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PubMed2004

Pirfenidone inhibits the induction of iNOS stimulated by interleukin-1beta at a step of NF-kappaB DNA binding in hepatocytes.

BACKGROUND/AIMS: Pirfenidone has antiinflammatory effects in animals with endotoxemia. We reported that pirfenidone inhibits the enhancement of inflammatory cytokines and inducible nitric oxide synthase (iNOS) in liver of endotoxin-treated rats, leading to the prevention of hepatic injury. However, the mechanisms involved in suppression of these gene inductions are obscure. Studies were performed to investigate whether pirfenidone directly influences iNOS induction in hepatocytes. METHODS: Cultured hepatocytes were treated with interleukin-1beta (IL-1beta) in the presence and absence of pirfenidone, and iNOS induction and its signal including NF-kappaB were analyzed. RESULTS: Pirfenidone inhibited the induction of iNOS mRNA and protein, resulting in the decrease of nitric oxide production. Gel shift assay demonstrated that pirfenidone inhibited the activation of NF-kappaB. Consistent with this observation, transfection experiments revealed that pirfenidone decreased transcriptional activation of iNOS gene promoter. In contrast, pirfenidone had no effect on the degradation of IkappaB, and could not prevent nuclear translocation of p50/p65. Finally, pirfenidone inhibited the activation of Akt and up-regulation of IL-1 receptor stimulated by IL-1beta. CONCLUSIONS: Results indicate that pirfenidone inhibits the induction of iNOS gene expression at a step of NF-kappaB DNA binding, but not its nuclear translocation, partly through the inhibition of IL-1 receptor induction in hepatocytes.

Animals↗

PubMed2004

Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma.

OBJECTIVES: Induction therapy is an important treatment option in locally advanced non-small cell lung cancer. F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has an important role in initial staging. The aim of this study was to assess the value of FDG-PET in restaging after induction therapy and in analyzing tumor viability, nodal status, distant metastases, and prognosis. METHODS: Forty-seven patients with locally advanced non-small cell lung cancer accepted for resection after induction therapy underwent FDG-PET. Images were interpreted visually for mediastinal nodal status and metastatic spread. The FDG accumulation in the tumor site was measured by using the maximum standardized uptake value. RESULTS: Unexpected metastases were detected by means of FDG-PET in 9 patients. Surgical intervention was not performed in 8 patients with confirmed metastases. The rate of unexpected findings increased from complete radiologic remission (0%) over partial remission (9%) to no change (67%). The standardized uptake value was higher in tumors with (n = 26) than in those without (n = 11) histologic proof of viability (6.4 +/- 5.3 vs 2.9 +/- 1.6, P = .006). All patients with standardized uptake values of greater than 5.8 had viable tumors. Sensitivity, specificity, and negative predictive value were 81%, 64%, and 58% for tumor viability and 50%, 88%, and 85% for persistent mediastinal disease. Median survival after resection was greater than 56 months for patients with tumor standardized uptake values of less than 4 and 19 months for patients with standardized uptake values of 4 or greater ( P < .001). CONCLUSION: FDG-PET helps in the selection of patients for resection after induction therapy. It can be used to detect unexpected distant metastases, especially after poor response to induction therapy. Its high negative predictive value in mediastinal restaging allows for omission of repeat mediastinoscopy. Tumor standardized uptake value after induction is a prognostic factor.

Adenocarcinoma↗

PubMed2004

The role of protein tyrosine kinases in CYP1A1 induction by omeprazole and thiabendazole in rat hepatocytes.

