A; Al-Otaibi, Mulfi Mubarak; Arfin, Misbahul; Al-Asmari, Abdulrahman K

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this case–control study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and -β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn’s disease (CD) =95) and 200 age- and sex-matched healthy controls were recruited. TNF-α and TNF-β genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (−308) and -β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (−308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (−308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (−308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population

  4. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected].

    Science.gov (United States)

    Cortis, Elisabetta; De Benedetti, Fabrizio; Insalaco, Antonella; Cioschi, Stefania; Muratori, Flaminia; D'Urbano, Leila E; Ugazio, Alberto G

    2004-12-01

    We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.

  5. Salivary gland anlage tumor. A case with widespread necrosis and large cyst formation.

    Science.gov (United States)

    Michal, M; Sokol, L; Mukensnabl, P

    1996-05-01

    We describe a case of the salivary gland anlage tumor (congenital pleomorphic adenoma). The tumor arose in the nasopharynx as a pedunculated mass. Microscopically most of the tumor contained large necrotic areas which revealed squamous cell metaplasia resulting in the formation of large cysts. This feature has never been described previously in this tumor and might lead to an erroneous diagnosis.

  6. 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.

  7. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications.

    Directory of Open Access Journals (Sweden)

    Anne Chastre

    Full Text Available BACKGROUND/AIMS: Acute liver failure (ALF due to ischemic or toxic liver injury is a clinical condition that results from massive loss of hepatocytes and may lead to hepatic encephalopathy (HE, a serious neuropsychiatric complication. Although increased expression of tumor necrosis factor-alpha (TNF-α in liver, plasma and brain has been observed, conflicting results exist concerning its roles in drug-induced liver injury and on the progression of HE. The present study aimed to investigate the therapeutic value of etanercept, a TNF-α neutralizing molecule, on the progression of liver injury and HE in mice with ALF resulting from azoxymethane (AOM hepatotoxicity. METHODS/PRINCIPAL FINDINGS: Mice were administered saline or etanercept (10 mg/kg; i.p. 30 minutes prior to, or up to 6 h after AOM. Etanercept-treated ALF mice were sacrificed in parallel with vehicle-treated comatose ALF mice and controls. AOM induced severe hepatic necrosis, leading to HE, and etanercept administered prior or up to 3 h after AOM significantly delayed the onset of coma stages of HE. Etanercept pretreatment attenuated AOM-induced liver injury, as assessed by histological examination, plasma ammonia and transaminase levels, and by hepatic glutathione content. Peripheral inflammation was significantly reduced by etanercept as shown by decreased plasma IL-6 (4.1-fold; p<0.001 and CD40L levels (3.7-fold; p<0.001 compared to saline-treated ALF mice. Etanercept also decreased IL-6 levels in brain (1.2-fold; p<0.05, attenuated microglial activation (assessed by OX-42 immunoreactivity, and increased brain glutathione concentrations. CONCLUSIONS: These results indicate that systemic sequestration of TNF-α attenuates both peripheral and cerebral inflammation leading to delayed progression of liver disease and HE in mice with ALF due to toxic liver injury. These results suggest that etanercept may provide a novel therapeutic approach for the management of ALF patients awaiting

  8. 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...

  9. 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...

  10. 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...

  11. Adenoviral Delivery of Tumor Necrosis Factor-α and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma.

    Science.gov (United States)

    Siurala, Mikko; Havunen, Riikka; Saha, Dipongkor; Lumen, Dave; Airaksinen, Anu J; Tähtinen, Siri; Cervera-Carrascon, Víctor; Bramante, Simona; Parviainen, Suvi; Vähä-Koskela, Markus; Kanerva, Anna; Hemminki, Akseli

    2016-08-01

    Adoptive T-cell transfer is a promising treatment approach for metastatic cancer, but efficacy in solid tumors has only been achieved with toxic pre- and postconditioning regimens. Thus, adoptive T-cell therapies would benefit from complementary modalities that enable their full potential without excessive toxicity. We aimed to improve the efficacy and safety of adoptive T-cell transfer by using adenoviral vectors for direct delivery of immunomodulatory murine cytokines into B16.OVA melanoma tumors with concomitant T-cell receptor transgenic OT-I T-cell transfer. Armed adenoviruses expressed high local and low systemic levels of cytokine when injected into B16.OVA tumors, suggesting safety of virus-mediated cytokine delivery. Antitumor efficacy was significantly enhanced with adenoviruses coding for murine interleukin-2 (mIL-2) and tumor necrosis factor-α (mTNFα) when compared with T-cell transfer alone or viruses alone. Further improvement in efficacy was achieved with a triple combination of mIL-2, mTNFα, and OT-I T-cells. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFα induces chemokine expression. Furthermore, adenovirus treatments enhanced tumor-infiltration of OT-I T-cells as demonstrated by SPECT/CT imaging of (111)In-labeled cells. Our results suggest the utility of cytokine-coding adenoviruses for improving the efficacy of adoptive T-cell therapies.

  12. Evaluation of dynamic contrast-enhanced T1-weighted perfusion MRI in the differentiation of tumor recurrence from radiation necrosis

    Energy Technology Data Exchange (ETDEWEB)

    Larsen, Vibeke A. [Glostrup University Hospital, Department of Radiology, Glostrup (Denmark); Glostrup University Hospital, Department of Radiology, Copenhagen Oe (Denmark); Simonsen, Helle J.; Larsson, Henrik B.W. [Glostrup University Hospital, Functional Imaging Unit, Glostrup (Denmark); Glostrup University Hospital, Department of Clinical Physiology, Glostrup (Denmark); Law, Ian [Nuclear Medicine and PET, Department of Clinical Physiology, Copenhagen Oe (Denmark); Hansen, Adam E. [Glostrup University Hospital, Department of Radiology, Glostrup (Denmark); Glostrup University Hospital, Functional Imaging Unit, Glostrup (Denmark)

    2013-03-15

    To investigate if perfusion measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to differentiate radiation necrosis from tumor recurrence in patients with high-grade glioma. The study was approved by the institutional review board and informed consent was obtained from all subjects. 19 patients were recruited following surgery and radiation therapy for glioma. Patients had contrast enhancing lesions, which during the standard MRI examination could not be exclusively determined as recurrence or radiation necrosis. DCE-MRI was used to measure cerebral blood volume (CBV), blood-brain barrier (BBB) permeability and cerebral blood flow (CBF). Subjects also underwent FDG-PET and lesions were classified as either metabolically active or inactive. Follow-up clinical MRI and lesion histology in case of additional tissue resection was used to determine whether lesions were regressing or progressing. Fourteen enhancing lesions could be classified as progressing (11) or regressing (three). An empirical threshold of 2.0 ml/100 g for CBV allowed detection of regressing lesions with a sensitivity of 100 % and specificity of 100 %. FDG-PET and DCE-MRI agreed in classification of tumor status in 13 out of the 16 cases where an FDG-PET classification was obtained. In two of the remaining three patients, MRI follow-up and histology was available and both indicated that the DCE-MRI answer was correct. CBV measurements using DCE-MRI may predict the status of contrast enhancing lesions and give results very similar to FDG-PET with regards to differentiation between tumor recurrence and radiation necrosis. (orig.)

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

    Science.gov (United States)

    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

    2015-11-17

    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) carboxylated cyanines, HQ5 and IRDye 800CW (800CW), which possess strong necrosis avidity. In vitro studies showed that both dyes selectively bind to cytoplasmic proteins of dead cells that have lost membrane integrity. Affinity for cytoplasmic proteins was confirmed using quantitative structure activity relations modeling. In vivo results, using NIRF and optoacoustic imaging, confirmed the necrosis avid properties of HQ5 and 800CW in a mouse 4T1 breast cancer tumor model of spontaneous necrosis. Finally, in a mouse EL4 lymphoma tumor model, already 24 h post chemotherapy, a significant increase in 800CW fluorescence intensity was observed in treated compared to untreated tumors. In conclusion, we show, for the first time, that the NIRF carboxylated cyanines HQ5 and 800CW possess strong necrosis avid properties in vitro and in vivo. When translated to the clinic, these dyes may be used for diagnostic or prognostic purposes and for monitoring in vivo tumor response early after the start of treatment.

  14. A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis

    DEFF Research Database (Denmark)

    Honne, Kyoko; Hallgrímsdóttir, Ingileif; Wu, Chunsen;

    2016-01-01

    BACKGROUND: Studies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings...... DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models. RESULTS...

  15. Pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis: efficacy of anti-tumor necrosis factor α therapy.

    Science.gov (United States)

    Bruzzese, Vincenzo

    2012-12-01

    We report the case of a patient with a simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis. This condition differs from both the PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome, in which arthritis is absent, and the PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, in which suppurative hidradenitis is lacking. Our patient failed to respond to etanercept therapy, whereas all dermatologic and rheumatic manifestations completely regressed following infliximab infusion. We therefore propose that simultaneous presence of pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis might represent a distinct syndrome that could be termed the PASS syndrome. Tumor necrosis factor α therapies seem to play selective roles.

  16. Tumor necrosis factor downregulates granulocyte-colony-stimulating factor receptor expression on human acute myeloid leukemia cells and granulocytes.

    OpenAIRE

    Elbaz, O; Budel, L M; Hoogerbrugge, H; Touw, I P; Delwel, R.; Mahmoud, L A; Löwenberg, B. (Bernward)

    1991-01-01

    Tumor necrosis factor (TNF) inhibits granulocyte-colony-stimulating factor (G-CSF)-induced human acute myeloid leukemia (AML) growth in vitro. Incubation of blasts from three patients with AML in serum-free medium with TNF (10(3) U/ml), and subsequent binding studies using 125I-G-CSF reveal that TNF downregulates the numbers of G-CSF receptors by approximately 70%. G-CSF receptor numbers on purified blood granulocytes are also downmodulated by TNF. Downregulation of G-CSF receptor expression ...

  17. Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein.

    OpenAIRE

    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 TNF alpha with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surf...

  18. 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

    interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55ATNFR had virtually identical affinities for TNF and LT alpha, as defined by Scatchard analysis......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...

  19. 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...... insulin resistance. METHOD AND RESULTS: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions...

  20. Characterization of a small molecule inhibitor of tumor necrosis factor-alpha production

    Institute of Scientific and Technical Information of China (English)

    YANG Gao-yun; XIE Zhi-qiang; QIAN Ge; CUI Wen-ying; ZHAO Jun-yin; ZHANG Jian-zhong; LIAN Shi

    2010-01-01

    Background Numerous studies have shown that reducing the level of tumor necrosis factor-alpha (TNFα) through the use of anti-TNF antibodies or soluble TNF receptor is a safe and efficacious treatment to inflammatory diseases such as rheumatoid arthritis. Therefore, novel approaches to achieve this outcome are desired. The aim of this study was to investigate the characterization of a small molecule inhibitor, Y316, which blocks TNF mRNA upregulation and TNF production by lipopolysaccharides (LPS) stimulated monocytes.Methods Peripheral blood mononuclear cells (PBMC) from healthy volunteers were plated in 24-well plates and stimulated with LPS (1 μg/ml), phorbol-12-myristate-13-acetate (PMA) (100 ng/ml), zymosan (10 μg/ml) and Tsst (100 ng/ml). Supernatants were collected after 4-hour culture at 37C, and quantitative determination of TNFα, interleukin-1β(IL-1β), IL-6, IL-8, IL-10 and IL-2 production in the supernatants was performed by colorimetric enzyme-linked immunosorbent assay (ELISA). Total RNA of PBMC was isolated and cytokine mRNA quantitation was performed by using a RNA level measuring kit (R & D Systems). PBMC were pretreated with Y316 (10 μmol/L, 1 μmol/L, 0.1 μmol/L,0.01 μmol/L and 0.001 μmol/L) or dimethyl sulfoxide at 37C for 10 minutes, and then stimulated with LPS or PMA,protein concentrations of p44.42, IKBα, P38 and Jun NH2-terminal kinase were determined by Western blotting. Cyclic adenosine-3',5'-monophosphate (cAMP) of PBMC was measured by enzyme immunoassay kit (Amersham Pharmacia Biotech).Results Y316 blocked TNF production and inhibited the upregulation of TNF mRNA levels in response to LPS, and also prevented the production of IL-1 and IL-6. In contrast, Y316 augmented the production of IL-10 in LPS-stimulated monocytes. Y316 failed to prevent the production of IL-2 and TNF in antigen-stimulated T cells, suggesting that its effects may be cell-type specific. Y316 prevented the phosphorylation and activation of the MAPK, ERK, and

  1. Ability of cell-sized beads bearing tumor cell membrane proteins to stimulate LAK cells to secrete interferon-gamma and tumor necrosis factor-alpha.

    Science.gov (United States)

    Chong, A S; Pinkard, J K; Lam, K S; Scuderi, P; Hersh, E M; Grimes, W J

    1991-04-15

    We recently reported that lymphokine activated killer (LAK) cells were stimulated to release both interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) when stimulated by a variety of tumor cells. We proposed then that the released cytokines may play a role in mediating tumor cell regression in vivo. In this paper, we provide further information on the nature of the signals, provided by the tumor cells (K562 erythroleukemia), that stimulate LAK cells to secrete IFN-gamma and TNF-alpha. Using a previously published protocol for coating tumor-membrane molecules onto cell-sized hydrophobic beads (also called pseudocytes), we demonstrate that the signal provided by the tumor cell is membrane associated. Beads coated with K562 membranes stimulated LAK cells to release IFN-gamma and TNF-alpha. The pretreatment of these beads with trypsin and sodium periodate eliminated the ability of these pseudocytes to stimulate cytokine release in LAK cells. The glycoproteins that stimulate LAK cells to secrete IFN-gamma and TNF-alpha were further enriched by their ability to bind concanavalin A (Con A, Jack Bean). To determine if the tumor-associated molecules that stimulate LAK cells to release IFN-gamma and TNF-alpha are also the molecules involved in mediating tumor cell lysis, we tested the ability of the Con A binding and nonbinding proteins to inhibit the LAK cell-mediated lysis of K562 cells. Our results demonstrate that molecules that inhibited LAK cell-mediated cytotoxicity were not enriched by Con A. These results are therefore consistent with the conclusion that different sets of tumor-associated molecules are involved in the stimulation of LAK cells to secrete cytokine and in the induction of LAK cells to mediate tumor cell cytolysis.

  2. The ecology and evolutionary biology of cancer: a review of mathematical models of necrosis and tumor cell diversity.

    Science.gov (United States)

    Nagy, John D

    2005-04-01

    Recent evidence elucidating the relationship between parenchyma cells and otherwise "healthy" cells in malignant neoplasms is forcing cancer biologists to expand beyond the genome-centered, "one-renegade-cell" theory of cancer. As it becomes more and more clear that malignant transformation is context dependent, the usefulness of an evolutionary ecology-based theory of malignant neoplasia becomes increasingly clear. This review attempts to synthesize various theoretical structures built by mathematical oncologists into potential explanations of necrosis and cellular diversity, including both total cell diversity within a tumor and cellular pleomorphism within the parenchyma. The role of natural selection in necrosis and pleomorphism is also examined. The major hypotheses suggested as explanations of these phenomena are outlined in the conclusions section of this review. In every case, mathematical oncologists have built potentially valuable models that yield insight into the causes of necrosis, cell diversity, and nearly every other aspect of malignancy; most make predictions ultimately testable in the lab or clinic. Unfortunately, these advances have gone largely unexploited by the empirical community. Possible reasons why are considered.

  3. Role of nitric oxide in recombinant tumor necrosis factor-alpha-induced circulatory shock : A study in patients treated for cancer with isolated limb perfusion

    NARCIS (Netherlands)

    Zwaveling, JH; Maring, JK; Moshage, H; vanGinkel, RJ; Hoekstra, HJ; Donse, IF; Girbes, ARJ; Schraffordt Koops, H.

    1996-01-01

    Objectives: To analyze the mechanism of vasodilation and circulatory shock occurring in patients who are treated with isolated limb perfusion with melphalan and recombinant tumor necrosis factor (TNF)-alpha for locally advanced malignant tumors, To determine the role of nitric oxide, if any, by

  4. Overlap syndrome between Familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome in a lupus patient.

    Science.gov (United States)

    Nonaka, Fumiaki; Migita, Kiyoshi; Iwasaki, Keisuke; Shimizu, Toshimasa; Kawakami, Atsushi; Yasunami, Michio; Eguchi, Katsumi

    2014-06-01

    Autoinflammatory diseases represent an expanding spectrum of genetic and non-genetic inflammatory diseases characterized by recurrent episodes of fever and systemic inflammation, affecting joints, skin and serosal surfaces. Familial Mediterranean fever (FMF) is the most common autosomal recessive hereditary autoinflammatory disease. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary autoinflammatory disease. They share some clinical manifestations such as a periodic fever and skin rash. We present here the association of FMF with TRAPS in a systemic lupus erythematosus (SLE) patient. A 54-year-old SLE patient with recurrent attacks of fever, arthritis, and skin rashes was referred to our hospital. She had been diagnosed with lupus nephritis at 19 years old. Her lupus nephritis was controlled by steroid treatments; however, since childhood she has suffered from recurrent episodes of periodic fever, abdominal pain, arthritis, and erythematous skin rashes. An initial diagnosis of FMF was suspected based on the genetic analysis, showing the compound heterozygous L110P/E148Q mutations in the MEFV gene that is responsible for FMF. Her symptoms responded to colchicine, but the febrile attacks were not completely resolved. Therefore, genetic testing for TRAPS was performed. The results revealed a heterozygous T61I mutation in the TNFRSF1A gene that encodes tumor necrosis factor-α receptor and is responsible for TRAPS. The patient was diagnosed with overlapping FMF and TRAPS, in addition to SLE. This is the first report of SLE associated with both FMF and TRAPS.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. A specific and sensitive method for visualization of tumor necrosis factor in the murine central nervous system

    DEFF Research Database (Denmark)

    Lambertsen, K L; Drøjdahl, N; Owens, T

    2001-01-01

    We present here sensitive, simple and robust methods for detection of tumor necrosis factor (TNF) mRNA and TNF in histological sections and homogenates of brain tissue from mice subjected to focal cerebral ischemia or hippocampal axonal lesioning. Both types of lesions are characterized by induct......We present here sensitive, simple and robust methods for detection of tumor necrosis factor (TNF) mRNA and TNF in histological sections and homogenates of brain tissue from mice subjected to focal cerebral ischemia or hippocampal axonal lesioning. Both types of lesions are characterized...... of individual cells, and can successfully be combined with immunohistochemical procedures. We also describe a sensitive immunohistochemical method for detection of TNF, which can be combined with visualization of an additional antigen. The specificity of the histological procedures are confirmed by RT......-PCR and Western blot analysis on homogenates prepared from microdissected brain regions. Advantages and disadvantages of the methods are discussed with emphasis on the specificity and sensitivity of the histological procedures. Our strategy for detection of TNF mRNA and protein provides a solid basis...

  7. Quiescent interplay between inducible nitric oxide synthase and tumor necrosis factor-alpha: influence on transplant graft vasculopathy in renal allograft dysfunction.

    Science.gov (United States)

    Elahi, Maqsood M; Matata, Bashir M; Hakim, Nadey S

    2006-06-01

    A healthy endothelium is essential for vascular homeostasis, and preservation of endothelial cell function is critical for maintaining transplant allograft function. Damage to the microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection, an important predictor of graft loss. It is also linked with transplant vasculopathy, often associated with chronic allograft nephropathy. Large bursts of nitric oxide in infiltrating monocytes/macrophages modulated by inducible nitric oxide synthase are considered pivotal in driving this mechanism. Indeed, it has been shown recently that increased circulating levels of tumor necrosis factor-alpha in the rejecting kidneys are largely responsible for triggering inducible nitric oxide synthase expression. This in turn suggests that several structural and functional features of graft rejection could be mediated by tumor necrosis factor-alpha. Despite the large body of evidence that supports immunologic involvement, knowledge concerning the cellular and biochemical mechanisms for nephritic cell dysfunction and death is incomplete. The role of tumor necrosis factor-alpha in mediating pathophysiological activity of inducible nitric oxide synthase during transplant vasculopathy remains contentious. Here, we discuss the effect of inducible nitric oxide synthase and tumor necrosis factor-alpha interaction on progressive damage to glomerular and vascular structures during renal allograft rejection. Selective inhibition of inducible nitrous oxide synthase and tumor necrosis factor-alpha as a potential therapy for ameliorating endothelial dysfunction and transplant graft vasculopathy is also discussed.

