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Müller MN, Vicente Ferreira Junior A, Zanardi Lamardo E, Yogui GT, Flores Montes MDJ, Silva MA, Lima EJAC, Rojas LAV, Jannuzzi LGDS, Cunha MDGGDS, Melo PAMDC, Carvalho VPCD, Carneiro YMM, Carreira RDS, Araujo M, Santos LPDS. Finding the needle in a haystack: Evaluation of ecotoxicological effects along the continental shelf break during the Brazilian mysterious oil spill. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 357:124422. [PMID: 38914197 DOI: 10.1016/j.envpol.2024.124422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/01/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Oceanic oil spills present significant ecological risks that have the potential to contaminate extensive areas, including coastal regions. The occurrence of the 2019 oil spill event in Brazil resulted in over 3000 km of contaminated beaches and shorelines. While assessing the impact on benthic and beach ecosystems is relatively straightforward due to direct accessibility, evaluating the ecotoxicological effects of open ocean oil spills on the pelagic community is a complex task. Difficulties are associated with the logistical challenges of responding promptly and, in case of the Brazilian mysterious oil spill, to the subsurface propagation of the oil that impeded remote visual detection. An oceanographic expedition was conducted in order to detect and evaluate the impact of this oil spill event along the north-eastern Brazilian continental shelf. The pursuit of dissolved and dispersed oil compounds was accomplished by standard oceanographic methods including seawater polycyclic aromatic hydrocarbons (PAHs) analysis, biomass stable carbon isotope (δ13C), particulate organic carbon to particulate organic nitrogen (POC:PON) ratios, nutrient analysis and ecotoxicological bioassays using the naupliar phase of the copepod Tisbe biminiensis. Significant ecotoxicological effects, reducing naupliar development by 20-40 %, were indicated to be caused by the presence of dispersed oil in the open ocean. The heterogeneous distribution of oil droplets aggravated the direct detection and biochemical indicators for oil are presented and discussed. Our findings serve as a case study for identifying and tracing subsurface propagation of oil, demonstrating the feasibility of utilizing standard oceanographic and ecotoxicological methods to assess the impacts of oil spill events in the open ocean. Ultimately, it encourages the establishment of appropriate measures and responses regarding the liability and regulation of entities to be held accountable for oil spills in the marine environment.
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Affiliation(s)
- Marius Nils Müller
- Department of Oceanography, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil; Macau Environmental Research Institute, Macau University of Science and Technology, Macau SAR, 999078, China.
| | | | - Eliete Zanardi Lamardo
- Department of Oceanography, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil
| | - Gilvan Takeshi Yogui
- Department of Oceanography, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil
| | | | - Marcus André Silva
- Department of Oceanography, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil
| | | | | | | | | | | | | | | | - Renato da Silva Carreira
- Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, RJ, 22451-900, Brazil
| | - Moacyr Araujo
- Department of Oceanography, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil
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Fan L, Bin Wang, Ma J, Ye Z, Nie X, Cheng M, Xie Y, Gu P, Zhang Y, You X, Zhou Y, Chen W. Role and mechanism of WNT5A in benzo(a)pyrene-induced acute lung injury and lung function decline. JOURNAL OF HAZARDOUS MATERIALS 2023; 460:132391. [PMID: 37651938 DOI: 10.1016/j.jhazmat.2023.132391] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/13/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023]
Abstract
Benzo(a)pyrene was sparsely studied for its early respiratory impairment. The non-canonical ligand WNT5A play a role in pneumonopathy, while its function during benzo(a)pyrene-induced adverse effects were largely unexplored. Individual benzo(a)pyrene, plasma WNT5A, and spirometry 24-hour change for 87 residents from Wuhan-Zhuhai cohort were determined to analyze potential role of WNT5A in benzo(a)pyrene-induced lung function alternation. Normal bronchial epithelial cell lines were employed to verify the role of WNT5A after benzo(a)pyrene treatment. RNA sequencing was adopted to screen for benzo(a)pyrene-related circulating microRNAs and differentially expressed microRNAs between benzo(a)pyrene-induced cells and controls. The most potent microRNA was selected for functional experiments and target gene validation, and their mechanistic link with WNT5A-mediated non-canonical Wnt signaling was characterized through rescue assays. We found significant associations between increased benzo(a)pyrene and reduced 24-hour changes of FEF50% and FEF75%, as well as increased WNT5A. The benzo(a)pyrene-induced inflammation and epithelial-mesenchymal transition in BEAS-2B and 16HBE cells were attenuated by WNT5A silencing. hsa-miR-122-5p was significantly and positively associated with benzo(a)pyrene and elevated after benzo(a)pyrene induction, and exerted its effect by downregulating target gene TP53. Functionally, WNT5A participates in benzo(a)pyrene-induced lung epithelial injury via non-canonical Wnt signaling modulated by hsa-miR-122-5p/TP53 axis, showing great potential as a preventive and therapeutic target.
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Affiliation(s)
- Lieyang Fan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Bin Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jixuan Ma
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zi Ye
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiuquan Nie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Man Cheng
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yujia Xie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Pei Gu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yingdie Zhang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaojie You
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yun Zhou
- School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Müller MN, Yogui GT, Gálvez AO, Gustavo de Sales Jannuzzi L, Fidelis de Souza Filho J, de Jesus Flores Montes M, Mendes de Castro Melo PA, Neumann-Leitão S, Zanardi-Lamardo E. Cellular accumulation of crude oil compounds reduces the competitive fitness of the coral symbiont Symbiodinium glynnii. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 289:117938. [PMID: 34391045 DOI: 10.1016/j.envpol.2021.117938] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/02/2021] [Accepted: 08/06/2021] [Indexed: 06/13/2023]
Abstract
Oil spill events in the marine environment can have a deleterious impact on the affected ecosystems, such as coral reefs, with direct consequences for their socioeconomic value. The mutualistic relationship between tropical corals and their dinoflagellate symbionts (Symbiodiniaceae) provide structural and nutritional basis for a high local biodiversity in oligotrophic waters. Here, we investigated effects of crude oil water-accommodated fraction on the competitive fitness of the model zooxanthellae species Symbiodinium glynnii. Results of laboratory essays demonstrate that crude oil carbon is incorporated into the cellular biomass with a concomitant change of δ13C isotopic value. Carcinogenic/mutagenic polycyclic aromatic hydrocarbons were identified in the culture media and were responsible for a linear reduction in population growth of S. glynnii, presumably related to energy relocation for DNA repair. Additionally, the experiments revealed that physiological effects induced by crude oil compounds are genetically inherited by the following generations under non-contaminated growth conditions, and induce a reduction in the competitive fitness to cope with other environmental parameters, such as low salinity. We suggest that the effects of crude oil contamination represent an imparing factor for S. glynnii coping with anthropogenic drivers (e.g. warming and acidification) and interfere with the delicate symbiont-host relationship of tropical corals. This is especially relevant in the coastal areas of northeastern Brazil where an oil spill event deposited crude oil on shallow water sediments with the potential to be resuspended to the water column by physical and/or biological activity, enhancing the risk of future coral bleaching events.
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Affiliation(s)
- Marius Nils Müller
- Department of Oceanography, Federal University of Pernambuco, Recife, 50740-550, Brazil.
| | - Gilvan Takeshi Yogui
- Department of Oceanography, Federal University of Pernambuco, Recife, 50740-550, Brazil
| | - Alfredo Olivera Gálvez
- Department of Fishing and Aquaculture, Federal Rural University of Pernambuco, Recife, 52171-900, Brazil
| | | | | | | | | | - Sigrid Neumann-Leitão
- Department of Oceanography, Federal University of Pernambuco, Recife, 50740-550, Brazil
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Li X, Cai F, Luan T, Lin L, Chen B. Pyrene metabolites by bacterium enhancing cell division of green alga Selenastrum capricornutum. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 689:287-294. [PMID: 31276996 DOI: 10.1016/j.scitotenv.2019.06.162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 06/09/2023]
Abstract
Collaborations between multiple microbial species are important for understanding natural clearance and ecological effects of toxic organic contaminants in the environment. However, the interactions between different species in the transformation and degradation of contaminants remain to address. In this study, the effects of pyrene and its bacterial metabolites on the algal growth (Selenastrum capricornutum) were examined. The specific growth rate of algal cells incubated with bacterial pyrene metabolites (1.18 d-1) was highest among all treatment, followed by the controls (1.07 d-1), treated with pyrene-free bacterial metabolites (1.04 d-1) and those treated with pyrene (0.55 d-1). G1 phase is the key growth phase for the cells to synthesize biomolecules for subsequent cell division in the cell cycle. Approximately 76.9% of the cells treated with bacterial pyrene metabolites were at the G1 phase and significantly lower than those with the controls (85.3%), pyrene-free bacterial metabolites (85.5%) and pyrene treatment (92.5%). Transcriptomic analysis of algae showed that the expression of 47 ribosomal unigenes was down-regulated by 5 mg L-1 of pyrene, while 308 unigenes related to the preparation of cell division (DNA replication and protein synthesis) were up-regulated by bacterial pyrene metabolites. It indicated that basal metabolism associated with the growth and proliferation of algal cells could be significantly promoted by bacterial pyrene metabolites. Overall, this study suggests a close relationship between algae and bacteria in the transformation and ecological effects of toxic contaminants.
