Purpose: Drug-induced liver injury (DILI) is the most common cause of acute liver failure. The aim of this study was to investigate the molecular mechanisms by which Ganoderma lucidum mushroom (GLM) may ameliorate cisplatin (CP)-induced hepatotoxicity theoretically and experimentally.
Materials and Methods: Thirty-six male Sprague-Dawley (SD) rats were divided into six groups, two of them are normal and Ganoderma lucidum control groups. Liver injury was induced by a single dose of CP (12 mg/kg i.p) in four groups, one of them is CP control group. Besides cisplatin injection in day 1, rats in groups (4– 6) were subjected to GLM (500 mg/kg/day) either every other day or daily oral dose or via i.p injection for 10 consecutive days.
Results: In this study, GLM supplementation caused significant reduction of elevated high-mobility group box-1 (HMGB-1) with a concurrent decline in TNF-α and upregulation of IL-10 compared to the CP group (P< 0.05). The histopathological and fibrosis evaluation significantly confirmed the improvement upon simultaneous treatment with GLM. Moreover, immunohistochemical examination also confirmed the recovery following GLM treatment indicated by downregulation of NF-κB, p53 and caspase-3 along with upsurge of B-cell lymphoma 2 (Bcl-2) expression (P< 0.05). GLM treatment significantly decreased serum levels of hepatic injury markers; ALT, AST, T. bilirubin as well as oxidative stress markers; MDA and H₂O₂ with a concomitant increase in hepatic GSH and SOD. Also, the performed docking simulation of ganoderic acid exhibited good fitting and binding with HMGB-1 through hydrogen bond formation with conservative amino acids which gives a strong evidence for its hepatoprotective effect and may interpret the effect of Ganoderma lucidum.
Conclusion: GLM attenuated hepatic injury through downregulation of HMGB-1/NF-kB and caspase-3 resulted in modulation of the induced oxidative stress and the subsequent cross-talk between the inflammatory and apoptotic cascade indicating its promising role in DILI.

Keywords: drug-induced liver injury, Ganoderma lucidum mushroom, ganoderic acid, cisplatin-induced hepatotoxicity, inflammatory cytokines, high-mobility group box-1


中文翻译：

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灵芝通过 Alarmin High Mobility Group Box-1 途径抑制顺铂诱导的大鼠肝损伤：理论和实验研究。


目的：药物性肝损伤（DILI）是急性肝衰竭的最常见原因。本研究的目的是从理论上和实验上探讨灵芝蘑菇（GLM）改善顺铂（CP）诱导的肝毒性的分子机制。

材料与方法： 36只雄性SD大鼠分为6组，其中2组为正常组和灵芝对照组。四组采用单剂量CP（12 mg/kg ip）诱导肝损伤，其中一组为CP对照组。除了第1天注射顺铂外，组（4-6）的大鼠每隔一天或每天口服或通过腹膜内注射接受GLM（500 mg/kg/天），连续10天。

结果：在本研究中，与 CP 组相比，补充 GLM 导致高迁移率组 box-1 (HMGB-1) 升高显着减少，同时 TNF-α 下降和 IL-10 上调 (P< 0.05) 。组织病理学和纤维化评估显着证实了 GLM 同时治疗后的改善。此外，免疫组织化学检查还证实了 GLM 治疗后的恢复，表现为 NF-κB、p53 和 caspase-3 的下调以及 B 细胞淋巴瘤 2 (Bcl-2) 表达的上升 (P< 0.05)。 GLM治疗显着降低了肝损伤标志物的血清水平； ALT、AST、T.胆红素以及氧化应激标记物； MDA 和 H ₂ O ₂伴随肝脏 GSH 和 SOD 增加。此外，进行的灵芝酸对接模拟通过与保守氨基酸形成氢键与HMGB-1表现出良好的拟合和结合，这为其保肝作用提供了有力的证据，并可以解释灵芝的作用。

结论： GLM 通过下调 HMGB-1/NF-kB 和 caspase-3 来减轻肝损伤，从而调节诱导的氧化应激以及随后炎症和凋亡级联反应之间的串扰，表明其在 DILI 中的潜在作用。


关键词:药物性肝损伤,灵芝, 灵芝酸, 顺铂肝毒性, 炎性细胞因子, 高迁移率group box-1