Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53(-/)- C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS(-/)- mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS(-/)- and p53(-/)- mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.
 ...
PMID:Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung. 1099 16

The antiproliferative effect of Tempol, a stable nitroxide free radical, was investigated on the p53-negative human leukemia cell line HL60. A concentration- and time-dependent inhibition of cell growth was observed that appears to be due to induction of apoptosis. Involvement of oxidative stress is indicated by a concentration-dependent increase in intracellular peroxides and a parallel decrease in total cellular glutathione; in addition, increased survival rates were observed in cells simultaneously treated with Tempol and the antioxidant N-acetylcysteine. Tempol did not affect the relative levels of Bax and Bcl2, whereas p21(WAF1/CIP1) was enhanced in a concentration- and time-dependent fashion; this effect was partially inhibited by N-acetylcysteine, was maintained for up to 8 h after Tempol removal, and seemed to depend on continuing protein synthesis. The increase in p21(WAF1/CIP1) was accompanied by a parallel accumulation of cells in the G(1) phase of the cycle and by a decrease in the 110 kDa form of pRb. Our results suggest that p53-independent induction of p21(WAF1/CIP1) mediates the antiproliferative effect of Tempol; on the basis of this observation, the nitroxide could be proposed as an useful adjunct to the treatment of p53-deficient tumors, which are often refractory to standard chemotherapy.
 ...
PMID:The nitroxide tempol induces oxidative stress, p21(WAF1/CIP1), and cell death in HL60 cells. 1103 15

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.
 ...
PMID:Apoptosis modulators in the therapy of neurodegenerative diseases. 1106 Jul 7

This study demonstrates that cupric 8-quinolinoxide (CuQ) has induced genetic toxicity in bacteria and mammalian cells through a mechanism of reactive oxygen species (ROS) generation. In the Ames test with rat liver S9, CuQ dose-dependently caused a point mutation in Salmonella typhimurium TA100. The effect of CuQ on DNA damage in HL60 and V79 cells identified in the comet assay is direct and enhanced by the addition of S9. Meanwhile, the tailing length of comet DNA is related to the increasing dosage of CuQ. The genotoxic effect of CuQ on either gene mutation in bacteria or DNA damage in culture cells can be generally blocked by several antioxidants, e.g. pyrrolidinedithiocarbamate, N-acetylcysteine, Vitamins C and E. Supportive of this observation, ROS generation induced by CuQ can be demonstrated both in vitro and in vivo by using the DCFH-DA fluoroprobe. The CuQ-induced intracellular ROS level is also dramatically inhibited by the above antioxidants. Above results imply that the CuQ-induced genotoxicity could be mediated by ROS generation. The nature of ferrous-dependent and S9-enhancing in CuQ-induced ROS generation hints a Fenton-like reaction or some specific enzymes activation could be involved in this process. Furthermore, a DNA damage- and oxidative stress-dependent protein, P53, could also been induced by CuQ treatments in a time-course and dose-dependent manners. Its expression level is recoverable by antioxidants too. In conclusion, our current study strongly suggests that CuQ induces gene mutation, global DNA damage, and P53 expression through a ROS-dependent mechanism.
 ...
PMID:Role of reactive oxygen species in cupric 8-quinolinoxide-induced genotoxic effect. 1128 97

The antioxidant pyrrolidinedithiocarbamate improves the therapeutic efficacy of 5-fluorouracil (5-FU) against HCT-15 colorectal cancer cell line xenografts in nude mice without increasing toxicity to normal intestinal or hematopoietic tissues. In the current study we have shown that a similar clinically licensed antioxidant, N-acetylcysteine (200 mg/kg), can modulate the activity of 5-FU (120 mg/kg) against HCT-15 tumor xenografts in nude mice. We demonstrate that this effect is accompanied by a sustained elevation in p53-independent apoptosis without accompanying alterations in cell cycle kinetics. Extensive tumor necrosis is also a prominent feature of treatment; however, no significant impairment of neovascularization as assessed by intratumor microvessel density occurred. We believe that the clinical efficacy of N-acetylcysteine as an adjunct to 5-FU in advanced colorectal cancer should be investigated further.
 ...
PMID:The antioxidant n-acetylcysteine increases 5-fluorouracil activity against colorectal cancer xenografts in nude mice. 1130 53

