共查询到20条相似文献,搜索用时 31 毫秒
1.
Arimura T Kojima-Yuasa A Watanabe S Suzuki M Kennedy DO Matsui-Yuasa I 《Chemico-biological interactions》2003,145(3):337-347
Herbal medicines are increasingly being utilized to treat a wide variety of disease processes. Evening primrose extract (EPE) is extracted from Oenothera biennis L., one species of evening primroses, which has been shown to have several pharmacological effects. However, anti-tumor activity in the extract of defatted seeds of O. biennis L. has not been defined thus far. In this study, we identified the major biochemical changes upon EPE treatment and investigated the functional relationship between these changes. We found that EPE-induced apoptosis in Ehrlich ascites tumor cells as evidenced by morphological changes. Furthermore, our results demonstrated rapid increase of intracellular peroxides levels, loss of mitochondrial membrane potential and the release of cytochrome c from mitochondria to cytosol. These results suggest that the rapid increase of intracellular peroxides levels after addition of EPE triggers off induction of apoptosis. 相似文献
2.
Summary. The programmed cell death is a very complex mechanism involving many factors, among them the intracellular concentration of biogenic amines (BA) appears to be important for apoptosis triggering. The mitochondrial damage is imputable to hydrogen peroxide and aldehydes, produced by amine oxidases (AO)-mediated oxidation of BA. On the other hands, the apoptosis protection observed by high BA concentration appears to be related to their scavenger effect of ROS and/or their interaction with membrane pores. Also monoamine oxidase (MAO) inhibitors, like propargylamines, preserve the mitochondria integrity by inhibiting MAO and therefore the production of H2O2 and aldehydes and, as cations, by regulating membrane pores, like BA.As general conclusion, apoptosis is protected by high concentration of BA and/or other cations while it is favoured by ROS produced by AOs or other mechanisms. 相似文献
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Tantini B Pignatti C Fattori M Fiumana E Facchini A Stefanelli C Caldarera CM Pegg AE Flamigni F 《Amino acids》2004,27(2):207-214
Summary. In a previous research, we have shown that adequate levels of polyamines are required in transformed mouse fibroblasts for the correlated activations of MAPK subtypes (ERK and JNK) and caspases induced by etoposide and leading to apoptosis. We report now that the treatment of fibroblasts with etoposide also elicited a progressive and sustained increase of NF-B activation. The DNA binding activity of p65 NF-B subunit was increased up to approximately 4-fold and was accompanied by enhancement of p65 phosphorylation. A two days pre-treatment of fibroblasts with -difluoromethylornithine (DFMO), which caused polyamine depletion, provoked a slight activating effect when given alone, but markedly inhibited the etoposide-induced increases in p65 DNA binding and phosphorylation. The NF-B inhibiting effect of DFMO was prevented by the addition of exogenous putrescine, which restored the intracellular content of polyamines. Selective inhibitors of the etoposide-stimulated MAPK subtypes also reduced NF-B activation. Moreover, pharmacological NF-B inhibition reduced the increase in caspase activity and cell death elicited by etoposide, suggesting that NF-B is involved in signaling to apoptosis. The results of the present study, together with our previous findings, suggest that polyamines play a permissive role in the pathways triggered by etoposide and leading to cell death of fibroblasts, by supporting the activation of MAPKs, NF-B and caspases. 相似文献
5.
Reactive oxygen species modify DNA, generating various DNA lesions including modified bases such as 8-oxoguanine (8-oxoG). These base-modified DNA lesions have been shown to trap DNA topoisomerase I (TOP1) into covalent cleavage complexes. In this study, we have investigated the role of TOP1 in hydrogen peroxide toxicity. We showed that ectopic expression of TOP1 in Saccharomyces cerevisiae conferred sensitivity to hydrogen peroxide, and this sensitivity was dependent on RAD9 checkpoint function. Moreover, in the mammalian cell culture system, hydrogen peroxide-induced growth inhibition and apoptosis were shown to be partly TOP1-dependent as evidenced by a specific increase in resistance to hydrogen peroxide in TOP1-deficient P388/CPT45 murine leukemia cells as compared with their TOP1-proficient parental cell line P388. In addition, hydrogen peroxide was shown to induce TOP1-DNA cross-links. These results support a model in which hydrogen peroxide promotes the trapping of TOP1 on oxidative DNA lesions to form TOP1-DNA cleavage complexes that contribute to hydrogen peroxide toxicity. 相似文献
6.
