Pyrazinamide (PZA) is an anti-tuberculosis drug known to causes liver injury. phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling protects against liver injury by promoting cellular antioxidant defenses and reducing intracellular reactive oxygen species (ROS) and lipid peroxidation. The regulatory mechanisms and functions of PI3K/Akt signaling during the hepatotoxicity of PZA are however not fully understood. Rats were administered PZA or/and the PI3K activator (740Y-P) for 7 days. The levels of serum parameters were examined via standard enzymatic techniques and the pathological status of the liver was confirmed by H & E staining. The levels of lipid peroxidation and antioxidant production were determined using commercial kits. Liver apoptosis was assessed by TUNEL staining. The expression of apoptosis-related proteins and PI3K/Akt signaling were assessed by western blot analysis. PZA treatment significantly increased serum alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase and tall bilirubin leading to liver damage in rats. PZA also facilitated lipid peroxidation and suppressed antioxidant defenses. PZA led to apoptotic induction in rat liver cells through the downregulation of Bcl-2 and the upregulation of Bax and caspase-3. PZA also dramatically inhibited PI3K/Akt signaling in rat liver cells. We further verified that PI3K/Akt signaling in response to 740Y-P could attenuate hepatic injury, lipid peroxidation and apoptosis in rat liver cells in response to PZA. We reveal that PZA-induced liver injury in rats occurs through PI3k/Akt signaling, the recovery of which prevents liver injury in rat models.

中文翻译：

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吡嗪酰胺可通过PI3k / Akt抑制作用增强脂质过氧化和抗氧化剂水平，从而诱发大鼠肝损伤。

吡嗪酰胺（PZA）是一种已知会引起肝损伤的抗结核药。磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K / Akt）信号传导可通过促进细胞抗氧化剂防御并减少细胞内活性氧（ROS）和脂质过氧化作用来保护肝脏免受损伤。然而，在PZA的肝毒性过程中，PI3K / Akt信号传导的调节机制和功能尚未完全了解。给大鼠施用PZA或/和PI3K激活剂（740Y-P）7天。通过标准酶技术检查血清参数水平，并通过H＆E染色确认肝脏的病理状态。使用商业试剂盒测定脂质过氧化和抗氧化剂产生的水平。通过TUNEL染色评估肝细胞凋亡。通过蛋白质印迹分析评估凋亡相关蛋白的表达和PI3K / Akt信号传导。PZA处理可显着增加血清丙氨酸转氨酶，天冬氨酸转氨酶，γ-谷氨酰胺转肽酶和高胆红素，从而导致大鼠肝损伤。PZA还促进脂质过氧化并抑制抗氧化防御。PZA通过Bcl-2的下调和Bax和caspase-3的上调导致大鼠肝细胞凋亡。PZA还显着抑制大鼠肝细胞中的PI3K / Akt信号传导。我们进一步证实，响应740Y-P的PI3K / Akt信号传导可以减轻大鼠肝细胞响应PZA的肝损伤，脂质过氧化和凋亡。我们发现PZA诱导的大鼠肝损伤通过PI3k / Akt信号传导发生，