  8. Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells.

    Science.gov (United States)

    Tian, Xin; Ma, Ping; Sui, Cheng-Guang; Meng, Fan-Dong; Li, Yan; Fu, Li-Ye; Jiang, Tao; Wang, Yang; Jiang, You-Hong

    2014-06-01

    Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a molecular chaperone involved in multidrug resistance and antiapoptosis in some human tumors, but its regulatory mechanisms have not been revealed in esophageal squamous cell carcinoma (ESCC). In this study, 138 specimens of ESCC were analyzed. TRAP1 was overexpressed in ESCC, particularly in poorly differentiated tumors. To further explore the molecular regulatory mechanism, we constructed specific small interfering RNA-expressing vectors targeting Trap1, and knocked down Trap1 expression in the esophageal cancer cell lines ECA109 and EC9706. Knockdown of Trap1 induced increases in reactive oxygen species and mitochondrial depolarization, which have been proposed as critical regulators of apoptosis. The cell cycle was arrested in G2/M phase, and in vitro inhibition of cell proliferation was confirmed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and bromodeoxyuridine assays. Furthermore, re-expression of TRAP1 in Trap1 small interfering RNA-transfected ESCC cells restored cell proliferation and cell apoptosis. Bioluminescence of subcutaneously xenografted ESCC tumor cells demonstrated significant inhibition of in vivo tumor growth by Trap1 knockdown. This study shows that TRAP1 was overexpressed in most patients with ESCC, and caused an increase in antiapoptosis potency. TRAP1 may be regarded as a target in ESCC biotherapy.

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

    OpenAIRE

    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-scFv fragments for purification of TNF-α produced by Raj...

  10. Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells.

    Science.gov (United States)

    Subbarayan, V; Sabichi, A L; Llansa, N; Lippman, S M; Menter, D G

    2001-03-15

    Cyclooxygenase (COX)-2 expression is elevated in some malignancies; however, information is scarce regarding COX-2 contributions to the development of prostate cancer and its regulation by inflammatory cytokines. The present study compared and contrasted the expression levels and subcellular distribution patterns of COX-1 and COX-2 in normal prostate [prostate epithelial cell (PrEC), prostate smooth muscle (PrSM), and prostate stromal (PrSt)] primary cell cultures and prostatic carcinoma cell lines (PC-3, LNCaP, and DU145). The basal COX-2 mRNA and protein levels were high in normal PrEC and low in tumor cells, unlike many other normal cells and tumor cells. Because COX-2 levels were low in prostate smooth muscle cells, prostate stromal cells, and tumor cells, we also examined whether COX-1 and COX-2 gene expression was elevated in response to tumor necrosis factor-alpha (TNF-alpha), a strong inducer of COX-2 expression. Northern blot analysis and reverse transcription-PCR demonstrated different patterns and kinetics of expression for COX-1 and COX-2 among normal cells and tumor cells in response to TNF-alpha. In particular, COX-2 protein levels increased, and the subcellular distribution formed a distinct perinuclear ring in the normal cells at 4 h after TNF-alpha exposure. The COX-2 protein levels also increased in cancer cells, but the subcellular distribution was less organized; COX-2 protein appeared diffuse in some cells and accumulated as focal deposits in the cytoplasm of other cells. TNF-alpha induction of COX-2 and prostaglandin E2 correlated inversely with induction of apoptosis. We conclude that COX-2 expression may be important to PrEC cell function. Although it is low in stromal and tumor cells, COX-2 expression is induced by TNF-alpha in these cells, and this responsiveness may play an important role in prostate cancer progression.

  11. Induction of apoptosis in osteogenic sarcoma cells by combination of tumor necrosis factor-related apoptosis inducing ligand and chemotherapeutic agents

    Institute of Scientific and Technical Information of China (English)

    SUN Jie; FU Zhi-min; FANG Chang-qing; LI Jian-hua

    2007-01-01

    Background Osteosarcoma is one of the most common primary malignant tumors of bone with poor prognosis.TNF-related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. TRAIL induces apoptosis in various tumor cell lines but is not found to be cytotoxic to many normal cell types in vitro. We investigated the cytotoxic activity of TRAIL and chemotherapeutic agents, including methotrexate (MTX), doxorubicin(DOX) and cisplatin (CDDP), on established osteosarcoma cell line-OS-732.Methods OS-732 cells were incubated with chemotherapeutic agents MTX,DOX and CDDP at various peak plasma concentrations(PPC), 0.1PPC,1PPC and 10PPC, alone or with 100 ng/ml of TRAIL for 24 hours or 48 hours. MTT was used to evaluate the cytotoxic activity of different agents on OS-732. The apoptosis proportion was assayed by flow cytometry. Cellular morphologic changes were observed by phase contrast microscope, scan electron microscope, and transmission electron microscope.Results The inhibitory rate was (24.438±3.414)% with TRAIL of 100 ng/ml for 24 hours. The cells were responsive to DOX and CDDP with a dose-effect relationship (P<0.05). In OS-732 cells, DOX and CDDP cooperated synergistically with TRAIL when incubated the cells with them for 24 hours (the combined inhibitory rate is (58.360±2.146)% and (54.101 ±2.721)%, respectively). TRAIL alone or drugs alone induced the apoptosis rate was less than 25% (P<0.05).However, the combination of TRAIL and MTX did not present synergistic effects on OS-732 cells (P>0.05, compared with TRAIL alone).Conclusions Osteosarcoma OS-732 cells were not responsive to TRAIL-induced apoptosis. DOX and CDDP sensitize osteosarcoma OS-732 cells to TRAIL-induced apoptosis. The combination of TRAIL and MTX presented no synergistic effects on killing OS-732 cells.

  12. [Purification of recombinant proteins with an example of tumor necrosis factor thymosin-alpha1].

    Science.gov (United States)

    Fedorov, T V; Korobov, V I; Nazarov, V G; Smolkina, A E; Shmelev, V A

    2010-01-01

    Hybrid protein, cancer necrosis factor thymosin-alpha1 (CNF-T), when synthesizing in strain-producer of Escherichia coli SG200-50 with plasmid pThy315, was a part of "inclusion bodies" mostly in the form of a high-molecular complex with other proteins due to the S-S bonds formation. An approach of purification of CNF-T has been proposed, which is based on the destruction of the complex in the presence of sodium dodecylsulfate (DDS-NA) and dithiotreitol (DDT) followed by gel-filtration on Sephadex G-100 and renaturation by ultrafiltration on hollow fibers. The method allows the isolation of electrophoretically homogeneous CNF-T containing no DDS-Na and having high cytotoxic activity against cancer cells of mouse adenocarcinome L-929. The yield of CNF-T achieved 80% relative its content in biomass and 30% relative the total protein.

  13. Evodiamine induces tumor cell death through different pathways: apoptosis and necrosis

    Institute of Scientific and Technical Information of China (English)

    YingZHANG; Li-junWU; Shin-ichiTASHIRO; SatoshiONODERA; TakashiIKEJIMA

    2004-01-01

    AIM: To study the different death pathways in human cervical cancer HeLa and melanoma A375-S2 cells initiated by evodiamine. METHODS: Viability of evodiamine-induced HeLa and A375-S2 cells was measured by MTT assay. Apoptotic cells with condensed or fragmented nuclei were visualized by Hoechst 33258 staining. Nucleosomal DNA fragmentation was assayed by agarose gel electrophoresis. Proportion of cell death through apoptotic and necrotic pathways was determined by LDH activity-based cytotoxicity assays. Cell cycle distribution was observed by flow cytometry. RESULTS: Evodiamine induced HeLa and A375-S2 cell death dose- and time-dependently.Caspase-3 and -8 were activated in apoptosis induced by evodiamine 15 μmol/L. However, over 24- h incubation of A375-S2 cells, evodiamine 15 μmol/L initiated necrosis related to p38 and ERK (extracellular signal-regulated kinases)activities. Evodiamine-induced HeLa cell death was preceded by an accumulation of cells at the G2/M phase of the cell cycle, but there was no significant effect of evodiamine on A375-S2 cell cycle. CONCLUSION: Evodiamineinduces caspase-3,8-dependent apoptosis in HeLa cells which is related to G2/M arrest of the cell cycle. On the other hand, in A375-S2 cells, evodiamine initiates caspase-3,8-mediated apoptosis at early stages and the induction of MAPK-mediated necrosis at later stages of cell culture.

  14. Staphylococcus aureus - induced tumor necrosis factor - related apoptosis - inducing ligand expression mediates apoptosis and caspase-8 activation in infected osteoblasts

    Directory of Open Access Journals (Sweden)

    Bost Kenneth L

    2003-04-01

    Full Text Available Abstract Background Staphylococcus aureus infection of normal osteoblasts induces expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL. Results Normal osteoblasts were incubated in the presence of purified bacterial products over a range of concentrations. Results demonstrate that purified surface structures and a selected superantigen present in the extracellular environment are not capable of inducing TRAIL expression by osteoblasts. Osteoblasts were co-cultured with S. aureus at various multiplicities of infection utilizing cell culture chamber inserts. Results of those experiments suggest that direct contact between bacteria and osteoblasts is necessary for optimal TRAIL induction. Finally, S. aureus infection of osteoblasts in the presence of anti-TRAIL antibody demonstrates that TRAIL mediates caspase-8 activation and apoptosis of infected cells. Conclusions Collectively, these findings suggest a mechanism whereby S. aureus mediates bone destruction via induction of osteoblast apoptosis.

  15. Treatment of early arthritis using arthrofoon (ultra-low doses of antibodies to tumor necrosis factor-α

    Directory of Open Access Journals (Sweden)

    Lyudmila V Sizova

    2011-01-01

    Full Text Available The main aim of treatment of early rheumatoid arthritis (RA should be to achieve clinical remission to prevent structural damage and physical disability. Arthrofoon modifies production/activity of endogenous inhibitors of tumor necrosis factor-α (TNF-α. The sublingual rout is the most acceptable to ambulatory treatment because it does not produce the adverse reactions associated with intravenous therapy. The treatment with arthrofoon in outpatient with early RA is analyzed here. This report is devoted to the 28-year-old Russian woman who received arthrofoon due to suspicion of early RA. The strategy of early prescription of ultra-low doses of TNF-α antibody within two years was confirmed by the clinical improvement and delay of radiological disease progression in patient with undifferentiated arthritis or probable RA initially.

  16. Association study of the interleukin-1 gene complex and tumor necrosis factor alpha gene with suicide attempts.

    Science.gov (United States)

    Sáiz, Pilar A; García-Portilla, Paz; Paredes, Begoña; Arango, Celso; Morales, Blanca; Alvarez, Victoria; Coto, Eliécer; Bascarán, María-Teresa; Bousoño, Manuel; Bobes, Julio

    2008-06-01

    To investigate the association between four functional polymorphisms in interleukin-1 (IL-1) [IL-1 alpha -889 C/T, IL-1 beta +3953 C/T, IL-1RA (86 bp)n] and tumor necrosis factor alpha (TNFalpha) (-308A/G) genes and suicide attempts. Distribution of the aforesaid polymorphisms was analyzed in 193 suicide attempters compared with 420 unrelated healthy controls from Asturias (Northern Spain). Genotypes were determined using standard methods. No significant differences were found in genotype or in allelic distribution of IL-1 alpha, IL-1 beta, IL-1RA, or TNFalpha gene polymorphisms. No relationship was found between genotypes and the impulsivity of the suicide attempt. Estimated IL-1 haplotype frequencies were similar in both groups (likelihood ratio test=13.26, df=14, P=0.506). Our data do not suggest that genetically determined changes in the IL-1 or TNFalpha genes confer increased susceptibility to suicidal behavior.

  17. Tumor necrosis factor-a and its role as a mediator in myocardial infarction:A brief review

    Institute of Scientific and Technical Information of China (English)

    Ming Tian; Yun-Chuan Yuan; Jia-Yi Li; Michael R. Gionfriddo; Rong-Chong Huang

    2015-01-01

    Tumor necrosis factor-a (TNF-a) contributes to myocardial infarction (MI) injury. Polymorphism of TNF-a gene promoter region and secretion and release of TNF-a and its transformation by a series of signaling pathways are all changed at different points of pathophysiological process in MI. Researches also investigated TNF-a antagonists and their potential therapeutic role in the setting of MI and heart failure at both molecular and clinical level. This article briefly reviews TNF-a and its mechanism as a mediator in MI. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

    DEFF Research Database (Denmark)

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

    2003-01-01

    -alpha was smaller (PTNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. CONCLUSIONS: These results support the concept that TNF-alpha could play a role......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...

  19. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Nyboe Andersen, Nynne; Pasternak, Björn; Basit, Saima;

    2014-01-01

    IMPORTANCE: A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data...... to evaluate these effects. OBJECTIVE: To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56......,146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry. MAIN OUTCOMES AND MEASURES: Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF...

  20. A Pilot Study of the Association of Tumor Necrosis Factor Alpha Polymorphisms with Psoriatic Arthritis in the Romanian Population

    Directory of Open Access Journals (Sweden)

    Olivia M. Popa

    2011-08-01

    Full Text Available Tumor necrosis factor alpha (TNF-alpha is an important pro-inflammatory cytokine implicated in the pathogenesis of psoriatic arthritis. We have performed a case-control association study of three TNF-alpha gene polymorphisms in a group of Romanian psoriatic arthritis patients versus ethnically matched controls. A second group of patients with undifferentiated spondyloarthritis was used in order to look for similarities in the genetic background of the two rheumatic disorders. The −857C/T polymorphism was associated with susceptibility to psoriatic arthritis in our population at the individual level (p = 0.03, OR 1.65, 95% CI 1.05–2.57 and in combined haplotypes with the −238G/A and −308G/A SNPs. Regarding the investigated polymorphisms and derived haplotypes, no potential association was found with the susceptibility to undifferentiated spondyloarthritis in Romanian patients.

  1. Inflammatory mediators, tumor necrosis factor-α and interferon-γ, induce EMT in human PTC cell lines.

    Science.gov (United States)

    Lv, Nannan; Gao, Yun; Guan, Haixia; Wu, Dan; Ding, Shuangning; Teng, Weiping; Shan, Zhongyan

    2015-10-01

    Inflammatory mediators, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, promote adverse outcomes in numerous types of cancer; however, their role in papillary thyroid cancer (PTC) remains unclear. The aim of the present study was to investigate the influence of TNF-α and IFN-γ on the migration, invasion and epithelial-mesenchymal transition (EMT) of the three PTC cell lines, TPC-1, BCPAP and K1. The effect of TNF-α and IFN-γ on cell migration and invasion was assessed by wound-healing and Transwell assays. In addition, the mRNA and protein expression levels of the EMT makers, E-cadherin, N-cadherin and vimentin, were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblot analysis. The wound-healing and Transwell experiments revealed that TNF-α and IFN-γ increased the migratory and invasive behavior of PTC cells (PPTC cells.

  2. Interleukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis.

    Science.gov (United States)

    Turner, P F; Rockett, K A; Ottesen, E A; Francis, H; Awadzi, K; Clark, I A

    1994-05-01

    Adverse reactions following treatment of onchocerciasis and bancroftian filariasis are common and frequently severe. They are generally caused not by direct drug toxicity but by host inflammatory responses to dying microfilariae. To define the responsible mechanism, serial blood levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were studied in 15 microfilaria-positive patients (10 with bancroftian filariasis, 5 with onchocerciasis) and 4 microfilaria-negative persons after diethylcarbamazine treatment. Elevations in IL-6 correlated with the occurrence and severity of clinical symptoms after treatment; for the onchocerciasis patients IL-6 levels directly reflected pretreatment intensity of infection. Serum TNF levels also rose but did not correlate directly with infection intensity or reaction severity. Microfilaria-negative controls remained asymptomatic with no significant rise in either cytokine. These findings suggest an etiologic role for systemically elevated cytokines in the inflammatory reactions developing after treatment of filarial infections in humans.

  3. Application of a stochastic modeling to evaluate tuberculosis onset in patients treated with tumor necrosis factor inhibitors

    CERN Document Server

    Agliari, Elena; Barra, Adriano; Scrivo, Rossana; Valesini, Guido

    2012-01-01

    This manuscript deals with the application of a stochastic model to face the risk of reactivation of latent tuberculosis infection in patients undergoing treatment with tumor necrosis factor inhibitors. Firstly, the paper reviews the approach proposed by R. S. Wallis, which consists in predicting the extent of side effects of a given drug through extremizing procedures on a simple set of parameters (such as the monthly rate of reactivation of a latent infection). Sec- ondly, the paper develops an analytical analysis of this approach by stochastic modeling. The rate for emergence of reactivation of latent tuberculosis in- fection is investigated by means of Markov chains and an exact solution for its temporal evolution is obtained. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excel- lent agreement. The framework outlined in this paper is quite general and could be extremely promising in contributing further to detecting drug ther- apies side effec...

  4. [Effects of tumor necrosis factor-α on nutritional status and proteolysis of respiratory muscles in rats with chronic obstructive pulmonary disease].

    Science.gov (United States)

    Liu, Jianming; Liao, Qiande; Tang, Wenxiang; Sun, Shenghua; Liu, Beizhan; Liu, Xinmin

    2012-04-01

    To investigate the effect of tumor necrosis factor-α (TNF-α) on nutritional status and proteolysis of respiratory muscle in a rat model of chronic obstructive pulmonary disease (COPD). Ninety healthy male adult Wistar rats were randomly divided into model group (A) and normal control group (B). COPD malnutrition rat models were established by cigarettes smoke and nutrient limitation and divided into normal nutrition COPD group (A(1)), malnutrition COPD group (A(2)), and malnutrition COPD intervention group (A(3)). In group A(3), the rats received intravenous injection of TNF-α mAb (0.1 mg/kg). TNF-α levels in the serum and respiratory muscle homogenates were measured using enzyme-linked immunosorbent assay (ELISA), and plasma levels of glucose, albumin, and triglyceride were measured with an automatic biochemistry analyzer. High-performance liquid chromatography was used to measure the contents of 3-methylhistidine and tyrosine in the respiratory muscle homogenates. The serum TNF-α level and plasma levels of glucose and triglyceride were significantly higher but the plasma albumin level was significantly lower in group A(2) than in groups B, A(1), and A(3) (P<0.01). The contents of 3-MH and Tyr in the respiratory muscle homogenates were significantly higher in group A(2) than in the other 3 groups (P<0.01, P<0.01). TNF-α in the respiratory muscle showed a strong positive correlation to 3-MH and Tyr. TNF-α is one of the causes of increased proteolysis of the respiratory muscle.

  5. A Parallel 2D Numerical Simulation of Tumor Cells Necrosis by Local Hyperthermia

    Science.gov (United States)

    Reis, R. F.; Loureiro, F. S.; Lobosco, M.

    2014-03-01

    Hyperthermia has been widely used in cancer treatment to destroy tumors. The main idea of the hyperthermia is to heat a specific region like a tumor so that above a threshold temperature the tumor cells are destroyed. This can be accomplished by many heat supply techniques and the use of magnetic nanoparticles that generate heat when an alternating magnetic field is applied has emerged as a promise technique. In the present paper, the Pennes bioheat transfer equation is adopted to model the thermal tumor ablation in the context of magnetic nanoparticles. Numerical simulations are carried out considering different injection sites for the nanoparticles in an attempt to achieve better hyperthermia conditions. Explicit finite difference method is employed to solve the equations. However, a large amount of computation is required for this purpose. Therefore, this work also presents an initial attempt to improve performance using OpenMP, a parallel programming API. Experimental results were quite encouraging: speedups around 35 were obtained on a 64-core machine.