Endo N Nishiyama K Okabe M Matsumoto M Kanouchi H Oka T 《Biochimica et biophysica acta》2007,1770(4):571-577
Hyperhomocysteinemia is an important risk factor for atherosclerosis. We previously reported that formation of early atherosclerosis in the rat aorta was associated with hyperhomocysteinemia and reduction of antioxidant activity caused by low concentration of vitamin B(6)in vivo. In the present study, we examined effects of vitamin B(6) on apoptosis of bovine endothelial cells (NM-1 cells) treated with homocysteine and copper. Homocysteine and copper induced extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. Cell viability was reduced to 30% compared to that of control cells. On the other hand, pyridoxal treatment as well as EDTA treatment increased viability of NM-1 cells treated with homocysteine and copper to about 60%, and significantly decreased extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. The treatment of catalase recovered cell viability and reduced the level of extracellular hydrogen peroxide and intracellular ROS. Cell death by homocysteine and copper was confirmed to be due to apoptosis by evaluation of DNA fragmentation and by TUNEL assay. However, apoptosis of NM-1 cells induced by homocysteine and copper was due to a caspase-independent pathway as it was not inhibited by the caspase inhibitor, Z-VAD-fmk. Apoptosis of NM-1 cells induced by homocysteine and copper accompanied with mitochondrial permeability but not cytochrome c release. These results suggest that pyridoxal treatment suppresses apoptosis of NM-1 cells induced by homocysteine and copper, most likely through antioxidant effects. 相似文献
7.
Endogenous production of hydrogen sulfide in mammals 总被引:7,自引:0,他引:7
Kamoun P 《Amino acids》2004,26(3):243-254
Summary. Hydrogen sulfide is one of three gases involved in biological functions and synthesized in vivo. Like NO and CO, it seems to act as a neuromodulator: it modulates NMDA glutamate receptor function. CBS seems to be the only source of hydrogen sulfide in the brain, whereas the liver synthesizes hydrogen sulfide via cystathionase. In the heart, the third pathway for the hydrogen sulfide synthesis, the 3-mercaptopyruvate pathway is used. Only two diseases characterized by alterations of hydrogen sulfide metabolism have been described: decreased hydrogen sulfide synthesis in the brains of Alzheimers disease patients and increased hydrogen sulfide synthesis due to the overexpression of CBS in Down syndrome patients. 相似文献
8.
Polyamines and cancer: Minireview article 总被引:4,自引:0,他引:4
Bachrach U 《Amino acids》2004,26(4):307-309
Summary. The naturally occurring polyamines, spermine, spermidine and the diamine putrescine are widespread in nature. They have been implicated in growth and differentiation processes. Polyamines accumulate in cancerous tissues and their concentration is elevated in body fluids of cancer patients. Assays of urinary and blood polyamines have been used to detect cancer and to determine the success of therapy. Drugs which inhibit the synthesis of polyamines can prevent cancer and may also be used for therapeutic purposes. Ornithine decarboxylase, which catalyzes the rate limiting step in polyamine synthesis, can serve as a marker of proliferation. Recently, a new in vitro chemosensitivity test, based on the disappearance of ornithine decarboxylase in drug-treated cancer cells has been developed. The increasing interest in polyamines and their physiological functions may lead to a more extensive application of these compounds or their derivatives in cancer diagnosis and treatment. 相似文献
9.
Our previous studies demonstrated that ricin induces the apoptotic death of U937 cells as evidenced by DNA fragmentation, nuclear morphological changes, and increases in caspase-like activities. In this study, we have found that intracellular NAD(+) and ATP levels decrease in ricin-treated U937 cells and that this decrease is followed by the ricin-mediated protein synthesis inhibition. The PARP inhibitor, 3-aminobenzamide (3-ABA), prevents the depletion in NAD(+) and ATP levels and concomitantly protects U937 cells from the lysis that follows ricin treatment. Hence, the protective action of 3-ABA is due to the inhibition of PARP and does not result from its other pharmacological side effects. Moreover, the enzymatic activity of PARP gradually increases and reaches a maximum level after ricin exposure for 3 h, whereas no significant change in activity was observed in untreated cells. However, 3-ABA has no effect on ricin-mediated DNA fragmentation. In addition, immunoblot analysis revealed that significant PARP cleavage occurred more than 12 h after ricin addition, while DNA fragmentation reached a maximum level within 6 h of incubation. Thus, in the case of ricin-induced apoptosis, it appears that PARP cleavage is not an early apoptotic event associated with the onset of apoptosis. Our results suggest that multiple apoptotic signaling pathways may be triggered by ricin-treatment. Probably, the pathway leading to cell lysis via PARP activation and NAD(+) depletion is independent of the pathway leading to DNA fragmentation in which caspases may be profoundly involved. Other protein synthesis inhibitors, including diphtheria toxin and cycloheximide, were less effective in terms of inducing DNA fragmentation and cytolysis, even at concentrations that cause significant inhibition of protein synthesis. Thus, a specific ricin action mechanism through which ribosomes are inactivated may be responsible for the apoptotic events induced by ricin. 相似文献
10.