Benzimidazoles compounds like omeprazole (OME) and thiabendazole (TBZ) mediate CYP1A1 induction differently from classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene (3-MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). To clarify the involvement of an intracellular signal pathway in CYP1A1 induction by OME and TBZ, the TBZ, OME and 3-MC signal-transducing pathways were compared by using specific protein tyrosine kinase inhibitors in primary culture of rat hepatocytes. The effect of OME and TBZ (75-250 microM) on cytochrome P450 1A1 (CYP1A1) expression was therefore studied in primary cultures of rat hepatocytes after 24 h, 48 h and 72 h of exposure. Both compounds provoked a dose- and time-dependent increase in CYP1A1 (EROD activity, protein and mRNA levels), but OME was less effective at all the concentrations and times tested. The mechanism of benzimidazole-mediated induction of CYP1A1 was investigated by comparison with 3-MC, a prototypical AhR ligand. As expected, OME and TBZ were unable to displace [(3)H]-TCDD from its binding sites to the AhR in competitive binding studies. Moreover, classic tyrosine kinase inhibitor herbimycin A (HA) inhibited the two benzimidazoles-mediated CYP1A1 inductions, but only partially inhibited the 3-MC-mediated one. Another two tyrosine kinase inhibitors, Lavendustin A (LA) and genistein (GEN), had no effect on CYP1A1 induction by benzimidazoles and 3-MC. These results are consistent with the implication of a tyrosine kinase, most probably the Src tyrosine kinase, in the mechanism of CYP1A1 induction in rat hepatocytes.

Animals↗

PubMed2005

In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver.

Effects of inhibiting protein kinases and phosphatases on induction of CYP2B by triphenyldioxane (TPD) and phenobarbital (PB) were investigated. Male Wistar rats were treated with test inhibitors before TPD or PB administration. Inhibitors of phosphatidylinositol-3-kinase (Wortmannin) and protein kinase C (bisindolylmaleimide I) did not have appreciable effects on TPD- or PB-induced pentoxyresorufin O-dealkylase (PROD) activity specific for CYP2B, although bisindolylmaleimide I did give substantial induction alone. W-7, an inhibitor of Ca2+/calmodulin-dependent kinase II, produced a 6-fold increase in the TPD-induced PROD activity and did not lead to a significant increase in basal PROD activity. Treatment of rats with okadaic acid (OA), an inhibitor of protein phosphatases PP1 and PP2A, caused considerable decreases in PROD activity during the induction by TPD and PB (8- and 2.5-fold, respectively). Results of multiplex RT-PCR showed that the increase in enzymatic activity from W7 and OA treatment reflected at least in part increased mRNA levels. CYP2B mRNA level in the liver of rats treated with W-7 and TPD was 1.5 times higher than in the liver of TPD-treated rats. This effect was not observed for PB-induction. OA treatment caused a decrease of the CYP2B mRNA levels of 44% and 33% respectively, for TPD- and PB-induction. Thus, our results are consistent with the hypothesis that phosphorylation/dephosphorylation signaling pathways are involved in regulation of CYP2B induction in rat liver.

Androstadienes↗

PubMedDate not supplied

Induction of heme oxygenase-1 in the donor reduces graft immunogenicity.

There is increasing evidence that the induction of the enzyme heme oxygenase-1 (HO-1) improves both graft function and survival. Although it has been shown that HO-1 promotes graft protection, it remains unknown whether it reduces graft immunogenicity by modulating dendritic cells. In the current experiment, we investigated the impact of HO-1 induction on frequencies and trafficking of donor-derived dendritic cells (DCs). Kidneys from DA rats were transplanted into untreated Lewis recipients. Donor animals were treated with cobalt protoporphyrin (CoPP; 5 mg/kg IP) 24 hours prior to organ harvesting to induce HO-1. Controls remained untreated or received zinc protoporphyrin (ZnPP; 20 mg/kg, IP) to block HO-1 induction. Analyses of grafts, spleens, lymph nodes and blood of Lewis recipients were performed at days 1 and 3 posttransplantation. Donor-specific DCs were determined by flow cytometry using haplotype-specific mAb against RT1(ab) and mAb against OX62(+) antigens. Cell markers (CD4/CD8(+) T cells, ED1(+) monocytes, MHC class II(+) CD86(+) DC) were measured by immunohistochemical staining. T-cell alloreactivity of recipient splenocytes was measured by ELISPOT. Induction of HO-1 reduced frequencies of donor-derived DCs in the graft and recipient compartments, which was associated with reduced frequencies of CD4(+) T cells and CD8(+) T cells and alloreactivity. Expression of costimulatory molecule CD86 and MHC class II antigens were also reduced, although not significantly. Thus, induction of HO-1 reduced graft immunogenicity. These mechanisms may explain the protective effects of HO-1 induction.

Animals↗

PubMed2004

The two steps of vulval induction in Oscheius tipulae CEW1 recruit common regulators including a MEK kinase.

