Investigation of the mechanism of paraquat toxicity -Identification of the genes which are breakthrough for the toxicity-

百草枯毒性机制研究 - 毒性突破基因的鉴定 -

• 批准号: 16590552
• 负责人: TOMITA Masafumi
• 金额: $ 2.24万
• 依托单位: Kawasaki Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590552/
• 关键词: Paraquat; Toxicology; Gene expression; real-time PCR; Oxidative Stress; Lung fibrosis; Immunohistochemistry; Animal model; マウスモデル; 初期マーカー; Real-time PCR; toxicology; 肺線維化モデル; fibroblast; Masson's Trichrome染色; マウス; 活性酸素; cDNA array; Real

We examined on gene expression levels to understand the mechanism of paraquat (PQ)-driven poisoning and the following results were obtained.1) We examined the effect of PQ on the gene expression levels of antioxidant enzymes (AOE) and glutathione (GSH) status in lungs 16 h post-administration. Although GSH levels as well as some AOE expression levels were increased, GSH did not play as a OH radical scavenger because GSH peroxidase (GPX) was not stimulated.2) Some genes related to oxidative stress, such as thioredoxin, GSH S-transferase, heme oxygenase 1(HO-1), NADPH-oxidoreductase 1 (NQO-1), showed a significant increase in their RNA expression at 3 h post-administration. Immunohistochemical analysis showed that HO-1 and NQO-1 were especially expressed in the bronchial epithelial cells of PQ-treated lung sections. In addition, the expression levels of some CYPs which are specific or dominant in female liver decreased markedly, while the male-specific CYPs showed an increase or no effec … More t.3) We obtained an increase of some genes in kidneys by 3 h after injection, and metallothionein-1 (MT-1) and HO-1 showed the biggest increase. However, the increases did not continue until 24 h after injection, and the second injection had less effect than the first. Up-regulation of these RNA levels was confirmed at the protein level. The MT-1 in kidneys had been consumed by the first injection. These results may explain the injury observed due to PQ uptake.4) We developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution. The pathological progression of lung injury in this model was very similar to that of patients suffering from PQ poisoning.5) Using the PQ-poisoned mouse model, we examined 45 gene expression levels at the initial destructive phase (within 5 days) that fibrosis has not completely developed. Some genes involved in inflammation and apoptosis showed the maximum increase within 1 day, while the genes involve in the development of fibrosis were significantly increased on day 5, not at 6 h nor at 24 h after PQ exposure. In addition, the RNA level of surfactant protein, EC-SOD, catalase decreased significantly time dependently. Less

我们通过检查基因表达水平来了解百草枯 (PQ) 引起的中毒机制，并获得以下结果。1) 我们检查了给药 16 小时后 PQ 对肺部抗氧化酶 (AOE) 和谷胱甘肽 (GSH) 状态的基因表达水平的影响。尽管GSH水平以及一些AOE表达水平有所增加，但GSH并没有发挥OH自由基清除剂的作用，因为GSH过氧化物酶（GPX）没有受到刺激。2）一些与氧化应激相关的基因，如硫氧还蛋白、GSH S-转移酶、血红素加氧酶1（HO-1）、NADPH-氧化还原酶1（NQO-1）在3 h时表现出RNA表达显着增加 后管理。免疫组织化学分析显示HO-1和NQO-1在PQ处理的肺切片的支气管上皮细胞中尤其表达。此外，女性肝脏中特异或显性的一些CYPs的表达水平明显下降，而男性特异的CYPs则表现出增加或无影响。 t.3)我们在注射后3小时内获得了肾脏中一些基因的增加，其中金属硫蛋白-1（MT-1）和HO-1的增加幅度最大。然而，这种增加直到注射后24小时才持续，并且第二次注射的效果不如第一次。这些 RNA 水平的上调在蛋白质水平上得到了证实。肾脏中的 MT-1 已被第一次注射消耗掉。这些结果可以解释由于PQ摄取而观察到的损伤。4)我们通过鼻内滴注PQ溶液建立了PQ诱导的肺损伤动物模型。该模型中肺损伤的病理进展与PQ中毒患者的病理进展非常相似。5）使用PQ中毒小鼠模型，我们检测了纤维化尚未完全发展的初始破坏阶段（5天内）的45个基因表达水平。一些涉及炎症和细胞凋亡的基因在1天内表现出最大增加，而涉及纤维化发展的基因在PQ暴露后第5天显着增加，而不是在6小时或24小时。此外，表面活性蛋白、EC-SOD、过氧化氢酶的RNA水平随时间显着下降。较少的

项目成果

パラコートが発現レベルに影響をおよぼすラット肺での遺伝子について(4)

大鼠肺部表达水平受百草枯影响的基因 (4)

• 发表时间: 2004
• 期刊: 日本法医誌 58・1
• 作者: Tomita M;et al.;富田 正文
• 通讯作者: 富田 正文

Early differential gene expression of rat lung after exposure to paraquat

百草枯暴露后大鼠肺早期差异基因表达

• 发表时间: 2004
• 期刊: Free Radical Res 38巻・8号
• 作者: 廣田良夫;Masafumi Tomita
• 通讯作者: Masafumi Tomita

Changes in gene expression level for defense system enzymes against oxidative stress and glutathione level in rat administered paraquat.

• DOI: 10.3892/ijmm.15.4.689
• 发表时间: 2005-04
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: M. Tomita;H. Katsuyama;T. Okuyama;Kazuo Hidaka;Y. Minatogawa

Gene expression in rat lungs during early response to paraquat-induced oxidative stress.

• DOI: 10.3892/ijmm.17.1.37
• 发表时间: 2006
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: M. Tomita;T. Okuyama;H. Katsuyama;Kazuo Hidaka;T. Otsuki;T. Ishikawa

Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells.

• DOI: 10.3892/ijmm.15.2.231
• 发表时间: 2005-02
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: H. Katsuyama;T. Otsuki;M. Tomita;M. Fukunaga;T. Fukunaga;N. Suzuki;K. Saijoh;Shigeko Fushimi;S. Sunami