Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.50
A. Rajpurkar, Yang Jiang, C. Dhabuwala, J. Dunbar, Haikun Li
In a previous studywe demonstrated the deleterious effect of cigarette smoke on spermatogenesis in the testis of peripubertal Sprague-Dawley rats. In this study we investigated the development of apoptosis as a possible contributing factor to the pathogenic mechanism underlying these effects. Peripubertal rats were exposed to cigarette smoke with the Walton Horizontal Smoking Machine. Similarly, age-matched control rats were exposed to room air with the smoking machine. Rats from both groups were sacrificed after 45 days of treatment and the testes were removed. Testes were stained utilizing the terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining technique. DNA fragmentation was further evaluated using gelectrophoresis. There was a significant increase in the incidence of apoptosis in the treated group compared to the control group as demonstrated by the larger amount of tubules containing > or = 3apoptotic bodies in the smoke-exposed group, that is, 36% versus 14% in the control group (p < 0.05). Agarose gel electrophoresis demonstrated the DNA ladder in the treated group but not in the control animals. In conclusion, chronic cigarette smoke induces apoptosis in the rat testis. Apoptosis may be one of the pathogenic mechanisms responsible for defective spermatogenesis in the rat following chronic cigarette smoking.
{"title":"Cigarette smoking induces apoptosis in rat testis.","authors":"A. Rajpurkar, Yang Jiang, C. Dhabuwala, J. Dunbar, Haikun Li","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.50","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.50","url":null,"abstract":"In a previous studywe demonstrated the deleterious effect of cigarette smoke on spermatogenesis in the testis of peripubertal Sprague-Dawley rats. In this study we investigated the development of apoptosis as a possible contributing factor to the pathogenic mechanism underlying these effects. Peripubertal rats were exposed to cigarette smoke with the Walton Horizontal Smoking Machine. Similarly, age-matched control rats were exposed to room air with the smoking machine. Rats from both groups were sacrificed after 45 days of treatment and the testes were removed. Testes were stained utilizing the terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining technique. DNA fragmentation was further evaluated using gelectrophoresis. There was a significant increase in the incidence of apoptosis in the treated group compared to the control group as demonstrated by the larger amount of tubules containing > or = 3apoptotic bodies in the smoke-exposed group, that is, 36% versus 14% in the control group (p < 0.05). Agarose gel electrophoresis demonstrated the DNA ladder in the treated group but not in the control animals. In conclusion, chronic cigarette smoke induces apoptosis in the rat testis. Apoptosis may be one of the pathogenic mechanisms responsible for defective spermatogenesis in the rat following chronic cigarette smoking.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81306084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.40
David Shi, B. Jiang
Reactive oxygen species (ROS) have been shown to cause a broad spectrum of damage to the biological system. ROS-mediated reactions are believed to play a key role in Cr(VI)-induced carcinogenesis. Using electron spin resonance (ESR) spin trapping, the present study shows that apple juice efficiently scavenged hydroxyl radicals generated by Cr(VI) reduction catalyzed byglutathione reductase/NADPH. Apple juice reduced Cr(VI)-induced lipid peroxidation, DNA damage, cell apoptosis, and NF-kappaB activation in human lung epithelial A549 cells. The lipid peroxidation was measured by a colorimetric assay, DNA damage by single cell gel electrophoresis assay, induction of cell apoptosis by flow cytometry, and activation of NF-kappaB by luciferase assay. The results show that through its antioxidant properties, apple juice can protect Cr(VI)-induced cellular injury and may help reduce its carcinogenic potentiaL
{"title":"Antioxidant properties of apple juice and its protection against Cr(VI)-induced cellular injury.","authors":"David Shi, B. Jiang","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.40","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.40","url":null,"abstract":"Reactive oxygen species (ROS) have been shown to cause a broad spectrum of damage to the biological system. ROS-mediated reactions are believed to play a key role in Cr(VI)-induced carcinogenesis. Using electron spin resonance (ESR) spin trapping, the present study shows that apple juice efficiently scavenged hydroxyl radicals generated by Cr(VI) reduction catalyzed byglutathione reductase/NADPH. Apple juice reduced Cr(VI)-induced lipid peroxidation, DNA damage, cell apoptosis, and NF-kappaB activation in human lung epithelial A549 cells. The lipid peroxidation was measured by a colorimetric assay, DNA damage by single cell gel electrophoresis assay, induction of cell apoptosis by flow cytometry, and activation of NF-kappaB by luciferase assay. The results show that through its antioxidant properties, apple juice can protect Cr(VI)-induced cellular injury and may help reduce its carcinogenic potentiaL","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78554916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.70
