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首页> 外文期刊>Journal of applied toxicology >Exogenous recombinant human thioredoxin‐1 prevents acetaminophen‐induced liver injury by scavenging oxidative stressors, restoring the thioredoxin‐1 system and inhibiting receptor interacting protein‐3 overexpression
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Exogenous recombinant human thioredoxin‐1 prevents acetaminophen‐induced liver injury by scavenging oxidative stressors, restoring the thioredoxin‐1 system and inhibiting receptor interacting protein‐3 overexpression

机译：外源性重组人硫喷氢素-1通过清除氧化应激源来预防乙酰氨基酚诱导的肝损伤，恢复硫喷妥昔林-1系统并抑制受体相互作用蛋白-3过表达

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Abstract Thioredoxin‐1 (Trx‐1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N ‐acetyl‐p‐aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP‐induced liver injury in a mouse model is associated with “necroptosis,” and if pretreatment with recombinant Trx‐1 prevents the hepatic injury caused by APAP overdose. We also explored the mechanism underlying the preventive action of Trx‐1 against APAP‐induced hepatic injury. In a prevention study, C3H/he mice received different doses (0, 10, 50 or 100?mg?kg –1 body weight) of recombinant human Trx‐1 intraperitoneally, followed by a single oral dose of 300?mg?kg –1 of APAP. In this experimental paradigm, liver injury and lethality were markedly decreased in rhTrx‐1–pretreated mice. In survival experiments, mice received rhTrx‐1 followed by oral administration of a lethal dose of APAP. APAP overdose caused a series of liver toxicity‐associated events, beginning with overexpression of c‐fos, excessive production of reactive oxygen species and reactive nitrogen species (RNS) and leading to decreased endogenous Trx‐1 expression and activation of JNK signaling pathways. Pretreatment with rhTrx‐1 inhibited all of these toxicological manifestations of APAP. In addition, rhTrx‐1 significantly reduced the expression of RIP‐3, a critical necrosome component. Taken together, our findings indicate that rhTrx‐1 prevents APAP‐induced liver injury through multiple action mechanisms, including scavenging reactive oxygen species and reactive nitrogen species, restoring endogenous Trx‐1 levels and inhibiting RIP‐3 overexpression.
机译：摘要Thioredoxin-1（TRX-1）是一种有效的治疗剂，其抗各种疾病，因为其作为凋亡的抗氧化剂和调节剂。 N-乙酰-P-氨基酚（APAP）通常称为乙酰氨基酚，产生过量的氧化应激和触发肝细胞死亡，以受调节的坏死例子举例说明。在本研究中，我们研究了在小鼠模型中的APAP诱导的肝损伤是否与“死区调”相关，如果具有重组TRX-1的预处理，则防止由APAP过量引起的肝损伤。我们还探讨了TRX-1预防措施对抗APAP诱导的肝损伤的机制。在预防研究中，C3h / He小鼠接受了腹膜内重组人Trx-1的不同剂量（0,110,50或100×mg？KG -1体重），其次是300×mg？kg - 1的apap。在这种实验范式中，rhtrx-1-preatroped小鼠中肝损伤和致命性显着降低。在存活实验中，小鼠接受rHTRX-1，然后口服致死剂量的APAP。 APAP过量导致一系列肝脏毒性相关的事件，从C-FOS过度表达开始，过度产生反应性氧物质和反应性氮物质（RNS）并导致内源性TRX-1表达和JNK信号传导途径的激活。用RHTRX-1预处理抑制APAP的所有这些毒理学表现。此外，RHTRX-1显着降低了RIP-3的表达，是临界坏泡组分。我们的研究结果表明，通过多种动作机制，rHTRX-1通过多种动作机制来防止APAP诱导的肝损伤，包括清除反应性氧物质和反应性氮物质，恢复内源TRX-1水平并抑制RIP-3过表达。

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