The cell interactions that specify the spatial pattern of vulval precursor cell (VPC) fates differ between the nematodes Oscheius tipulae CEW1 and Caenorhabditis elegans. In the former, the centered pattern of fates is obtained by two successive inductions from the gonadal anchor cell, whereas in the latter, a single inductive step by the anchor cell (EGF-Ras-MAP kinase pathway) can act as a morphogen and is reinforced by lateral signaling between the vulval precursors (Notch pathway). We performed a genetic screen for vulva mutants in O. tipulae CEW1. Here we present the mutants that specifically affect the vulval induction mechanisms. Phenotypic and epistatic analyses of these mutants show that both vulval induction steps share common components, one of which appears to be MEK kinase(s). Moreover, the inductive pathway (including MEK kinase) influences the competence of the vulval precursor cells and more strikingly their division pattern as well, irrespective of their vulval fate. Finally, a comparison of vulval mutant phenotypes obtained in C. elegans and O. tipulae CEW1 highlights the evolution of vulval induction mechanisms between the two species.

Animals↗

PubMed2005

Gli function is essential for motor neuron induction in zebrafish.

The Gli family of zinc-finger transcription factors mediates Hedgehog (Hh) signaling in all vertebrates. However, their roles in ventral neural tube patterning, in particular motor neuron induction, appear to have diverged across species. For instance, cranial motor neurons are essentially lost in zebrafish detour (gli1(-)) mutants, whereas motor neuron development is unaffected in mouse single gli and some double gli knockouts. Interestingly, the expression of some Hh-regulated genes (ptc1, net1a, gli1) is mostly unaffected in the detour mutant hindbrain, suggesting that other Gli transcriptional activators may be involved. To better define the roles of the zebrafish gli genes in motor neuron induction and in Hh-regulated gene expression, we examined these processes in you-too (yot) mutants, which encode dominant repressor forms of Gli2 (Gli2(DR)), and following morpholino-mediated knockdown of gli1, gli2, and gli3 function. Motor neuron induction at all axial levels was reduced in yot (gli2(DR)) mutant embryos. In addition, Hh target gene expression at all axial levels except in rhombomere 4 was also reduced, suggesting an interference with the function of other Glis. Indeed, morpholino-mediated knockdown of Gli2(DR) protein in yot mutants led to a suppression of the defective motor neuron phenotype. However, gli2 knockdown in wild-type embryos generated no discernable motor neuron phenotype, while gli3 knockdown reduced motor neuron induction in the hindbrain and spinal cord. Significantly, gli2 or gli3 knockdown in detour (gli1(-)) mutants revealed roles for Gli2 and Gli3 activator functions in ptc1 expression and spinal motor neuron induction. Similarly, gli1 or gli3 knockdown in yot (gli2(DR)) mutants resulted in severe or complete loss of motor neurons, and of ptc1 and net1a expression, in the hindbrain and spinal cord. In addition, gli1 expression was greatly reduced in yot mutants following gli3, but not gli1, knockdown, suggesting that Gli3 activator function is specifically required for gli1 expression. These observations demonstrate that Gli activator function (encoded by gli1, gli2, and gli3) is essential for motor neuron induction and Hh-regulated gene expression in zebrafish.

Animals↗

PubMed2002

Coordinate regulation of UDP-glucuronosyltransferase UGT1A6 induction by 3-methylcholanthrene and multidrug resistance protein MRP2 expression by dexamethasone in primary rat hepatocytes.