Y. Shukla, P. Taneja
Cypermethrin (CYP) is a synthetic pyrethroid insecticide considered to be environmentally safe and widely used in agriculture and veterinary medicine. To ascertain the validity of this opinion, we investigated the mutagenic potential of CYP using the dominant lethal assay in male Swiss albino mice. CYP was administered by gavage at the dose of 20, 40, and 80 mg/kg body weight, dissolved in 0.2 mL corn oil. Treated mice from all groups were mated with untreated virgin females for a period of 6 weeks that covers the entirespermatogenetic cycle. In the pregnant females, we found a high rate of pre- and post-implantation losses. Dominant lethal mutations were induced in a benzo(a)pyrene-treated group (positive control), and a reduction in the number of total implants was found in all CYP-treated groups only during the initial mating weeks. No significant pre-implantation losses were noted in any of the tested doses. However, significant postimplantation losses were identified in the medium and high doses of CYP. A dose-dependent decline in the number of living implants was noticed in all CYP-treated animals during the first 3 weeks, but decreased in the later weeks. The average mutagenic index of 6 weeks was significantly increased only in the high CYP dose. Our results showed that CYP has mutagenic activity, inducing dominant lethal mutations in male germ cells of mice and caution is recommended in the use of this insecticide.
{"title":"Mutagenic potential of cypermethrin in mouse dominant lethal assay.","authors":"Y. Shukla, P. Taneja","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.70","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.70","url":null,"abstract":"Cypermethrin (CYP) is a synthetic pyrethroid insecticide considered to be environmentally safe and widely used in agriculture and veterinary medicine. To ascertain the validity of this opinion, we investigated the mutagenic potential of CYP using the dominant lethal assay in male Swiss albino mice. CYP was administered by gavage at the dose of 20, 40, and 80 mg/kg body weight, dissolved in 0.2 mL corn oil. Treated mice from all groups were mated with untreated virgin females for a period of 6 weeks that covers the entirespermatogenetic cycle. In the pregnant females, we found a high rate of pre- and post-implantation losses. Dominant lethal mutations were induced in a benzo(a)pyrene-treated group (positive control), and a reduction in the number of total implants was found in all CYP-treated groups only during the initial mating weeks. No significant pre-implantation losses were noted in any of the tested doses. However, significant postimplantation losses were identified in the medium and high doses of CYP. A dose-dependent decline in the number of living implants was noticed in all CYP-treated animals during the first 3 weeks, but decreased in the later weeks. The average mutagenic index of 6 weeks was significantly increased only in the high CYP dose. Our results showed that CYP has mutagenic activity, inducing dominant lethal mutations in male germ cells of mice and caution is recommended in the use of this insecticide.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74793137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.20
D. Bishop-Bailey, S. Calatayud, T. Warner, T. Hla, J. Mitchell
Increased expression of inducible cyclooxygenase (COX-2) is associated with a wide variety of tumors. In addition, inhibitors of COX have shown a great deal of promise in vitro and in animal models as potential antitumor therapies. COX enzymes use the substrate arachidonic acid to produce prostaglandin (PG)H2, the precursor to all the prostanoids. Therefore, the release of individual prostanoids depends on the abundance and functional coupling to individual PG synthase isoenzymes. Colony stimulating factors (CSFs) are also potential antitumor agents via their ability to augment the immune response. When COX-2 is expressed, the CSF, granulocyte macrophage (GM)-CSF, and granulocyte (G)-CSF are exquisitely sensitive to endogenous PGs. In addition, the ability of COX-2 to suppress GM-CSF release is mediated via traditional IP/EP prostanoid receptors linked to cAMP-dependent pathways. Therefore, inhibition of COX-2 in tumors may have the important side effect of enhancing the immune response. Recently, novel signaling pathways for PG derivatives have been discovered; in particular the PGD2 dehydration product 15-deoxy-delta(12,14)-(15d)-PGJ2 was identified as a ligand for the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor (PPAR)-gamma. PPARgamma is present at high levels in a number of tumors, and is also present in endothelial cells. 15d-PGJ2 as well as other nonprostanoid PPARgamma ligands are antitumor, and antiangiogenic, by dramatically inhibiting the growth of tumor cells and endothelial cells by either causing terminal differentiation, and/or by inducing apoptosis. We have recently found that, in addition to IP and EP ligands generated by COX-2, PPARgamma ligands similarly inhibit GM-CSF release. Effecting individual prostanoid pathways at the level of COX expression, profile of PG products produced or selective PG receptor activation may produce novel therapies, either dependent or independent of CSF release, to target cancers.