  6. T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.

    Science.gov (United States)

    Marigo, Ilaria; Zilio, Serena; Desantis, Giacomo; Mlecnik, Bernhard; Agnellini, Andrielly H R; Ugel, Stefano; Sasso, Maria Stella; Qualls, Joseph E; Kratochvill, Franz; Zanovello, Paola; Molon, Barbara; Ries, Carola H; Runza, Valeria; Hoves, Sabine; Bilocq, Amélie M; Bindea, Gabriela; Mazza, Emilia M C; Bicciato, Silvio; Galon, Jérôme; Murray, Peter J; Bronte, Vincenzo

    2016-09-12

    Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

  7. Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors

    NARCIS (Netherlands)

    B. van Etten (Boudewijn); A.N. van Geel (Albert); J.H.W. de Wilt (Johannes); A.M.M. Eggermont (Alexander)

    2003-01-01

    textabstractBACKGROUND: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older p

  8. Effect of Moderate Alcohol Consumption on Adiponectin, Tumor Necrosis Factor-α, and Insulin Sensitivity

    NARCIS (Netherlands)

    Sierksma, A.; Patel, H.; Ouchi, N.; Kihara, S.; Funahashi, T.; Heine, R.J.; Grobbee, D.E.; Kluft, C.; Hendriks, H.F.J.

    2004-01-01

    OBJECTIVE - Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sens

  9. 重症肺炎患者血浆可溶性髓系细胞触发受体1、肿瘤坏死因子α和白细胞介素10水平变化的研究%Changes of Plasma Levels of Soluble Triggering Receptor Expressed on Myeloid Cell-1, Tumor Necrosis Factor-α and Interleukin-10 in Severe Pneumonia

    Institute of Scientific and Technical Information of China (English)

    唐朝霞; 曾勉; 卢桂芳

    2011-01-01

    Objective To observe the changes of soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) and inflammatory mediators levels in plasma of severe pneumonia patients,and explore the significance of systemic inflammatory response state. Methods Plasma levels of sTREM-1, tumor necrosis factor-a (TNF-a) and interleukin-10 ( IL-10) were examined in 40 patients with severe pneumonia,25 patients with uncomplicated pneumonia,and 15 healthy volunteers. Plasma levels of TNF-a, IL-10 and sTREM-1 in survival and non-survival severe pneumonia were observed on days 1,4,7 and the day of discharge or death. Results Plasma levels of TNF-a,IL-10,and sTREM-1 [ (44. 25 ± 10. 81) pg/mL, (58. 21 ± 16. 41) pg/mL, (51. 75 ± 18.51 ) pg/mL, respectively] in the patients with severe pneumonia were higher than those with uncomplicated pneumonia [ (24. 36 ± 6. 45) pg/mL, (24. 56 ± 7. 1 ) pg/mL, (25.55±7.72) pg/mL, respectively] and the normal controls [ (13. 82 ±4. 04) pg/mL,( 15. 30 ±4.45) pg/mL,(14. 37 ±4. 82) pg/mL,respectively] (P <0.001 ). Plasma levels of TNF-a,IL-10,and sTREM-1 were gradually decreased in the survivors,while maintained at high levels or increased in the non-survivors. The levels of these mediators were all significantly higher in the non-survivors than the survivors at all time points. The ratio of TNF-a/IL-10 level was higher in the severe pneumonia patients than the uncomplicated pneumonia patients and the control subjects (1. 286 ±0. 177 vs. 1.077 ±0. 410 and 0.932 ±0. 154) on day 1. The ratio of TNF-a/IL-10 level was higher in the non-survivors than the survivors at all time points. There was negative correlation between plasma levels of sTREM-1 and TNF-ot on day 1 (r = -0. 479,P =0.002) , and positive correlation between plasma levels of sTREM-1 and IL-10 on day 1 (r =0. 326, P = 0. 040). Conclusions There are excessive release of inflammatory mediators and unbalanced systemic inflammatory response in patients with severe pneumonia, especially

  10. Effects of tumor necrosis factor α on leptin-sensitive intestinal vagal mechanoreceptors in the cat.

    Science.gov (United States)

    Quinson, Nathalie; Vitton, Véronique; Bouvier, Michel; Grimaud, Jean-Charles; Abysique, Anne

    2013-11-01

    The involvement of tumour necrosis factor α (TNF-α) in inflammatory bowel disease (IBD) has been established, and anti-TNF-α has been suggested as a therapeutic approach for the treatment of these pathologies. We studied the effects of TNF-α on leptin-sensitive intestinal vagal units to determine whether TNF-α exerts its effects through the intestinal vagal mechanoreceptors and to investigate its interactions with substances regulating food intake. The activity of intestinal vagal mechanoreceptors was recorded via microelectrodes implanted into the nodose ganglion in anesthetized cats. TNF-α (1 μg, i.a.) increased the discharge frequency of leptin-activated units (type 1 units; P < 0.05) and had no effect on the discharge frequency of leptin-inhibited units (type 2 units). When TNF-α was administered 20 min after sulfated cholecystokinin-8 (CCK), its excitatory effects on type 1 units were significantly enhanced (P < 0.0001) and type 2 units were significantly (P < 0.05) activated. Pre-treatment with Il-1ra (250 μg, i.a.) blocked the excitatory effects of TNF-α on type 1 units whereas the excitatory effects of TNF-α administration after CCK treatment on type 2 units were not modified. The activation of leptin-sensitive units by TNF-α may explain, at least in part, the weight loss observed in IBD.

  11. Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection.

    Science.gov (United States)

    Yee, L J; Tang, J; Herrera, J; Kaslow, R A; van Leeuwen, D J

    2000-08-01

    Pro-inflammatory cytokines including tumour necrosis factor (TNF) mediate the pathogenesis of hepatitis C virus (HCV) infection. The distribution of TNF gene polymorphisms was examined among cirrhotic and non-cirrhotic patients infected with HCV. Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin alpha and TNF-receptor type I using PCR-based techniques. Variability in the progression of HCV-related cirrhosis was assessed in a multivariate model including genetic and non-genetic factors such as gender, estimated duration of infection, alcohol consumption, and viral genotype. Viral genotype and non-genetic host features were not independently related to the occurrence or rate of development of cirrhosis in the patient population. In contrast, the TNF promoter variants TNF2 (-238A) and TNF3 (-308A) conferred a 3.2-fold and 5.1-fold risk of cirrhosis respectively (P = 0.03 for both). Reciprocal effects were observed with several TNF alleles and haplotypes defined by the -238G/A and -308G/A dimorphic sequences. Polymorphisms in the TNF alpha promoter appear to be associated with variability in the histological severity of chronic hepatitis C infection.

  12. Association of two polymorphisms of tumor necrosis factor gene with acute biliary pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Dian-Liang Zhang; Jie-Shou Li; Zhi-Wei Jiang; Bao-Jun Yu; Xing-Ming Tang; Hong-Mei Zheng

    2003-01-01

    AIM: To investigate TNF-α-308 and TNFB polymorphisms in acute biliary pancreatitis (ABP) and to related them to the plasma TNF-α levels.METHODS: Genomic DNA was prepared from peripheral blood leukocytes. Genotypes and allele frequencies were determined in patients (n=127) and healthy controls (n=-102)using restriction fragment length polymorphism analysis of polymerase chain reaction (PCR) products. Reading the size of digested bands from polyacrylamide gel demonstrated the two alleles TNF1 and TNF2, or the two alleles TNFB1and TNFB2.RESULTS: The frequencies of TNF2 polymorphism and TNFB2 polymorphism were both similar in patients with mild or severe pancreatitis, so were in pancreatitis patients and in controls. Patients with septic shock showed a significantly higher prevalence of the TNF2 than those without. No significant differences were found in the genotype distribution of TNF-α-308 and TNFB among different groups. Plasma TNF-α levels did not differ significantly in ASBP patients displaying different alleles of the TNF gene studied.CONCLUSION: Results indicate that TNF gene polymorphisms studied play no part in determination of disease severity or susceptibility to acute biliary pancreatitis; however, TNF2polymorphism is associated with septic shock from ASBP.Genetic factors are not important in determining plasma TNF-α levels in ASBP.

  13. Highly Multiplexed Profiling of Low Abundance Tumor Mutations in Plasma

    Science.gov (United States)

    Wiggin, Matthew; Pel, Joel; Vysotskaia, Valentina; Broemeling, David; Marziali, Andre; Hanson, Dan

    2013-01-01

    We have demonstrated a novel somatic mutation enrichment methodology demonstrating multiplexed detection of tumor mutations in plasma with sensitivity as low as 0.01% compared to normal DNA. This highly sensitive detection of low abundance mutations is achieved using electrophoretic separation and enrichment of DNA fragments containing point mutations over their wild-type counterparts. Commercialized as the OnTarget platform by Boreal Genomics, the system enriches nucleic acid samples for specific targets prior to amplification and detection, enabling the use of next-generation sequencing (NGS) or other detection assays for plasma or FFPE-based mutation detection and profiling. We present data demonstrating highly sensitive and multiplexed detection of panels of up to 100 mutations in plasma samples, improving the sensitivity of NGS assays to below 0.01% mutant content. We also report on concordance studies comparing low tumor content FFPE tissue and matched plasma in human samples demonstrating that OnTarget represents a robust, highly sensitive and multiplexed platform for non-invasive tumor monitoring.

  14. Role of tumor necrosis factor-α and interleukin-1β in anorexia induction following oral exposure to the trichothecene deoxynivalenol (vomitoxin) in the mouse.

    Science.gov (United States)

    Wu, Wenda; Zhang, Haibin

    2014-01-01

    The trichothecene deoxynivalenol (DON), a foodborne mycotoxin found in grain-based foods, has been associated with human and animal food poisoning. Although induction of anorexia has been described as a hallmark of DON-induced toxicity in many animal species, the mechanistic basis for this adverse effect is not fully understood. The purpose of this research was to determine the role of two proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in DON-induced anorexia. In a nocturnal mouse food consumption model, DON-induced anorectic response occurred at 1 hr and lasted up to 6 hr. Similar anorectic effects were observed following acute administration of exogenous TNF-α and IL-1β. Oral exposure to DON at 5 mg/kg bw stimulated splenic and hepatic mRNA and plasma protein elevations of TNF-α and IL-1β that corresponded to anorexia induction. Pretreatment with the TNF-α receptor (TNFR) antagonist R-7050 dose-dependently attenuated both TNF-α- and DON-induced anorexia. While, the type 1 IL-1 receptor (IL-1R1) antagonist IL-1RA dose-dependently attenuated both IL-1β- and DON-induced anorexia. Taken together, the results suggest that both TNF-α and IL-1β play contributory role in anorexia induction following oral exposure to DON.

  15. Angiotensin Ⅱ type Ⅰ receptor agonistic autoantibody-induced apoptosis in neonatal rat cardiomyocytes is dependent on the generation of tumor necrosis factor-α

    Institute of Scientific and Technical Information of China (English)

    Weiran Chai; Wenhui Zhang; Zhu Jin; Yiping Feng; Yanping Kuang; Jianming Zhi

    2012-01-01

    Angiotensin Ⅱ type Ⅰ receptor agonistic autoantibodies (AT1-AA) are related to pre-eclampsia and hypertension and have a direct effect of stimulating the production of tumor necrosis factor-alpha (TNF-α) in the placenta.TNF-α is a known mediator of apoptosis.However,few studies have reported the role of TNF-α and its relationship within AT1-AA-induced apoptosis of cardiomyocytes.In this study,neonatal rat cardiomyocytes were treated with various concentrations of AT1-AA.The apoptosis of neonatal rat cardiomyocytes was determined using TUNEL assay and flow cytometry.The level of secreted TNF-α was measured by enzyme-linked immunosorbent assay,and caspase-3 activity was measured by a fluorogenic protease assay kit.AT1 receptor blockade and TNF inhibitor were added to determine whether they could inhibit the apoptotic effect of AT1-AA.Results showed that AT1-AA induced the apoptosis of neonatal rat cardiomyocytes in a dose-dependent and time-dependent manner.AT1-AA increased TNF secretion and caspase-3activities.AT1 receptor blockade completely abrogated AT1-AA-induced TNF-α secretion,caspase-3 activation,and cardiomyocyte apoptosis.TNF-α receptor inhibitor significantly attenuated AT1-AA-induced neonatal rat cardiomyocyte apoptosis.AT1-AA in the plasma of preeclamptic patients promoted neonatal rat cardiomyocyte apoptosis through a TNF-caspase signaling pathway.

  16. Identification and characterization of a membrane-bound cytotoxin of murine cytolytic lymphocytes that is related to tumor necrosis factor/cachectin

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chauching; Detmers, P.A.; Jiang, Shibo; Young, J.D.E (Rockefeller Univ., New York, NY (USA))

    1989-05-01

    Cytotoxic T lymphocytes (CTLs) kill their targets by a contact-dependent mechanism. The authors investigated the possibility that the CTL membranes themselves could exert direct cytotoxic activity. Murine CTLs that had been fixed with paraformaldehyde retained a slow cytotoxic activity toward various target cells that are also sensitive to another cytokine, tumor necrosis factor (TNF)/cachectin. This cytotoxic activity was neutralized by antibodies specific for TNF. Membrane fractions obtained from CTLs were cytotoxic to TNF-sensitive targets but not to several TNF-resistant cell lines. Immunoblot analysis revealed a membrane protein band of 50-60 kDa from CTLs that reacts with anti-TNF antibodies. The surface localization of this cytokine was further ascertained by flow cytometry, indirect immunofluorescence, and immunoelectron microscopy studies using TNF-specific antibodies. Radioiodination of CTL surface proteins followed by immunoprecipitation with anti-TNF antibodies confirmed the presence of a TNF-related cytokine in the plasma membranes of CTLs that migrated with an apparent molecular mass of 50-60 kDa under disulfide-reducing conditions. This cytokine can be removed from membranes by treatment with detergents but not with high-salt buffers, suggesting that it may be an integral membrane protein.

  17. A pathogenic trace of Tannerella forsythia - shedding of soluble fully active tumor necrosis factor α from the macrophage surface by karilysin.

    Science.gov (United States)

    Bryzek, D; Ksiazek, M; Bielecka, E; Karim, A Y; Potempa, B; Staniec, D; Koziel, J; Potempa, J

    2014-12-01

    Tannerella forsythia is implicated as a pathogen causing chronic and aggressive periodontitis. However, its virulence factors, including numerous putative proteases, are mostly uncharacterized. Karilysin is a newly described matrix metalloprotease-like enzyme of T. forsythia. Since pathogen-derived proteases may affect the host defense system via modulation of the cytokine network, the aim of this study was to determine the influence of karilysin on tumor necrosis factor-α (TNF-α). The results showed that karilysin cleaved the membrane form of TNF-α on the surface of macrophages, and that this led to an increased concentration of soluble TNF-α in the conditioned medium. Importantly, despite partial degradation of soluble TNF-α by karilysin, the released cytokine retained its biological activity, inducing apoptosis and stimulating autocrine pathway of pro-inflammatory gene expression. Notably, the observed effect required proteolytic activity by karilysin, since a catalytically inactive mutant of the enzyme did not affect TNF-α secretion. The shedding was independent of the activity of ADAM17, a major endogenous TNF-α converting enzyme. Karilysin-dependent TNF-α release from the cell surface is likely to occur in vivo because human plasma, the main constituent of gingival crevicular fluid, only slightly affected the sheddase activity of karilysin. Taken together, these results indicate that karilysin modulates the host immune response through regulation of TNF-α secretion, and should therefore be considered as a new virulence factor of T. forsythia.

  18. Partial liquid ventilation decreases tissue and serum tumor necrosis factor-α concentrations in acute lung injury model of immature piglet induced by oleic acid

    Institute of Scientific and Technical Information of China (English)

    ZHU Yao-bin; FAN Xiang-ming; LI Xiao-feng; LI Zhi-qiang; WANG Qiang; SUN Li-zhong; LIU Ying-long

    2012-01-01

    Background Pediatric patients are susceptible to lung injury.Acute lung injury in children often results in high mortality.Partial liquid ventilation (PLV) has been shown to markedly improve oxygenation and reduce histologic evidence of injury in a number of lung injury models.This study was designed to examine the hypothesis that PLV would attenuate the production of local and systemic tumor necrosis factor (TNF)-α in an immature piglet model of acute lung injury induced by oleic acid (OA).Methods Twelve Chinese immature piglets were induced acute lung injury by OA.The animals were randomly assigned to two groups of six animals,(1) conventional mechanical ventilation (MV) group and (2) PLV with 10 ml/kg FC-77 group.Results Compared with MV group,the PLV group had better cardiopulmonary variables (P <0.05).These variables included heart rate,mean blood pressure,blood pH,partial pressure of arterial oxygen (PaO2),PaO2/inspired O2 fraction (FiO2) and partial pressure of arterial carbon dioxide (PaCO2).PLV reduced TNF-α levels both in plasma and tissue compared with MV group (P <0.05).Conclusion PLV provides protective effects against TNF-a response in OA-induced acute lung injury in immature piglets.

  19. A case of coexisting Warthin tumor and langerhans cell histiocytosis associated with necrosis, eosinophilic abscesses and a granulomatous reaction in intraparotid lymph nodes

    Directory of Open Access Journals (Sweden)

    Fredrik Petersson

    2011-04-01

    Full Text Available We present a patient (50-year-old male with coexisting Warthin tumor and involvement of two intraparotid lymph nodes by Langerhans cell histiocytosis associated with necrosis, eosinophilic abscesses and a granulomatous reaction. This is the second documented case of this unusual combination of histological changes in nodal Langerhans cell histiocytosis and the first case involving intraparotid lymph nodes occurring together with an ipsilateral Warthin tumor.

  20. RXFP1 is targeted by complement C1q Tumor Necrosis Factor-related factor 8 (CTRP8 in brain cancer

    Directory of Open Access Journals (Sweden)

    Thatchawan eThanasupawat

    2015-08-01

    Full Text Available The relaxin-like - RXFP1 ligand-receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/ Tumor Necrosis Factor-related protein (CTRP family, as a novel ligand of the relaxin receptor RXFP1 with functions in brain cancer. Here we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma.

  1. Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.

    Science.gov (United States)

    Molinsky, Jan; Klanova, Magdalena; Koc, Michal; Beranova, Lenka; Andera, Ladislav; Ludvikova, Zdenka; Bohmova, Martina; Gasova, Zdenka; Strnad, Miroslav; Ivanek, Robert; Trneny, Marek; Necas, Emanuel; Zivny, Jan; Klener, Pavel

    2013-02-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.

  2. 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.

  3. CIDE-3 interacts with lipopolysaccharide-induced tumor necrosis factor, and overexpression increases apoptosis in hepatocellular carcinoma.