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Affiliation(s)
- Xujie Li
- School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Fengshan Cai
- School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Tiangang Luan
- School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Li Lin
- School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
| | - Baowei Chen
- Southern Marine Science and Engineering Guangdong Laboratory, School of Marine Sciences, Sun Yat-Sen University, Zhuhai 519082, China; Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
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5
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Benzo[a]pyrene mediated time- and dose-dependent alteration in cellular metabolism of primary pig bladder cells with emphasis on proline cycling. Arch Toxicol 2019; 93:2593-2602. [DOI: 10.1007/s00204-019-02521-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 07/18/2019] [Indexed: 12/16/2022]
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Inflammation and the chemical carcinogen benzo[a]pyrene: Partners in crime. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2017; 774:12-24. [DOI: 10.1016/j.mrrev.2017.08.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/02/2017] [Accepted: 08/19/2017] [Indexed: 12/12/2022]
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Yuan L, Lv B, Zha J, Wang Z. Benzo[a]pyrene induced p53-mediated cell cycle arrest, DNA repair, and apoptosis pathways in Chinese rare minnow (Gobiocypris rarus). ENVIRONMENTAL TOXICOLOGY 2017; 32:979-988. [PMID: 27323304 DOI: 10.1002/tox.22298] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 05/16/2016] [Accepted: 05/21/2016] [Indexed: 06/06/2023]
Abstract
The p53 pathways play an important role in carcinogenesis. In mammals, p53 and p53 target genes have been extensively studied, but little is known about their functions and regulation in fish. In this study, the cDNA fragments of p53 network genes, including p53, p21, mdm2, gadd45α, gadd45β, igfbp-3, and bax, were cloned from Chinese rare minnow (Gobiocypris rarus). These genes displayed high amino acid sequence identities with their zebrafish orthologs. The mRNA levels of p53 network genes and pathological changes in the liver were determined after adult rare minnow were exposed to 0.4, 2, and 10 µg/L of benzo[a]pyrene (BaP) for 28 days. The results showed that p53, p21, mdm2, gadd45α, and bax mRNA expressions in the livers from males and females were significantly upregulated compared with those of the controls (p < 0.05), but gadd45β and igfbp-3 expression was not significantly changed. Microphotographs revealed enlargement of the cell nuclei and cellular degeneration in males, while atrophy and vacuolization of hepatocytes were observed in females (10 µg/L). These results suggested that BaP induced liver DNA repair and apoptosis pathways and caused adverse pathological changes in rare minnow. The strongly responsive p53 network genes in the livers suggest that rare minnow is suitable as an experimental fish to screen environmental carcinogens. In addition, the p53 network genes in rare minnow could feasibly be used to identify the mechanism of environmental carcinogenesis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 979-988, 2017.
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Affiliation(s)
- Lilai Yuan
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Biping Lv
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Jinmiao Zha
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
| | - Zijian Wang
- Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
- State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China
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Huang J, Lu H, Lu Y, Hung P, Lin Y, Lin C, Yang C, Wong T, Lu S, Lin C. Enhancement of the genotoxicity of benzo[a]pyrene by arecoline through suppression of DNA repair in HEp-2 cells. Toxicol In Vitro 2016; 33:80-7. [DOI: 10.1016/j.tiv.2016.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 01/06/2016] [Accepted: 02/13/2016] [Indexed: 01/02/2023]
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Peters RE, Wickstrom M, Siciliano SD. Do biomarkers of exposure and effect correlate with internal exposure to PAHs in swine? Biomarkers 2016; 21:283-91. [DOI: 10.3109/1354750x.2016.1138322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Nakanishi Y. Implementation of modern therapy approaches and research for non-small cell lung cancer in Japan. Respirology 2016; 20:199-208. [PMID: 25594902 DOI: 10.1111/resp.12460] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 10/28/2014] [Accepted: 11/25/2014] [Indexed: 12/14/2022]
Abstract
The genetic backgrounds of the Japanese (or Asians) are, at least in part, different from those of Caucasians. It is necessary to recognize this difference to develop medicine that is both optimized and individualized. In particular, the consideration of ethnic differences is becoming increasingly important for lung cancer medicine. Japanese clinical practice guidelines indicate that some clinical biomarkers, such as epidermal growth factor receptor gene mutations, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene and uridine diphosphate glucuronosyltransferase genotypes should be determined in appropriate lung cancer patients. At the present time, tests for these biomarkers are covered by the Japanese national health-care programme, as is treatment with certain targeted drugs and cytotoxic agents. Therefore, most patients with lung cancer in Japan receive these tests as part of daily practice if their performance status and organ function are judged to be eligible. In addition, ethnic differences in bone marrow toxicity caused by cytotoxic drugs are reflected in treatment choice, and the requirements for the development of treatment modalities suitable for rare targeted populations are also increasing. To meet these requirements, many collaborative groups in Japan that have improved their infrastructure for investigator-initiated trials and conducted important activities need to provide further optimal treatment modalities for Japanese and Asian patients with lung cancer. Here, the characteristics of lung cancer in Japanese patients, general aspects of medical treatment and the care system in Japan, and representative studies on lung cancer in Japan are reviewed.
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Affiliation(s)
- Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Hu H, Yu T, Arpiainen S, Lang MA, Hakkola J, Abu-Bakar A. Tumour suppressor protein p53 regulates the stress activated bilirubin oxidase cytochrome P450 2A6. Toxicol Appl Pharmacol 2015; 289:30-9. [PMID: 26343999 DOI: 10.1016/j.taap.2015.08.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 08/31/2015] [Accepted: 08/31/2015] [Indexed: 12/20/2022]
Abstract
Human cytochrome P450 (CYP) 2A6 enzyme has been proposed to play a role in cellular defence against chemical-induced oxidative stress. The encoding gene is regulated by various stress activated transcription factors. This paper demonstrates that p53 is a novel transcriptional regulator of the gene. Sequence analysis of the CYP2A6 promoter revealed six putative p53 binding sites in a 3kb proximate promoter region. The site closest to transcription start site (TSS) is highly homologous with the p53 consensus sequence. Transfection with various stepwise deletions of CYP2A6-5'-Luc constructs--down to -160bp from the TSS--showed p53 responsiveness in p53 overexpressed C3A cells. However, a further deletion from -160 to -74bp, including the putative p53 binding site, totally abolished the p53 responsiveness. Electrophoretic mobility shift assay with a probe containing the putative binding site showed specific binding of p53. A point mutation at the binding site abolished both the binding and responsiveness of the recombinant gene to p53. Up-regulation of the endogenous p53 with benzo[α]pyrene--a well-known p53 activator--increased the expression of the p53 responsive positive control and the CYP2A6-5'-Luc construct containing the intact p53 binding site but not the mutated CYP2A6-5'-Luc construct. Finally, inducibility of the native CYP2A6 gene by benzo[α]pyrene was demonstrated by dose-dependent increases in CYP2A6 mRNA and protein levels along with increased p53 levels in the nucleus. Collectively, the results indicate that p53 protein is a regulator of the CYP2A6 gene in C3A cells and further support the putative cytoprotective role of CYP2A6.