{"title":"Prostaglandins and the regulation of tumor growth.","authors":"D. Bishop-Bailey, S. Calatayud, T. Warner, T. Hla, J. Mitchell","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.20","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.20","url":null,"abstract":"Increased expression of inducible cyclooxygenase (COX-2) is associated with a wide variety of tumors. In addition, inhibitors of COX have shown a great deal of promise in vitro and in animal models as potential antitumor therapies. COX enzymes use the substrate arachidonic acid to produce prostaglandin (PG)H2, the precursor to all the prostanoids. Therefore, the release of individual prostanoids depends on the abundance and functional coupling to individual PG synthase isoenzymes. Colony stimulating factors (CSFs) are also potential antitumor agents via their ability to augment the immune response. When COX-2 is expressed, the CSF, granulocyte macrophage (GM)-CSF, and granulocyte (G)-CSF are exquisitely sensitive to endogenous PGs. In addition, the ability of COX-2 to suppress GM-CSF release is mediated via traditional IP/EP prostanoid receptors linked to cAMP-dependent pathways. Therefore, inhibition of COX-2 in tumors may have the important side effect of enhancing the immune response. Recently, novel signaling pathways for PG derivatives have been discovered; in particular the PGD2 dehydration product 15-deoxy-delta(12,14)-(15d)-PGJ2 was identified as a ligand for the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor (PPAR)-gamma. PPARgamma is present at high levels in a number of tumors, and is also present in endothelial cells. 15d-PGJ2 as well as other nonprostanoid PPARgamma ligands are antitumor, and antiangiogenic, by dramatically inhibiting the growth of tumor cells and endothelial cells by either causing terminal differentiation, and/or by inducing apoptosis. We have recently found that, in addition to IP and EP ligands generated by COX-2, PPARgamma ligands similarly inhibit GM-CSF release. Effecting individual prostanoid pathways at the level of COX expression, profile of PG products produced or selective PG receptor activation may produce novel therapies, either dependent or independent of CSF release, to target cancers.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82810442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I1.10
Jeannine H. Powell, P. Gannett
Aryl hydrazines carcinogenesis has been studied for over 25 years and remains poorly understood, although most aryl hydrazines are toxic, tumorigenic, or carcinogenic. In this article, aryl hydrazine carcinogenesis is reviewed comprehensively. The relevant chemistry and biochemistry of aryl hydrazines are first addressed and provide the framework for understanding how aryl hydrazines are metabolized, the reactive intermediates that are produced, and the biological reactive intermediates and products that are formed. Issues of DNA damage, mutagenicity, and enzyme activation are next addressed followed by a brief review of aryl hydrazine tumorigenicity studies. Because several related substrates are metabolized to the same intermediates as are aryl hydrazines, they are briefly discussed. The review concludes with a short discussion of the possible mechanism of carcinogenesis by aryl hydrazines.
