Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:009512 (tumor necrosis factor)
 58,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic stem cells are capable of self-replication and differentiation to lineage-committed progenitor cells. The progenitors proliferate and differentiate to lineage-specific, morphologically recognizable precursors and, finally, to terminal circulating blood cells. These homeostatic mechanisms are regulated by a complex set of interacting growth stimulatory and inhibitory factors that are produced by, or in collaboration with, the tissue's regulatory microenvironment. A number of well-characterized cytokines have been implicated in the negative regulation of hematopoiesis: ferritin H-subunit (HF), lactoferrin (Lf), prostaglandin E (PGE), tumor necrosis factor (TNF), interferon (IFN), transforming growth factor-beta (TGF beta), acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) or thymosin-beta 4, pyroGlu-Glu-Asp-Cys-Lys (pEEDCK), macrophage inflammatory protein-1 alpha (MIP-1 alpha), inhibin, superoxide dismutase (SOD), glutathione (GSH) and others not well-known yet. The role of inhibitors in restraining stem cells from entering the cell cycle and protecting them from the toxic side effects of chemotherapeutic drugs is opening an alternate strategy for the treatment of cancer patients.
 ...
PMID:[Biomolecules suppressing myelopoiesis]. 134 39

We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release.
 ...
PMID:Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2. 154 73

Based on findings that the cytotoxic effects of tumor necrosis factor (TNF) are closely related to levels of intracellular oxygen radicals, and on the results of TNF gene transfection studies, the hypothesis was made that endogenous TNF (enTNF) acts as a protective factor against exogenous TNF by inducing inhibitors or scavengers of oxygen radicals. In order to test this hypothesis, we investigated the intracellular levels of manganous superoxide dismutase (MnSOD) and glutathione (GSH) in L-M(pNTnF) cells carrying a TNF gene induced by dexamethasone (DM). When L-M(pNTnF) cells were treated with DM they expressed enTNF, and acquired resistance to exogenous TNF. There was no change in the GSH concentration after enTNF induction, but a 1.9- to 3.9-fold increase in MnSOD levels was noted. Our findings suggest that enTNF exerts its protective function against the cytocidal effect of exogenous TNF by inducing MnSOD production.
 ...
PMID:Induction of synthesis of manganous superoxide dismutase in L-M(pNTnF) cells carrying an inducible TNF gene. 173 14

The effect of tumor necrosis factor-alpha (TNF) on hyperoxia-induced endothelial injury in vitro was investigated. TNF caused a time- and dose-dependent reduction in the number of viable pulmonary artery endothelial cells. The TNF-mediated endothelial cytotoxicity was more pronounced under hyperoxia (95% O2 and 5% CO2) than under normoxia (95% air and 5% CO2). Pretreatment of endothelial cells with TNF (0.01 micrograms/ml or 240 U/ml) for 18 h at normoxia reduced the intracellular concentration of total glutathione (GSH), whereas the concentration of oxidized GSH was increased. These TNF-treated endothelial cells were more susceptible to hyperoxia- or hydrogen peroxide-mediated cytotoxicity. TNF also induced changes in endothelial morphology and in the distribution and density of actin filaments. Exogenous GSH or L-2-oxothiazolidine-4-carboxylate, which enhanced endothelial GSH concentrations, partially protected endothelial cells against TNF-mediated cytotoxicity, morphologic changes, and actin filament redistribution, especially under the hyperoxic condition. These results suggest an important role of GSH in modulating endothelial response to TNF.
 ...
PMID:Tumor necrosis factor enhances endothelial cell susceptibility to oxygen toxicity: role of glutathione. 195 83