    Science.gov (United States)

    Min, Jie; Zhang, Wei; Gu, Yu; Hong, Liu; Yao, Li; Li, Fanfan; Zhao, Daqing; Feng, Yingming; Zhang, Helong; Li, Qing

    2011-12-01

    Cell death-inducing DFF45-like effector-3 (CIDE-3) is a novel member of an apoptosis-inducing protein family, but its function is unknown. CIDE-3 shows a different distribution pattern in hepatocellular carcinoma (HCC) tissues and normal adjacent tissues. Therefore, this work tested the hypothesis that CIDE-3 induces apoptosis in HCC cells, inhibiting oncogenesis and tumor development. We used immunohistochemistry to evaluate the expression of CIDE-3 in 82 HCC samples and 51 adjacent liver tissues. Overexpression of CIDE-3 induced apoptosis, as detected by flow cytometry, in the HCC cell line SMMC-7721, which had undetectable levels of CIDE-3 in the absence of CIDE-3 overexpression. A yeast two-hybrid system was employed to screen for proteins that interact with CIDE-3. The expression of CIDE-3 was decreased in HCC tissue, compared to adjacent normal tissues, and CIDE-3 expression and HCC differentiation were positively correlated. CIDE-3 expression levels were lower in poorly differentiated HCC tissue than in well-differentiated HCC tissue. Overexpressed CIDE-3 inhibited proliferation and induced apoptosis in HCC cells. We found that lipopolysaccharide-induced tumor necrosis factor (LITAF) interacted with CIDE-3 in hepatic cells. This is the first demonstrated interaction between CIDE-3 and LITAF, and the first report that CIDE-3 induces apoptosis in hepatocellular carcinoma.

  4. Tumor Necrosis Factor-related Apoptosis Ligand Induces Apoptosis in Prostate Cancer PC-3M Cell Line

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhohui; WANG Huafang; GU Longjie; YE Zhewei; XIAO Yajun

    2005-01-01

    To study the effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)on PC-3M cell line, PC-3M cell line was incubated with gradient concentrations of TRAIL for 4-24h. Annixin-Ⅴ fluorescence staining and TUNEL method were employed to detect the apoptosis of PC-3M cells. The morphology of apoptotic PC-3M cells was observed by electron microscopy. The relationship between TRAIL concentrations and the percentage of apoptotic cells was evaluated by flow cytometry. The proliferation inhibitory ratio was calculated by using MTT colorimetry. Our results showed that apoptosis of PC-3M cells could be induced by treatment with TRAIL for at most 4 h. The results of flow cytometry and MTT colorimetry demonstrated a time- and concentration-dependent relationship between cell apoptosis rate and TRAIL concentration. It is concluded that apoptosis of PC-3M cells can be induced by TRAIL. Because of the selective killing effect of TRAIL on tumor ceils, it may become a potential alternative for the treatment of advanced prostate cancer.

  5. 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.

  6. Evaluation of exome sequencing to estimate tumor burden in plasma.

    Science.gov (United States)

    Klevebring, Daniel; Neiman, Mårten; Sundling, Simon; Eriksson, Louise; Darai Ramqvist, Eva; Celebioglu, Fuat; Czene, Kamila; Hall, Per; Egevad, Lars; Grönberg, Henrik; Lindberg, Johan

    2014-01-01

    Accurate estimation of systemic tumor load from the blood of cancer patients has enormous potential. One avenue is to measure the presence of cell-free circulating tumor DNA in plasma. Various approaches have been investigated, predominantly covering hotspot mutations or customized, patient-specific assays. Therefore, we investigated the utility of using exome sequencing to monitor circulating tumor DNA levels through the detection of single nucleotide variants in plasma. Two technologies, claiming to offer efficient library preparation from nanogram levels of DNA, were evaluated. This allowed us to estimate the proportion of starting molecules measurable by sequence capture (libraries with a varying size distribution. On average, this improved sequence coverage by 38% in comparison to standard tools. By exploiting the redundant information in PCR-duplicates the background noise was reduced to ∼1/35,000. By applying our optimized analysis pipeline to a simulation analysis, we determined the current sensitivity limit to ∼1/2400, starting with 30 ng of cell-free DNA. Subsequently, circulating tumor DNA levels were assessed in seven breast- and one prostate cancer patient. One patient carried detectable levels of circulating tumor DNA, as verified by break-point specific PCR. These results demonstrate exome sequencing on cell-free DNA to be a powerful tool for disease monitoring of metastatic cancers. To enable a broad implementation in the diagnostic settings, the efficiency limitations of sequence capture and the inherent noise levels of the Illumina sequencing technology must be further improved.

  7. 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

  8. Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis : The RAMSES Study

    NARCIS (Netherlands)

    Reinhart, K; Menges, T; Gardlund, B; Zwaveling, JH; Smithes, M; Vincent, JL; Tellado, JM; Salgado-Remigio, A; Zimlichman, R; Withington, S; Tschaikowsky, K; Brase, R; Damas, P; Kupper, H; Kempeni, J; Eiselstein, J; Kaul, M

    Objective: This study investigated whether treatment with the anti-tumor necrosis factor-or monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/ml, Design: Multicenter, double-blind, randomized, placebo-controlled study.

  9. Value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin during hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan

    NARCIS (Netherlands)

    van Ginkel, RJ; Limburg, PC; Piers, DA; Hoekstra, HJ; Schraffordt Koops, H.

    Background: The aim of this study was to analyze the value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin (RISA) in patients treated with hyperthermic isolated limb perfusion with tumor necrosis factor-alpha (TNFalpha) and melphalan. Methods: Forty-eight

  10. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

    DEFF Research Database (Denmark)

    Hollegaard, Mads Vilhelm; Grove, Jakob; Thorsen, Poul

    2008-01-01

    OBJECTIVE: To investigate the relation between 19 selected single nucleotide polymorphisms in three cytokine genes, tumor necrosis factor alpha (TNFA), interleukin 1-beta (IL1B) and interleukin 6 (IL6) and preterm birth (<37 weeks' gestation). DESIGN: Case-control association study. SAMPLE: A tot...

  11. Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity

    NARCIS (Netherlands)

    Herwaarden, N. van; Broeder, A.A. den; Jacobs, W.; Maas, A. van der; Bijlsma, J.W.J.; Vollenhoven, R.F. van; Bemt, B.J.F van den

    2014-01-01

    BACKGROUND: Anti-tumor necrosis factor (TNF) agents are effective in treating patients with rheumatoid arthritis (RA), but they are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared wit

  12. 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 Hjelm; Lambertsen, Kate Lykke; Babcock, Alicia

    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...

  13. Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression.

    NARCIS (Netherlands)

    Netea, M.G.; Radstake, T.R.D.J.; Joosten, L.A.B.; Meer, J.W.M. van der; Barrera Rico, P.; Kullberg, B.J.

    2003-01-01

    OBJECTIVE: Patients treated with antibodies to tumor necrosis factor alpha (TNFalpha) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti-TNF treatment. The aim of this study was to identi

  14. ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production and protects mice from lethal endotoxic shock

    NARCIS (Netherlands)

    Tumurkhuu, Gantsetseg; Koide, Naoki; Hiwasa, Takaki; Ookoshi, Motohiro; Dagvadorj, Jargalsaikhan; Noman, Abu Shadat Mohammod; Iftakhar-E-Khuda, Imtiaz; Naiki, Yoshikazu; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

    2011-01-01

    ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production in RAW 264.7 macrophage-like cells wa

  15. Tumor necrosis factor- α infliximab inhibits osteoclast formation of peripheral blood mononuclear cells but does not affect periodontal ligament fibroblast-mediated osteoclast formation

    NARCIS (Netherlands)

    de Vries, T.J.; Yousovich, J.; Schoenmaker, T.; Scheres, N.; Everts, V.

    2016-01-01

    Background and Objective: The inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is elevated in inflamed periodontal tissues and may contribute to periodontitis progression. TNF-α stimulates formation and activity of osteoclasts, the cells that are recruited in periodontitis, that cause alveo

  16. Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation

    NARCIS (Netherlands)

    Huang, Song; Dudez, Tecla; Scerri, Isabelle; Thomas, Marc A; Giepmans, Ben N G; Suter, Susanne; Chanson, Marc

    2003-01-01

    Tumor necrosis factor-alpha (TNF-alpha) signaling is central to the transmission of the innate immune response and subsequent activation of the adaptive immune system. The functioning of both systems is required for optimal clearance of pathogens from the airways. In cystic fibrosis (CF),

  17. Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis : The RAMSES Study

    NARCIS (Netherlands)

    Reinhart, K; Menges, T; Gardlund, B; Zwaveling, JH; Smithes, M; Vincent, JL; Tellado, JM; Salgado-Remigio, A; Zimlichman, R; Withington, S; Tschaikowsky, K; Brase, R; Damas, P; Kupper, H; Kempeni, J; Eiselstein, J; Kaul, M

    2001-01-01

    Objective: This study investigated whether treatment with the anti-tumor necrosis factor-or monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/ml, Design: Multicenter, double-blind, randomized, placebo-controlled study. S

  18. Inhibiting interleukin-1 and tumor necrosis factor-α does not reduce induction of plasminogen activator inhibitor type-1 by endotoxin in rats in vivo

    NARCIS (Netherlands)

    Emeis, J.E.; Hoekzema, R.; Vos, A.F. de

    1995-01-01

    In experimental animals and humans, intravenous (IV) injection of endotoxin induces large increases in circulating plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of blood fibrinolysis. A similar increase is seen after the injection of interleukin-1 (IL-1) or of tumor necrosis

  19. 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.

    2007-01-01

    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, medi

  20. Ultrasound Evaluation of the Entheses in Daily Clinical Practice during Tumor Necrosis Factor-alpha Blocking Therapy in Patients with Ankylosing Spondylitis

    NARCIS (Netherlands)

    Wink, Freke; Bruyn, George A.; Maas, Fiona; Griep, Ed N.; van der Veer, Eveline; Bootsma, Hendrika; Brouwer, Elisabeth; Arends, Suzanne; Spoorenberg, Anneke

    Objective. To assess structural and inflammatory ultrasound (US) lesions of entheses in ankylosing spondylitis (AS) patients with active disease and to evaluate inflammatory lesions after 6 months of tumor necrosis factor (TNF-alpha) blocking therapy, in daily clinical practice. Methods. Consecutive

  1. Pretreatment with high-fat enteral nutrition reduces ondotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock

    NARCIS (Netherlands)

    Luyer, M.D.; Buurman, W.A.; Hadfoune, M.; Jacobs, J.A.; Konstantinov, S.R.; Dejong, C.H.; Greve, J.W.

    2004-01-01

    Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model

  2. Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation

    NARCIS (Netherlands)

    Huang, Song; Dudez, Tecla; Scerri, Isabelle; Thomas, Marc A; Giepmans, Ben N G; Suter, Susanne; Chanson, Marc

    2003-01-01

    Tumor necrosis factor-alpha (TNF-alpha) signaling is central to the transmission of the innate immune response and subsequent activation of the adaptive immune system. The functioning of both systems is required for optimal clearance of pathogens from the airways. In cystic fibrosis (CF), dysfunctio

  3. Tumor necrosis factor primes neutrophils to kill Staphylococcus aureus by an oxygen-dependent mechanism and Plasmodium falciparum by an oxygen-independent mechanism.

    Science.gov (United States)

    Kowanko, I C; Ferrante, A; Clemente, G; Kumaratilake, L M

    1996-08-01

    The cytokine tumor necrosis factor (TNF) plays the important role of priming neutrophils for increased antimicrobial activity. We now demonstrate that human neutrophils which lack the ability to generate oxygen radicals, from patients with chronic granulomatous disease, show TNF-induced enhancement of killing of intraerythrocytic stages of Plasmodium falciparum but not of Staphylococcus aureus.

  4. Tumor necrosis factor primes neutrophils to kill Staphylococcus aureus by an oxygen-dependent mechanism and Plasmodium falciparum by an oxygen-independent mechanism.

    OpenAIRE

    Kowanko, I C; Ferrante, A.; Clemente, G.; Kumaratilake, L M

    1996-01-01

    The cytokine tumor necrosis factor (TNF) plays the important role of priming neutrophils for increased antimicrobial activity. We now demonstrate that human neutrophils which lack the ability to generate oxygen radicals, from patients with chronic granulomatous disease, show TNF-induced enhancement of killing of intraerythrocytic stages of Plasmodium falciparum but not of Staphylococcus aureus.

  5. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stimulates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins

    Science.gov (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  6. Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling.

    Science.gov (United States)

    Insulin resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF-a) and hepatic overproduction of very low density lipoproteins (VLDL). In the present study, we examined the potential mechanistic link between TNF-a and hepatic overproduction of ap...

  7. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stumlates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins

    Science.gov (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  8. The influence of tumor necrosis factor-alpha and interleukin-10 gene promoter polymorphism on the inflammatory response in experimental human endotoxemia

    NARCIS (Netherlands)

    Fijen, J W; Tulleken, J E; Hepkema, B G; van der Werf, T S; Ligtenberg, J J; Zijlstra, J G

    2001-01-01

    In this study, we show that there is no correlation between tumor necrosis factor-alpha gene promoter polymorphism at position -308, interleukin-10 gene promoter polymorphism at position -1082, and the cytokine levels they produce in the human endotoxemia model.

  9. Inhibiting interleukin-1 and tumor necrosis factor-α does not reduce induction of plasminogen activator inhibitor type-1 by endotoxin in rats in vivo

    NARCIS (Netherlands)

    Emeis, J.E.; Hoekzema, R.; Vos, A.F. de

    1995-01-01

    In experimental animals and humans, intravenous (IV) injection of endotoxin induces large increases in circulating plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of blood fibrinolysis. A similar increase is seen after the injection of interleukin-1 (IL-1) or of tumor necrosis fact

  10. Pretreatment with high-fat enteral nutrition reduces ondotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock

    NARCIS (Netherlands)

    Luyer, M.D.; Buurman, W.A.; Hadfoune, M.; Jacobs, J.A.; Konstantinov, S.R.; Dejong, C.H.; Greve, J.W.

    2004-01-01

    Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model

  11. 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....

  12. Granulomatous salmonella osteomyelitis associated with anti-tumor necrosis factor therapy in a non-sickle cell patient: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Gould, Elaine S.; Gilet, Anthony G. [State University of New York at Stony Brook, Department of Radiology, Stony Brook, NY (United States); Vigorita, Vincent J. [SUNY Health Sciences Center Brooklyn, Department of Pathology and Orthopedics, Brooklyn, NY (United States)

    2010-08-15

    Salmonella osteomyelitis is seen most commonly in patients with sickle cell disease and in those with compromised immune systems. We report on the clinical, histological and imaging findings of salmonella osteomyelitis with intraosseous abscess formation occurring in a non-sickle cell patient receiving anti-tumor necrosis factor (TNF) alpha therapy. (orig.)

  13. Implication of snail in metabolic stress-induced necrosis.

    Directory of Open Access Journals (Sweden)

    Cho Hee Kim

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings demonstrate that Snail is implicated in metabolic stress-induced necrosis, providing a new function for Snail in tumor progression.

  14. Antioxidants and tumor necrosis factor alpha-inhibiting activity of sesame oil against doxorubicin-induced cardiotoxicity.

    Science.gov (United States)

    Saleem, Mohamed T S; Chetty, Madhusudhana C; Kavimani, S

    2014-02-01

    Oxidative stress is currently considered to be the key factor in doxorubicin-induced cardiotoxicity. Comparatively small quantity of the endogenous antioxidant content of the heart is assumed to be the predisposing factor for doxorubicin-induced cardiotoxicity. The present research was designed to evaluate the antioxidant potential and tumor necrosis factor alpha-(TNF-α) inhibiting activity of sesame oil against acute doxorubicin-induced cardiotoxicity. Male Wistar albino rats (180-200 g) were administered sesame oil in two dissimilar doses (5 and 10 ml/kg body weight, orally) for 30 days, followed by a single dose of doxorubicin (30 mg/kg s.c.). In the doxorubicin-treated group, increased oxidative stress was proven by a significant rise of thiobarbituric acid reactive substances level and a decrease of myocardial superoxide dismutase, catalase and reduced glutathione content. Histopathological studies showed myocardial necrosis with accumulation of inflammatory cells, vacuolization and overall enlargement of the myocardium. Western blot analysis showed marked expression of TNF-α in the myocardium. Alteration in biochemical parameters by doxorubicin administration was prevented significantly (p sesame oil treated rat hearts. Treatment with 5 and 10 ml/kg of sesame oil reduced the doxorubicin-induced TNF-α expression in the myocardium, which was associated with reduced myocyte injury. The overall effect of sesame oil was comparable with probucol, which shows similar protection. The chronic oral administration of sesame oil prevents acute doxorubicin-induced cardiotoxicity by enhancing cardiac endogenous antioxidants and decreasing myocardial TNF-α expression.

  15. Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

    Institute of Scientific and Technical Information of China (English)

    Lynnette R Ferguson; Claudia Huebner; Ivonne Petermann; Richard B Gearry; Murray L Barclay; Pieter Demmers; Alan McCulloch; Dug Yeo Han

    2008-01-01

    AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies.METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor:-238 G→A, -308 G→A and -857C→T, using a TaqmanRassay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies.RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, x2 = 17.36, P < 0.0001)increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, x2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variantdecreased the risk of ileocolonic CD (OR = 0.56, x2 =4.32, P = 0.037), and the need for a bowel resection(OR = 0.59, x2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis,(OR = 0.48, x2 = 4.86, P = 0.028).CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The-857 C/T SNP may decrease IBD risk in certain groups.Pharmaco- or nutrigenomic approaches may be desir-able for individuals with such affected genotypes.

  16. The effects of high fat, low carbohydrate and low fat, high carbohydrate diets on tumor necrosis factor superfamily proteins and proinflammatory cytokines in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Mahshid Sirjani

    2014-08-01

    Full Text Available There has been considerable inconsistency regarding the potential relationship between dyslipidemia and bone metabolism. The inflammatory stimulation through the receptor activator of the nuclear factor kappa-B ligand (RANKL/ receptor activator of the nuclear factor kappa-B (RANK/ osteoprotegerin (OPG pathway could be the infrastructural mechanism for hypercholesterolemia-induced bone loss.In this study, we investigated the effect of dyslipidemia on RANKL and OPG alongside with pro-inflammatory cytokines. Thirty male C57Bl/6 mice (4 weeks old were randomized to two purified diet groups (15 animals in each group, high fat, low carbohydrate diet (HFLCD and its matched low fat, high carbohydrate diet (LFHCD. After 12 weeks of feeding in standard situations, the plasma concentration of lipid profile, interleukin (IL 1Beta, IL-6, tumor necrosis factor-alpha (TNF-α and RANKL, OPG, and RANKL: OPG ratio were measured.In the present study, although the body weight significantly increased during 12 weeks in HFLCD and LFHCD groups, there were no significant differences in food intake, food efficiency ratio and weight gain between the two groups. The LFHCD group had significantly higher median RANKL and RANKL/OPG ratio. There was no significant difference in plasma IL-1β, IL-6 and TNF-α concentration between LFHCD and HFLCD groups.These unexpected findings from LFHCD, that seem to be as a result of its higher carbohydrate proportion in comparison to HFLCD, implicate dietary carbohydrate rather than dietary fat as a more significant nutritional factor contributing to change in RANKL level and RANKL: OPG ratio.

  17. 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

  18. Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats.

    Science.gov (United States)

    Altintas, Nejat; Erboga, Mustafa; Aktas, Cevat; Bilir, Bulent; Aydin, Murat; Sengul, Aysun; Ates, Zehra; Topcu, Birol; Gurel, Ahmet

    2016-02-01

    We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate

  19. Mutation analysis of tumor necrosis factor alpha-induced protein 3 gene in Hodgkin lymphoma.

    Science.gov (United States)

    Etzel, Barbara-Magdalena; Gerth, Melanie; Chen, Yuan; Wünsche, Elisa; Facklam, Tina; Beck, James F; Guntinas-Lichius, Orlando; Petersen, Iver

    2017-03-01

    Survival and proliferation of Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (CHL), are dependent on constitutive activation of nuclear factor kB (NF-κB). A20, encoded by TNF alpha-induced protein 3 (TNFAIP3), one of the inhibitors of NF-kB, was found to be inactivated by deletions and/or point mutations in CHL. TNFAIP3 mutations were examined in 37 patients with CHL by using PCR and direct sequencing. In addition, protein expression of A20 was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) status of HL samples was determined by EBV EBER chromogenic in situ hybridization (ISH). We identified 8 mutation positive cases in a collective of 37 investigated cases (22%). Mutations were most frequent in the nodular sclerosis subtype. Our results revealed the tendency that cases harboring A20 mutations were negative for A20 staining. None of A20 mutation-positive CHL cases showed EBV infection. Our study confirms the involvement of the TNFAIP3 tumor suppressor gene in CHL. A20 may represent a suppressor of human lymphoma and provide a critical molecular link between chronic inflammation and cancer. None of A20 mutation-positive CHL cases showed EBV infection. This fact suggests complementing functions of TNFAIP3 inactivation and EBV infection in CHL pathogenesis and may represent an interesting point of further investigations. Copyright © 2016 Elsevier GmbH. All rights reserved.

