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目的基于Nrf2-ARE信号通路探讨异甘草酸镁对雷公藤甲素损伤L-02细胞的保护作用及相关机制。方法体外培养正常人肝L-02细胞,通过免疫荧光技术检测异甘草酸镁(60μmol·L^-1)对雷公藤甲素(80nmol·L^-1)损伤L-02细胞中Nrf2核转移的影响;采用Western blotting测定细胞核中Nrf2及细胞中细胞色素P450 3A4(CYP3A4)、多药耐药相关蛋白2(multidrug resistance associated protein 2,MRP2)和胆盐输出泵(bile salt export pump,BSEP)的蛋白表达。结果雷公藤甲素对L-02细胞核中Nrf2具有诱导作用(P<0.01),并促进Nrf2核内转移;异甘草酸镁预处理组较雷公藤甲素组降低L-02细胞核中Nrf2的表达(P<0.01);异甘草酸镁预处理后对雷公藤甲素损伤L-02细胞中CYP3A4、MRP2和BSEP蛋白表达具有诱导作用(P<0.01)。结论异甘草酸镁可减轻雷公藤甲素对L-02细胞造成的损伤作用,其机制可能与诱导细胞核中Nrf2以及细胞中CYP3A4、MRP2和BSEP受体有关。 相似文献
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《实用医药杂志(山东)》2015,(5)
目的考察栀子和黄芩对钩藤总碱致肝损伤的拮抗作用。方法 30只SD大鼠随机分为阴性对照组、阳性对照组和实验组,钩藤总碱30 mg/kg灌胃给药28 d造成肝损伤,同时浓缩栀子和黄芩水煎煮液治疗。结果钩藤总碱给药大鼠体重增长减慢,血中谷草转氨酶(AST)、谷丙转氨酶(ALT)含量升高,并且有肝细胞炎性损伤,栀子和黄芩水煎煮液可抑制钩藤总碱导致的AST、ALT升高和炎性损伤。结论栀子和黄芩的水提物能对抗钩藤总碱的肝毒性。 相似文献
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《中国药理学通报》2019,(6)
目的建立基于Nrf2-ARE通路的报告基因筛选模型,筛选黄芩中基于雌激素受体发挥抗氧化作用的活性成分。方法 ARE荧光素酶报告质粒p GL4. 37和海肾荧光素酶报告质粒pRL-TK共同转染293T细胞。将黄芩中汉黄芩素、黄芩素、黄芩苷等3个主要活性成分和(或)雌激素受体(ER)特异性抑制剂加入Nrf2-ARE双荧光素酶报告基因系统,检测其是否通过ER影响Nrf2-ARE通路,发挥抗氧化作用。将筛选出的成分和(或) ER抑制剂、Nrf2-ARE通路抑制剂加入Ha Ca T细胞中,验证是否通过ER影响Nrf2-ARE通路发挥抗氧化作用。结果黄芩苷(100μmol·L~(-1))可明显激活293T细胞中的Nrf2-ARE通路,诱导表达倍数为空白组的(1. 56±0. 01)倍(P <0. 01)。预给予ER抑制剂后,诱导表达倍数下降至(1. 02±0. 23)倍,抗氧化作用消失。分别预给予ER抑制剂、Nrf2-ARE通路抑制剂后,黄芩苷干预UVB损伤的Ha Ca T细胞中的ROS值明显上升,SOD值明显下降。结论黄芩苷可以通过ER影响Nrf2-ARE通路,发挥抗氧化作用。 相似文献
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汉黄芩素对大鼠致畸敏感期的毒性试验 总被引:3,自引:0,他引:3
目的:观察汉黄芩素对大鼠致畸敏感期的毒性反应。方法:将SD大鼠随机分为4组,每组16只,设空白对照组和汉黄芩素40,13.3,4.4mg·kg^-1剂量组,在受孕大鼠致畸敏感期(受孕第6~15d)给药,观察各组孕鼠的毒性情况。结果:汉黄芩素高剂量组孕鼠体重增长缓慢,躯干骨的胸骨数、骶尾椎数,前肢手掌骨的中手骨数、指骨总数和后肢脚掌骨的中足骨数、趾骨总数减少,与空白对照组相比差异也有显著性意义;高、中剂量组胎鼠的头顶骨、侧头骨和后头骨骨化不全数,与空白对照组相比差异有显著性意义(P〈0.01)。结论:未发现汉黄芩素对胎鼠有明显致畸作用。但该药高剂量可使胎鼠骨骼发育迟缓。 相似文献
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目的 探究蛇床子素(osthole,Ost)对L02细胞的毒性损伤和作用机制,为中药蛇床子及其制剂的安全合理应用提供实验依据。方法 以不同浓度Ost作用于L02细胞,MTT法检测细胞活性;乳酸脱氢酶(LDH)试剂盒测定细胞LDH释放率;Hoechst 33342染色法检测细胞核形态;Annexin V/PI双染法检测细胞凋亡;Western blot检测Bcl-2、Bax、pro-caspase-3、cleaved-caspase-3(p17)、p-Histon H3(Ser10)的表达。结果 L02细胞在Ost作用下活性下降,LDH释放率提高,且呈浓度依赖;Hoechst 33342染色荧光下可见细胞核皱缩碎裂;AnnexinV/PI双染法结果表明凋亡率随浓度提高而上升。与对照组比较,50,100,200 μmol·L-1 Ost作用24 h后,Bcl-2、pro-caspase-3、p-Histon H3(Ser10)表达水平降低,Bax、cleaved-caspase-3表达水平升高。结论 Ost对L02细胞有毒性损伤作用,呈一定的时间和浓度依赖性,可促进细胞凋亡,抑制细胞增殖。 相似文献
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《中国药理学与毒理学杂志》2019,(10)
雷公藤具有祛风除湿,活血通络,消肿止痛,杀虫解毒等功效,临床上常用于治疗类风湿性关节炎,但雷公藤的肝毒性严重限制了其临床应用。近年来的研究表明甘草中的有效成分甘草酸,又称甘草甜素,可水解为甘草次酸和两分子葡萄糖醛酸,通过降低血清中的谷草转氨酶、谷丙转氨酶和乙醇脱氢酶的数值以及肝脏中白介素18和肿瘤坏死因子α蛋白表达,并激活Nrf2-ARE信号通路,促进Nrf2相关蛋白表达,调控下游Ⅱ相解毒酶促进雷公藤毒物的代谢,从而对肝脏产生保护作用。本文将就甘草提取物甘草酸对雷公藤所致肝毒性的防治作用进行综述,已期在临床上为开发利用甘草酸提供一定理论依据。 相似文献
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Liu He Jiangli Xu Limei Guo Linling Que Wencheng Yin Baoshan Cao Siwang Yu 《中国药学》2017,26(10):709-718
Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the expression of a wide array of antioxidant response element (ARE)-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts (MEFs) and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2–/–mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-inducedhepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin. 相似文献
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Protective effects of diallyl disulfide on carbon tetrachloride‐induced hepatotoxicity through activation of Nrf2