Concentration-dependent regulation of 3-methylcholanthrene (MC) inducibility of UDP-glucuronosyltransferase UGT1A6 by the synthetic glucocorticoid, dexamethasone (DEX) was studied. Treatment of cultured rat hepatocytes with MC, 0.1, 1, and 10 microM DEX, and MC combined with DEX, resulted in different induction patterns measured in the intact cells compared to that observed in the microsomes prepared from the same cells. DEX treatment in various concentrations caused a concentration-dependent increase in p-nitrophenol (p-NP) conjugation in intact cells (3-, 4-, and 5-fold over control, respectively), and it positively regulated MC induction (4-, 5-, and 6-fold over control, respectively). In contrast, DEX had smaller effect on microsomal p-NP conjugation (115, 200, 220% of control, respectively) and although MC induction was increased significantly by 0.1 microM DEX (520% of control), but higher concentrations of DEX (10 microM) decreased the degree of induction to 410%. Similar results obtained from in vivo experiments showed that at high DEX concentration (100mg/kg), the rate of MC induction (540%) decreased (420%). Permeabilization of the plasma membrane resulted in a 15-fold increase of p-NP conjugation indicating the importance of transport in the rate of overall p-NP elimination, and the induction pattern was similar to that observed in microsomes isolated from cells. Hyper-osmolarity (405 mOsmol/L) led to a 3-fold decrease of p-NP conjugation, the loss of DEX inducibility and reduction of the MRP2 protein level. Our results suggest coordinated regulation of UGT1A6 inducibility and substrate or product transport by DEX.

Animals↗

PubMed1996

Induction of cytochrome P4501A1 by photooxidized tryptophan in Hepa lclc7 cells.

Mouse hepatoma Hepa-lclc7 (Hepa-1) cells were cultivated in the presence of UV-irradiated amino acids. The results demonstrated that all of the amino acids tested, UV-oxidized tryptophan caused the highest induction of 7-ethoxyresorufin O-deethylase (EROD) activity compared with the controls (P < 0.01). The induction of EROD activity by oxidized tryptophan was dose dependent, and maximal induction was obtained at 12 hr after administration. Studies with various Hepa-1 mutants, which are defective in either the aryl hydrocarbon (Ah) receptor or Ah receptor nuclear translocator protein, indicated that the induction of EROD activity by oxidized tryptophan occurs through the Ah receptor. Gel mobility shift assays using nuclear extracts of Hepa-1 cells revealed that oxidized products of tryptophan can induce both Ah receptor transformation and binding of the liganded Ah receptor complex to its specific DNA recognition site. CYP1A1 mRNA, quantified by reverse transcription-polymerase chain reaction, and CYP1A1 protein were induced markedly in the oxidized tryptophan group compared with the controls. Injection of isolated oxidized tryptophan products into adult male rats caused significant induction of EROD activity in the pulmonary and hepatic microsomes compared with the controls (P < 0.01). These results demonstrated that oxidized tryptophan induces Ah receptor activation and binding of the liganded Ah receptor complex to its specific DNA recognition site, thereby initiating transcription and translation of the CYP1A1 gene with concomitant increase of EROD activity in Hepa-1 cells. Induction of EROD activity in the liver and lungs after injection of isolated oxidized tryptophan products into rats suggests that a similar mechanism may be operative in vivo.

Animals↗

PubMed1999

Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors.

To gain insights into the cellular responses evoked by nitric oxide (NO), we have studied the effects of NO donors with distinct chemistries on the expression of heme oxygenase-1 mRNA by northern blot analysis. The expression levels of heme oxygenase-1 mRNA were increased significantly in DLD-1 human colorectal adenocarcinoma cells by treatment with each of three NO donors: sodium nitroprusside (SNP), S-nitroso-L-glutathione (GSNO), and 3-morpholinosydnonimine (SIN-1). A combination of SIN-1 plus SNP or GSNO additively increased heme oxygenase-1 mRNA expression, whereas synergistic induction was seen with SNP plus GSNO. The SNP-mediated induction was not affected noticeably by extracellular superoxide dismutase, catalase, or mannitol, while the induction by SIN-1 was attenuated by superoxide dismutase. Thus, the SNP-mediated induction of heme oxygenase-1 mRNA expression may be independent of reactive oxygen species, and the induction by SIN-1 is mediated partly by peroxynitrite, which is generated by immediate reaction of NO and superoxide anion. Transient transfection assays suggested that treatment with SNP, but not with GSNO or SIN-1, increased the expression of a reporter gene through a cis-acting element, including the cadmium-responsive element, of the human heme oxygenase-1 gene. These results suggest that SNP induces heme oxygenase-1 mRNA expression through a mechanism different from that for GSNO or SIN-1. We therefore propose that induction of heme oxygenase-1 represents a common cellular response in sensing the signals evoked by distinct NO donors.