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Affiliation(s)
- Hao Hu
- The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland, Australia.
| | - Ting Yu
- The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland, Australia.
| | - Satu Arpiainen
- Institute of Biomedicine, Department of Pharmacology and Toxicology and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
| | - Matti A Lang
- The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland, Australia.
| | - Jukka Hakkola
- Institute of Biomedicine, Department of Pharmacology and Toxicology and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
| | - A'edah Abu-Bakar
- The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland, Australia.
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Cerezo MI, Agustí S. PAHs reduce DNA synthesis and delay cell division in the widespread primary producer Prochlorococcus. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2015; 196:147-155. [PMID: 25463708 DOI: 10.1016/j.envpol.2014.09.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 09/22/2014] [Accepted: 09/25/2014] [Indexed: 06/04/2023]
Abstract
The cyanobacteria Prochlorococcus is the most abundant primary producer in the ocean. In a global study across the Atlantic, Indian and Pacific Oceans, we tested the effect of organic pollutants on the growth and cell division of natural Prochlorococcus populations. Sub-lethal concentrations of Polycyclic Aromatic Hydrocarbons (PAHs) altered Prochlorococcus cell division by reducing DNA synthesis and decreasing the percentage of cells entering mitosis. Cell division time increased with PAHs dosage by 1.2 h per μg L(-1) of mixture added. At PAHs dosages >1 μg L(-1), Prochlorococcus cell division tended to arrest at S-phase (DNA synthesis). As a consequence, population growth was significantly reduced in the presence of PAHs. The presence of PAHs resulted in a predictable alteration of the cell cycle of the widespread cyanobacteria.The dosages tested are above concentrations in the open ocean, but found in the coastal ocean, where Prochlorococcus growth must be inhibited.
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Affiliation(s)
- Maria Isabel Cerezo
- Department of Global Change Research, IMEDEA (CSIC-UIB), Instituto Mediterraneo de Estudios Avanzados, Miquel Marques 21, 07190 Esporles,
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Abstract
Lung cancer develops in a stepwise fashion, with an accumulation of molecular alterations progressing through preinvasive steps to invasive disease. This progression could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. Preclinical and clinical findings relating to different classes of candidate chemopreventive agents provide support for this strategy as an active and promising approach for controlling this disease.
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Affiliation(s)
- Victor Cohen
- Department of Oncology, Sir Mortimer B Davis-Jewish General Hospital, McGill University School of Medicine, 3755 Cote Ste. Catherine Road, Suite E-177, Montreal, Quebec, H3T-1E2, Canada.
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A role for benzo[a]pyrene and Slug in invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis: A potential molecular link between smoking and radiographic progression. Joint Bone Spine 2013; 80:621-5. [DOI: 10.1016/j.jbspin.2013.02.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 02/10/2013] [Indexed: 11/24/2022]
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Liffers ST, Tilkorn DJ, Stricker I, Junge CG, Al-Benna S, Vogt M, Verdoodt B, Steinau HU, Tannapfel A, Tischoff I, Mirmohammadsadegh A. Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas. BMC Cancer 2013; 13:490. [PMID: 24144362 PMCID: PMC3854645 DOI: 10.1186/1471-2407-13-490] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 10/15/2013] [Indexed: 12/02/2022] Open
Abstract
Background Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed. Methods To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-κB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation. Results The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-κB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes. Conclusions Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.
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Affiliation(s)
- Sven-T Liffers
- Institute of Pathology, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany.
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Wright BE, Schmidt KH, Minnick MF. Kinetic models reveal the in vivo mechanisms of mutagenesis in microbes and man. Mutat Res 2013; 752:129-137. [PMID: 23274173 PMCID: PMC3631585 DOI: 10.1016/j.mrrev.2012.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 12/14/2012] [Accepted: 12/18/2012] [Indexed: 06/01/2023]
Abstract
This review summarizes the evidence indicating that mutagenic mechanisms in vivo are essentially the same in all living cells. Unique metabolic reactions to a particular environmental stress apparently target specific genes for increased rates of transcription and mutation, resulting in higher mutation rates for those genes most likely to solve the problem. Kinetic models which have demonstrated predictive value are described and are shown to simulate mutagenesis in vivo in Escherichia coli, the p53 tumor suppressor gene, and somatic hypermutation. In all three models, direct correlations are seen between mutation frequencies and transcription rates. G and C nucleosides in single-stranded DNA (ssDNA) are intrinsically mutable, and G and C silent mutations in p53 and in VH framework regions provide compelling evidence for intrinsic mechanisms of mutability, since mutation outcomes are neutral and are not selected. During transcription, the availability of unpaired bases in the ssDNA of secondary structures is rate-limiting for, and determines the frequency of mutations in vivo. In vitro analyses also verify the conclusion that intrinsically mutable bases are in fact located in ssDNA loops of predicted stem-loop structures (SLSs).
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Affiliation(s)
- Barbara E Wright
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States.
| | - Karen H Schmidt
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States
| | - Michael F Minnick
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, United States
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Anticancer activity of esculetin via-modulation of Bcl-2 and NF-κB expression in benzo[a]pyrene induced lung carcinogenesis in mice. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.bionut.2012.11.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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18
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Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core promoter element. Toxicol In Vitro 2012; 26:678-85. [DOI: 10.1016/j.tiv.2012.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2011] [Revised: 02/24/2012] [Accepted: 03/07/2012] [Indexed: 11/19/2022]
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Tieri P, Termanini A, Bellavista E, Salvioli S, Capri M, Franceschi C. Charting the NF-κB pathway interactome map. PLoS One 2012; 7:e32678. [PMID: 22403694 PMCID: PMC3293857 DOI: 10.1371/journal.pone.0032678] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/28/2012] [Indexed: 01/05/2023] Open
Abstract
Inflammation is part of a complex physiological response to harmful stimuli and pathogenic stress. The five components of the Nuclear Factor κB (NF-κB) family are prominent mediators of inflammation, acting as key transcriptional regulators of hundreds of genes. Several signaling pathways activated by diverse stimuli converge on NF-κB activation, resulting in a regulatory system characterized by high complexity. It is increasingly recognized that the number of components that impinges upon phenotypic outcomes of signal transduction pathways may be higher than those taken into consideration from canonical pathway representations. Scope of the present analysis is to provide a wider, systemic picture of the NF-κB signaling system. Data from different sources such as literature, functional enrichment web resources, protein-protein interaction and pathway databases have been gathered, curated, integrated and analyzed in order to reconstruct a single, comprehensive picture of the proteins that interact with, and participate to the NF-κB activation system. Such a reconstruction shows that the NF-κB interactome is substantially different in quantity and quality of components with respect to canonical representations. The analysis highlights that several neglected but topologically central proteins may play a role in the activation of NF-κB mediated responses. Moreover the interactome structure fits with the characteristics of a bow tie architecture. This interactome is intended as an open network resource available for further development, refinement and analysis.
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Affiliation(s)
- Paolo Tieri
- CIG Luigi Galvani Interdept Center, University of Bologna, Bologna, Italy.
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Notch and the p53 clan of transcription factors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 727:223-40. [PMID: 22399351 DOI: 10.1007/978-1-4614-0899-4_17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Notch 1 to 4 and the p53 clan, comprising p53, p63 and p73 plus numerous isoforms thereof, are gene transcription regulators that are critically involved in various aspects of cell differentiation, stem cell maintenance and tumour suppression. It is thus perhaps no surprise that extensive crosstalk between the Notch and p53 pathways is implemented during these processes. Typically, Notch together with p53 and even more so with transactivation competent p63 or p73, drives differentiation, whereas Notch combined with transactivation impaired p63 or p73 helps maintain undifferentiated stem cell compartments. With regard to cancer, it seems that Notch acts as a tumour suppressor in cellular contexts where Notch signalling supports p53 activation and both together can bring on its way an anti-proliferative programme of differentiation, senescence or apoptosis. In contrast, Notch often acts as an oncoprotein in contexts where it suppresses p53 activation and activity and where differentiation is unwanted. It is no accident that the latter pathways-the inhibition by Notch of p53 and differentiation-are operative in somatic stem cells as well as in tumour cells.