Naoko Endo Kazuo Nishiyama Masaaki Okabe Mitsuharu Matsumoto Hiroaki Kanouchi Tatsuzo Oka 《Biochimica et Biophysica Acta (BBA)/General Subjects》2007
Hyperhomocysteinemia is an important risk factor for atherosclerosis. We previously reported that formation of early atherosclerosis in the rat aorta was associated with hyperhomocysteinemia and reduction of antioxidant activity caused by low concentration of vitamin B6in vivo. In the present study, we examined effects of vitamin B6 on apoptosis of bovine endothelial cells (NM-1 cells) treated with homocysteine and copper. Homocysteine and copper induced extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. Cell viability was reduced to 30% compared to that of control cells. On the other hand, pyridoxal treatment as well as EDTA treatment increased viability of NM-1 cells treated with homocysteine and copper to about 60%, and significantly decreased extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. The treatment of catalase recovered cell viability and reduced the level of extracellular hydrogen peroxide and intracellular ROS. Cell death by homocysteine and copper was confirmed to be due to apoptosis by evaluation of DNA fragmentation and by TUNEL assay. However, apoptosis of NM-1 cells induced by homocysteine and copper was due to a caspase-independent pathway as it was not inhibited by the caspase inhibitor, Z-VAD-fmk. Apoptosis of NM-1 cells induced by homocysteine and copper accompanied with mitochondrial permeability but not cytochrome c release. These results suggest that pyridoxal treatment suppresses apoptosis of NM-1 cells induced by homocysteine and copper, most likely through antioxidant effects. 相似文献
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U937 human myeloid leukemia cells respond to mild treatment with hydrogen peroxide and hyperthermia by undergoing apoptosis, an active mode of cell suicide. Higher concentrations of hydrogen peroxide, or longer incubation at the hyperthermic temperature, change the mode of cell death from apoptosis to the passive necrosis. Stress treatments cause a severe drop in the intracellular NAD concentration. 3-Aminobenzamide (3-ABA), a specific inhibitor of poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme which is activated by breaks in DNA to catabolize intracellular NAD, is capable of relieving such a drop. This suggests that breaks in DNA have been induced by both oxidative stress and heat shock, thereby activating PARP. Upon stress, NAD concentration has a first initial sharp drop; then, for mild stress treatments, it recovers, just when apoptosis begins to be detectable (8 h of recovery). At 20 h, when the apoptotic ladder-like pattern of DNA is visible, NAD concentration has dropped again, probably because of a second PARP activation due to the extensive DNA degradation that accompanies apoptosis. The presence of 3-ABA, concomitantly with the preservation of the intracellular NAD content, reduces the extent of apoptosis upon oxidative stress and strongly enhances cell survival, thus suggesting a role for PARP in triggering stress-induced apoptosis. All apoptotic U937 cells have a reduced NAD content, independently of the inducing agent; however, upon treatments which do not cause immediate DNA breaks, the drop in NAD concentration occurs only after the apoptotic ladder is detectable and can be ascribed to the activation of PARP by the free ends of DNA formed during the endonucleolitic degradation. Moreover, in these instances the inhibition of PARP, although effective in blocking the drop in NAD concentration, has no effect on apoptosis, thus being only circumstantial. 相似文献
13.