Adenocarcinoma↗

PubMed1998

Induction of heme oxygenase-1 after hyperosmotic opening of the blood-brain barrier.

The induction of the stress protein heme oxygenase-1 (HO-1) was studied in the rat brain after intracarotid administration of hyperosmolar mannitol. HO-1 was immunolocalized in fixed sections of brain 24 h to 7 days after injection. Immunoglobulin G (IgG) was immunolocalized in adjacent sections to demonstrate areas of breakdown of the blood-brain barrier. Induction of HO-1 was also evaluated by Western immunoblots, performed at 24 h after the insult. Immunofluorescent double labelling with monoclonal antibodies to HO-1 and either glial fibrillary acidic protein or the complement C3bi receptor was used to determine if glia/macrophages expressed HO-1. There was pronounced, widespread induction of HO-1 in the ipsilateral hemisphere and cerebellum by 24 h both by immunocytochemistry and by Western blots. This induction was markedly attenuated at later times. HO-1 was induced in astrocytes and microglia/macrophages in the ipsilateral hemisphere. In addition, the protein was induced in Bergmann glia and scattered microglia/macrophages in the cerebellum. The mechanism of induction of HO-1 in glia after opening of the blood-brain barrier could include exposure to heme proteins, denatured proteins and other plasma constituents known to induce HO-1. This glial induction may reflect a protective response of these cells.

Animals↗

PubMed1997

Quantitative reverse transcriptase/PCR assay for the measurement of induction in cultured hepatocytes.

Hepatic enzyme induction is often evoked as the cause for a variety of effects in animal studies, e.g. hepatic hypertrophy and secondary thyroid neoplasms in rodents. In clinical practice, enzyme induction often enhances drug clearance and may result in reduced efficacy. For example, carbamazepine or rifampin treatment induces P450 3A in humans, and as a result, dramatically reduces the efficacy of midazolam or cyclosporine. Due to species differences in substrate specificity and the regulation of various drug-metabolizing enzymes, assessing enzyme induction in human tissues is a desirable goal. Since induction often occurs as a result of increased synthesis of mRNA coding for a particular enzyme, induction may be quantified by measuring specific mRNA levels. We describe an approach to quantifying mRNA levels using reverse transcriptase-polymerase chain reaction (RT-PCR). This approach makes use of either radiolabeled PCR primers or fluorimetric quantification of product and does not require the synthesis of a competitor RNA or DNA molecule. Thus, Cyp2B1/2 mRNA can be shown to be induced 17-fold in the H4IIE rat hepatoma cell line. Likewise, Cyp3A and Cyp2A6 mRNAs can be shown to be induced in primary human hepatocytes cultured on collagen-coated plates and treated with rifampin for 72 h. By contrast, mRNA levels for Cyp1A1 and Cyp2E1 were not increased by rifampin treatment. This report demonstrates the potential of this approach for examining a number of mRNAs from drug-treated cultured cells, as a means of assessing metabolic enzyme induction.

Adult↗

PubMed1998

Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously.

OBJECTIVE: To compare the obstetric characteristics of singleton pregnancies conceived by IVF and ovulation induction with those conceived spontaneously. DESIGN: Case-control study. SETTING: Tertiary care medical center. PATIENT(S): All singleton pregnancies that were achieved by IVF (n = 169) and ovulation induction (n = 646) and were delivered from January 1989 through December 1994 were evaluated. Each group was compared with a separate control group that conceived spontaneously (n = 469 and n = 1,902 for the IVF and ovulation induction groups, respectively) and delivered during the same period and was matched in terms of maternal age, gestational age, and parity. INTERVENTION(S): Ovulation induction, IVF-ET. MAIN OUTCOME MEASURE(S): Obstetric complications. RESULT(S): Multivariate analysis showed that patients who conceived by IVF and ovulation induction had a significantly higher risk for gestational diabetes mellitus (odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.23-3.30 and OR = 1.9, 95% CI = 1.09-1.79, respectively), pregnancy-induced hypertension (OR = 2.1, 95% CI = 1.04-4.10 and OR = 1.5, 95% CI = 1.04-2.02, respectively), and cesarean section (OR = 3.6, 95% CI = 2.44-5.29 and OR = 1.4, 95% CI = 1.09-1.79, respectively) compared with their matched controls. CONCLUSION(S): After controlling for maternal age, gestational age, and parity, we demonstrated that singleton pregnancies conceived by IVF and ovulation induction are at increased risk for maternal gestational diabetes mellitus and pregnancy-induced hypertension, and at greater risk for delivery by cesarean section.