{"title":"Mechanisms of carcinogenicity of aryl hydrazines, aryl hydrazides, and arenediazonium ions.","authors":"Jeannine H. Powell, P. Gannett","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I1.10","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I1.10","url":null,"abstract":"Aryl hydrazines carcinogenesis has been studied for over 25 years and remains poorly understood, although most aryl hydrazines are toxic, tumorigenic, or carcinogenic. In this article, aryl hydrazine carcinogenesis is reviewed comprehensively. The relevant chemistry and biochemistry of aryl hydrazines are first addressed and provide the framework for understanding how aryl hydrazines are metabolized, the reactive intermediates that are produced, and the biological reactive intermediates and products that are formed. Issues of DNA damage, mutagenicity, and enzyme activation are next addressed followed by a brief review of aryl hydrazine tumorigenicity studies. Because several related substrates are metabolized to the same intermediates as are aryl hydrazines, they are briefly discussed. The review concludes with a short discussion of the possible mechanism of carcinogenesis by aryl hydrazines.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75025055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.30
Zhuo Zhang, Fei Chen, Chuanshu Huang, Xianglin Shi
Vanadium compounds exert potent toxic and carcinogenic effects on a wide variety of biological systems. The mechanisms involved in their toxicity and carcinogenesis require investigation. Cell growth arrest and its regulation are important mechanisms in maintaining genomic stability and integrity in response to environmental stress. The p53 tumor suppressor plays a central role in the regulation of the normal cell cycle. To investigate the role of p53 in vanadate-induced cell growth arrest and its regulation, two cell lines--normal mouse embryo fibroblasts [p53(+/+)] and p53-deficient mouse embryo fibroblasts [p53(-/-)],--were used in this study. Flow cytometry was used to analyze cell growth arrest at G0/G1, S, or G2/M phase. Western blotting analysis was performed to determine several cell growth regulatory proteins. The results showed that in p53(-/-) cells vanadate induced G2/M phase arrest in a dose- and time-dependent manner without alteration of S phase. In p53(+/+) cells, vanadate treatment increased the S phase with no significant change in the G2/M phase. Furthermore, Western blotting results showed that in p53(-/-) cells vanadate caused cdc25C degradation and activation of phospho-cdc2 without alteration of the p21 level. In p53(+/+) cells, vanadate increased the expression of p21 and degraded cdc25A instead of cdc25C without any effect on cdc2. These results demonstrate that vanadate induced G2/M phase arrest in p53-deficient mouse embryo fibroblasts, and promoted S phase entry in p53 wild-type mouse embryo fibroblasts.
{"title":"Vanadate induces G2/M phase arrest in p53-deficient mouse embryo fibroblasts.","authors":"Zhuo Zhang, Fei Chen, Chuanshu Huang, Xianglin Shi","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.30","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.30","url":null,"abstract":"Vanadium compounds exert potent toxic and carcinogenic effects on a wide variety of biological systems. The mechanisms involved in their toxicity and carcinogenesis require investigation. Cell growth arrest and its regulation are important mechanisms in maintaining genomic stability and integrity in response to environmental stress. The p53 tumor suppressor plays a central role in the regulation of the normal cell cycle. To investigate the role of p53 in vanadate-induced cell growth arrest and its regulation, two cell lines--normal mouse embryo fibroblasts [p53(+/+)] and p53-deficient mouse embryo fibroblasts [p53(-/-)],--were used in this study. Flow cytometry was used to analyze cell growth arrest at G0/G1, S, or G2/M phase. Western blotting analysis was performed to determine several cell growth regulatory proteins. The results showed that in p53(-/-) cells vanadate induced G2/M phase arrest in a dose- and time-dependent manner without alteration of S phase. In p53(+/+) cells, vanadate treatment increased the S phase with no significant change in the G2/M phase. Furthermore, Western blotting results showed that in p53(-/-) cells vanadate caused cdc25C degradation and activation of phospho-cdc2 without alteration of the p21 level. In p53(+/+) cells, vanadate increased the expression of p21 and degraded cdc25A instead of cdc25C without any effect on cdc2. These results demonstrate that vanadate induced G2/M phase arrest in p53-deficient mouse embryo fibroblasts, and promoted S phase entry in p53 wild-type mouse embryo fibroblasts.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77108607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.30