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Malik AI, Williams A, Lemieux CL, White PA, Yauk CL. Hepatic mRNA, microRNA, and miR-34a-target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2012; 53:10-21. [PMID: 21964900 PMCID: PMC3525943 DOI: 10.1002/em.20668] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 06/18/2011] [Accepted: 06/20/2011] [Indexed: 05/04/2023]
Abstract
Benzo(a)pyrene (BaP) is a mutagenic carcinogen that is ubiquitous in our environment. To better understand the toxic effects of BaP and to explore the relationship between toxicity and toxicogenomics profiles, we assessed global mRNA and microRNA (miRNA) expression in Muta™Mouse. Adult male mice were exposed by oral gavage to 25, 50, and 75 mg/kg/day BaP for 28 days. Liver tissue was collected 3 days following the last treatment. Initially, we established that exposure to BaP led to the formation of hepatic DNA adducts and mutations in the lacZ transgene of the Muta™Mouse. We then analyzed hepatic gene expression profiles. Microarray analysis of liver samples revealed 134 differentially expressed transcripts (adjusted P < 0.05; fold changes > 1.5). The mRNAs most affected were involved in xenobiotic metabolism, immune response, and the downstream targets of p53. In this study, we found a significant 2.0 and 3.6-fold increase following exposure to 50 and 75 mg/kg/day BaP, respectively, relative to controls for miR-34a. This miRNA is involved in p53 response. No other significant changes in miRNAs were observed. The protein levels of five experimentally confirmed miR-34a targets were examined, and no major down-regulation was present. The results suggest that liver miRNAs are largely unresponsive to BaP doses that cause both DNA adducts and mutations. In summary, the validated miRNA and mRNA expression profiles following 28 day BaP exposure reflect a DNA damage response and effects on the cell cycle, consistent with the observed increases in DNA adducts and mutations.
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Wright BE, Schmidt KH, Hunt AT, Lodmell JS, Minnick MF, Reschke DK. The roles of transcription and genotoxins underlying p53 mutagenesis in vivo. Carcinogenesis 2011; 32:1559-67. [PMID: 21803733 DOI: 10.1093/carcin/bgr177] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Transcription drives supercoiling which forms and stabilizes single-stranded (ss) DNA secondary structures with loops exposing G and C bases that are intrinsically mutable and vulnerable to non-enzymatic hydrolytic reactions. Since many studies in prokaryotes have shown direct correlations between the frequencies of transcription and mutation, we conducted in silico analyses using the computer program, mfg, which simulates transcription and predicts the location of known mutable bases in loops of high-stability secondary structures. Mfg analyses of the p53 tumor suppressor gene predicted the location of mutable bases and mutation frequencies correlated with the extent to which these mutable bases were exposed in secondary structures. In vitro analyses have now confirmed that the 12 most mutable bases in p53 are in fact located in predicted ssDNA loops of these structures. Data show that genotoxins have two independent effects on mutagenesis and the incidence of cancer: Firstly, they activate p53 transcription, which increases the number of exposed mutable bases and also increases mutation frequency. Secondly, genotoxins increase the frequency of G-to-T transversions resulting in a decrease in G-to-A and C mutations. This precise compensatory shift in the 'fate' of G mutations has no impact on mutation frequency. Moreover, it is consistent with our proposed mechanism of mutagenesis in which the frequency of G exposure in ssDNA via transcription is rate limiting for mutation frequency in vivo.
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Silva BAKD, Aydos RD, Silva IS, Pereira DM, Carvalho PDTCD, Dourado DM, Reis FAD, Nacer RS. Lung apoptosis after intra-pulmonary instillation of Benzo(a)pyrene in Wistar rats. Acta Cir Bras 2010; 25:117-20. [DOI: 10.1590/s0102-86502010000100023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 11/25/2009] [Indexed: 11/21/2022] Open
Abstract
PURPOSE: To evaluate the influence of pulmonary instillation of Benzo[a]pyrene in lung apoptosis of Wistar rats. METHODS: Male Rattus norvegicus albinus, Wistar lineage was carried through an intra-pulmonary instillation of the Benzo[a]pyrene (B[a]P) dilution in alcohol 70%. Three experimental groups had been formed with 08 animals each: Control Group (Alcohol 70%); B[a]P Group 40 mg/kg; e B[a]P Group 80mg/kg, submitted to euthanasia 16 and 18 weeks after the experimental procedure. The pulmonary sections had been processed by TUNEL method and submitted to the histomorphometric analysis to quantify the apoptotic cell number. RESULTS: After 16 weeks, mean of apoptotic cells number in control group (19,3±3,2) was greater than 40mg/Kg group (11,8±1,9; p<0,01) and 80mg/Kg group (7,0±1,4; p<0,01). Significant difference also observed between 40mg/Kg and 80mg/Kg (p<0,05). After 18 weeks, mean of apoptotic cells number in control group (18,0±2,2) was greater than 40mg/Kg group (8,8±1,7; p<0,01) and 80mg/Kg group (5,5±1,3; p<0,01). Significant difference wasn't observed between 40mg/Kg and 80mg/Kg (ns). CONCLUSION: Intra-pulmonary instillation of Benzo[a]pyrene induces significant decrease of apoptotic activity in lung tissue.
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Guo Z, Wang J, Yang J, Wu NH, Zhang Y, Shen YF. An inhibitory role of p53 via NF-κB element on the cyclin D1 gene under heat shock. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2009; 1789:758-62. [DOI: 10.1016/j.bbagrm.2009.09.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Revised: 09/24/2009] [Accepted: 09/24/2009] [Indexed: 12/28/2022]
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Abstract
Understanding the complexity of cancer depends on an elucidation of the underlying regulatory networks, at the cellular and intercellular levels and in their temporal dimension. This Opinion article focuses on the multilevel crosstalk between the Notch pathway and the p53 and p63 pathways. These two coordinated signalling modules are at the interface of external damaging signals and control of stem cell potential and differentiation. Positive or negative reciprocal regulation of the two pathways can vary with cell type and cancer stage. Therefore, selective or combined targeting of the two pathways could improve the efficacy and reduce the toxicity of cancer therapies.
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Affiliation(s)
- G Paolo Dotto
- Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.
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Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009; 15:425-30. [PMID: 19147746 DOI: 10.1158/1078-0432.ccr-08-0149] [Citation(s) in RCA: 531] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. Although acute inflammation that persists for short-term mediates host defense against infections, chronic inflammation that lasts for long term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3), two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NF-kappaB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kappaB; fifth, chemotherapeutic agents and gamma-irradiation activate NF-kappaB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis, and metastasis are regulated by NF-kappaB and STAT3; seventh, suppression of NF-kappaB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kappaB and STAT3 activation pathways. Thus, suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer.
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Affiliation(s)
- Bharat B Aggarwal
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Manna S, Mukherjee S, Roy A, Das S, Panda CK. Tea polyphenols can restrict benzo[a]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1. J Nutr Biochem 2009; 20:337-49. [DOI: 10.1016/j.jnutbio.2008.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Revised: 03/17/2008] [Accepted: 04/01/2008] [Indexed: 12/23/2022]
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Kobayashi S, Okamoto H, Iwamoto T, Toyama Y, Tomatsu T, Yamanaka H, Momohara S. A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47:1317-22. [PMID: 18617548 DOI: 10.1093/rheumatology/ken259] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis. METHODS Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with alpha-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD-AhR interaction, we used inhibitors of nuclear factor-kappaB (NF-kappaB) and extra-cellular stimulus-activated kinase (ERK). RESULTS Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1beta, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-kappaB and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-alpha. CONCLUSION TNF-alpha activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappaB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.
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Affiliation(s)
- S Kobayashi
- Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku, Tokyo 162-0054, Japan
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Yoshino I, Maehara Y. Impact of smoking status on the biological behavior of lung cancer. Surg Today 2007; 37:725-34. [PMID: 17713724 DOI: 10.1007/s00595-007-3516-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2006] [Accepted: 01/21/2007] [Indexed: 11/28/2022]
Abstract
Cigarette smoking is the most established risk factor for lung carcinogenesis; however, its effects on the progression of lung cancer are still unclear. We reviewed the clinical investigations on this issue, which imply that smoking status is a treatment predictor and prognostic factor for several subtypes of lung cancer. Moreover, gene alterations and various protein expressions of tumor progression were recognized more frequently in the tumor tissues of smokers than in those of the never smokers. A cellular analysis revealed that tobacco-specific chemical compounds cause genetic or epigenetic alterations, modulate expressions of large numbers of genes that include molecules related to proliferation, invasion and metastasis, and deteriorate anti-tumor immunity. Our findings suggest that smoking promotes the progression of lung cancer, and that elucidating the molecular mechanisms may help to clarify the therapeutic targets.