Adult↗

PubMed2001

Kinetics and inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) in rats.

The kinetic properties and the inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) were studied in Wistar rats following subcutaneous (s.c.) injections. For assessing the dose-response, rats were treated with a single dose of 3. 10 or 30 microg H7CDD/kg body wt. Tissue concentrations and enzyme induction were measured 1, 2, and 3 weeks after treatment, and in the 30 microg/kg group additionally after 6, 20 and 57 weeks. Tissue concentrations increased dose-dependently from 3 to 30 microg/kg. Concentrations in liver were always higher than in adipose tissue, the concentration ratio: liver/adipose tissue varied between 32 and 67. The activity of (ethoxyresorufin O-deethylase) (EROD) in liver microsomes was clearly induced by H7CDD, reaching maximal induction three weeks after treatment. (3-fold at 3 microg/kg, 5-fold at 10 microg/kg and nearly 30-fold at 30 microg/kg). For assessing the time dependency, tissue levels and hepatic enzyme induction were monitored over a period of 57 weeks after a single s.c.-injection of 30 microg H7CDD/kg body wt. Hepatic concentrations of the congener remained rather constant from the 2nd to the 20th week after treatment (280 ng/g and 319 ng/g, respectively). In contrast, concentrations in adipose tissue and thymus increased 2-fold during this period, and 20 weeks after injection reached a maximum of 11 ng/g and 3 ng/g, respectively. Thereafter, the concentrations decreased and tissue levels of 91 ng/g (liver), 3 ng/g (adipose tissue) and 2 ng/g (thymus) were detected 57 weeks after treatment. The elimination half-life (t 1/2) calculated from our data was 140 days in liver and 130 days in adipose tissue. The reasonable explanation for the increase in tissue concentrations of H7CDD up to 20 weeks after treatment is the slow release of this congener from the subcutaneous injection site. Induction of hepatic EROD activity always closely followed changes in the hepatic concentrations of H7CDD, reaching a maximum 3 weeks after treatment and remaining at this level until the 20th week. Correlation analysis of hepatic H7CDD concentrations versus the extent of EROD induction indicated a linear relationship in a double-logarithmic plot. When compared with TCDD, the hepatic monooxygenase-inducing potency of H7CDD within the low dose range was found in the rat to be 170 to 440-times lower than that of TCDD. Measurement of 14C-caffeine demethylation, using a 14CO2 breath test, revealed a similar time course in vivo when compared with the microsomal EROD activity ex vivo.

Animals↗

PubMed2003

The impact of residual multi-level N2 disease after induction therapy for non-small cell lung cancer.

BACKGROUND: The presence of residual N2 disease following induction therapy for locally advanced non-small cell lung cancer (NSCLC) has been proposed as a contraindication to surgery. However, single level N2 metastases found in the operative specimens of patients with clinical N0 NSCLC who did not receive induction therapy is associated with prolonged survival. In order to investigate whether residual single level N2 disease following induction therapy was similarly associated with prolonged survival, we conducted a retrospective review of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy followed by surgery. METHODS: A retrospective review was performed of the hospital records of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy consisting of chemotherapy and/or radiotherapy followed by tumor resection and mediastinal lymph node dissection at 11 Japanese national referral hospitals. Survival was analyzed by the Kaplan-Meier method and prognostic factors were determined by the log-rank and Cox regression methods. RESULTS: One hundred thirty-one patients underwent induction therapy of NSCLC stages IIIa (n=95) and IIIb (n=36) followed by complete tumor resection during a 12-year interval. Clinical N2 disease was present in 114 (87%) patients and N3 disease in 17 (13%) patients. Median follow up was 48 months. Eighteen patients had residual single level N2 disease and 25 patients had multiple residual N2 level metastases. The 5-year survival was 54% for patients with pathologic single level N2 disease and 11% for patients with multiple N2 level disease (P<0.01). In a multivariate analysis, only the pathologic N status significantly influenced survival. CONCLUSION: Patents who have multiple levels of N2 disease have a much worse prognosis than patients who have single level of N2.

