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  • 1
    ISSN: 1432-0851
    Keywords: Key words: ONO-4007 – Lipid A – Antitumor effect – TNF – TIM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. ONO-4007 is a novel synthetic analog of lipid A subunit and has been shown to exert antitumor activities on various experimental tumors with less toxicity than lipopolysaccharide. It remains unclear, however, what biological activities of this compound are relevant to its antitumor effects. We therefore investigated the activation of macrophages by ONO-4007 in vitro and in vivo and its implication in antitumor effects, using mouse MM46 mammary tumor as an experimental model. Intravenous injection of ONO-4007 produced significant therapeutic effects on this solid tumor. ONO-4007 could stimulate glycogen-elicited peritoneal macrophages in vitro, not only to produce tumor necrosis factor (TNF), but also to exert cytocidal activities against MM46 cells in vitro. Substantial TNF production was induced in tumor tissue by i. v. injection of ONO-4007, and its successive administration to tumor-bearing mice gave tumor-infiltrating macrophages a prominent in vitro tumoricidal activity and primed them for in vitro TNF secretion. These results suggest that activation of tumor-infiltrating macrophages to a direct tumoricidal state as well as to TNF secretion in tumor tissues may be at least some of the antitumor effects of this novel lipid A analog.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0851
    Keywords: ONO-4007 ; Lipid A ; Antitumor effect ; TNF ; TIM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract ONO-4007 is a novel synthetic analog of lipid A subunit and has been shown to exert antitumor activities on various experimental tumors with less toxicity than lipopolysaccharide. It remains unclear, however, what biological activities of this compound are relevant to its antitumor effects. We therefore investigated the activation of macrophages by ONO-4007 in vitro and in vivo and its implication in antitumor effects, using mouse MM46 mammary tumor as an experimental model. Intravenous injection of ONO-4007 produced significant therapeutic effects on this solid tumor. ONO-4007 could stimulate glycogen-elicited peritoneal macrophages in vitro, not only to produce tumor necrosis factor (TNF), but also to exert cytocidal activities against MM46 cells in vitro. Substantial TNF production was induced in tumor tissue by i. v. injection of ONO-4007, and its successive administration to tumor-bearing mice gave tumor-infiltrating macrophages a prominent in vitro tumoricidal activity and primed them for in vitro TNF secretion. These results suggest that activation of tumor-infiltrating macrophages to a direct tumoricidal state as well as to TNF secretion in tumor tissues may be at least some of the antitumor effects of this novel lipid A analog.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-3040
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Abstract. Pre-imbibed cocklebur (Xanthium penn-sylvanicum Wallr.) seeds displayed bimodal germination-temperature responses with two optima at 8 and 33° C. Such germination responses occurred subsequent to bimodal respiration-temperature upsurges at lower and higher temperature regions. At lower temperatures, cocklebur seeds respired predominantly through a cyanide-sensitive cytochrome pathway. A rise in temperature resulted in a marked increase in flux via an alternative pathway, a propyl gallate- (PG) or benzohydroxamic-acid- (BHAM) sensitive pathway, thus resulting in an increase in the ratio of this pathway relative to the cytochrome pathway. Both an increased capacity for the alternative pathway and an increase in the ratio of this pathway to the cytochrome pathway were obtained when pre-imbibed seeds were exposed to either 8 or 33°C for a short period. The effects of low temperature were reduced as the exposure time was prolonged beyond 3d, resulting in a reduction in germination. Neither PG nor BHAM had an inhibitory effect on the chilling-induced germination, but the germination-stimulating effect of high temperatures was less pronounced in the presence of PG or BHAM. At high temperatures, on the other hand, KCN and NaN3 were ineffective or, rather, slightly inhibited germination. It was thus concluded that low and high temperatures exert their germination-stimulating effects by an essentially similar manner which increases fluxes both via the cytochrome pathway and, especially, via the alternative pathway and, as a result, raises the ratio of the latter to the former.