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In‐Chul Lee Sung‐Hwan Kim Hyung‐Seon Baek Changjong Moon Sung‐Ho Kim Yun‐Bae Kim Won‐Kee Yun Hyoung‐Chin Kim Jong‐Choon Kim 《Environmental toxicology》2015,30(5):538-548
This study was conducted to investigate the potential effects of diallyl disulfide (DADS) on carbon tetrachloride (CCl4)‐induced acute hepatotoxicity and to determine the molecular mechanisms of protection offered by DADS in rats. DADS was administered orally at 50 and 100 mg/kg/day once daily for 5 consecutive days prior to CCl4 administration. The single oral dose of CCl4 (2 mL/kg) caused a significant elevation in serum aspartate and alanine aminotransferase activities, which decreased upon pretreatment with DADS. Histopathological examinations showed extensive liver injury, characterized by extensive hepatocellular degeneration/necrosis, fatty changes, inflammatory cell infiltration, and congestion, which were reversed following pretreatment with DADS. The effects of DADS on cytochrome P450 2E1 (CYP2E1), the major isozyme involved in CCl4 bioactivation, were also investigated. DADS pretreatment resulted in a significant decrease in CYP2E1 protein levels in dose‐dependent manner. In addition, CCl4 caused a decrease in protein level of cytoplasmic nuclear factor E2‐related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2 concurrent with downregulation of detoxifying phase II enzymes and a decrease in antioxidant enzyme activities. In contrast, DADS prevented the depletion of cytoplasmic Nrf2 and enhanced nuclear translocation of Nrf2, which, in turn, upregulated antioxidant and/or phase II enzymes. These results indicate that the protective effects of DADS against CCl4‐induced hepatotoxicity possibly involve mechanisms related to its ability to induce antioxidant or detoxifying enzymes by activating Nrf2 and block metabolic activation of CCl4 by suppressing CYP2E1. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 538–548, 2015. 相似文献
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Cyclic nitroxides are a large group of compounds composed of diverse stable radicals also known as synthetic antioxidants. Although nitroxides are valuable for use in several skin conditions, in in vivo conditions they have several drawbacks, such as nonspecific dispersion in normal tissue, preferential renal clearance and rapid reduction of the nitroxide to the corresponding hydroxylamine. However, these drawbacks can be easily addressed by encapsulating the nitroxides within microemulsions. This approach would allow nitroxide activity and therefore their valuable effects (e.g. activation of the Keap1-Nrf2-EpRE pathway) to continue. In this work, nitroxides were encapsulated in a microemulsion composed of biocompatible ingredients. The nanometric size and shape of the vehicle microemulsion and nitroxide microemulsion displayed high similarity, indicating that the stability of the microemulsions was preserved. Our studies demonstrated that nitroxide microemulsions were more potent inducers of the Keap1-Nrf2-EpRE pathway than the free nitroxides, causing the activation of phase II enzymes. Moreover, microemulsions containing nitroxides significantly reduced UVB-induced cytotoxicity in the skin. Understanding the mechanism of this improved activity may expand the usage of many other Nrf2 modulating molecules in encapsulated form, as a skin protection strategy against oxidative stress-related conditions. 相似文献