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

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    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.

  1. Soluble tumor necrosis factor receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy.

    Science.gov (United States)

    Shiraishi, Masahiro; Ichiyama, Takashi; Matsushige, Takeshi; Iwaki, Takuma; Iyoda, Kuniaki; Fukuda, Ken; Makata, Haruyuki; Matsubara, Tomoyo; Furukawa, Susumu

    2008-05-30

    Enterohemorrhagic Escherichia coli (EHEC) induces hemorrhagic colitis and hemolytic uremic syndrome (HUS). Morbidity and mortality are increased in HUS patients with neurologic complications. To determine the pathogenesis of the central nervous system (CNS) involvement in HUS by EHEC, we determined the serum concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), IL-10, interferon-gamma (IFN-gamma), IL-2, IL-4, soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) during the acute stage in children with HUS with or without CNS involvement. Serum concentrations of IL-6, IL-10, sTNFR1, sE-selectin, MMP-9, and TIMP-1, but not TNF-alpha, IFN-gamma, IL-2, or IL-4, were significantly higher in patients with HUS with encephalopathy compared with controls. Serum IL-6, sTNFR1 and TIMP-1 concentrations were significantly higher in patients with HUS with encephalopathy compared with those with HUS without encephalopathy (P=0.031, P=0.005, and P=0.007, respectively) and those with acute colitis without HUS (P=0.011, Pencephalopathy. Our preliminary study suggests that serum IL-6, sTNFR1 and TIMP-1 levels, particularly sTNFR1 and TIMP-1, are important for predicting neurological complications in patients with HUS.

  2. Effect of tumor necrosis factor-alpha in rats with hepatic ischemia-reper fusion injur y

    Institute of Scientific and Technical Information of China (English)

    Mao Ma; Zhen-Hua Ma

    2008-01-01

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

  3. Hydrogen sulfide attenuated tumor necrosis factor-α-induced inflammatory signaling and dysfunction in vascular endothelial cells.

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    Li-Long Pan

    Full Text Available BACKGROUND: Hydrogen sulfide (H(2S, the third physiologically relevant gaseous molecule, is recognized increasingly as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the effects and mechanisms of sodium hydrosulfide (NaHS, a H(2S donor on tumor necrosis factor (TNF-α-induced human umbilical vein endothelial cells (HUVEC dysfunction. METHODOLOGY AND PRINCIPAL FINDINGS: Application of NaHS concentration-dependently suppressed TNF-α-induced mRNA and proteins expressions of intercellular adhesion molecule-1 (ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1, mRNA expression of P-selectin and E-selectin as well as U937 monocytes adhesion to HUVEC. Western blot analysis revealed that the expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1, was induced and coincident with the anti-inflammatory action of NaHS. Furthermore, TNF-α-induced NF-κB activation assessed by IκBα degradation and p65 phosphorylation and nuclear translocation and ROS production were diminished in cells subjected to treatment with NaHS. SIGNIFICANCE: H(2S can exert an anti-inflammatory effect in endothelial cells through a mechanism that involves the up-regulation of HO-1.

  4. Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer

    Science.gov (United States)

    Kuo, Yi-Zih; Fang, Wei-Yu; Huang, Cheng-Chih; Tsai, Sen-Tien; Wang, Yi-Ching; Yang, Chih-Li; Wu, Li-Wha

    2017-01-01

    Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer. PMID:28107185

  5. Clinical signs, symptoms and serum level of interleukin-6 and tumor necrosis factor in women with or without endometriosis

    Institute of Scientific and Technical Information of China (English)

    Wachyu Hadisaputra

    2013-01-01

    Objective: To evaluate clinical signs and symptoms and serum levels of interleukin-6 ( IL-6), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor (VEGF) as non-invasive methods to diagnose endometriosis. Methods: Eighty women scheduled to laparoscopy underwent blood sampling for measurement of IL-6, TNF-α, MMP-2, and VEGF. The diagnosis of endometriosis was established by laparoscopy using The American Fertility Society visual diagnosis. The presence or absence of endometriosis was correlated with clinical signs and symptoms and with serum levels of those substances. Results:The sensitivity and specificity to detect endometriosis of infertility (OR 134.3) were 78 % and 98%, dysmenorrhoea (OR 11.7) were 63 % and 88 %, and chronic pelvic pain (OR 13.0) were 28 % and 100 %. The presence of rectovaginal nodules had a sensitivity 25 % and specificity 100 %. (OR 11.3, 95 %). The sensitivity and specificity of biologic markers IL-6 (OR 2.5) were 68 % and 53%, and TNF-α (OR 28.1) were 68% and 60 %. Conclusions: History of infertility, dysmenorrhea, chronic pelvic pain, dyspareunia, cervical tenderness and rectovaginal nodule are clinical signs and symptoms suggesting endometriosis. IL-6 and TNF-α appears to be best serum markers for endometriosis.

  6. Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti-Tumor Necrosis Factor-α Antibody.

    Science.gov (United States)

    Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Verissimo, Vivianne L; Cervelli, Jessica A; Vayas, Kinal N; Hall, LeRoy; Laskin, Jeffrey D; Laskin, Debra L

    2015-11-01

    Nitrogen mustard (NM) is a bifunctional alkylating agent that causes acute injury to the lung that progresses to fibrosis. This is accompanied by a prominent infiltration of macrophages into the lung and upregulation of proinflammatory/profibrotic cytokines including tumor necrosis factor (TNF)α. In these studies, we analyzed the ability of anti-TNFα antibody to mitigate NM-induced lung injury, inflammation, and fibrosis. Treatment of rats with anti-TNFα antibody (15 mg/kg, iv, every 9 days) beginning 30 min after intratracheal administration of NM (0.125 mg/kg) reduced progressive histopathologic alterations in the lung including perivascular and peribronchial edema, macrophage/monocyte infiltration, interstitial thickening, bronchiolization of alveolar walls, fibrin deposition, emphysema, and fibrosis. NM-induced damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage (BAL) protein and cell content, was also reduced by anti-TNFα antibody, along with expression of the oxidative stress marker, heme oxygenase-1. Whereas the accumulation of proinflammatory/cytotoxic M1 macrophages in the lung in response to NM was suppressed by anti-TNFα antibody, anti-inflammatory/profibrotic M2 macrophages were increased or unchanged. Treatment of rats with anti-TNFα antibody also reduced NM-induced increases in expression of the profibrotic mediator, transforming growth factor-β. This was associated with a reduction in NM-induced collagen deposition in the lung. These data suggest that inhibiting TNFα may represent an efficacious approach to mitigating lung injury induced by mustards.

  7. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    Directory of Open Access Journals (Sweden)

    Kanami Orihara

    2008-10-01

    Full Text Available Kanami Orihara, Akio MatsudaDepartment of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, JapanAbstract: Chronic obstructive pulmonary disease (COPD and bronchial asthma are common respiratory diseases that are caused by chronic infl ammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma.Keywords: TNF-α, CXC chemokines, corticosteroid, pulmonary microvessels, COPD, asthma

  8. Molecular characterization and functional analysis of tumor necrosis factor receptor-associated factor 2 in the Pacific oyster.

    Science.gov (United States)

    Huang, Baoyu; Zhang, Linlin; Du, Yishuai; Li, Li; Tang, Xueying; Zhang, Guofan

    2016-01-01

    Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of crucial adaptors, playing vital roles in mediating signal transduction in immune signaling pathways, including RIG-I-like receptor (RLR) signaling pathway. In the present study, a new TRAF family member (CgTRAF2) was identified in the Pacific oyster, Crassostrea gigas. Comparison and phylogenetic analysis revealed that CgTRAF2 could be a new member of the invertebrate TRAF2 family. Quantitative real-time PCR revealed that CgTRAF2 mRNA was highly expressed in the digestive gland, gills, and hemocytes, and it was significantly up-regulated after Vibrio alginolyticus and ostreid herpesvirus 1 (OsHV-1) challenge. The CgTRAF2 mRNA expression profile in different developmental stages of oyster larvae suggested that CgTRAF2 could function in early larval development. CgTRAF2 mRNA expression pattern, after the silence of CgMAVS (Mitochondrial Antiviral Signaling) -like, indicated that CgTRAF2 might function downstream of CgMAVS-like. Moreover, the subcellular localization analysis revealed that CgTRAF2 was localized in cytoplasm, and it may play predominately important roles in signal transduction. Collectively, these results demonstrated that CgTRAF2 might play important roles in the innate immunity and larval development of the Pacific oyster.

  9. Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae.

    Science.gov (United States)

    Mohler, J; Fantin, B; Mainardi, J L; Carbon, C

    1994-05-01

    The kinetics of tumor necrosis factor (TNF) levels in serum during therapy with cell wall-active agents (ceftriaxone, imipenem) and gentamicin were investigated in rabbits with experimental endocarditis caused by an isogenic pair of Klebsiella pneumoniae strains: a TEM-3 beta-lactamase-producing strain (KpR) or its susceptible variant (KpS). In vitro, KpR was resistant to ceftriaxone and was susceptible to gentamicin and imipenem, while KpS was susceptible to all three antibiotics. Serum TNF levels were determined in control rabbits hourly after bacterial inoculation and then daily; they were determined in treated animals hourly after the first antibiotic injection and then daily during a 4-day therapy with either imipenem (60 mg/kg of body weight four times daily), ceftriaxone (75 mg/kg once daily), or gentamicin (4 mg/kg once daily) alone or in combination with ceftriaxone. After a transient peak (10.2 +/- 3.1 ng/ml) at 90 min following bacterial challenge, serum TNF levels remained low and stable in control animals. The peak in the serum TNF levels occurred 4 h after the first antibiotic injection and with ceftriaxone was significantly higher (P ceftriaxone were significantly higher (P mechanism of action and the susceptibility of the strain at the early phase of therapy, without any effect of the rapidity of bacterial killing, and (ii) the final reduction of the bacterial count at a later stage of therapy.

  10. Efficacy of incentive spirometer exercise on pulmonary functions of patients with ankylosing spondylitis stabilized by tumor necrosis factor inhibitor therapy.

    Science.gov (United States)

    So, Min Wook; Heo, Hyun Mi; Koo, Bon San; Kim, Yong-Gil; Lee, Chang-Keun; Yoo, Bin

    2012-09-01

    To evaluate the effect of combining incentive spirometer exercise (ISE) with a conventional exercise (CE) on patients with ankylosing spondylitis (AS) stabilized by tumor necrosis factor (TNF) inhibitor therapy by comparing a combination group with a CE-alone group. Forty-six patients (44 men, 2 women) were randomized to the combination group (ISE plus CE; n=23) or the CE group (n=23). The CE regimen of both groups consisted of 20 exercises performed for 30 min once a day. The ISE was performed once a day for 30 min. The trial duration was 16 weeks. Patients were assessed before and at the end of treatment by measuring the Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (BASFI), chest expansion, finger to floor distance, pulmonary function measures, and 6-min walk distance. Both groups improved significantly in terms of chest expansion (pexercise program. However, only the combination group showed significant improvements in the forced vital capacity (p<0.05), total lung capacity (p<0.01), and vital capacity (p<0.05). Although this did not achieve statistical significance, the combination group was mildly superior to the CE-alone group in functional disability and pulmonary function measures. Combining ISE with a CE can provide positive results in patients whose AS has been clinically stabilized by TNF inhibitor therapy.

  11. Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report.

    Science.gov (United States)

    Radhakrishna, Suhas M; Grimm, Amy; Broderick, Lori

    2017-04-20

    Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is the second most common heritable autoinflammatory disease, typically presenting in pre-school aged children with fever episodes lasting 1-3 weeks. Systemic symptoms can include rash, myalgia, ocular inflammation, and serositis. Here we report an unusual presentation of TRAPS in a 7 month old girl who presented with only persistent fever. She was initially diagnosed with incomplete Kawasaki Disease and received IVIG and infliximab; however, her fevers quickly recurred. Subsequent testing revealed a urinary tract infection, but she did not improve despite appropriate therapy. As fever continued, she developed significant abdominal distension with imaging concerning for appendicitis, followed by hyperthermia and hemodynamic instability. Given her protracted clinical course and maternal history of a poorly defined inflammatory condition, an autoinflammatory disease was considered. Therapy with anakinra was initiated, resulting in rapid resolution of fever and normalization of inflammatory markers. She was found to have a previously unreported mutation, Thr90Pro, in the TNFRSF1A gene associated with TRAPS. This novel mutation was also confirmed in the patient's mother and maternal uncle. This report reviews a severe case of TRAPS in infancy associated with a novel mutation, Thr90Pro, in the TNFRSF1A gene, and emphasizes that autoinflammatory disease should be considered in the differential of infants with fever of unknown origin.

  12. Facile purification of Escherichia coli expressed tag-free recombinant human tumor necrosis factor alpha from supernatant.

    Science.gov (United States)

    Zhang, Chun; Liu, Yongdong; Zhao, Dawei; Li, Xiunan; Yu, Rong; Su, Zhiguo

    2014-03-01

    Fusing affinity tag at N-terminus was reported to decrease the biological activity of the recombinant human tumor necrosis factor alpha. Although preparation of tag-free rhTNF-α has already been achieved, the processes were yet laborious, especially in large scale. In this paper, tag-free rhTNF-α was almost equally synthesized by Escherichia coli in both soluble and insoluble forms. A two-step ion exchange chromatography, DEAE-Sepharose combined with CM-Sepharose, was developed to purify the soluble specie from supernatant after cell lysis. Native PAGE and HP-SEC showed the rhTNF-α extracted from supernatant existed in a homogeneous form. HP-SAX and SDS-PAGE analysis demonstrated the purity of the final fraction was over 98% with a very high recovery of 75%. Circular dichroism spectrum demonstrated that β-sheet structure was dominant and fluorescence analysis suggested no dramatic exposure of aromatic amino acid residues on the protein surface. Bioassay indicated that purified rhTNF-α was biologically active with a specific activity of approximately 2.0×10(7)U/mg. All these results suggested that this two-step ion exchange chromatography is efficient for preparation of biologically active tag-free rhTNF-α from supernatant.

  13. Modulation of tumor necrosis factor {alpha} expression in mouse brain after exposure to aluminum in drinking water

    Energy Technology Data Exchange (ETDEWEB)

    Tsunoda, M.; Sharma, R.P. [Georgia Univ., Athens (Greece). College of Veterinary Medicine

    1999-11-01

    Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor {alpha} (TNF{alpha}), interleukin-1{beta} (IL-1{beta}), and interferon {gamma} (IFN{gamma}), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNF{alpha} mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNF{alpha} mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNF{alpha} in this brain region. Because the aluminum-induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water. (orig.)

  14. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses.

    Science.gov (United States)

    Chen, Yuehong; Sun, Jianhong; Yang, Yuan; Huang, Yupeng; Liu, Gang

    2016-01-01

    The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.

  15. Tumor necrosis factor α sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine

    Directory of Open Access Journals (Sweden)

    Spicarova Diana

    2010-08-01

    Full Text Available Abstract Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor α (TNFα, is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNFα and its receptors (TNFR in dorsal root ganglion (DRG cells and in the spinal cord has been shown to play an important role in neuropathic and inflammatory pain conditions. Transient receptor potential vanilloid 1 (TRPV1 receptors are known as molecular integrators of nociceptive stimuli in the periphery, but their role on the spinal endings of nociceptive DRG neurons is unclear. The endogenous TRPV1 receptor agonist N-oleoyldopamine (OLDA was shown previously to activate spinal TRPV1 receptors. In our experiments the possible influence of TNFα on presynaptic spinal cord TRPV1 receptor function was investigated. Using the patch-clamp technique, miniature excitatory postsynaptic currents (mEPSCs were recorded in superficial dorsal horn neurons in acute slices after incubation with 60 nM TNFα. A population of dorsal horn neurons with capsaicin sensitive primary afferent input recorded after the TNFα pretreatment had a basal mEPSC frequency of 1.35 ± 0.20 Hz (n = 13, which was significantly higher when compared to a similar population of neurons in control slices (0.76 ± 0.08 Hz; n = 53; P

  16. Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling.

    Science.gov (United States)

    Eidson, Lori N; Inoue, Kiyoshi; Young, Larry J; Tansey, Malu G; Murphy, Anne Z

    2017-02-01

    Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4)-mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (solTNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1β and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively preserving the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid-induced immune signaling, tolerance, and addiction.

  17. The functional tumor necrosis factor-α (308A/G) polymorphism modulates attentional selection in elderly individuals.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2013-11-01

    There has been increasing interest in understanding the role of inflammatory processes for cognitive functions in aging using molecular genetic approaches. Though this has mostly been evaluated in pathological aging, little is known about the relevance for cognitive functions in healthy aging in humans. On the basis of behavioral data and neurophysiological data (event-related potentials and time-frequency decomposition) we show that the A-allele of the functional tumor necrosis factor (TNF)-α -308 A/G polymorphism confers dysfunction in a number of cognitive processes: prolonged attentional selection indexed by a delayed P1/N1 complex, an increased P3a, which is interpreted as an enhanced distractibility by nonrelevant stimuli and compromised response selection mechanisms, as indexed by a reduced frontocentral N2. Time-frequency analyses show that allelic variations further exert their effects by modulating alpha and beta frequency oscillations. On a neurobiological level, these effects might be because of the interaction of TNF-α with glutamatergic neural transmission by which TNF-α is known to boost apoptotic mechanisms in elderly individuals.

  18. Association between genetic variations in tumor necrosis factor receptor genes and survival of patients with T-cell lymphoma

    Institute of Scientific and Technical Information of China (English)

    Kan Zhai; Jiang Chang; Chen Wu; Ning Lu; Li-Ming Huang; Tong-Wen Zhang; Dian-Ke Yu; Wen Tan; Dong-Xin Lin

    2012-01-01

    The prognosis of T-cell lymphoma (TCL) has been shown to be associated with the clinical characteristics of patients.However,there is little knowledge of whether genetic variations also affect the prognosis of TCL.This study investigated the associations between single nucleotide polymorphisms (SNPs) in tumor necrosis factor receptor superfamily (TNFRSF) genes and the survival of patients with TCL.A total of 38tag SNPs in 18 TNFRSF genes were genotyped using Sequenom platform in 150 patients with TCL.Kaplan-Meier survival estimates were plotted and significance was assessed using log-rank tests.Cox proportional hazard models were used to analyze each of these 38 SNPs with adjustment for covariates that might influence patient survival,including sex and international prognostic Index score.Hazard ratios (HRs) and their 95% confidence intervals (Cls) were calculated.Among the 38 SNPs tested,3 were significantly associated with the survival of patients with TCL.These SNPs were located at LTβR (rs3759333C>T) and TNFRSF17 (rs2017662C >T and rs2071336C>T).The 5-year survival rates were significantly different among patients carrying different genotypes and the HRs for death between the different genotypes ranged from 0.45 to 2.46.These findings suggest that the SNPs in TNFRSF genes might be important determinants for the survival of TCL patients.

  19. Status epilepticus induces vasogenic edema via tumor necrosis factor-α/ endothelin-1-mediated two different pathways.

    Directory of Open Access Journals (Sweden)

    Ji-Eun Kim

    Full Text Available Status epilepticus (SE induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB. However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-α (TNF-α stimulated endothelin-1 (ET-1 release and expression in neurons and endothelial cells. In addition, TNF-α-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-α-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.