Adult↗

PubMed2000

Heme oxygenase induction by menadione bisulfite adduct-generated oxidative stress in rat liver.

The in vivo effect of menadione bisulfite adduct on both hepatic oxidative stress and heme oxygenase induction was studied. A marked increase in lipid peroxidation was observed 1 h after menadione bisulfite adduct administration. To evaluate liver antioxidant enzymatic defenses, superoxide dismutase, catalase and glutathione peroxidase activities were determined. Antioxidant enzymes significantly decreased 3 h after menadione bisulfite adduct injection. Heme oxygenase activity appeared 6 h after treatment, peaking 9 h after menadione bisulfite adduct administration. Such induction was preceded by a decrease in the intrahepatic GSH pool and an increase in hydrogen peroxide steady-state concentration, both effects taking place some hours before induction of heme oxygenase. Iron ferritin levels and ferritin content began to increase 6 h after heme oxygenase induction, and these increases were significantly higher 15 h after treatment and remained high for at least 24 h after menadione bisulfite adduct injection. Administration of bilirubin entirely prevented heme oxygenase induction as well as the decrease in hepatic GSH and the increase in lipid peroxidation when administered 2 h before menadione bisulfite adduct treatment. These results indicate that the induction of heme oxygenase by menadione bisulfite adduct may be a general response to oxidant stress, by increasing bilirubin and ferritin levels and could therefore provide a major cellular defense mechanism against oxidative damage.

Animals↗

PubMed1997

The origins of the neural crest. Part I: embryonic induction.

Neural crest cells form at the border between the neural plate and the epidermis. The tissue interactions that underlie neural crest cell induction have been investigated primarily by heterotopic grafting experiments in vivo and by conjugating different tissues in vitro. Three models have been proposed to explain the induction of neural crest cells at the neural plate border, i.e. (1) the influence of signals from the mesoderm, (2) changes in ectodermal competence and (3) local interactions between neural and non-neural ectoderm. The weight of the evidence supports the last model, although there are data that suggest a role for signals from the mesoderm. FGFs seem to be necessary but not sufficient for neural crest cell induction. BMP-4 is sufficient to induce neural crest cells from chick neural explants in vitro and intermediate levels of BMP-4-signalling induce neural crest cell markers in Xenopus animal cap assays. These data suggest a gradient model in which neural crest cells are induced by a particular range of BMP-4 activity, although a single-signal model may be too simplistic. Neural crest cell induction may be an ongoing process, in which an initial induction at the neural plate border is followed by further induction within the dorsal neural tube.

Animals↗

PubMed1995

Role of quinone-mediated generation of hydroxyl radicals in the induction of glutathione S-transferase gene expression.

Induction of glutathione S-transferase (GST) Ya gene expression by a variety of chemical agents is mediated by a regulatory element composed of two adjacent AP-1-like binding sites and activated by the Fos/Jun heterodimeric complex (AP-1). We have previously shown that the induction of GST Ya gene expression and of AP-1 binding activity is regulated by intracellular glutathione (GSH) levels. To study the role of reactive oxygen species in the induction of AP-1 activity and GST Ya gene expression and their effect on intracellular GSH levels, we have exposed hepatoma cells to adriamycin and two synthetic quinones, Qcb and Qn, with different capacities to generate oxygen radicals. The kinetics of quinone-mediated generation of hydroxyl radicals were monitored in intact cells by a spin trapping technique and EPR spectral measurements. We find that quinones which can chelate Fe(III) ions, adriamycin and Qcb, are more effective in hydroxyl radical production than the nonchelating quinone Qn. Furthermore, we show that the induction of AP-1 binding activity and GST Ya gene expression by these quinones correlates with their oxygen radical production, adriamycin and Qcb being stronger inducers that Qn. The present study indicates that the AP-1-mediated induction of GST Ya gene expression is part of the response to oxidative stress. A transient increase by 2.5-fold in the intracellular GSH level was observed 30 min after exposure of cells to quinone and was followed by a rapid depletion of GSH. This increase in the GSH level represents an induction of GSH synthesis since it was blocked by buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