Recent studies in cell culture have shown that isothiocyanates (ITCs) induce apoptosis via activation of mitogen-activated protein (MAP) kinases and p53 pathways, suggesting a potential for ITCs or their conjugates to inhibit tumorigenesis during the postinitiation phase. To evaluate whether ITC compounds administered after carcinogen treatment inhibit lung tumorigenesis, we investigated in A/J mice the effects of the N-acetylcysteine (NAC) conjugates of benzyl (BITC-NAC) and phenethyl ITC (PEITC-NAC) in the diet (15 micromol/g) administered after a single dose of 20 micromol benzo(a)pyrene [B(a)P]. The formation of lung adenomas was examined 140 days after B(a)P dosing. Both the BITC-NAC and PEITC-NAC-treated groups showed a significant reduction in lung tumor multiplicity from 6.1 +/- 3.1 tumors/mouse in the B(a)P group fed the control diet to 3.7 +/- 2.9 and 3.4 +/- 2.7 tumors/mouse (P = 0.018 and 0.006, respectively). To investigate the mechanisms of tumor inhibition, lung tissues were obtained at 21, 84, and 140 days at interim sacrifices during the bioassay. These tissues showed a significant increase in apoptosis as determined by in situ end-labeling for both ITC-NAC-treated groups. The MAP kinase pathway was activated in the ITC-NAC-treated groups. The activation of c-Jun NH(2)-terminal kinase was higher in the BITC-NAC and PEITC-NAC groups when compared with B(a)P-treated control. The phosphorylation of p38 and extracellular signal-regulated kinases (ErKs) 1 and 2 was also induced by these treatments. To determine the downstream target of MAP kinases, activator protein-1 (AP-1) and nuclear factor-kappaB activities were evaluated by gel shift assay. The AP-1 binding activity was remarkably increased in lung tissue from both the BITC-NAC and PEITC-NAC groups. No change in nuclear factor-kappaB binding activity was found, however. Phosphorylation of p53 was also higher than the constitutive levels in both ITC-NAC-treated groups, but no induction of p53 expression was detected. This study demonstrates the chemopreventive efficacy of the NAC conjugates of PEITC and BITC administered in the diet after a single dose of B(a)P for lung tumorigenesis and provides the first in vivo evidence that activation of MAP kinases, AP-1 transcription factors, p53 phosphorylation, and the induction of apoptosis may be involved in the chemopreventive activity of these compounds.
 ...
PMID:Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary N-acetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis. 1178 48

Some recent evidence has suggested a protective role of zinc against cancer. The mechanism by which zinc exerts this action has not been defined and, in particular, it has not been clarified whether zinc may directly act on cancer cells and the molecular mechanisms involved in this effect. In this study, we examined the in vitro effect of zinc on the apoptosis of mouse TS/A mammary adenocarcinoma cells, studying the zinc-dependent modulation of the intracellular levels of reactive oxygen species (ROS) and of p53 and Fas/Fas ligand pathways. We showed that zinc concentrations ranging from 33.7 to 75 muM Zn(2+) induced apoptosis in mammary cancer cells. The apoptosis was associated with an increased production of intracellular ROS, and of p53 and Fas/Fas ligand mRNA and protein. Zn(2+) induced a faint metallothionein response in TS/A cells in comparison with mouse lymphocytes. The treatment of tumor cells with the antioxidant N-acetylcysteine was able to prevent Zn(2+)-induced apoptosis, as well as the increase of p53 and Fas ligand protein induced by zinc. The data demonstrate that zinc exerts a direct action on mammary cancer cells inducing ROS-mediated apoptosis and that the effect may be mediated by the ROS-dependent induction of p53 and Fas/Fas ligand.
 ...
PMID:Reactive oxygen species modulate Zn(2+)-induced apoptosis in cancer cells. 1186 83