Protective effects of intracellular glutathione (GSH) against the cytotoxicity of human recombinant tumor necrosis factor (TNF) were investigated. Three tumor cell lines (L-M, B-16, HeLa) were used as target cells. Exposure of these cells to buthionine sulfoximine (BSO) or diethyl maleate (DEM) resulted in the depletion of intracellular GSH content to 5.2-43.0% of control values and enhancement of their susceptibility to TNF cytotoxicity. The hydroxyl radical production in L-M cells stimulated by TNF was increased by treatment with BSO or DEM. These results are consistent with the suggestion that intracellular GSH exerts its protective function against the cytocidal effect of TNF by inhibiting the hydroxyl radical production stimulated by TNF.
 ...
PMID:Suppressive effects of intracellular glutathione on hydroxyl radical production induced by tumor necrosis factor. 217 72

The effect of systemic glutathione (GSH) depletion on sensitization of bladder cancer cells to various antineoplastic agents was investigated using murine model, MBT-2. Subcutaneous injection(s) of buthionine sulfoximine (BSO) significantly depleted the GSH content in the tumor and organs. BSO pretreatment produced significant enhancement in the antitumor effect of cyclophosphamide (CY), though it failed to sensitize the tumors to doxorubicin hydrochloride (Adriamycin), cisplatin, mitomycin C, JM-8, methotrexate, vinblastine, and tumor necrosis factor. Mice tolerated cytotoxic agents alone and in combination with BSO except for cisplatin in combination with BSO. A 29 percent (4/14) mortality rate was observed in mice treated with BSO and divided schedule of cisplatin.
 ...
PMID:Effect of systemic glutathione depletion by buthionine sulfoximine on sensitivity of murine bladder cancer to cytotoxic agents. 259 83

Single, preexposure, parenteral injection with both recombinant tumor necrosis factor/cachectin (TNF/C) and interleukin-1 (IL-1) prolonged the survival of rats (144 +/- 9 h) in continuous hyperoxia (greater than 99% O2 at 1 atm) when compared with rats injected with boiled TNF/C and boiled IL-1 (61 +/- 2 h), TNF/C alone (61 +/- 2 h), IL-1 alone (62 +/- 2 h), or saline (64 +/- 3 h). After exposure to hyperoxia for 52 h, pleural effusion volume, pulmonary artery pressure, total pulmonary resistance, and lung morphologic damage were decreased in those rats given TNF/C and IL-1 as compared with saline-injected rats. In parallel, ratios of reduced (GSH) to oxidized (GSSG) glutathione were greater (P less than 0.05) in lungs of TNF/C + IL-1-injected rats (91 +/- 20) than of saline-injected rats (30 +/- 4) that had been exposed to hyperoxia for 52 h. No differences were found in superoxide dismutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, or catalase activities in lungs of TNF/C + IL-1- or saline-treated, hyperoxia-exposed rats. Our results indicate that pretreatment with TNF/C and IL-1 favorably altered lung glutathione redox status, decreased lung injury, and enhanced survival of rats exposed to hyperoxia.
 ...
PMID:Recombinant tumor necrosis factor/cachectin and interleukin 1 pretreatment decreases lung oxidized glutathione accumulation, lung injury, and mortality in rats exposed to hyperoxia. 349 53

We studied the acute effects of cigarette smoke condensate (CSC), H2O2, and tumor necrosis factor (TNF)-alpha on the glutathione (GSH) redox system in a human type II epithelial cell line (A549) in vitro. CSC, in vitro and in vivo after intratracheal instillation of CSC in the rat, produced a depletion of intracellular soluble GSH, concomitant with GSH-conjugate formation, without significant elevation of oxidized GSH (GSSG), protein-GSH mixed disulfides (PrSSG), nor any GSH efflux from the cells. By contrast, H2O2 (500 microM) after 5-min exposure to A549 cells caused significant depletion of intracellular GSH associated with an efflux of GSSG and a significant increase in the formation of PrSSG. TNF-alpha, in concentrations of 100 U/ml and 1,000 U/ml, produced a significant depletion of GSH in A549 cells after 4- and 24-h exposure, with an associated elevation of GSSG. The activities of glutathione peroxidase, gamma-glutamylcysteine synthetase, and glucose-6-phosphate dehydrogenase were significantly decreased in epithelial cells and in rat lungs after CSC exposure, without change in glutathione S-transferase and glutathione reductase activities. By contrast, H2O2 and TNF-alpha did not alter these enzyme activities in epithelial cells. Thus GSH depletion and alteration in enzyme activities in alveolar epithelial cells by CSC, H2O2, and TNF-alpha occur by different mechanisms.
 ...
PMID:Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress. 757 60