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Affiliation(s)
- Ichiro Yoshino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan
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Sugihara N, Toyama K, Okamoto T, Kadowaki M, Terao K, Furuno K. Effects of benzo(e)pyrene and benzo(a)pyrene on P-glycoprotein-mediated transport in Caco-2 cell monolayer: A comparative approach. Toxicol In Vitro 2007; 21:827-34. [PMID: 17408918 DOI: 10.1016/j.tiv.2007.02.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2006] [Revised: 02/03/2007] [Accepted: 02/09/2007] [Indexed: 11/25/2022]
Abstract
The previous studies from our laboratory reported that benzo(a)pyrene (Bap) influenced efflux transport of rhodamine 123 (Rho-123) by induction of P-glycoprotein (P-gp) in Caco-2 cells. The present study investigated whether induction of P-gp and the enhanced efflux transport of Rho-123 were caused by benzo(e)pyrene (Bep), which has a structure similar to Bap, but is not a carcinogenic compound. In Caco-2 monolayer exposed to 50 microM Bep for 72 h, the ratio of the apparent permeability coefficient (P(app)) of Rho-123 efflux increased significantly compared to that of the control monolayer. Similarly, a significant increase in expression of MDR1 mRNA and of P-gp at the protein level were detected by RT-PCR and by Western blot analysis, respectively, in Caco-2 cells exposed to Bep, compared to that of the control. Caco-2 cells exposed to Bep showed oxidative stress that was detected by fluorescence microscopy using aminophenyl fluorescein. However, the oxidative stress was weaker compared with that of Bap. The cellular GSH content was decreased to 80% or 59% of control cells, respectively, in Caco-2 cells exposed to either Bep or Bap. Our results further show that Bep or Bap-induced P-gp in Caco-2 cells might have been the result of oxidative stress rather than DNA damage.
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Affiliation(s)
- Narumi Sugihara
- Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzou, Fukuyama, Hiroshima 729-0292, Japan.
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Bolotina NA, Gasparian AV, Dubovaja TK, Evteev VA, Kobliakov VA. Benzo[a]pyrene-dependent activation of transcription factors NF-κB and AP-1 related to tumor promotion in hepatoma cell cultures. BIOCHEMISTRY (MOSCOW) 2007; 72:552-7. [PMID: 17573710 DOI: 10.1134/s0006297907050124] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The activation by the carcinogenic polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) of transcription factors NF-kappaB and AP-1 in hepatoma 27 and HepG2 cell cultures was studied. In contrast to the hepatoma HepG2 cells, cytochrome P450 isoforms and Ah-receptor are not expressed in the hepatoma 27 cells. The transcription factor NF-kappaB was activated only in the hepatoma 27 cells by BP treatment but not by its noncarcinogenic isomer benzo[e]pyrene (BeP). Conversely to NF-kappaB activation the transcription factor AP-1 was activated in the hepatoma HepG2 cells by cell treatment with BP but not in the hepatoma 27 cells. It is concluded that the NF-kappaB activation is caused by nonmetabolized BP molecule and not related to activation of the Ah-receptor. The transcription factor AP-1 seems to be activated as a result of the interaction of BP with the Ah-receptor. The realization of tumor promotion stage by carcinogenic PAHs treatment in dependence on the cytochrome P450 and Ah-receptor levels in the initiated cells is discussed.
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Affiliation(s)
- N A Bolotina
- Blokhin Institute of Carcinogenesis, Russian Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia
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Bopp SK, Lettieri T. Gene regulation in the marine diatom Thalassiosira pseudonana upon exposure to polycyclic aromatic hydrocarbons (PAHs). Gene 2007; 396:293-302. [PMID: 17540515 DOI: 10.1016/j.gene.2007.03.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2006] [Revised: 03/23/2007] [Accepted: 03/23/2007] [Indexed: 11/20/2022]
Abstract
Diatoms are eukaryotic algae, which can be found worldwide in oceans and freshwaters. These organisms are ecologically relevant due to their key role in the global carbon cycle, contributing to about 25% to the global primary production [Falciatore, A., Bowler, C., 2002. Revealing the molecular secrets of marine diatoms. Annu. Rev. Plant Biol. 53, 109-130]. We investigated the effects of three polycyclic aromatic hydrocarbons (PAHs, pyrene, fluoranthene, and benzo[a]pyrene), either as single compound or as mixture, at molecular level. Dose-response curves for growth inhibition were determined and four concentrations eliciting from "no effect" up to a severe growth inhibition were chosen for further investigation to detect alterations at gene expression level by Real-Time PCR. Among the eight selected genes, two were strongly influenced by the PAH treatment. lacsA, which is involved in the fatty acid metabolism, was found to be strongly up-regulated by all single PAHs, as well as by the mixture. sil3, involved in the formation of the silica shell, was repressed by a factor up to three even at low PAH concentrations not eliciting any growth inhibition. For other genes, involved e.g. in photosynthesis, a slight down-regulation was detected. Based on the effects at gene expression level it can be assumed that PAHs impair the fatty acid metabolism and silica shell formation.
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Affiliation(s)
- Stephanie K Bopp
- European Commission -- DG Joint Research Centre, Institute for Environment and Sustainability, Rural, Water, and Ecosystem Resources Unit, T.P. 300, Via E. Fermi 1, 21020 Ispra (VA), Italy
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Knaapen AM, Curfs DM, Pachen DM, Gottschalk RW, de Winther MPJ, Daemen MJ, Van Schooten FJ. The environmental carcinogen benzo[a]pyrene induces expression of monocyte-chemoattractant protein-1 in vascular tissue: a possible role in atherogenesis. Mutat Res 2007; 621:31-41. [PMID: 17376491 DOI: 10.1016/j.mrfmmm.2006.12.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2006] [Revised: 12/12/2006] [Accepted: 12/13/2006] [Indexed: 01/07/2023]
Abstract
Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) has been implicated in the aetiology of atherosclerosis. Previously we showed that chronic exposure of ApoE-/- mice to the prototype PAH benzo[a]pyrene (B[a]P) causes enhanced progression of atherosclerosis, which was characterised by an increased inflammatory cell content in the atherosclerotic plaques. The aim of the present study was to evaluate the effect of B[a]P on vascular expression of monocyte-chemoattractant protein 1 (MCP-1), which is a crucial molecule promoting the recruitment of monocytes into atherosclerotic lesions. We hypothesised that B[a]P-induced expression of MCP-1 is mediated through aryl hydrocarbon receptor (AhR) activation. Initially we performed in vivo studies showing that acute treatment with B[a]P induces MCP-1 gene expression in aortic tissue of ApoE-/- mice. These observations could be confirmed by in vitro studies with human endothelial cells (RF24 cell line and primary HUVEC), showing a dose- and time-dependent increase in MCP-1 expression upon exposure to B[a]P. This was paralleled by an induction of cytochrome P450 1A1 and 1B1, indicating Ah receptor activation. No increased gene expression (MCP-1, CYP1A1 and 1B1) was found upon incubation with the structural isomer benzo[e]pyrene, which is a weak AhR agonist. Moreover, B[a]P-induced MCP-1 gene and protein expression was inhibited by co-treatment with the AhR antagonist alpha-naphthoflavone. In addition to its effect on basal gene expression, we showed that B[a]P significantly enhanced TNFalpha-induced expression of MCP-1. We were unable to block B[a]P-induced MCP-1 expression by antioxidant treatment. In contrast, we found that addition of N-acetylcysteine or vitamin C enhanced transcription of MCP-1 by B[a]P. In conclusion, our studies revealed potent vascular pro-inflammatory effects of B[a]P, as evidenced by AhR-mediated induction of MCP-1. These observations further contribute to the concept that induction of inflammation is a crucial process in PAH-enhanced atherogenesis.