B. Brüne, A. von Knethen
The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
{"title":"The role of nitric oxide and cyclooxygenase-2 in attenuating apoptosis.","authors":"B. Brüne, A. von Knethen","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.30","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.30","url":null,"abstract":"The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80899906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.60
K. Chun, Jee-Young Kang, O. Kim, Hoil Kang, Y. Surh
Certain medicinal plants contain anti-inflammatory and antioxidative substances that can exert chemopreventive effects. Our previous studies have demonstrated that the methanol extract of Alpinia oxyphylla Miquel (Zingiberaceae) inhibits tumor promotion in mouse skin. Two major diarylheptanoids named yakuchinone A (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) andyakuchinone B (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-1-en-3-one) have been isolated from this medicinal plant. Both compounds have strong inhibitory effects on the synthesis of prostaglandins and leukotrienes in vitro. In the present work, we show that both yakuchinone A and yakuchinone B inhibit the expression of cyclooxygenase-2 (COX-2) and of inducible nitric oxide synthase (iNOS) as well as the expression of tumor necrosis factor (TNF)-alpha mRNA in mouse skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application on mouse skin of these diarylheptanoids also attenuated the TPA-induced DNA binding activity of the ubiquitous eukaryotic transcription factor NF-kappaB that plays a crucial role in regulating the expression of the aforementioned proinflammatory enzymes and cytokines in response to a wide variety of external stimuli. These findings suggest that diarylheptanoids contained in Alpinia oxyphylla down-regulate COX-2 and iNOS expression through suppression of NF-kappaB activation in the TPA-treated mouse skin.
{"title":"Effects of yakuchinone A and yakuchinone B on the phorbol ester-induced expression of COX-2 and iNOS and activation of NF-kappaB in mouse skin.","authors":"K. Chun, Jee-Young Kang, O. Kim, Hoil Kang, Y. Surh","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.60","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.60","url":null,"abstract":"Certain medicinal plants contain anti-inflammatory and antioxidative substances that can exert chemopreventive effects. Our previous studies have demonstrated that the methanol extract of Alpinia oxyphylla Miquel (Zingiberaceae) inhibits tumor promotion in mouse skin. Two major diarylheptanoids named yakuchinone A (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) andyakuchinone B (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-1-en-3-one) have been isolated from this medicinal plant. Both compounds have strong inhibitory effects on the synthesis of prostaglandins and leukotrienes in vitro. In the present work, we show that both yakuchinone A and yakuchinone B inhibit the expression of cyclooxygenase-2 (COX-2) and of inducible nitric oxide synthase (iNOS) as well as the expression of tumor necrosis factor (TNF)-alpha mRNA in mouse skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application on mouse skin of these diarylheptanoids also attenuated the TPA-induced DNA binding activity of the ubiquitous eukaryotic transcription factor NF-kappaB that plays a crucial role in regulating the expression of the aforementioned proinflammatory enzymes and cytokines in response to a wide variety of external stimuli. These findings suggest that diarylheptanoids contained in Alpinia oxyphylla down-regulate COX-2 and iNOS expression through suppression of NF-kappaB activation in the TPA-treated mouse skin.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77748226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.80
T. Kawamori, K. Wakabayashi
Accumulating evidence indicates that COX-2 inhibitors are involved in colon and breast cancer development. Our previous studies indicated that nimesulide and celecoxib, selective COX-2 inhibitors, show inhibitory effects of intestinal carcinogenesis in azoxymethane-treated rats and mice and in Min mice models. We recently found that nimesulide suppressed PhIP-induced breast cancer in female SD rats in which COX-2 protein was overexpressed. These results led us to investigate the effects of prostaglandin E2 (PGE2) in the target tissues. PGE2 showed its biological activity through binding to its membrane receptors, EP(1 to approximately 4). We also investigated the effects of EP receptors on colon carcinogenesis. We used receptor knockout mice and selective receptor antagonists. Our results indicated that the EP1 receptor plays a pivotal role in colon carcinogenesis. Selective EP1 receptor antagonists may be a new class of chemopreventive agents against colon cancer.