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  • 4
    ISSN: 1365-3040
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Abstract. The mechanism involved in a bimodal germination-temperature response in pre-soaked cocklebur (Xanthium pennsylvanicum Wallr.) seeds was studied with special reference to adenylate metabolism. Exposure to either low (optimal at 8°C) or high (optimal at 34°C) temperature which was effective in inducing the germination of the seeds brought about the accumulation of ATP in them. The ATP level remained unchanged at temperatures around 23°C. Pretreatment with KCN, stimulating germination even at 23°C, subsequently increased the ATP content, total adenylate pool and energy charge (EC) in the axial tissue prior to germination above those of the untreated controls. The lower the treatment temperature, the greater the inhibitory effect of KCN on ATP formation. An increase in germination following an increasing duration of pre-soaking at 8°C was comparable to increasing both the ATP content and total adenylate pool of axes, but not the EC value. Similarly, changes in germination following an increased exposure duration at 8°C correlated with changes in ATP content rather than EC value in the axes. Unlike the case of chilling, an increase in ATP level in response to 34°C was greater in the early period of water imbibition, during which times its germination-stimulating effect appeared more striking than in the later period, and it occurred without a concomitant rise in EC value because of the increased supply of AMP. Such a supply of AMP was reduced in the presence of benzohydroxamic acid or propyl gallale, inhibitors of an alternative respiratory pathway. It was thus concluded that both low temperature, coupled with warm temperature, and high temperature, by itself, can induce seed germination by increasing the ATP level as well as the total adenylate pool, but not the EC value, in the axial tissue. Further, that increases in both the ATP level and the adenylate pool especially are required for seed germination to proceed, probably depending on the activities of the cytochrome and alternative respiration pathways, respectively.
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  • 5
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: We have recently shown that TNF is produced in liver rapidly after partial hepatectomy and that TNF can stimulate DNA synthesis of hepatocyte primary culture with its inhibition by interleukin 6 and transforming growth factor-β, indicating a pivotal role of TNF and TNF-driven cytokine induction in liver regeneration. We here examined the effects of biological or inflammatory mediators of low molecular weight on the in vitro DNA synthesis of hepatocytes stimulated by TNF. Simultaneous addition of dexamethasone markedly suppressed the growth-stimulating action of TNF, maximally at 10-7 M and effectively at about 10-8 M. However, the growth-stimulating effect of EGF was not affected by dexamethasone at all. Physiological glucocorticoids, corticosterone, and hydrocortisone showed virtually the same effect, but other steroid hormones, β-estradiol, or progesterone did not. Retinoic acid at 10-7 M, however, enhanced TNF-stimulated hepatocyte DNA synthesis and even more effectively the growth response to FGF. PGD2 at 20 μM was markedly suppressive but PGE2 was not. The addition of indomethacin enhanced the hepatocyte in vitro growth by TNF and EGF at 2-20 μM. These results indicate that the growth of hepatocytes stimulated by TNF is up and down-regulated by inflammatory mediators and hormones as well as cytokines and suggest the biological significance of TNF and TNF-driven inflammatory reactions in liver regeneration. © 1993 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: In a previous study, we revealed that tumor necrosis factor (TNF) was secreted in mouse liver at an early phase of liver regeneration after partial hepatectomy. Here, we investigated direct actions of TNF on the in vitro DNA synthesis of adult mouse hepatocytes in primary culture. TNF enhanced both 3H-TdR uptake and the number of 3H-TdR-labeled nuclei of hepatocytes. Their time courses were similar to those by epidermal growth factor (EGF) with about a 15 h lag period and a peak period of 24-48 h. This action of TNF was abrogated by DNA polymerase α inhibitor, aphidicolin and blocked specifically by anti-TNF antibody. The actions of rm TNF were not distinguishable; ED50 was about 7.5U/ml (5ng/ml) and 30U/ml (20ng/ml) for maximal response (about 2-fold or more of control). Other inflammatory monokines showed differential effects on in vitro DNA synthesis of hepatocyte. Neither type of interleukin 1 affected hepatocyte DNA synthesis in the range examined (up to 50 ng/ml). IL-6 markedly inhibited the hepatocyte DNA synthesis stimulated by TNF and EGF. The action of TNF was completely suppressed by transforming growth factor β, which is known as a potent inhibitor of hepatocyte growth. Interferon γ also blocked this TNF action when added simultaneously. These results indicate that the activation of tissue macrophages and local secretion of TNF in liver after partial hepatectomy is of physiological importance in liver regeneration, in part by a direct stimulation of hepatocyte DNA synthesis. Cytokines induced by TNF may also participate in the later termination of liver regeneration.
    Additional Material: 5 Ill.
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