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Affiliation(s)
- Ad M Knaapen
- Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), The Netherlands.
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Wright B, Reimers J, Schmidt K, Burkala E, Davis N, Wei P. Mechanisms of genotoxin-induced transcription and hypermutation in p53. Cancer Cell Int 2006; 6:27. [PMID: 17140443 PMCID: PMC1702552 DOI: 10.1186/1475-2867-6-27] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2006] [Accepted: 12/01/2006] [Indexed: 01/10/2023] Open
Abstract
It is widely assumed that genotoxin-induced damage (e.g., G-to-T transversions) to the tumor suppressor gene, p53, is a direct cause of cancer. However, genotoxins also induce the stress response, which upregulates p53 transcription and the formation of secondary structures from ssDNA. Since unpaired bases are thermodynamically unstable and intrinsically mutable, increased transcription could be the cause of hypermutation, and thus cancer. Support for this hypothesis has been obtained by analyzing 6662 mutations in all types of cancer compared to lung and colon cancers, using the p53 mutation database. The data suggest that genotoxins have two independent effects: first, they induce p53 transcription, which increases the number of mutable bases that determine the incidence of cancer. Second, genotoxins may alter the fate, or ultimate mutation of a mutable base, for example, by causing more of the available mutable Gs to mutate to T, leaving fewer to mutate to A. Such effects on the fate of mutable bases have no impact on the incidence of cancer, as both types of mutations lead to cancer.
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Affiliation(s)
- Barbara Wright
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
| | - Jacqueline Reimers
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
| | - Karen Schmidt
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
| | - Evan Burkala
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
| | - Nick Davis
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
| | - Ping Wei
- Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA
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Bruno T, De Nicola F, Iezzi S, Lecis D, D'Angelo C, Di Padova M, Corbi N, Dimiziani L, Zannini L, Jekimovs C, Scarsella M, Porrello A, Chersi A, Crescenzi M, Leonetti C, Khanna KK, Soddu S, Floridi A, Passananti C, Delia D, Fanciulli M. Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint. Cancer Cell 2006; 10:473-86. [PMID: 17157788 DOI: 10.1016/j.ccr.2006.10.012] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2005] [Revised: 07/18/2006] [Accepted: 10/05/2006] [Indexed: 12/14/2022]
Abstract
Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.
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Affiliation(s)
- Tiziana Bruno
- Experimental Chemotherapy Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy
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Han X, Chesney RW. Is TauT an anti-apoptotic gene? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 583:59-67. [PMID: 17153589 DOI: 10.1007/978-0-387-33504-9_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Xiaobin Han
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
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Park SY, Lee SM, Ye SK, Yoon SH, Chung MH, Choi J. Benzo[a]pyrene-induced DNA damage and p53 modulation in human hepatoma HepG2 cells for the identification of potential biomarkers for PAH monitoring and risk assessment. Toxicol Lett 2006; 167:27-33. [PMID: 17029827 DOI: 10.1016/j.toxlet.2006.08.011] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2006] [Revised: 08/14/2006] [Accepted: 08/18/2006] [Indexed: 12/31/2022]
Abstract
To identify potential biomarkers for the monitoring and risk assessment of benzo[a]pyrene (BaP), the oxidative stress-related DNA damage and p53 modification were investigated in human hepatoma HepG2 cells. Benzo[a]pyrene exposure induced a decrease in the cell viability, but increased the antioxidant enzyme activity as well as the DNA and lipid damage. The p53 protein activation appeared to have been a downstream response to the benzo[a]pyrene-induced DNA damage, suggesting p53 plays important roles in the defense against benzo[a]pyrene-induced genotoxicity. The response of phosphorylated p53 may be more sensitive towards benzo[a]pyrene exposure than normal p53. Following DNA damage, the activation of p53 acts as a transcriptional regulator of several target genes, including, p21 protein; a gene that encodes the Cdk inhibitor and is induced by exposure to benzo[a]pyrene. The p53 mRNA level was increased after the treatment of cells with benzo[a]pyrene, as well as following the induction of p53 protein, suggesting the benzo[a]pyrene-stimulated p53 accumulation may also be transcriptionally induced. The overall results suggest that benzo[a]pyrene leads to serious DNA damage, which leads to the transcription of the p53 gene; that the subsequent p53 protein accumulation up-regulates the cellular p21 protein. Oxidative DNA damage and p53 accumulation seem to be related to benzo[a]pyrene toxicity; however, their potential as biomarkers in environmental monitoring and risk assessment needs to be validated in the context of their specificity and sensitivity.
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Affiliation(s)
- Sun-Young Park
- Faculty of Environmental Engineering, College of Urban Study, University of Seoul, Republic of Korea
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Manna S, Banerjee S, Saha P, Roy A, Das S, Panda CK. Differential Alterations in Metabolic Pattern of the Spliceosomal UsnRNAs during Pre-Malignant Lung Lesions Induced by Benzo(a)pyrene: Modulation by Tea Polyphenols. Mol Cell Biochem 2006; 289:149-57. [PMID: 16718374 DOI: 10.1007/s11010-006-9158-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2005] [Accepted: 02/14/2006] [Indexed: 10/24/2022]
Abstract
The differential alterations of the spliceosomal UsnRNAs (U1, U2, U4, U5, and U6) were reported to be associated with cellular proliferation and development. The attempt was made in this study to analyze the metabolic pattern of the spliceosomal UsnRNAs during the development of pre-malignant lung lesions induced in experimental mice model system by benzo(a)pyrene (BP) and also to see how tea polyphenols, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), modulate the metabolism of these UsnRNAs during the lung carcinogenesis. No significant changes in the level of the UsnRNAs were seen in the inflammatory lung lesions at 9th week due to treatment of BP. However, there was significant increase in the level of U1 ( approximately 2.5 fold) and U5 ( approximately 47%) in the hyperplastic lung lesions at 17th week. But in the mild dysplastic lung lesions at 26th week, the level of UsnRNAs did not change significantly. Whereas, in the dysplastic lung lesions at 36th week there was significant increase in the level of the U2 ( approximately 2 fold), U4 ( approximately 2.5 fold) and U5 ( approximately 2 fold). Due to the EGCG and ECG treatment the lung lesions at 9th week appeared normal and in the 17th, 26th, and 36th week it appeared as hyperplasia. The level of the UsnRNAs was significantly low in the lung lesions at 9th week (only U2 and U4 by EGCG), at 17th week (only U1 by EGCG/ECG), at 26th week (U1 by ECG; U2, U4 and U5 by EGCG/ECG) and at 36th week (U1 by ECG, U2 and U4 by EGCG/ECG). Whereas, there was significant increase in the level of U5 (by EGCG/ECG) and U6 (by EGCG only) in the lung lesions at 36th and 26th week respectively. This indicates that the metabolism of the spliceosomal UsnRNAs differentially altered during the development of pre-malignant lung lesions by BP as well as during the modulation of the lung lesions by the tea polyphenols.
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Affiliation(s)
- Sugata Manna
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, India
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Yoshino I, Kawano D, Oba T, Yamazaki K, Kometani T, Maehara Y. Smoking Status as a Prognostic Factor in Patients with Stage I Pulmonary Adenocarcinoma. Ann Thorac Surg 2006; 81:1189-93. [PMID: 16564239 DOI: 10.1016/j.athoracsur.2005.09.028] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2005] [Revised: 08/29/2005] [Accepted: 09/01/2005] [Indexed: 10/24/2022]
Abstract
BACKGROUND Cigarette smoking is a well-known risk factor for lung carcinogenesis; however, its effect on tumor progression is still unclear. We herein investigated the influence of cigarette smoking on postoperative prognosis in patients with non-small cell lung cancer (NSCLC). METHODS The postoperative survival and pathologic stage of 999 patients with NSCLC who underwent a curative resection were retrospectively investigated in relation to the pack-year index (PYI). RESULTS Adenocarcinoma patients with a PYI of less than 20 showed a more favorable prognosis than those with a PYI of 20 or more, whereas no difference was observed among the subgroups of squamous cell carcinoma patients. In adenocarcinoma, stage I disease was a significantly larger population in never-smokers than in smokers. A multivariate analysis revealed that the smoking habit (yes or no) and stage (IA or IB), but not gender or histologic subtype (bronchioloalveolar type or not), are independent prognostic factors in stage I adenocarcinoma with hazard ratios of 1.8 and 2.3, respectively. CONCLUSIONS The smoking status is a significant prognostic factor for stage I pulmonary adenocarcinoma.
