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Autonomous regulation of inducible nitric oxide synthase and cytochrome P450 2E1-mediated oxidative stress in maneb- and paraquat-treated rat polymorphs
Pesticide Biochemistry and Physiology ( IF 4.2 ) Pub Date : 2021-07-31 , DOI: 10.1016/j.pestbp.2021.104944
Deepali Singh 1 , Archana Yadav 1 , Chetna Singh 1
Affiliation  

Maneb (MB)- and paraquat (PQ)-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) is regulated in parallel by cytochrome P450 2E1 (CYP2E1) and inducible nitric oxide synthase (iNOS). However, mechanism underlying their regulation is not yet understood. The study investigated the role of nuclear factor- kappa B (NF-κB) and mitogen-activated protein kinase/extracellular signal regulated kinase/protein kinase C (MEK/ERK/PKC) pathway in the regulation of iNOS- and CYP2E1-induced oxidative stress in PMNs. MB + PQ-induced changes in nitrite content, lipid peroxidation (LPO), iNOS expression/activity and inflammatory mediators were alleviated by aminoguanidine (AG), an iNOS inhibitor, without any change in CYP2E1. Alternatively, diallyl sulphide (DAS), a CYP2E1 inhibitor, rescued from MB + PQ-induced changes in CYP2E1 activity/expression, free radical generation, superoxide dismutase (SOD) activity, LPO and pro-inflammatory cytokines without any alterations in nitrite content and iNOS activity/expression. Pyrrolidine dithiocarbamate (PDTC), NF-κB inhibitor, did not alter CYP2E1 but mitigated free radical generation, SOD activity, LPO, nitrite content, iNOS activity/expression and levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukine-1β and interleukine-4). Ex-vivo treatment with MEK inhibitor (PD98059), ERK1/2 inhibitor (AG126) or PKC inhibitor (rottlerin) ameliorated MB + PQ-induced increase in free radical generation and CYP2E1 activity/expression in PMNs. While PD98059 and AG126 abated MB + PQ-induced increase in ERK1/2, PKC-α/δ and CYP2E1 levels, rottlerin restored PKC-α/δ and CYP2E1 towards normalcy without affecting ERK1/2 level in MB + PQ-treated group. The results suggest that iNOS and CYP2E1 contributing to MB + PQ-induced oxidative stress in rat PMNs exhibit differential regulatory mechanisms. The inflammatory mediators regulate iNOS expression while CYP2E1 expression is triggered via MEK-ERK1/2-PKC pathway.



中文翻译:

诱导型一氧化氮合酶和细胞色素 P450 2E1 介导的氧化应激在 maneb 和百草枯处理的大鼠多态性中的自主调节

Maneb (MB) 和百草枯 (PQ) 诱导的大鼠多形核白细胞 (PMN) 氧化应激受细胞色素 P450 2E1 (CYP2E1) 和诱导型一氧化氮合酶 (iNOS) 的平行调节。然而,其调控的机制尚不清楚。该研究调查了核因子-κB (NF-κB) 和丝裂原活化蛋白激酶/细胞外信号调节激酶/蛋白激酶 C (MEK/ERK/PKC) 通路在调节 iNOS-和 CYP2E1 诱导的氧化过程中的作用。 PMN 中的压力。MB + PQ 诱导的亚硝酸盐含量、脂质过氧化 (LPO)、iNOS 表达/活性和炎症介质的变化被 iNOS 抑制剂氨基胍 (AG) 缓解,而 CYP2E1 没有任何变化。或者,二烯丙基硫醚 (DAS),一种 CYP2E1 抑制剂,从 MB + PQ 诱导的 CYP2E1 活性/表达变化中拯救出来,自由基生成、超氧化物歧化酶 (SOD) 活性、LPO 和促炎细胞因子,亚硝酸盐含量和 iNOS 活性/表达没有任何改变。吡咯烷二硫代氨基甲酸酯 (PDTC),NF-κB 抑制剂,不会改变 CYP2E1,但会减轻自由基的产生、SOD 活性、LPO、亚硝酸盐含量、iNOS 活性/表达和促炎细胞因子(肿瘤坏死因子-α、白细胞介素-1β)的水平和白细胞介素-4)。用 MEK 抑制剂 (PD98059)、ERK1/2 抑制剂 (AG126) 或 PKC 抑制剂 (rottlerin) 进行体外治疗可改善 MB + PQ 诱导的自由基生成增加和 PMN 中 CYP2E1 活性/表达的增加。虽然 PD98059 和 AG126 减轻 MB + PQ 诱导的 ERK1/2、PKC-α/δ 和 CYP2E1 水平的增加,但 Rottlerin 使 PKC-α/δ 和 CYP2E1 恢复正常,而不影响 MB + PQ 治疗组的 ERK1/2 水平。结果表明,iNOS 和 CYP2E1 有助于 MB + PQ 诱导的大鼠 PMN 氧化应激表现出不同的调节机制。炎症介质调节 iNOS 表达,而 CYP2E1 表达通过 MEK-ERK1/2-PKC 途径触发。

更新日期:2021-08-23
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