Unahara Y Kojima-Yuasa A Higashida M Kennedy DO Murakami A Ohigashi H Matsui-Yuasa I 《Amino acids》2007,33(3):469-476
Summary. 1′-Acetoxychavicol acetate (ACA) has been shown to inhibit tumor cell growth, but there is limited information on its effects
on cell signaling and the cell cycle control pathway. In this study, we sought to determine how ACA alters cell cycle and
its related control factors in its growth inhibitory effect in Ehrlich ascites tumor cells (EATC). ACA caused an accumulation
of cells in the G1 phase and an inhibition of DNA synthesis, which were reversed by supplementation with N-acetylcysteine
(NAC) or glutathione ethyl ester (GEE). Furthermore, ACA decreased hyperphosphorylated Rb levels and increased hypophosphorylated
Rb levels. NAC and GEE also abolished the decease in Rb phosphorylation by ACA. As Rb phosphorylation is regulated by G1 cyclin
dependent kinase and CDK inhibitor p27kip1, which is an important regulator of the mammalian cell cycle, we estimated the amount of p27kip1 levels by western blotting. Treatment with ACA had virtually no effect on the amount of p27kip1 levels, but caused a decrease in phosphorylated p27kip1 and an increase in unphosphorylated p27kip1 as well as an increase in the nuclear localization of p27kip1. These events were abolished in the presence of NAC or GEE. These results suggest that in EATC, cell growth inhibition elicited
by ACA involves decreases in Rb and p27kip1 phosphorylation and an increase in nuclear localization of p27kip1, and these events are dependent on the cellular thiol status. 相似文献
14.
M Fiorani M Fumo P Sestili F Cattabeni O Cantoni 《Chemico-biological interactions》1990,76(1):129-139
The DNA synthesis inhibitory effect of hydrogen peroxide has been examined under a number of experimental conditions. Results have indicated that the effect of the oxidant is more pronounced when the treatment is performed at 37 degrees C than at 4 degrees C and in low density as compared to high density cultures. In addition, similar levels of inhibition were achieved by measuring the incorporation of radiolabelled thymidine in the presence of, or following treatment with, the oxidant. Although early events seem to be responsible for the decreased rate of DNA synthesis, it would appear that hydrogen peroxide does not alter thymidine extracellularly and/or decrease the transport of the nucleoside across the plasma membrane, which may actually be slightly augmented. Thus, the previously illustrated results may represent an underestimate of the actual capacity of the oxidant to reduce DNA synthesis. This inference is further supported by the fact that the effect of hydrogen peroxide appears markedly enhanced in cells preloaded with the radiolabelled precursor. A temporal relationship seems to exist between the steady state level of DNA single strand breaks and the extent of DNA synthesis inhibition by hydrogen peroxide. The oxidant has no effect on DNA chain elongation. In conclusion, data presented in this paper suggest that early events, involving selective effects on replicon initiation, mediate the DNA synthesis inhibitory effect of hydrogen peroxide. 相似文献
15.
Shin JS Kang KA Kim ES Zhang R Piao MJ Ko DO Wang ZH Maeng YH Eun SY Chae S Chung HS Hyun JW 《Cell biology international》2008,32(9):1099-1107
We have elucidated the cytoprotective effect of annphenone (2,4-dihyroxy-6-methoxy-acetophenone 4-O-beta-d-glucopyranoside) against oxidative stress-induced apoptosis. Annphenone scavenged intracellular reactive oxygen species (ROS) and increased antioxidant enzyme activities. It thereby prevented lipid peroxidation and DNA damage, which was demonstrated by the inhibition of the formation of thiobarbituric acid reactive substance (TBARS), inhibition of the comet tail and decreased phospho-H2A.X expression. Annphenone protected Chinese hamster lung fibroblast (V79-4) cells from cell death via the inhibition of apoptosis induced by hydrogen peroxide (H(2)O(2)), as shown by decreased apoptotic nuclear fragmentation, decreased sub-G(1) cell population and inhibited mitochondrial membrane potential (Deltapsi) loss. Taken together, these findings suggest that annphenone exhibits antioxidant properties by inhibiting ROS generation and thus protecting cells from H(2)O(2)-induced cell damage. 相似文献
16.
Marra M Agostinelli E Tempera G Lombardi A Meo G Budillon A Abbruzzese A Giuberti G Caraglia M 《Amino acids》2007,33(2):273-281
Summary. A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein
synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid
hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines
such as interferonα (IFNα) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment
of cancer cells with IFNα and the protein synthesis inhibitor fusion protein TGFα/Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation
of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously
to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several
cell types. The enzymatic oxidation products of polyamine, H2O2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide
or docetaxel, in cancer cells is potentiated in the presence of BSAO/Spermine. In conclusion, polyamine metabolites could
be useful in the design of new therapeutic strategies. 相似文献
17.