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Affiliation(s)
- Ichiro Yoshino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Sugihara N, Toyama K, Michihara A, Akasaki K, Tsuji H, Furuno K. Effect of benzo[a]pyrene on P-glycoprotein-mediated transport in Caco-2 cell monolayer. Toxicology 2006; 223:156-65. [PMID: 16647797 DOI: 10.1016/j.tox.2006.03.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Revised: 03/16/2006] [Accepted: 03/21/2006] [Indexed: 11/21/2022]
Abstract
The main exposure pathway of benzo[a]pyrene (Bap) for humans is considered to be via the daily diet. The purpose of this study was to investigate the effect of BaP on the intestinal transport of chemicals mediated by P-glycoprotein (P-gp). The intestinal epithelial membrane transport of rhodamine-123 (Rho-123), a substrate of P-gp, was examined using a monolayer of the human Caco-2 cell line grown in transwells. In the monolayer exposed to Bap for 72 h before transport experiments, the ratio of the apparent permeability coefficients (P(app)) of Rho-123 efflux increased compared to that of the control. The permeability of rhodamine-B (Rho-B), not a substrate of P-gp, showed no difference between the monolayers. Treatment with quinidine or cyclosporine A, which are P-gp inhibitors, decreased the P(app) of Rho-123 to the same degree in both monolayers. The transport of Rho-123 was not influenced by the presence of Bap. Thus, Bap seemed not to act directly on the efflux activity of P-gp and be a binding site competitor of Rho-123. In the Caco-2 cells that enhanced the efflux of Rho-123 by the treatment with Bap, an increase in mRNA expression of MDR 1 (P-gp) was confirmed compared to that of control by RT-PCR. Furthermore, Western blot analysis using a monoclonal antibody, C219, demonstrated the increase of P-gp in Caco-2 cells exposed to Bap, compared with controls. It was inferred that Bap exposure induced the expression of P-gp, which led to the observed increase in efflux transport of Rho-123. The possibility was suggested that Bap might affect the disposition of medicines by increasing P-gp expression.
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Affiliation(s)
- Narumi Sugihara
- Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzou, Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
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Kim SJ, Ko CB, Park C, Kim BR, Sung TH, Koh DH, Kim NS, Oh KJ, Chung SY, Park R. p38 MAP kinase regulates benzo(a)pyrene-induced apoptosis through the regulation of p53 activation. Arch Biochem Biophys 2005; 444:121-9. [PMID: 16297369 DOI: 10.1016/j.abb.2005.10.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Revised: 10/06/2005] [Accepted: 10/13/2005] [Indexed: 11/27/2022]
Abstract
Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP), are widespread in the environment and cause untoward effects, including carcinogenesis, in mammalian cells. However, the molecular mechanism of apoptosis by BaP is remained to be elusive. Pharmacological inhibition of p38 kinase markedly inhibited the BaP-induced cytotoxicity, which was proven as apoptosis characterized by an increase in sub-G(0)/G(1) fraction of DNA content, ladder-pattern fragmentation of genomic DNA, and catalytic activation of caspase-3 with PARP cleavage. Our data also demonstrated that activation of caspase-3 was accompanied with activation of caspase-9 and mitochondrial dysfunction, which was also apparently suppressed by pretreatment with p38 kinase inhibitors. Also, pharmacological inhibition of p38 markedly inhibited the phosphorylation, accumulated expression, and transactivation activity of p53 in BaP-treated cells. Adenoviral overexpression of human p53 (wild-type) further augmented in increase of PARP cleavage and the sub-G(0)/G(1) fraction of DNA content. Furthermore, p53 mediated apoptotic activity in BaP-treated cells was inhibited by p38 kinase inhibitor. The current data collectively indicate that BaP induces apoptosis of Hepa1c1c7 cells via activation of p53-related signaling, which was, in part, regulated by p38 kinase.
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Affiliation(s)
- Se Jin Kim
- Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk 570-749, Republic of Korea
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Han X, Chesney RW. Regulation of TauT by cisplatin in LLC-PK1 renal cells. Pediatr Nephrol 2005; 20:1067-72. [PMID: 15942793 DOI: 10.1007/s00467-005-1887-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2004] [Revised: 01/24/2005] [Accepted: 01/28/2005] [Indexed: 10/25/2022]
Abstract
Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. Since cisplatin-induced renal injury is mainly confined to the S3 segment of renal proximal tubules-the primary site for renal adaptive regulation of TauT-we hypothesize that TauT functions as an anti-apoptotic gene and plays a role in protecting renal cells from drug-induced nephrotoxicity. In the present study we demonstrated that expression of TauT was significantly reduced by cisplatin (50 muM) in LLC-PK1 cells. Down-regulation of TauT by cisplatin occurs at the transcriptional level in a dose-dependent manner, as demonstrated through a reporter gene driven by the TauT promoter. It appears that cisplatin down-regulates TauT expression, at least in part, through the p53-dependent pathway, since cisplatin induces the p53 expression, which, in turn, represses TauT. Cisplatin induces apoptosis of LLC-PK1 cells in a dose-dependent manner. However, forced over-expression of TauT by stable transfection of a taurine transporter cDNA (pNCT) in LLC-PK1 cells was able to attenuate cisplatin-induced down-regulation of taurine uptake by LLC-PK1 cells and protect renal tubular cells from apoptosis. The mechanism by which TauT serves as an anti-apoptotic gene in cisplatin-induced renal injury remains to be determined, but could relate to taurine-dependent cell volume regulation.
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Affiliation(s)
- X Han
- Department of Pediatrics, University of Tennessee, Memphis, 38103, USA.
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Johansen C, Flindt E, Kragballe K, Henningsen J, Westergaard M, Kristiansen K, Iversen L. Inverse Regulation of the Nuclear Factor-κB Binding to the p53 and Interleukin-8 κB Response Elements in Lesional Psoriatic Skin. J Invest Dermatol 2005; 124:1284-92. [PMID: 15955105 DOI: 10.1111/j.0022-202x.2005.23749.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.
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Affiliation(s)
- Claus Johansen
- Department of Dermatology, Marselisborg Hospital, University of Aarhus, Aarhus C, Denmark.
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Lecureur V, Ferrec EL, N'diaye M, Vee ML, Gardyn C, Gilot D, Fardel O. ERK-dependent induction of TNFalpha expression by the environmental contaminant benzo(a)pyrene in primary human macrophages. FEBS Lett 2005; 579:1904-10. [PMID: 15792794 DOI: 10.1016/j.febslet.2005.01.081] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2004] [Revised: 12/22/2004] [Accepted: 01/31/2005] [Indexed: 02/06/2023]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are toxic environmental contaminants known to enhance production of pro-inflammatory cytokines such as IL-1beta. The present study was designed in order to determine whether TNFalpha, another cytokine acting in inflammation, may also constitute a target for these chemicals. Both TNFalpha mRNA and TNFalpha secretion levels were found to be enhanced in human BP-treated macrophages. Dioxin, a contaminant activating the aryl hydrocarbon receptor (AhR) like PAHs, was also shown to increase TNFalpha expression. BP-mediated TNFalpha induction was however not suppressed by AhR antagonists, making unlikely the involvement of the typical AhR signalling pathway. BP-exposure of macrophages did not enhance NF-kappaB DNA binding activity, but it activated the MAP kinase ERK1/2. In addition, the use of chemical inhibitors of extracellular signal-regulated protein kinase (ERK) activation fully abrogated induction of TNFalpha production in BP-treated macrophages. These data likely indicate that PAHs enhance TNFalpha expression in human macrophages through an ERK-related mechanism. Such a regulation may contribute to confer pro-inflammatory properties to these widely-distributed environmental contaminants.
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Affiliation(s)
- Valérie Lecureur
- INSERM U620, Faculté de Pharmacie, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France.