  20. Lactobacillus plantarum inhibits epithelial barrier dysfunction and interleukin-8 secretion induced by tumor necrosis factor-α

    Institute of Scientific and Technical Information of China (English)

    Jae Sung Ko; Hye Ran Yang; Ju Young Chang; Jeong Kee Seo

    2007-01-01

    AIM: To determine whether Lactobacillus plantarum can modify the deleterious effects of tumor necrosis factor-α(TNF-α) on intestinal epithelial cells.METHODS: Caco-2 cells were incubated with TNF-α alone or in the presence of L. plantarum. Transepithelial electrical resistance was used to measure epithelial barrier function. Interleukin 8 (IL-8) secretion by intestinal epithelial cells was measured using an ELISA.Cellular lysate proteins were immunoblotted using the anti-extracellular regulated kinase (ERK), anti-phospho-ERK and anti-IκB-α.RESULTS: A TNF-α-induced decrease in transepithelial electrical resistance was inhibited by L. plantarum. TNF-α-induced IL-8 secretion was reduced by L. plantarum.L. plantarum inhibited the activation of ERK and the degradation of IκB-α in TNF-α-treated Caco-2 cells.CONCLUSION: Induction of epithelial barrier dysfunction and IL-8 secretion by TNF-α is inhibited by L. plantarum.Probiotics may preserve epithelial barrier function and inhibit the inflammatory response by altering the signal transduction pathway.

  1. A Disaccharide that Inhibits Tumor Necrosis Factor α is Formed from the Extracellular Matrix by the Enzyme Heparanase

    Science.gov (United States)

    Lider, Ofer; Cahalon, Liora; Gilat, Dalia; Hershkoviz, Rami; Siegel, Daniel; Margalit, Raanan; Shoseyov, Oded; Cohen, Irun R.

    1995-05-01

    The activation of T cells by antigens or mitogens leads to the secretion of cytokines and enzymes that shape the inflammatory response. Among these molecular mediators of inflammation is a heparanase enzyme that degrades the heparan sulfate scaffold of the extracellular matrix (ECM). Activated T cells use heparanase to penetrate the ECM and gain access to the tissues. We now report that among the breakdown products of the ECM generated by heparanase is a trisulfated disaccharide that can inhibit delayed-type hypersensitivity (DTH) in mice. This inhibition of T-cell mediated inflammation in vivo was associated with an inhibitory effect of the disaccharide on the production of biologically active tumor necrosis factor α (TNF-α) by activated T cells in vitro; the trisulfated disaccharide did not affect T-cell viability or responsiveness generally. Both the in vivo and in vitro effects of the disaccharide manifested a bell-shaped dose-response curve. The inhibitory effects of the trisulfated disaccharide were lost if the sulfate groups were removed. Thus, the disaccharide, which may be a natural product of inflammation, can regulate the functional nature of the response by the T cell to activation. Such a feedback control mechanism could enable the T cell to assess the extent of tissue degradation and adjust its behavior accordingly.

  2. Tumor Necrosis Factor Type α , a Potent Inhibitor of Endothelial Cell Growth in vitro, is Angiogenic in vivo

    Science.gov (United States)

    Frater-Schroder, Marijke; Risau, Werner; Hallmann, Rupert; Gautschi, Peter; Bohlen, Peter

    1987-08-01

    Tumor necrosis factor type α (TNF-α ) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-α per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-α is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-α does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-α (10 μ g) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-α stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-α implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.

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

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

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

  4. The Role of Tumor Necrosis Factor-α Blockers in Psoriatic Disease. Therapeutic Options in Psoriatic Arthritis.

    Science.gov (United States)

    Addimanda, Olga; Possemato, Niccolò; Caruso, Andrea; Pipitone, Nicolò; Salvarani, Carlo

    2015-11-01

    Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting peripheral and axial joints, usually associated with psoriasis (PsO) and involving various systems and organs (eye inflammation, such as uveitis; and involvement of nail and enthesis), and it usually requires a multidisciplinary treatment approach. Tumor necrosis factor-α (TNF-α) is overexpressed in psoriatic synovium and skin plaques and its selective inhibition by anti-TNF-α agents has been demonstrated to reduce TNF-α levels in the articular environment, reversing the synovial hyperproliferative phenotype. Studies performed on anti-TNF-α agents in PsA demonstrated that they are able to reduce neutrophil and macrophage infiltration as well as vascular cell adhesion protein 1 expression with ensuing synovial thickness normalization. The efficacy of anti-TNF-α agents for all PsA manifestations (peripheral arthritis, axial involvement, enthesopathy, and skin disease) suggests that anti-TNF-α efficacy might be related to the ability to influence angiogenesis and osteoclastogenesis, reduce synovial inflammation, and slow radiological disease progression. This review describes the role of anti-TNF-α in each manifestation of PsA.

  5. Structural insights of homotypic interaction domains in the ligand-receptor signal transduction of tumor necrosis factor (TNF)

    Science.gov (United States)

    Park, Young-Hoon; Jeong, Mi Suk; Jang, Se Bok

    2016-01-01

    Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer. [BMB Reports 2016; 49(3): 159-166] PMID:26615973

  6. Ginsenoside Rg1 inhibits proliferation of vascular smooth muscle cells stimulated by tumor necrosis factor-α

    Institute of Scientific and Technical Information of China (English)

    Zeng-chun MA; Yue GAO; Yu-guang WANG; Hong-ling TAN; Cheng-rong XIAO; Sheng-qi WANG

    2006-01-01

    Aim: To investigate the proliferation of vascular smooth muscle cells (VSMC) affected by ginsenoside Rg1 and further explore the molecular mechanism of ginsenoside Rg1 using proteomics. Methods: The proliferation of VSMC was measured by MTS assay kit and flow cytometry. Proteomic alterations were analyzed using two-dimensional electrophoresis and peptide mass fingerprinting. Differential proteins found in proteomics were confirmed by RT-PCR. Results: The proliferation of VSMC was enhanced significantly after tumor necrosis factor-α (TNF-α) treatment, and ginsenoside Rg1 treatment inhibited proliferation in a dose-dependent manner. Proteomic analysis showed 24 protein spots were changed, including 17 spots that were increased and 7 spots that were decreased. Ginsenoside Rg1 could restore the expression levels of these proteins, at least partly, to basic levels of untreated cells. The expression of G-protein coupled receptor kinase, protein kinase C (PKC)-ζ, N-ras protein were decreased, while cycle related protein p21 was increased by ginsenoside Rg1 in TNF-α treated VSMC. Conclusion: PKC-ζ, and p21 pathway might be the mechanism for inhibitory effects of ginsenoside Rg1 on proliferation of VSMC.

  7. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    Directory of Open Access Journals (Sweden)

    Alessandra Costa

    2014-01-01

    Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

  8. Evaluation of salivary tumor necrosis factor-alpha in patients with the chronic periodontitis: A case-control study

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    Hojatollah Yousefimanesh

    2013-01-01

    Full Text Available Context: Periodontitis is a chronic infectious disease that leads to inflammation of the tissues supporting the teeth, bone loss, attachment loss progressively. In chronic periodontitis for starting the host response and inflammatory reaction, the presence of the infectious agent is necessary. Aims: One of inflammatory factors is tumor necrosis factor-alpha (TNF-α that appear to be important in the destruction of periodontal tissues that were examined in this study. Materials and Methods: This study was performed in the laboratory and case-control study. The samples of study collected from 30 individuals with chronic periodontitis and 30 healthy controls that matched for age and sex, together. Unstimulated saliva samples were collected from patients and then TNF-α level were measured by enzyme-linked immunosorbent assay and were compared with the control group. Statistical Analysis Used: In this study for statistical analysis, Mann-Whitney was used. Results: There were differences in mean salivary concentrations of TNF-α in controls and patients. The average concentration in the case group was 9.1 (pg/ml and the control group was 8.7 (pg/ml, but there was no significant difference between case and control groups (P > 0.05. Conclusions: The results of this analysis showed no significant relationship between two groups TNF-α concentration.This biomarker can not seem to be a good index to evaluate or predict periodontal disease.

  9. 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).

  10. Serum interleukin-1beta and tumor necrosis factor-alpha in febrile seizures: is there a link?

    Science.gov (United States)

    Mahyar, Abolfazl; Ayazi, Parviz; Orangpour, Reza; Daneshi-Kohan, Mohammad Mahdi; Sarokhani, Mohammad Reza; Javadi, Amir; Habibi, Morteza; Talebi-Bakhshayesh, Mousa

    2014-10-01

    Febrile seizures are induced by fever and are the most common type of seizures in children. Although numerous studies have been performed on febrile seizures, their pathophysiology remains unclear. Recent studies have shown that cytokines may play a role in the pathogenesis of febrile seizures. The present study was conducted to identify potential links between serum interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and febrile seizures. Ninety-two patients with simple or complex febrile seizures (46 patients per seizure type), and 46 controls with comparable age, sex, and severity of temperature were enrolled. The median concentrations of serum IL-1β in the simple, complex febrile seizure, and control groups were 0.05, 0.1, and 0.67 pg/mL, respectively (P=0.001). Moreover, the median concentrations of TNF-α in the simple, complex febrile seizure, and control groups were 2.5, 1, and 61.5 pg/mL, respectively (P=0.001). Furthermore, there were significant differences between the case groups in serum IL-1β and TNF-α levels (Pfebrile seizures.

  11. RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis.

    Science.gov (United States)

    Ramakrishnan, Vijay R; Gonzalez, Joseph R; Cooper, Sarah E; Barham, Henry P; Anderson, Catherine B; Larson, Eric D; Cool, Carlyne D; Diller, John D; Jones, Kenneth; Kinnamon, Sue C

    2017-09-01

    Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder in which many pathways contribute to end-organ disease. Small proline-rich proteins (SPRR) are polypeptides that have recently been shown to contribute to epithelial biomechanical properties relevant in T-helper type 2 inflammation. There is evidence that genetic polymorphism in SPRR genes may predict the development of asthma in children with atopy and, correlatively, that expression of SPRRs is increased under allergic conditions, which leads to epithelial barrier dysfunction in atopic disease. RNAs from uncinate tissue specimens from patients with CRS and control subjects were compared by RNA sequencing by using Ingenuity Pathway Analysis (n = 4 each), and quantitative polymerase chain reaction (PCR) (n = 15). A separate cohort of archived sinus tissue was examined by immunohistochemistry (n = 19). A statistically significant increase of SPRR expression in CRS sinus tissue was identified that was not a result of atopic presence. SPRR1 and SPRR2A expressions were markedly increased in patients with CRS (p < 0.01) on RNA sequencing, with confirmation by using real-time PCR. Immunohistochemistry of archived surgical samples demonstrated staining of SPRR proteins within squamous epithelium of both groups. Pathway analysis indicated tumor necrosis factor (TNF) alpha as a master regulator of the SPRR gene products. Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with CRS and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction.

  12. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus methotrexate.

    Science.gov (United States)

    Wu, Jashin J; Guérin, Annie; Sundaram, Murali; Dea, Katherine; Cloutier, Martin; Mulani, Parvez

    2017-01-01

    Psoriasis is associated with increased risk for cardiovascular disease. To compare major cardiovascular event risk in psoriasis patients receiving methotrexate or tumor necrosis factor-α inhibitor (TNFi) and to assess TNFi treatment duration impact on major cardiovascular event risk. Adult psoriasis patients with ≥2 TNFi or methotrexate prescriptions in the Truven MarketScan Databases (Q1 2000-Q3 2011) were classified as TNFi or methotrexate users. The index date for each of these drugs was the TNFi initiation date or a randomly selected methotrexate dispensing date, respectively. Cardiovascular event risks and cumulative TNFi effect were analyzed by using multivariate Cox proportional-hazards models. By 12 months, TNFi users (N = 9148) had fewer cardiovascular events than methotrexate users (N = 8581) (Kaplan-Meier rates: 1.45% vs 4.09%: P event hazards than methotrexate users (hazard ratio = 0.55; P event risk reduction (P = .02). Lack of clinical assessment measures. Psoriasis patients receiving TNFis had a lower major cardiovascular event risk compared to those receiving methotrexate. Cumulative exposure to TNFis was associated with a reduced risk for major cardiovascular events. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  13. Tumor necrosis factor-alpha allele 2 shows an association with insulin-dependent diabetes mellitus in Latvians.

    Science.gov (United States)

    Shtauvere-Brameus, A; Dabadghao, P; Rumba, I; Sanjeevi, C B

    2002-04-01

    Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA-DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF-alpha) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF-alpha production and susceptibility to autoimmune and infectious diseases. Ninety-two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age- and sex-matched healthy controls were analyzed for the frequency of TNF-alpha alleles to test the hypothesis that TNF-alpha is associated with IDDM. We found that TNF-alpha microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF-alpha allele 2 with IDDM showed that both are independently associated with the disease.

  14. Polymorphism and expression of the tumor necrosis factor receptor II gene in cows infected with the bovine leukemia virus.

    Science.gov (United States)

    Stachura, A; Brym, P; Bojarojć-Nosowicz, B; Kaczmarczyk, E

    2016-01-01

    A single T>C nucleotide polymorphism (rs42686850) of bovine tumor necrosis factor receptor type II gene (TNF-RII) is located within a sequence with allele-specific affinity to bind E2F transcription factors, considered pivotal in the regulation of cell cycle and cell proliferation. The objective of the study was to determine the effect of this SNP and BLV infection on the TNF-RII gene expression at the mRNA and protein levels in peripheral blood mononuclear cells (PBMC). We noted that analyzed TNF-RII gene polymorphism influenced the expression of the TNF-RII gene at the mRNA level but only in BLV-positive cows. Concurrently, no statistically significant association was found between gene polymorphism and TNF-RII expression at the protein level. However, we found a significant effect of BLV infection status on the amount of TNF-RII mRNA and the percentage of PBMC expressing TNF-RII. These results show an unclear effect of considered T>C polymorphism on TNF-RII gene expression in bovine leukocytes and they suggest the involvement of BLV in modifying the TNF-RII expression in BLV-infected cows potentially implying the EBL (Enzootic Bovine Leukosis) associated pathogenesis.

  15. Human gamma interferon and tumor necrosis factor exert a synergistic blockade on the replication of herpes simplex virus.

    Science.gov (United States)

    Feduchi, E; Alonso, M A; Carrasco, L

    1989-03-01

    The replication of herpes simplex virus type 1 (HSV-1) is not inhibited in either HeLa or HEp-2 cells treated with human alpha interferon (HuIFN-alpha), particularly when high multiplicities of infection are used. However, HuIFN-gamma partially inhibits HSV-1 translation in HEp-2 cells infected at low multiplicities. Under these conditions, the transcription of genes alpha 22, TK, and gamma 0 is greatly diminished. The combined addition of human tumor necrosis factor (TNF) and HuIFN-gamma to HEp-2 cells exerts a synergistic inhibition of HSV-1 translation. Cells treated with both cytokines continue synthesizing cellular proteins, even 20 h after HSV-1 infection. As little as 10 U of IFN-gamma per ml blocked HSV-1 DNA replication, provided that TNF was also present in the medium. Analyses of HSV-1 gene transcription suggest that the action of both TNF and IFN-gamma blocked a step that comes at or prior to early HSV-1 gene expression. This early step in HSV-1 replication inhibited by TNF and IFN-gamma occurs after virus attachment and entry into cells, since the internalization of radioactive HSV-1 virion particles was not blocked by the presence of the two cytokines. Therefore, we conclude that the synergistic action of TNF plus IFN-gamma affects a step in HSV-1 replication that comes after virus entry but before or at the transcription of immediate-early genes.

  16. Substance P induces tumor necrosis factor-alpha release from human skin via mitogen-activated protein kinase.

    Science.gov (United States)

    Okabe, T; Hide, M; Koro, O; Yamamoto, S

    2000-06-16

    Substance P plays an important role in neurogenic inflammation with granulocyte infiltration. To investigate cytokines involved in the substance P-induced inflammation and the mechanism of cell activation, we studied the release of TNF (tumor necrosis factor)-alpha and histamine from human skin slices in response to substance P and antigen. Substance P induced the release of histamine and TNF-alpha in a dose-dependent manner at concentrations from 0.8 to 100 microM. PD 098059 (2'-amino-3'-methoxyflavone) selectively inhibited the release of TNF-alpha, but not the release of histamine induced by either substance P or antigen. SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-++ +imida zole]) slightly inhibited TNF-alpha release induced by antigen, but not that induced by substance P, and slightly enhanced histamine release induced by either stimulation. The release of TNF-alpha in response to either stimulation was inhibited by 1 nM-1 microM dexamethasone, but histamine release was not affected. These results suggest that substance P, in addition to antigen, induced TNF-alpha release from human skin by a mitogen-activated protein (MAP) kinase, predominantly extracellular signaling-regulated protein kinase (ERK)-dependent, and dexamethasone-sensitive pathway, which is separate from that for histamine release from mast cells.

  17. Apoptotic neutrophils containing Staphylococcus epidermidis stimulate macrophages to release the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6.

    Science.gov (United States)

    Wilsson, Asa; Lind, Sara; Ohman, Lena; Nilsdotter-Augustinsson, Asa; Lundqvist-Setterud, Helen

    2008-06-01

    Staphylococcus epidermidis infections are usually nosocomial and involve colonization of biomaterials. The immune defense system cannot efficiently control the bacteria during these infections, which often results in protracted chronic inflammation, in which a key event is disturbed removal of neutrophils by tissue macrophages. While ingesting uninfected apoptotic neutrophils, macrophages release anti-inflammatory cytokines that lead to resolution of inflammation. In clinical studies, we have previously found elevated levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in synovial fluid from prostheses infected with coagulase negative staphylococci. We show that macrophages phagocytosing apoptotic neutrophils containing S. epidermidis released TNF-alpha and interleukin-6, whereas macrophages phagocytosing spontaneously apoptotic neutrophils did not. This difference was not due to dissimilar phagocytic capacities, because macrophages ingested both types of neutrophils to the same extent. The activation was induced mainly by the apoptotic neutrophils themselves, not by the few remaining extracellular bacteria. Macrophages were not activated by apoptotic neutrophils that contained paraformaldehyde-killed S. epidermidis. Proinflammatory reactions induced by clearance of apoptotic neutrophils containing S. epidermidis might represent an important mechanism to combat the infective agent. This activation of macrophages may contribute to the development of chronic inflammation instead of inflammation resolution.

  18. In Silico Analysis of Tumor Necrosis Factor α-Induced Protein 8-Like-1 (TIPE1 Protein.

    Directory of Open Access Journals (Sweden)

    Pei Shen

    Full Text Available Tumor necrosis factor α-induced protein 8 (TNFAIP8-like protein 1 (TIPE1 was a member of TNFAIP8 family. Previous studies have shown that TIPE1 could induce apoptosis in hepatocellular carcinoma. In this study, we attempted to predict its potential structure. Bioinformatic analysis of TIPE1 was performed to predict its potential structure using the bioinfomatic web services or softwares. The results showed that the amino acid sequences of TIPE1 were well conserved in mammals. No signal peptide and no transmembrane domain existed in human TIPE1. The aliphatic index of TIPE1 was 100.75 and the theoretical pI was 9.57. TIPE1 was a kind of stable protein and its grand average of hydropathicity was -0.108. Various post-translational modifications were also speculated to exist in TIPE1. In addition, the results of Swiss-Model Server and Swiss-Pdb Viewer program revealed that the predicted three-dimensional structure of TIPE1 protein was stable and it may accord with the rule of stereochemistry. TIPE1 was predicted to interact with FBXW5, caspase8 and so on. In conclusion, TIPE1 may be a stable protein with no signal peptide and no transmembrane domain. The bioinformatic analysis of TIPE1 will provide the basis for the further study on the function of TIPE1.