Advanced glycation end products (AGE) have been implicated in the pathogenesis of glomerulosclerosis in diabetes. However, their involvement in the development of the early phase of diabetic nephropathy has not been fully elucidated. We investigated the effects of AGE on growth and on vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) expression in human cultured mesangial cells. We prepared three immunochemically distinct AGE by incubating bovine serum albumin (BSA) with glucose, glyceraldehyde, or glycolaldehyde. When human mesangial cells were cultured with various types of AGE-BSA, viable cell numbers as well as DNA syntheses were significantly decreased. All of the AGE-BSA were found to significantly increase p53 and Bax protein accumulations and subsequently induce apoptotic cell death in mesangial cells. An antioxidant, N-acetylcysteine, significantly prevented the AGE-induced apoptotic cell death in mesangial cells. Human mesangial cells stimulated prostacyclin production by co-cultured glomerular endothelial cells. Furthermore, various types of AGE-BSA were found to up-regulate the levels of mRNAs for VEGF and stimulate the secretion of VEGF and MCP-1 proteins in mesangial cells. The results suggest that AGE disturbed glomerular homeostasis by inducing apoptotic cell death in mesangial cells and elicited hyperfiltration and microalbuminuria by stimulating the secretion of VEGF and MCP-1 proteins, thereby being involved in the pathogenesis of the early phase of diabetic nephropathy.
 ...
PMID:Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. 1191 19

We demonstrate that by simply raising extracellular pyruvate levels, and hence increasing metabolic supply, human diploid fibroblasts undergo a concentration-dependent induction of cellular senescence. Fibroblasts treated with pyruvate undergo a rapid growth arrest accompanied by elevated levels of the cell-cycle regulatory molecules p53, p21, and p16. These cells also exhibit a rise in mitochondrial oxidant production and a fall in intracellular glutathione levels. Exposure of pyruvate treated cells to the antioxidant and glutathione precursor N-acetylcysteine restores cell growth and reverses the increase in senescence-associated beta-galactosidase activity. Similarly, we demonstrate that by increasing mitochondrial number via retroviral-mediated expression of the mitochondrial biogenesis regulator PGC-1 there is also a reduction in cell growth and the more rapid induction of senescence. These results suggest that mitochondria appear to play a central role in regulating cellular life span.
 ...
PMID:A role for mitochondria as potential regulators of cellular life span. 1205 1

Tetrandrine (TET), a plant alkaloid, is known primarily as a non-selective Ca(2+) channel blocker. On the contrary to the cytoprotective effect on ischemia/reperfusion injury, TET has also been reported to cause cytotoxicity. In this study, we wished to understand the apparently disparate effects of this potential drug and thus investigated molecular mechanisms on proliferation and apoptosis and its effect on oxidative stress-induced apoptosis in Neuro 2a mouse neuroblastoma cells. We showed that TET, at high concentrations, induced cell cycle arrest and apoptosis through oxidative stress with following observations. Firstly, 10 microM TET elevated the reactive oxygen species (ROS) level and accordingly depleted glutathione (GSH) content. Secondly, pretreatment with antioxidants (NAC or GSH) protected cells from TET-induced apoptosis. We also demonstrated that treatment with 10 microM TET caused not only induction of p53, p21(waf1), and Bax, but also nuclear translocation of p53 and hypo-phosphorylation of pRb concurrently. Our important finding is that the concentration-dependent dual effect of TET, either inhibiting or promoting cell death induced by H(2)O(2) was observed, probably through regulating redox balance, which was well reflected on the GSH content in each condition. Besides, inhibition of Ca(2+) influx protected cells from H(2)O(2)-induced apoptosis even in the presence of 10 microM TET. Taken together, our data suggest that TET regulation of cellular redox states may play a major role in its dual action of cytotoxicity and cytoprotection.
 ...
PMID:Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells. 1217 98


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