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Halachmi S, Yaar M, Gilchrest BA. Avancées dans le domaine du vieillissement cutané et du photovieillissement. Ann Dermatol Venereol 2005; 132:362-7. [PMID: 15886566 DOI: 10.1016/s0151-9638(05)79284-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- S Halachmi
- Harvard Student Health Service, Cambridge, MA, USA
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Bae JS, Jang KH, Yim H, Park SC, Jin HK. Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice. World J Gastroenterol 2005; 11:577-9. [PMID: 15641149 PMCID: PMC4250814 DOI: 10.3748/wjg.v11.i4.577] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.
METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4, PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.
RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.
CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.
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Affiliation(s)
- Jae-Sung Bae
- College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea
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Riis JL, Johansen C, Gesser B, Møller K, Larsen CG, Kragballe K, Iversen L. 1alpha,25(OH)(2)D(3) regulates NF-kappaB DNA binding activity in cultured normal human keratinocytes through an increase in IkappaBalpha expression. Arch Dermatol Res 2004; 296:195-202. [PMID: 15372276 DOI: 10.1007/s00403-004-0509-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2004] [Revised: 08/05/2004] [Accepted: 08/11/2004] [Indexed: 01/28/2023]
Abstract
NF-kappaB is a dimeric transcription factor which regulates transcription of a number of different genes including IL-8 and p53. In resting cells NF-kappaB is usually retained in an inactive state in the cytoplasm through binding to a member of the inhibitory kappaB (IkappaB) protein family. The purpose of this study was to determine the effect of 1alpha,25(OH)(2)D(3) on NF-kappaB activation in both unstimulated and stimulated (IL-1alpha) cultured normal human keratinocytes. NF-kappaB DNA binding activity was determined by EMSA using two different oligonucleotides containing the kappaB sequence from either the IL-8 or the p53 promoter. IkappaBalpha and p53 expression was determined by Western blotting and IL-8 expression by ELISA. In unstimulated keratinocytes no NF-kappaB binding to the IL-8 kappaB binding sequence was detectable, whereas stimulation with IL-1alpha (10 ng/ml) led to a significant ( P<0.05) induction of NF-kappaB binding. In contrast NF-kappaB binding to the p53 kappaB binding sequence was detectable in unstimulated cells, although it was significantly increased after IL-1alpha (10 ng/ml) stimulation. Incubation with 1alpha,25(OH)(2)D(3) (10(-8)-10(-7) M) was shown to significantly ( P<0.05) stimulate the expression of IkappaBalpha and in parallel experiments with normal human keratinocytes stimulated with IL-1alpha (10 ng/ml) a significant ( P<0.05) time and dose-dependent decrease in NF-kappaB binding to the IL-8 kappaB binding sequence and in IL-8 expression were seen. A less-pronounced decrease in NF-kappaB binding to the p53 kappaB response element was seen after preincubation with 1alpha,25(OH)(2)D(3) and IL-1alpha stimulation, and it did not result in any change in p53 expression. These results demonstrate that 1alpha,25(OH)(2)D(3) inhibits NF-kappaB binding to the IL-8 kappaB binding sequence more potently than binding to the p53 kappaB binding sequence. We propose that this selectivity may be mediated through an increased expression of IkappaBalpha which leads to an inhibition of specific NF-kappaB subunits resulting in a selective regulation of NF-kappaB-induced gene transcription.
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Affiliation(s)
- Jette L Riis
- Department of Dermatology, Aarhus Sygehus, Aarhus University Hospital, P.P. Orumsgade 11, 8000 Aarhus C, Denmark
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48
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Wang S, Chen F, Zhang Z, Jiang BH, Jia L, Shi X. NF-kappaB prevents cells from undergoing Cr(VI)-induced apoptosis. Mol Cell Biochem 2004; 255:129-37. [PMID: 14971654 DOI: 10.1023/b:mcbi.0000007269.74532.98] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The transcription factor NF-kappaB has been reported to prevent cells from undergoing apoptosis as well as promote cell apoptosis. To investigate the role of NF-kappaB in Cr(VI)-induced apoptosis, two cell lines were developed from human bronchial epithelial BEAS-2B cells: IKK cells, which were stably transfected with IkappaBalpha expression vector, that have normal NF-kappaB activity, and KM cells, which were stably transfected with mutated IkappaBalpha kinase expression vector, that exhibit very little NF-kappaB activity. With Cr(VI) stimulation, KM cells, but not IKK cells, exhibited substantial cell death. Cell morphological and TUNEL analyses indicated that the KM cells showed apoptotic features. These results suggest that NF-kappaB activation is required to prevent the cells from undergoing Cr(VI)-induced apoptosis.
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Affiliation(s)
- Suwei Wang
- Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
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49
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Ko CB, Kim SJ, Park C, Kim BR, Shin CH, Choi S, Chung SY, Noh JH, Jeun JH, Kim NS, Park R. Benzo(a)pyrene-induced apoptotic death of mouse hepatoma Hepa1c1c7 cells via activation of intrinsic caspase cascade and mitochondrial dysfunction. Toxicology 2004; 199:35-46. [PMID: 15125997 DOI: 10.1016/j.tox.2004.01.039] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2003] [Revised: 01/21/2004] [Accepted: 01/21/2004] [Indexed: 11/16/2022]
Abstract
Benzo(a)pyrene (BaP), a potent carcinogen, has been shown to induce apoptosis via activation of caspase-3. However, the upstream of caspase-3 and other apoptosis signaling remain to be elusive. Herein, we demonstrated that treatment of Hepa1c1c7 cells with BaP increased the transcriptional expression of aryl hydrocarbon nuclear transporter and cytochrome p450 1A1 in a time and dose-dependent manner but did not aromatic hydrocarbon receptor. Also, the catalytic activation of caspase-3 and caspase-9 was induced whereas that of caspase-3 and caspase-9 was not by the addition of BaP. BaP also induced the mitochondrial dysfunction, including transition of mitochondria membrane potential and cytosolic release of cytochrome c. Furthermore, a decrease in the expression of Bcl-2 to Bax ratio and phosphorylation of p53(Ser 15) were observed in BaP-treated cells. Taken together, these results demonstrated that BaP-induced apoptosis of Hepa1c1c7 cells via activation of intrinsic caspase pathway including caspase-3, caspase-9, with mitochondrial dysfunction and p53 activation.
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Affiliation(s)
- Chang-Bo Ko
- Vestibulocochlear Research Center and Department of Microbiology, Wonkwang University School of Medicine, 344-2 Shinyong-dong, Iksan, Jeonbuk 570-749, South Korea
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50
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Aleyasin H, Cregan SP, Iyirhiaro G, O'Hare MJ, Callaghan SM, Slack RS, Park DS. Nuclear factor-(kappa)B modulates the p53 response in neurons exposed to DNA damage. J Neurosci 2004; 24:2963-73. [PMID: 15044535 PMCID: PMC6729853 DOI: 10.1523/jneurosci.0155-04.2004] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Previous studies have shown that DNA damage-evoked death of primary cortical neurons occurs in a p53 and cyclin-dependent kinase-dependent (CDK) manner. The manner by which these signals modulate death is unclear. Nuclear factor-kappaB (NF-kappaB) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NF-kappaB is activated shortly after induction of DNA damage in a manner independent of the classic IkappaB kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NF-kappaB via expression of a stable IkappaB mutant, downregulation of the p65 NF-kappaB subunit by RNA interference (RNAi), or pharmacological NF-kappaB inhibitors significantly protected against DNA damage-induced neuronal death. NF-kappaB inhibition also reduced p53 transcripts and p53 activity as measured by the p53-inducible messages, Puma and Noxa, implicating the p53 tumor suppressor in the mechanism of NF-kappaB-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NF-kappaB inhibition, indicating that p53 acts downstream of NF-kappaB. Interestingly, neurons cultured from p65 or p50 NF-kappaB-deficient mice were not resistant to death and did not show diminished p53 activity, suggesting compensatory processes attributable to germline deficiencies, which allow p53 activation still to occur. In contrast to acute NF-kappaB inhibition, prolonged NF-kappaB inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NF-kappaB serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.
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Affiliation(s)
- Hossein Aleyasin
- Ottawa Health Research Institute, Neurosciences, East Division, Ottawa, Ontario, Canada K1H 8M5
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