  19. 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 periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

  20. Variants of tumor necrosis factor-induced protein 3 gene are associated with left ventricular hypertrophy in hypertensive patients

    Institute of Scientific and Technical Information of China (English)

    XUE Hao; WANG Shu-xia; WANG Xiao-jian; XIN Ying; WANG Hu; SONG Xiao-dong; SUN Kai; WANG Yi-bo; HUI Ru-tai

    2011-01-01

    Background Tumor necrosis factor-induced protein 3 (TNFAIP3) gene has been shown important in cardiac remodeling. The aim of the present study was to investigate whether the variants of TNFAIP3 gene are associated with left ventricular hypertrophy (LVH) in hypertensive patients.Methods Four representatives of all the other single nucleotide polymorphisms (SNPs) in TNFAIP3 gene were tested for association with hypertrophy in two independent hypertensive populations (n=2120 and n=324).Results We found that only the tag SNP (rs5029939) was consistently lower in the hypertensives with cardiac hypertrophy than in those without cardiac hypertrophy in the two study populations, indicating a protective effect on LVH (odds ratio (OR) (95% confidence interval (CI))0.58 (0.358-0.863), P=0.035; OR (95% CI)=0.477 (0.225-0.815), P<0.05,respectively). Multiple regression analyses confirmed that the patients with G allele of rs5029939 had less thickness in inter-ventricular septum, left ventricular posterior wall, relative wall thickness and left ventricular mass index than did those with CC allele in the hypertensive patients in both study populations (all P<0.01).Conclusion These findings indicate that the SNP (rs5029939) in the TNFAIP3 gene may serve as a novel protective genetic marker for the development of LVH in patients with hypertension.

  1. Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase: role in endothelial cell migration and angiogenesis.

    Science.gov (United States)

    Pan, Shi; An, Ping; Zhang, Rong; He, Xiangrong; Yin, Guoyong; Min, Wang

    2002-11-01

    Tumor necrosis factor (TNF) is a cytokine that mediates many pathophysiologial processes, including angiogenesis. However, the molecular signaling involved in TNF-induced angiogenesis has not been determined. In this study, we examined the role of Etk/Bmx, an endothelial/epithelial tyrosine kinase involved in cell adhesion, migration, and survival in TNF-induced angiogenesis. We show that TNF activates Etk specifically through TNF receptor type 2 (TNFR2) as demonstrated by studies using a specific agonist to TNFR2 and TNFR2-deficient cells. Etk forms a preexisting complex with TNFR2 in a ligand-independent manner, and the association is through multiple domains (pleckstrin homology domain, TEC homology domain, and SH2 domain) of Etk and the C-terminal domain of TNFR2. The C-terminal 16-amino-acid residues of TNFR2 are critical for Etk association and activation, and this Etk-binding and activating motif in TNFR2 is not overlapped with the TNFR-associated factor type 2 (TRAF2)-binding sequence. Thus, TRAF2 is not involved in TNF-induced Etk activation, suggesting a novel mechanism for Etk activation by cytokine receptors. Moreover, a constitutively active form of Etk enhanced, whereas a dominant-negative Etk blocked, TNF-induced endothelial cell migration and tube formation. While most TNF actions have been attributed to TNFR1, our studies demonstrate that Etk is a TNFR2-specific kinase involved in TNF-induced angiogenic events.

  2. CD5-Positive Primary Intraocular B-Cell Lymphoma Arising during Methotrexate and Tumor Necrosis Factor Inhibitor Treatment

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    Kenji Nagata

    2015-09-01

    Full Text Available Purpose: To report a case of CD5+ primary intraocular B-cell lymphoma arising during methotrexate (MTX and tumor necrosis factor (TNF inhibitor treatment in a young patient with rheumatoid arthritis and uveitis. Case Presentation: A 39-year-old woman treated with MTX and a TNF inhibitor for rheumatoid arthritis and uveitis had steroid-resistant vitreous opacity. A vitreous sample was obtained by using diagnostic vitrectomy and was categorized as class V based on cytologic examination. Flow cytometric analysis of the vitreous sample revealed that abnormal cells were CD5+, CD10-, CD19+, CD20+ and immunoglobulin light-chain kappa+, suggesting the diagnosis of CD5+ primary intraocular B-cell lymphoma. Polymerase chain reaction (PCR detected immunoglobulin heavy-chain gene rearrangement. Epstein-Barr virus (EBV DNA was detected in the vitreous sample by using PCR, and immunohistochemistry revealed EBV latent membrane protein-1 expression in the abnormal cells infiltrating the vitreous. Optic nerve invasion was observed on magnetic resonance imaging. Conclusion: Primary intraocular lymphoma (PIOL may develop in patients receiving MTX and TNF inhibitor treatment. EBV infection may play an important role in the pathogenesis of PIOL arising during immunosuppressive therapy.

  3. Sensitivity enhancement of capacitive tumor necrosis factor-α detection by deposition of nanoparticles on interdigitated electrode

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    Yagati, Ajay Kumar; Park, Jinsoo; Kim, Jungsuk; Ju, Heongkyu; Chang, Keun-A.; Cho, Sungbo

    2016-06-01

    An interdigitated electrodes (IDE) modified with gold nanoparticles (AuNPs) was fabricated to enhance the capacitive detection of tumor necrosis factor-α (TNF-α) and compared with a bare IDE. A TNF-α immunosensor was developed by covalently conjugating TNF-α antibodies with 3-mercaptopropionic acid by a carbodiimide/N-hydroxysuccinimide reaction on the AuNP/IDE. After the application of human serum samples containing various concentrations of TNF-α to the sensing electrode, changes in both the impedance spectrum and the electrode interfacial capacitance were measured. The capacitance changes were dependent on the TNF-α concentration in the range of 1 pg ml-1 to 10 ng ml-1, and the device had the calculated detection limit of 0.83 pg ml-1. The developed AuNP/IDE-based immunosensor was successfully used for the capacitive detection of the binding of TNF-α to its antibody, and was found to be feasible for the analysis of TNF-α in human blood serum.

  4. TUMOR NECROSIS FACTOR ALPHA DECREASES NOS3 EXPRESSION PRIMARILY VIA RHO/RHO KINASE IN THE THICK ASCENDING LIMB

    Science.gov (United States)

    Ramseyer, Vanesa; Hong, Nancy; Garvin, Jeffrey L.

    2013-01-01

    Inappropriate Na+ reabsorption by thick ascending limbs (THALs) induces hypertension. Nitric oxide (NO) produced by NO synthase type 3 (NOS3 or eNOS) inhibits NaCl reabsorption by THALs. Tumor necrosis factor alpha (TNF-α) decreases NOS3 expression in endothelial cells and contributes to increases in blood pressure. However, the effects of TNF-α on THAL NOS3 and the signaling cascade are unknown. TNF-α activates several signaling pathways including Rho/Rho kinase (ROCK) which is known to reduce NOS3 expression in endothelial cells. Therefore, we hypothesized that TNF-α decreases NOS3 expression via Rho/ROCK in rat THAL primary cultures. THAL cells were incubated with either vehicle or 1 nmol/L TNF-α for 24 hrs and NOS3 expression was measured by Western blot. TNF-α decreased NOS3 expression by 51±6% (pNOS3 expression by 30±8% (pNOS3 expression by 66±15 % (pNOS3 expression. We conclude that TNF-α decreases NOS3 expression primarily via Rho/ROCK in rat THALs. These data suggest that some of the beneficial effects of ROCK inhibitors in hypertension could be due to the mitigation of TNF-α-induced reduction in NOS3 expression. PMID:22566503

  5. Garlic (Allium sativum) stimulates lipopolysaccharide-induced tumor necrosis factor-alpha production from J774A.1 murine macrophages.

    Science.gov (United States)

    Sung, Jessica; Harfouche, Youssef; De La Cruz, Melissa; Zamora, Martha P; Liu, Yan; Rego, James A; Buckley, Nancy E

    2015-02-01

    Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion.

  6. Cardioinductive network guiding stem cell differentiation revealed by proteomic cartography of tumor necrosis factor alpha-primed endodermal secretome.

    Science.gov (United States)

    Arrell, D Kent; Niederländer, Nicolas J; Faustino, Randolph S; Behfar, Atta; Terzic, Andre

    2008-02-01

    In the developing embryo, instructive guidance from the ventral endoderm secures cardiac program induction within the anterolateral mesoderm. Endoderm-guided cardiogenesis, however, has yet to be resolved at the proteome level. Here, through cardiopoietic priming of the endoderm with the reprogramming cytokine tumor necrosis factor alpha (TNFalpha), candidate effectors of embryonic stem cell cardiac differentiation were delineated by comparative proteomics. Differential two-dimensional gel electrophoretic mapping revealed that more than 75% of protein species increased >1.5-fold in the TNFalpha-primed versus unprimed endodermal secretome. Protein spot identification by linear ion trap quadrupole (LTQ) tandem mass spectrometry (MS/MS) and validation by shotgun LTQ-Fourier transform MS/MS following multidimensional chromatography mapped 99 unique proteins from 153 spot assignments. A definitive set of 48 secretome proteins was deduced by iterative bioinformatic screening using algorithms for detection of canonical and noncanonical indices of secretion. Protein-protein interaction analysis, in conjunction with respective expression level changes, revealed a nonstochastic TNFalpha-centric secretome network with a scale-free hierarchical architecture. Cardiovascular development was the primary developmental function of the resolved TNFalpha-anchored network. Functional cooperativity of the derived cardioinductive network was validated through direct application of the TNFalpha-primed secretome on embryonic stem cells, potentiating cardiac commitment and sarcomerogenesis. Conversely, inhibition of primary network hubs negated the procardiogenic effects of TNFalpha priming. Thus, proteomic cartography establishes a systems biology framework for the endodermal secretome network guiding stem cell cardiopoiesis.

  7. Tumor Necrosis Factor Receptor 1 Expression Is Upregulated in Dendritic Cells in Patients with Chronic HCV Who Respond to Therapy

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    Raul Cubillas

    2010-01-01

    Full Text Available The present studies assessed the level of tumor necrosis factor receptor (TNFR expression in peripheral blood mononuclear cells (PBMCs subsets from patients with chronic HCV undergoing interferon /ribavirin-based therapy (Ifn/R. Methods. TNFR family member mRNA expression was determined using quantitative real-time PCR assays (RTPCRs in PBMC from 39 HCV+ patients and 21 control HCV− patients. Further subset analysis of HCV + patients (untreated (U, sustained virological responders (SVR, and nonresponders (NR/relapsers (Rel PBMC was performed via staining with anti-CD123, anti-CD33, anti-TNFR1 or via RTPCR for TNFR1 mRNA. Results. A similar level of TNFR1 mRNA in PBMC from untreated HCV+ genotype 1 patients and controls was noted. TNFR1 and TNFR2 mRNA levels in PBMC from HCV+ patients with SVR were statistically different than levels in HCV(− patients. A significant difference was noted between the peak values of TNFR1 of the CD123+ PBMC isolated from SVR and the NR/Rel. Conclusion. Upregulation of TNFR1 expression, occurring in a specific subset of CD123+ dendritic cells, appeared in HCV+ patients with SVR.

  8. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease

    Science.gov (United States)

    Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian J; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; Heimke-Brinck, Ralph; Reuter, Eva; Dörje, Frank; Rau, Tilman T; Uter, Wolfgang; Wang, Thomas D; Kiesslich, Ralf; Vieth, Michael; Hannappel, Ewald; Neurath, Markus F

    2015-01-01

    As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn’s disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn’s disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn’s disease and autoimmune or inflammatory disorders. PMID:24562382

  9. Interferon-gamma enhances tumor necrosis factor-alpha production by inhibiting early phase interleukin-10 transcription.

    Science.gov (United States)

    Shakhov, A N; Woerly, G; Car, B D; Ryffel, B

    1996-12-01

    The ability of cytokine synthesis inhibitory factor or interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) to modulate the production of tumor necrosis factor (TNF-alpha) induced by lipopolysaccharide (LPS) was examined in mouse bone marrow-derived macrophages (BMDM). IFN-gamma profoundly enhances LPS-stimulated TNF-alpha production, whereas IL-10 is markedly inhibitory, demonstrating the opposing effects of IFN-gamma and IL-10 on BMDM. Early neutralization of endogenously produced, LPS-stimulated IL-10 markedly enhanced short term TNF-alpha production, an effect further amplified by the absence of IFN-gamma priming. The regulatory effects of IFN-gamma and IL-10 apparently occurred at the translational (or post-translational) level, with TNF-alpha mRNA steady-state levels remaining unchanged. Furthermore, IFN-gamma exerts its enhancing effect on TNF synthesis by the transcriptional inhibition of IL-10. This in vitro finding was also confirmed in vivo. In the absence of LPS, IFN-gamma was not capable of inducing TNF-alpha production in BMDM, indicating that LPS or other signals are necessary for transcriptional activation. Reduced but significant TNF-alpha production in LPS-injected IFN-gamma receptor -/- mice suggests that IFN-gamma is not an absolute requirement and that other cytokines or cell types contribute in a secondary fashion to the priming of LPS-induced TNF-alpha production in vivo.

  10. Evaluation of exome sequencing to estimate tumor burden in plasma.

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    Daniel Klevebring

    Full Text Available Accurate estimation of systemic tumor load from the blood of cancer patients has enormous potential. One avenue is to measure the presence of cell-free circulating tumor DNA in plasma. Various approaches have been investigated, predominantly covering hotspot mutations or customized, patient-specific assays. Therefore, we investigated the utility of using exome sequencing to monitor circulating tumor DNA levels through the detection of single nucleotide variants in plasma. Two technologies, claiming to offer efficient library preparation from nanogram levels of DNA, were evaluated. This allowed us to estimate the proportion of starting molecules measurable by sequence capture (<5%. As cell-free DNA is highly fragmented, we designed and provide software for efficient identification of PCR duplicates in single-end libraries with a varying size distribution. On average, this improved sequence coverage by 38% in comparison to standard tools. By exploiting the redundant information in PCR-duplicates the background noise was reduced to ∼1/35,000. By applying our optimized analysis pipeline to a simulation analysis, we determined the current sensitivity limit to ∼1/2400, starting with 30 ng of cell-free DNA. Subsequently, circulating tumor DNA levels were assessed in seven breast- and one prostate cancer patient. One patient carried detectable levels of circulating tumor DNA, as verified by break-point specific PCR. These results demonstrate exome sequencing on cell-free DNA to be a powerful tool for disease monitoring of metastatic cancers. To enable a broad implementation in the diagnostic settings, the efficiency limitations of sequence capture and the inherent noise levels of the Illumina sequencing technology must be further improved.

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

    Directory of Open Access Journals (Sweden)

    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

  12. Adalimumab (tumor necrosis factor-blocker) reduces the expression of glial fibrillary acidic protein immunoreactivity increased by exogenous tumor necrosis factor alpha in an organotypic culture of porcine neuroretina.

    Science.gov (United States)

    Fernandez-Bueno, I; Garcia-Gutierrez, M T; Srivastava, G K; Gayoso, M J; Gonzalo-Orden, J M; Pastor, J C

    2013-01-01

    To determine if exogenous addition of tumor necrosis factor alpha (TNFα) exacerbates retinal reactive gliosis in an organotypic culture of porcine neuroretina and to evaluate if concomitant adalimumab, a TNF-blocker, diminishes it. Porcine retinal explants from 20 eyeballs were cultured. Cultures with 100 pg/ml TNFα, 10 µg/ml adalimumab, 100 pg/ml TNFα plus 10 µg/ml adalimumab, or controls without additives were maintained for 9 days. Freshly detached retinas were processed in parallel. TNFα levels in control culture supernatants were quantified with enzyme-linked immunosorbent assay. Cryostat sections were doubly immunostained for glial fibrillary acidic protein (GFAP), a marker for reactive gliosis, and cellular retinaldehyde-binding protein (CRALBP), a marker for Müller cells. Sections were also labeled with the isolectin IB4, a label for microglia/macrophages. TNFα in control culture supernatants was detected only at day 1. Compared to the fresh neuroretinal samples, upregulation of GFAP and downregulation of CRALBP occurred during the 9 days of culture. Exogenous TNFα stimulated glial cells to upregulate GFAP and downregulate CRALBP immunoreactivity. TNFα-treated cultures also initiated the growth of gliotic membranes and underwent retinal disorganization. Adalimumab inhibited the spontaneous increases in GFAP and maintained CRALBP. In combination with TNFα, adalimumab reduced GFAP expression and conserved CRALBP, with only slight retinal disorganization. No appreciable changes in IB4 labeling were observed under the different culture conditions. In cultured porcine neuroretina, spontaneous reactive gliosis and retinal disorganization were exacerbated by exogenous TNFα. Adalimumab reduced spontaneous changes and those induced by TNFα. Therefore, inhibiting TNFα may represent a novel approach to controlling retinal fibrosis observed in some human diseases.

  13. The effect of capsaicin on circulating biomarkers, soluble tumor necrosis factor and soluble tumor necrosis factor-receptor-1 and -2 levels in vivo using lipopolysaccharide-treated mice

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    Yoshio Ijiri

    2014-01-01

    Full Text Available The circulating soluble tumor necrosis factor (sTNF and sTNF-receptor (R 1 and -R2 have known as septic biomarker. The pungent component of capsicum, capsaicin (Cap, has several associated physiological activities, including anti-oxidant, anti-bacterial and anti-inflammatory effects. The aim of this study was to elucidate the effect of Cap on circulating sTNF and sTNF-R1 and -R2 in vivo using lipopolysaccharide (LPS-treated mice. LPS (20 mg/kg, ip-treated group was significantly increased circulating sTNF, sTNF-R1, and -R2 and TNF-α mRNA expression levels compared to the vehicle group. Treatment with LPS (20 mg/kg, ip + Cap (4 mg/kg, sc-treated group was significantly decreased both circulating sTNF levels (after 1 h only and TNF-α mRNA expression (after 6 h compared to the LPS-treated group. There is an early increase in circulating sTNF, sTNR-R1, and -R2 observed in the LPS-treated mice. Since Cap inhibits this initial increase as biomarkers, circulating sTNF, it is considered a potent treatment option for TNF-α-related diseases, such as septicemia. In conclusion, Cap interferes with TNF-α mRNA transcription and exerts an inhibiting effect on TNF-α release from macrophages in the early phase after LPS stimulation. Thus, Cap is considered a potent agent for the treatment of TNF-α-related diseases, such as septicemia.

  14. Pengaruh Interleukin-1β (IL-1β dan Tumor Necrosis Factor-α (TNF-α terhadap Dopamin pada Cerebral Palsy

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    SATIMIN HADIWIDJAJA

    2004-05-01

    Full Text Available The caused of disability on cerebral palsy is unknown, but the humancerebral hypoxic, which affected to the motor cortex and motor pathways in the brain is believed cause of it. The major clinical manifestations are abnormality of movements and posture patterns. The immunity against the cerebral palsy (CP is unknown, but interleukine-1β (IL-1β and tumor necrosis factor-α (TNF-α are expressed in cerebral damage including cerebral palsy. By biological effects of IL-1β and TNF-α, they affect to the neuron dopaminergic in the brain, so dopamine in the vesicle of this neuron delivered to the extracellular tissue and to the intravascular compartment. Expressed dopamine in the extracellular and intravascular compartment has effects on motor pathways. IL-1β, TNF-α and dopamine all together detectable in cerebrospinal fluid and in the blood. The aim of this study is to known the effects of IL-1β and TNF-α as collectively to the dopamine in cerebral palsy. Diagnosis of the cerebral palsy is based on clinical manifestation in childhood by the abnormality of movements and posture patterns without involve the alteration of IL-1β and TNF-α and dopamine in blood. This study is conducted by observational method as cross-sectional study. Material of this study is serum from the blood plasma, take by peripheral venous blood vessels; IL-1β and TNF-α are analysis by ELISA and dopamine is analyzed by RIA. The results of this study show, that IL-1β and TNF-α as collectively affect dopamine in cerebral palsy. The result of this study is very suggested in the cerebral palsy.