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Microcystins (MCs), as the most dominant bloom‐forming strains in eutrophic surface water, can induce hepatotoxicity by oxidative stress. Alpha‐lipoic acid (α‐LA) is a super antioxidant that can induce the synthesis of antioxidants, such as glutathione (GSH), by nuclear factor erythroid 2‐related factor 2 (Nrf2). However, the potential molecular mechanism of α‐LA regeneration of GSH remains unclear. The present study aimed to investigate whether α‐LA could reduce the toxicity of MCs induced in human hepatoma (HepG2), Bel7420 cells, and BALB/c mice by activating Nrf2 to regenerate GSH. Results showed that exposure to 10 μM microcystin‐leucine arginine (MC‐LR) reduced viability of HepG2 and Bel7402 cells and promoted the formation of reactive oxygen species (ROS) compared with untreated cells. Moreover, the protection of α‐LA included reducing the level of ROS, increasing superoxide dismutase activity, and decreasing malondialdehyde. Levels of reduced glutathione (rGSH) and rGSH/oxidized glutathione were significantly increased in cells cotreated with α‐LA and MC‐LR compared to those treated with MC‐LR alone, indicating an ability of α‐LA to attenuate oxidative stress and MC‐LR‐induced cytotoxicity by increasing the amount of rGSH. α‐LA can mediate GSH regeneration through the Nrf2 pathway under the action of glutathione reductase in MC‐LR cell lines. Furthermore, the data also showed that α‐LA‐induced cytoprotection against MC‐LR is associated with Nrf2 mediate pathway in vivo. These findings demonstrated the potential of α‐LA to resist MC‐LR‐induced oxidative damage of liver. 相似文献
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Chieko Saito 《Toxicology and applied pharmacology》2010,242(2):182-745
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the US. Metallothionein (MT) expression attenuates APAP-induced liver injury. However, the mechanism of this protection remains incompletely understood. To address this issue, C57BL/6 mice were treated with 100 μmol/kg ZnCl2 for 3 days to induce MT. Twenty-four hours after the last dose of zinc, the animals received 300 mg/kg APAP. Liver injury (plasma ALT activities, area of necrosis), DNA fragmentation, peroxynitrite formation (nitrotyrosine staining), MT expression, hepatic glutathione (GSH), and glutathione disulfide (GSSG) levels were determined after 6 h. APAP alone caused severe liver injury with oxidant stress (increased GSSG levels), peroxynitrite formation, and DNA fragmentation, all of which were attenuated by zinc-induced MT expression. In contrast, MT knockout mice were not protected by zinc. Hydrogen peroxide-induced cell injury in primary hepatocytes was dependent only on the intracellular GSH levels but not on MT expression. Thus, the protective effect of MT in vivo was not due to the direct scavenging of reactive oxygen species. Zinc treatment had no effect on the early GSH depletion kinetics after APAP administration, which is an indicator of the metabolic activation of APAP to its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). However, MT was able to effectively trap NAPQI by covalent binding. We conclude that MT scavenges some of the excess NAPQI after GSH depletion and prevents covalent binding to cellular proteins, which is the trigger for the propagation of the cell injury mechanisms through mitochondrial dysfunction and nuclear DNA damage. 相似文献