{"title":"COX-2 and prostanoid receptors: good targets for chemoprevention.","authors":"T. Kawamori, K. Wakabayashi","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.80","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I2.80","url":null,"abstract":"Accumulating evidence indicates that COX-2 inhibitors are involved in colon and breast cancer development. Our previous studies indicated that nimesulide and celecoxib, selective COX-2 inhibitors, show inhibitory effects of intestinal carcinogenesis in azoxymethane-treated rats and mice and in Min mice models. We recently found that nimesulide suppressed PhIP-induced breast cancer in female SD rats in which COX-2 protein was overexpressed. These results led us to investigate the effects of prostaglandin E2 (PGE2) in the target tissues. PGE2 showed its biological activity through binding to its membrane receptors, EP(1 to approximately 4). We also investigated the effects of EP receptors on colon carcinogenesis. We used receptor knockout mice and selective receptor antagonists. Our results indicated that the EP1 receptor plays a pivotal role in colon carcinogenesis. Selective EP1 receptor antagonists may be a new class of chemopreventive agents against colon cancer.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77180493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01DOI: 10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.80
K. Sadakane, H. Takano, T. Ichinose, R. Yanagisawa, T. Shibamoto
Formaldehyde (FA) irritates the skin, eyes, and respiratory system and is considered to be a typical air pollutant. We investigated the effects of FA on the manifestations of airway inflammation caused by a house-dust mite allergen (Der f). ICR mice were exposed to 0.5% FA mist once a week for 4 weeks. The mice were sensitized intraperitoneally with Der f and ALUM prior to FA exposure. After the last FA exposure, theywere instilled intratracheally with Der f. The airway inflammation was subsequently examined. The Der f-specific IgG1 and IgE in plasma as well as the asthma-relevant cytokines in the lungs were measured. We found an increase in the plasma IgG1 production of and in the expression of interleukin-5 (IL-5) and regulated on activation, normal T cell expressed, and presumably secreted (RANTES) in the lungs of mice treated with Der f. The FA exposure enhanced the manifestation ofthe histopathological changes caused by Der f. This observation corresponded to the enhancement of IL-5 and RANTES production. However, the antigen-specific IgG1 antibody did not increase. The IL-4 cytokine level induced by Der fwith or without FA was the same as that of the control. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and antigen-specific IgE were not detected. FA exposure enhanced the eosinophilic airway inflammation and the proliferation of goblet cells, which were induced by a mite allergen responsible for the increased local expression of IL-5 and RANTES.
{"title":"Formaldehyde enhances mite allergen-induced eosinophilic inflammation in the murine airway.","authors":"K. Sadakane, H. Takano, T. Ichinose, R. Yanagisawa, T. Shibamoto","doi":"10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.80","DOIUrl":"https://doi.org/10.1615/JENVIRONPATHOLTOXICOLONCOL.V21.I3.80","url":null,"abstract":"Formaldehyde (FA) irritates the skin, eyes, and respiratory system and is considered to be a typical air pollutant. We investigated the effects of FA on the manifestations of airway inflammation caused by a house-dust mite allergen (Der f). ICR mice were exposed to 0.5% FA mist once a week for 4 weeks. The mice were sensitized intraperitoneally with Der f and ALUM prior to FA exposure. After the last FA exposure, theywere instilled intratracheally with Der f. The airway inflammation was subsequently examined. The Der f-specific IgG1 and IgE in plasma as well as the asthma-relevant cytokines in the lungs were measured. We found an increase in the plasma IgG1 production of and in the expression of interleukin-5 (IL-5) and regulated on activation, normal T cell expressed, and presumably secreted (RANTES) in the lungs of mice treated with Der f. The FA exposure enhanced the manifestation ofthe histopathological changes caused by Der f. This observation corresponded to the enhancement of IL-5 and RANTES production. However, the antigen-specific IgG1 antibody did not increase. The IL-4 cytokine level induced by Der fwith or without FA was the same as that of the control. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and antigen-specific IgE were not detected. FA exposure enhanced the eosinophilic airway inflammation and the proliferation of goblet cells, which were induced by a mite allergen responsible for the increased local expression of IL-5 and RANTES.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79580509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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