  15. Typical and severe tumor necrosis factor receptor-associated periodic syndrome in the absence of mutations in the TNFRSF1A gene: a case series.

    Science.gov (United States)

    Cantarini, Luca; Lucherini, Orso Maria; Cimaz, Rolando; Rigante, Donato; Baldari, Cosima Tatiana; Laghi Pasini, Franco; Galeazzi, Mauro

    2012-12-01

    Tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-α. TRAPS is characterized by recurrent attacks of fever, typically lasting from 1 to 3 weeks. In addition to fever, common clinical features include periorbital edema, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthralgia or arthritis. Serosal membrane inflammation is also a common feature, usually in the form of polyserositis. To date, at least 40 different TNFRSF1A mutations have been identified, but few patients with symptoms highly suggestive of TRAPS with no mutations in the TNFRSF1A gene have recently been described, thus suggesting that not all mutations are yet known or that alternative mechanisms might be involved in the pathogenesis of the disease. We report on three such patients here.

  16. Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice.

    Science.gov (United States)

    Khuman, Jugta; Meehan, William P; Zhu, Xiaoxia; Qiu, Jianhua; Hoffmann, Ulrike; Zhang, Jimmy; Giovannone, Eric; Lo, Eng H; Whalen, Michael J

    2011-02-01

    Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (Pcell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI.

  17. Imbalance of the “ligandreceptor” tumor necrosis factor αsystem and TNFRI expression in thyroid tissue in patients with Graves' disease

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    T V Saprina

    2013-09-01

    Full Text Available The aim of the study was to examine the system of tumor necrosis factor α(TNFα, depending on the functional and morphological outcome of Graves’ disease (GD. It has been shown that activation of TNFαis associated with a “soft” and “benign” clinical course of GD and appearance of morphological markers of autoimmune thyroiditis (Hurthlecells transformation of thyroid epithelium.

  18. The Necrosis-Avid Small Molecule HQ4-DTPA as a Multimodal Imaging Agent for Monitoring Radiation Therapy-Induced Tumor Cell Death

    OpenAIRE

    Marieke A. Stammes; Maeda, Azusa; Bu, Jiachuan; Scollard, Deborah A.; Kulbatski, Iris; Medeiros, Philip J; Sinisi, Riccardo; Dubikovskaya, Elena A.; Thomas J A Snoeks; van Beek, Ermond R.; Chan, Alan B.; Löwik, Clemens W. G. M.; DaCosta, Ralph S.

    2016-01-01

    textabstractPurpose: Most effective antitumor therapies induce tumor cell death. Non-invasive, rapid and accurate quantitative imaging of cell death is essential for monitoring early response to antitumor therapies. To facilitate this, we previously developed a biocompatible necrosis-avid near-infrared fluorescence (NIRF) imaging probe, HQ4, which was radiolabeled with 111Indium-chloride (111In-Cl3) via the chelate diethylene triamine pentaacetic acid (DTPA), to enable clinical translation. T...

  19. Modulation of Anti-Tumor Necrosis Factor Alpha (TNF-α) Antibody Secretion in Mice Immunized with TNF-α Kinoid

    OpenAIRE

    Assier, Eric; Semerano, Luca; Duvallet, Emilie; Delavallée, Laure; Bernier, Emilie; Laborie, Marion; Grouard-Vogel, Géraldine; Larcier, Patrick; Bessis, Natacha; Boissier, Marie-Christophe

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) blockade is an effective treatment for patients with TNF-α-dependent chronic inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-α kinoid, a heterocomplex of human TNF-α and keyhole limpet hemocyanin (KLH) (TNF-K), is an active immunotherapy targeting TNF-α. Since the TNF-K approach is an active immunization, and patients receiving this therapy also receive immunosuppressant treatment, we evaluated the effect of some imm...

  20. Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses

    OpenAIRE

    1990-01-01

    We describe here a monoclonal antibody (H398) that immunoprecipitates a human 60-kD tumor necrosis factor (TNF) membrane receptor (p60) and competes with TNF binding to p60 but not to p85 TNF receptors. Despite partial inhibition of TNF binding capacity of cells coexpressing both TNF receptor molecules, H398 uniformly and completely inhibits very distinct TNF responses on a variety of cell lines. These data suggest a limited structural heterogeneity in those components actually contributing t...

  1. Distinct domains of M-T2, the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition.

    OpenAIRE

    Schreiber, M; Sedger, L; McFadden, G

    1997-01-01

    The myxoma virus tumor necrosis factor (TNF) receptor homolog, M-T2, is expressed both as a secreted glycoprotein that inhibits the cytolytic activity of rabbit TNF-alpha and as an endoglycosidase H-sensitive intracellular species that prevents myxoma virus-infected CD4+ T lymphocytes from undergoing apoptosis. To compare the domains of M-T2 mediating extracellular TNF inhibition and intracellular apoptosis inhibition, recombinant myxoma viruses expressing nested C-terminal truncations of M-T...

  2. Induction of steroid sulfatase expression by tumor necrosis factor-α through phosphatidylinositol 3-kinase/Akt signaling pathway in PC-3 human prostate cancer cells

    OpenAIRE

    Suh, Bo-Young; Jung, Jin-Joo; Park, Nahee; Seong, Cheul-Hun; Im, Hee-Jung; Kwon, Yeojung; Kim, Donghak; Chun, Young-Jin

    2011-01-01

    Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and has a pivotal role in regulating the formation of biologically active estrogens. STS may be considered a new promising drug target for treating estrogen-mediated carcinogenesis. However, the molecular mechanism of STS expression is not well-known. To investigate whether tumor necrosis factor (TNF)-α is able to regulate gene transcription of STS, we studied the effect of TNF-α on STS expression in ...

  3. Irvalec inserts into the plasma membrane causing rapid loss of integrity and necrotic cell death in tumor cells.

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    José M Molina-Guijarro

    Full Text Available Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca(2+ influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn(2+. Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self-organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity.

  4. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

    Science.gov (United States)

    Weinberger, Jeremy F; Raison, Charles L; Rye, David B; Montague, Amy R; Woolwine, Bobbi J; Felger, Jennifer C; Haroon, Ebrahim; Miller, Andrew H

    2015-07-01

    Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP⩽5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation.

  5. Continuous Improvement of Physical Functioning in Ankylosing Spondylitis Patients by Tumor Necrosis Factor Inhibitors: Three-Year Followup and Predictors.

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    van Weely, Salima F E; Kneepkens, Eva L; Nurmohamed, Mike T; Dekker, Joost; van der Horst-Bruinsma, Irene E

    2016-10-01

    To establish the 3-year outcome and course of physical functioning and spinal mobility impairments in patients routinely treated with tumor necrosis factor inhibitors (TNFi) and to find predictors of physical functioning and spinal mobility impairments. Ankylosing spondylitis (AS) patients eligible for TNFi were followed in a 3-year prospective observational study. Prediction models were developed with linear mixed modeling. Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) were used as outcome measures for physical functioning and spinal mobility. A total of 257 patients were included and treated with etanercept (n = 174) or adalimumab (n = 83). Physical functioning improved significantly during the first 6 months after the start of TNFi. The BASFI score decreased from mean ± SD 5.4 ± 2.4 to 3.3 ± 2.6 at 6 months, and stabilized thereafter (BASFI third year score mean ± SD 3.6 ± 2.5). The BASMI showed no significant changes over time. Lower baseline BASFI and BASMI scores predicted a better level of physical functioning and spinal mobility after 3 years of TNFi therapy. Other predictors for a better 3-year outcome and course of physical functioning included absence of comorbidity, physical activity, younger age, and lower body mass index at baseline. Physical functioning in routinely TNFi-treated AS patients improved up to 6 months and stabilized thereafter. Therefore, it would be better to extend the period of evaluation of TNFi treatment to 6 months rather than the 3 months currently used. The risk factors of long-term physical functioning found in this study might help to identify patients at risk at an earlier stage and improve treatment strategy. © 2016, American College of Rheumatology.

  6. Incidences of serious infections and tuberculosis among patients receiving anti-tumor necrosis factor-α therapy.

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    Yoo, In Kyung; Choung, Rok Seon; Hyun, Jong Jin; Kim, Seung Young; Jung, Sung Woo; Koo, Ja Seol; Lee, Sang Woo; Choi, Jai Hyun; Kim, Ho; Lee, Hong Sik; Keum, Bora; Kim, Eun Sun; Jeen, Yoon Tae

    2014-03-01

    Anti-tumor necrosis factor-alpha (TNF-α) medications represent a major advancement in the management of chronic inflammatory diseases. However, these agents are associated with increased risks of tuberculosis (TB) and other serious infections. The aim of this study was to evaluate the incidences of such disease among tertiary hospitals in Korea. We retrospectively studied patients who received anti-TNF-α therapy; we reviewed serious infections including TB that developed within 6 months after initiation of anti-TNF-α therapy. Data concerning patient demographics, types of anti-TNF-α agents, concomitant immunosuppressive drugs use, and infection details were collected. A total 175 patients treated with infliximab (n=72) or adalimumab (n=103) with the following conditions were enrolled: Crohn's disease, 34 (19.4%); ulcerative colitis, 20 (11.4%); ankylosing spondylitis, 82 (46.9%); and rheumatoid arthritis, 39 (22.2%). There were 18 cases (6.0%) of serious infections. The most common site of serious infection was the intra-abdomen (n=6), followed by TB (n=3), skin and soft tissue (n=3), bone and joints (n=2), ocular neurons (n=2), lower respiratory tract (n=1), and urinary tract (n=1). Of the 175 patients, only 3 cases showed development of TB. Furthermore, of all those who developed TB, none had taken anti-TB chemoprophylaxis prior to treatment with an anti-TNF agent due to negative screening results. Serious infections with anti-TNF-α therapy were uncommon among tertiary hospitals in Korea; TB was the second most frequent infection. Nevertheless, there were no TB reactivations after anti-TB chemoprophylaxis. Accordingly, physicians should be aware of TB in subjects undergoing anti-TNF-α therapy, especially in countries with a high prevalence of TB.

  7. Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein 1 Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population

    Institute of Scientific and Technical Information of China (English)

    Jian-Wen Han; Yong Wang; Chulu Alateng; Hong-Bin Li; Yun-Hua Bai; Xin-Xiang Lyu; Rina Wu

    2016-01-01

    Background:Psoriasis is a common immune-mediated inflammatory dermatosis.Generalized pustular psoriasis (GPP) is the severe and rare type of psoriasis.The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 (TNIP1) gene and psoriasis was confirmed in people with multiple ethnicities.This study was to investigate the association between TNIP1 gene polymorphisms and pustular psoriasis in Chinese Han population.Methods:Seventy-three patients with GPP,67 patients with palmoplantar pustulosis (PPP),and 476 healthy controls were collected from Chinese Han population.Six single nucleotide polymorphisms (SNPs) of the TNIP1 gene,namely rs3805435,rs3792798,rs3792797,rs869976,rs17728338,and rs999011 were genotyped by using polymerase chain reaction-ligase detection reaction.Statistical analyses were performed using the PLINK 1.07 package.Allele frequencies and genotyping frequencies for six SNPs were compared by using Chi-square test,odd ratio (OR) (including 95% confidence interval) were calculated.The haplotype analysis was conducted by Haploview software.Results:The frequencies of alleles of five SNPs were significantly different between the GPP group and the control group (P≤ 7.22 × 10-3),especially in the GPP patients without psoriasis vulgaris (PsV).In the haplotype analysis,the most significantly different haplotype was H4:ACGAAC,with 13.1% frequency in the GPP group but only 3.4% in the control group (OR =4.16,P =4.459 × 10-7).However,no significant difference in the allele frequencies was found between the PPP group and control group for each of the six SNPs (P > 0.05).Conclusions:Polymorphisms in TNIP1 are associated with GPP in Chinese Han population.However,no association with PPP was found.These findings suggest that TNIP1 might be a susceptibility gene for GPP.

  8. Sputum interleukin-6, tumor necrosis factor-α and Salivary cortisol as new biomarkers of depression in lung cancer patients.

    Science.gov (United States)

    Du, Yi-jie; Zhang, Hong-ying; Li, Bei; Wu, Xiao; Lv, Yu-bao; Jin, Hua-liang; Cao, Yu-xue; Sun, Jing; Luo, Qing-li; Gong, Wei-yi; Liu, Bao-jun; Wu, Jin-feng; Shi, Shen-xun; Dong, Jing-cheng

    2013-12-02

    Depression is common among lung cancer patients. Increasing evidence has suggested that hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines may play a key role in the pathophysiology of depression as well as cancer. This pilot study investigated the efficacy of sputum interleukin (IL)-6, tumor necrosis factor (TNF)-α and salivary cortisol as new markers to support the diagnosis of depression in lung cancer patients. The diurnal rhythms of sputum IL-6, sputum TNF-α and salivary cortisol were measured in lung cancer patients with and without depression as well as depressed controls and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated. Receiver operating characteristic (ROC) analysis was performed. Patients with co-morbid depression and lung cancer showed highest level of sputum IL-6 AUC, sputum TNF-α AUC and lowest level of cortisol VAR (Pcortisol VAR demonstrated an optimal cutoff point at 77.8% (AUC=0.94; 95% CI, 0.85-0.98), which is associated with a sensitivity of 82.1% and a specificity of 96.0%. Sputum IL-6 AUC demonstrated a sensitivity of 74.4% and a specificity of 92.0% (AUC=0.81; 95% CI, 0.69-0.90). These findings suggested that higher 24h overall levels of sputum IL-6, TNF-α and flattened diurnal salivary cortisol slopes were associated with depression in lung cancer patients. Sputum IL-6 AUC and salivary cortisol VAR performed best as biomarkers in the diagnosis of depression in lung cancer patients.

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

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    Melanie Vincent

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  10. Circulating Tumor Necrosis Factor α Receptors Predict the Outcomes of Human IgA Nephropathy: A Prospective Cohort Study.

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    Yun Jung Oh

    Full Text Available The circulating tumor necrosis factor receptors (TNFRs could predict the long-term renal outcome in diabetes, but the role of circulating TNFRs in other chronic kidney disease has not been reported. Here, we investigated the correlation between circulating TNFRs and renal histologic findings on kidney biopsy in IgA nephropathy (IgAN and assessed the notion that the circulating TNFRs could predict the clinical outcome. 347 consecutive biopsy-proven IgAN patients between 2006 and 2012 were prospectively enrolled. Concentrations of circulating TNFRs were measured using serum samples stored at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; ≥ 30% decline compared to baseline. Mean eGFR decreased and proteinuria worsened proportionally as circulating TNFR1 and TNFR2 increased (P < 0.001. Tubulointerstitial lesions such as interstitial fibrosis and tubular atrophy were significantly more severe as concentrations of circulating TNFRs increased, regardless of eGFR levels. The risks of reaching the primary endpoint were significantly higher in the highest quartile of TNFRs compared with other quartiles by the Cox proportional hazards model (TNFR1; hazard ratio 7.48, P < 0.001, TNFR2; hazard ratio 2.51, P = 0.021. In stratified analysis according to initial renal function classified by the eGFR levels of 60 mL/min/1.73 m2, TNFR1 and TNFR2 were significant predictors of renal progression in both subgroups. In conclusion, circulating TNFRs reflect the histology and clinical severity of IgAN. Moreover, elevated concentrations of circulating TNFRs at baseline are early biomarkers for subsequent renal progression in IgAN patients.

  11. Estrogen-induced nongenomic calcium signaling inhibits lipopolysaccharide-stimulated tumor necrosis factor α production in macrophages.

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    Limin Liu

    Full Text Available Estrogen is traditionally thought to exert genomic actions through members of the nuclear receptor family. Here, we investigated the rapid nongenomic effects of 17β-estradiol (E2 on tumor necrosis factor α (TNF-α production following lipopolysaccharide (LPS stimulation in mouse bone marrow-derived macrophages (BMMs. We found that LPS induced TNF-α production in BMMs via phosphorylation of p38 mitogen-activated protein kinase (MAPK. E2 itself did not affect the MAPK pathway, although it attenuated LPS-induced TNF-α production through suppression of p38 MAPK activation. Recently, G protein-coupled receptor 30 (GPR30 was suggested to be a membrane estrogen receptor (mER that can mediate nongenomic estradiol signaling. We found that BMMs expressed both intracellular estrogen receptors (iER and mER GPR30. The specific GPR30 antagonist G-15 significantly blocked effects of estradiol on LPS-induced TNF-α production, whereas an iER antagonist did not. Moreover, E2 induced a rapid rise in intracellular free Ca(2+ that was due to the influx of extracellular Ca(2+ and was not inhibited by an iER antagonist or silencing of iER. Ca(2+ influx was also induced by an impermeable E2 conjugated to BSA (E2-BSA, which has been used to investigate the nongenomic effects of estrogen. Consequently, Ca(2+, a pivotal factor in E2-stimulated nongenomic action, was identified as the key mediator. The inhibitory effects of E2 on LPS-induced TNF-α production and p38 MAPK phosphorylation were dependent on E2-triggered Ca(2+ influx because BAPTA, an intracellular Ca(2+ chelator, prevented these effects. Taken together, these data indicate that E2 can down-regulate LPS-induced TNF-α production via blockade of p38 MAPK phosphorylation through the mER-mediated nongenomic Ca(2+ signaling pathway in BMMs.

  12. Tumor necrosis factor-alpha inhibitor combined with methotrexate for ankylosing spondylitis: a systematic review and meta-analysis

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    Shaopeng Lin

    2014-06-01

    Full Text Available To evaluate the benefits and harms of combination of tumor necrosis factor-alpha (TNF-α inhibitor and methotrexate (MTX compared with TNF-α inhibitor monotherapy in the treatment of ankylosing spondylitis (AS. Randomized controlled trials were identified from Medline, Embase, Cinahl, Central and Clinical Trials Registry Platform, as well as from the reference sections of retrieved articles. The risk of bias was evaluated in all included trials. Data were extracted by two reviewers independently using a specially designed extraction form. The Cochrane Collaboration’s Review Manager 5.2 software was used for data analysis. The search retrieved 852 titles, of which 3 original trials were included, involving 187 participants. The overall risk of bias is low in all three trials. Only one study was placebo controlled, and all of them examined small samples. The analysis showed no significant advantage of the MTX combination versus monotherapy. Two trials assessed Assessment of Ankylosing Spondylitis (ASAS 40 and the pooled risk ratio (RR was 1.37 and 95% confidence interval 0.84 to 2.23. The RR for ASAS20 was 1.16 (0.88 to 1.52. Likewise, there were no significant difference between two groups in partial remission, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Magnetic resonance imaging activity score and other secondary outcomes. Withdrawals for side effects and for any reason were similar in two groups, RR were 1.89 (0.71 to 5.02 and 1.11 (0.67 to 1.84, respectively. The evidence available did not support any benefit of adding MTX to TNF-α inhibitor for the treatment of AS.

  13. Tumor necrosis factor-alpha concentration in the aqueous humor of healthy and diseased dogs: a preliminary pilot study.

    Science.gov (United States)

    Durieux, P; Etchepareborde, S; Fritz, D; Rosolen, S G

    2015-04-01

    To determine reference values of tumor necrosis factor-alpha (TNF-α) concentrations in the aqueous humor of control dogs. To show whether these values are significantly different from those obtained in dogs affected with intraocular pathology: acute anterior uveitis (AAU) or chronic primary angle closure glaucoma (PACG). Forty-four dogs were included in the study and were divided into two groups: a control group and a group with intraocular disease. Twenty-seven dogs (9 males and 18 females) were examined and found to be normal after a complete ophthalmological examination (control group), 7 (6 females and 1 male) presented with PACG, and 10 (7 females and 3 males) presented with AAU secondary to corneal perforation. One aqueous humor