Zhang HM Rao JN Guo X Liu L Zou T Turner DJ Wang JY 《The Journal of biological chemistry》2004,279(21):22539-22547
Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is regulated by numerous factors including polyamines. Although the exact roles of polyamines in apoptotic pathway are still unclear, inhibition of polyamine synthesis promotes the resistance of intestinal epithelial cells to apoptosis. Akt is a serine-threonine kinase that has been established as an important intracellular signaling in regulating cell survival. The current studies test the hypothesis that polyamines are involved in the control of Akt activity in normal intestinal epithelial cells (IEC-6 line) and that activated Akt mediates suppression of apoptosis following polyamine depletion. Depletion of cellular polyamines by alpha-difluoromethylornithine induced levels of phosphorylated Akt and increased Akt kinase activity, although it had no effect on expression of total Akt, pERK, p38, and Bcl-2 proteins. This activated Akt was associated with both decreased levels of active caspase-3 and increased resistance to tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Inactivation of Akt by either treatment with LY294002 or ectopic expression of a dominant negative Akt mutant (DNMAkt) not only enhanced the caspase-3 activation in polyamine-deficient cells but also prevented the increased resistance to tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Phosphorylation of glycogen synthase kinase-3, a downstream target of Akt, was also increased in alpha-difluoromethylornithine-treated cells, which was prevented by inactivation of Akt by LY294002 or DNMAkt overexpression. These results indicate that polyamine depletion induces the Akt activation mediating suppression of apoptosis via inhibition of caspase-3 in normal intestinal epithelial cells. 相似文献
18.
Polyamines, namely putrescine, spermidine, and spermine, are essential for cell survival and proliferation. A decrease in intracellular polyamine levels is associated with apoptosis. In this study, we used inhibitors of polyamine biosynthesis to examine the effect of polyamine depletion. A combination of inhibitors of ornithine decarboxylase, S-adenosylmethionine decarboxylase, or spermidine synthase decreased intracellular polyamine levels and induced cell death in a WEHI231 murine B cell line. These cells exhibited apoptotic features including chromatin condensation and oligonucleosomal DNA fragmentation. Addition of exogenous polyamines reversed the observed features of apoptotic cell death. Similar effects were also observed in other cell lines: a human B cell line Ramos and a human T cell line Jurkat. Depletion of polyamines induced activation of caspase-3 and disruption of the mitochondrial membrane potential (Delta psi m). Inhibition of caspase activities by an inhibitor prevented the apoptotic nuclear changes but not Delta psi m disruption induced by polyamine depletion. Overexpression of Bcl-xl, an anti-apoptotic Bcl-2 family protein, completely inhibited Delta psi m disruption, caspase activation, and cell death. These results indicate that the depletion of intracellular polyamines triggers the mitochondria-mediated pathway for apoptosis, resulting in caspase activation and apoptotic cell death. 相似文献
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The influence of polyamines on the various activities of DNA polymerase I from Escherichia coli (EC 2.7.7.7) has been investigated. For all high molecular weight DNAs spermine and spermidine caused up to 80% inhibition when present in high concentrations, i.e. above 1 mM for spermine and 2 mM for spermidine. In the presence of low concentrations of polyamines a small activation was seen for some DNAs. The diamines cadaverine and putrescine had little influence on the rate of synthesis with natural occurring DNAs. In the case of d(A--T)n the activation/inhibition was found to be markedly dependent on the molecular weight of the samples used. With a low molecular weight DNA, 5.6 S, addition of spermidine resulted in up to 3-fold stimulation of activity. The activation was dependent on the concentration of MgCl2 and ionic strength; increasing concentration of these gave a decrease in the degree of activation. Polyamines also had a dramatic effect on the rate of synthesis using the homopolymers (dA)n . (dT)10 and (rA)n . (dT)10 . (20:1) as primers. Putrescine, in particular, increased the activity up to 10-fold with (rA)n . (dT)10 and somewhat less for (dA)n . (dT)10. The apparent Km for the primer (rA)n . (dT)10 decreased approx. 35-fold in the presence of 6.6 mM putrescine. There was no influence on the apparent Km for dTTP. The influence of polyamines on both the 5' leads to 3' and 3' leads to 5' nuclease activity was also investigated. Inhibition of nuclease activity was observed in the presence of polyamines, particularly with spermine. Thus with d(A--T)n and T7 DNA as substrates addition of 0.7 mM spermine resulted in almost complete inhibition of the activity. The dramatic inhibition observed with high concentrations of spermine (spermidine) both in the case of polymerizing and nuclease activity is thought to be due to polyamine-induced aggregation of DNA molecules. 相似文献