This study demonstrates that human immunodeficiency virus type 1 (HIV-1) Tat protein amplifies the activity of tumor necrosis factor (TNF), a cytokine that stimulates HIV-1 replication through activation of NF-kappa B. In HeLa cells stably transfected with the HIV-1 tat gene (HeLa-tat cells), expression of the Tat protein enhanced both TNF-induced activation of NF-kappa B and TNF-mediated cytotoxicity. A similar potentiation of TNF effects was observed in Jurkat T cells and HeLa cells treated with soluble Tat protein. TNF-mediated activation of NF-kappa B and cytotoxicity involves the intracellular formation of reactive oxygen intermediates. Therefore, Tat-mediated effects on the cellular redox state were analyzed. In both T cells and HeLa cells HIV-1 Tat suppressed the expression of Mn-dependent superoxide dismutase (Mn-SOD), a mitochondrial enzyme that is part of the cellular defense system against oxidative stress. Thus, Mn-SOD RNA protein levels and activity were markedly reduced in the presence of Tat. Decreased Mn-SOD expression was associated with decreased levels of glutathione and a lower ratio of reduced:oxidized glutathione. A truncated Tat protein (Tat1-72), known to transactivate the HIV-1 long terminal repeat (LTR), no longer affected Mn-SOD expression, the cellular redox state or TNF-mediated cytotoxicity. Thus, our experiments demonstrate that the C-terminal region of HIV-1 Tat is required to suppress Mn-SOD expression and to induce pro-oxidative conditions reflected by a drop in reduced glutathione (GSH) and the GSH:oxidized GSH (GSSG) ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. 785 43

One of the mechanisms of cytotoxicity by tumor necrosis factor (TNF) and heat is the induction of reactive oxygen molecules. Cells producing endogenous tumor necrosis factor (enTNF) show resistance to the cytotoxicity of exogenous TNF and heat by inducing manganous superoxide dismutase (MnSOD) to scavenge the reactive oxygen molecules. Intracellular hydroxyl radical production is also involved in adriamycin-induced cytotoxicity. In this study, we therefore examined the possibility that enTNF may act as a protective protein against adriamycin-induced cytotoxicity in a manner similar to that in which it protects against exogenous TNF and heat. Adriamycin-sensitive L-M (mouse tumorigenic fibroblast) cells, originally expressing no enTNF, were transfected with an expression vector which directs the synthesis of non-secretory-type human TNF (enTNF). The stable transformants became resistant to adriamycin with increased levels of MnSOD. Conversely, when HeLa (human uterine cervical cancer) cells, which originally produce an appreciable amount of enTNF, were transfected with an anti-sense TNF mRNA expression vector to inhibit enTNF synthesis, their intracellular MnSOD activity was suppressed and adriamycin sensitivity was enhanced. However, no alterations in expression of multidrug-resistant gene products--P-170 glycoprotein, glutathione S-transferase pi (GST-pi) and the intracellular concentrations of glutathione (GSH)--were observed in these transfectants as compared to their parent cells. These results indicate that enTNF exerts its intracellular protective effect against adriamycin-induced cytotoxicity by the same mechanism as that against exogenous TNF and heat, namely scavenging reactive oxygen with induced MnSOD.
 ...
PMID:Endogenous tumor necrosis factor functions as a resistant factor against adriamycin. 791 82


1 2 3 4 5 6 7 8 9 10 Next >>