Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Department of Biocosmetics, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Biomed Pharmacother. 2022 Apr;148:112740. doi: 10.1016/j.biopha.2022.112740. Epub 2022 Feb 21.
BN82002 is well-known as an inhibitor of the CDC25 phosphatase. However, it was recently reported that BN82002 also selectively suppressed AKT2 and reduced inflammatory responses in lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. Therefore, in this study, we evaluated the alleviating efficacy of BN82002 in sepsis in vivo. BN82002 (50 μM) suppressed the mRNA levels of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in LPS-treated peritoneal macrophages without cytotoxicity. The septic in vivo mouse model was established on the basis of the endotoxin model using poly(I:C) (10 mg/kg) and LPS (54 mg/kg). In histological analysis, peritoneal injection of BN82002 (20 mg/kg) significantly reduced lung, kidney, and liver damage. Lung edema and serum alanine transaminase (ALT), aspartate transaminase (AST), TNF-α, IL-1β, and nitric oxide (NO) levels also were decreased by BN82002 (20 mg/kg). In addition, BN82002 (20 mg/kg) suppressed the mRNA levels of TNF-α in lung and liver tissues. Gene expression levels of IL-1β and IL-6 were decreased in lung, kidney, and liver in the BN82002 (20 mg/kg) group. Furthermore, p-AKT2 and p-IκBα levels were reduced by BN82002 (20 mg/kg). Finally, all septic mice died 7 days after poly(I:C)/LPS-injection, whereas 4 mice in the BN82002 (20 mg/kg) group, survived strongly suggesting that BN82002 reduces sepsis mortality. In conclusion, we verified that pre-treatment with BN82002 protects against tissue damage and increases survival by inhibiting AKT2-NF-κB signaling in septic mice. These results suggest that BN82002 could be utilized in the treatment of sepsis.
BN82002 是一种已知的 CDC25 磷酸酶抑制剂。然而，最近有报道称，BN82002 还选择性地抑制 AKT2，并减少脂多糖 (LPS) 刺激的巨噬细胞样 RAW264.7 细胞中的炎症反应。因此，在本研究中，我们评估了 BN82002 在体内脓毒症中的缓解效果。BN82002（50 μM）在没有细胞毒性的情况下，抑制 LPS 处理的腹腔巨噬细胞中环氧化酶 (COX)-2、诱导型一氧化氮合酶 (iNOS)、肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-1β 和 IL-6 的 mRNA 水平。基于聚肌苷酸 (10 mg/kg) 和 LPS (54 mg/kg) 的内毒素模型建立了体内脓毒症小鼠模型。在组织学分析中，腹腔注射 BN82002（20 mg/kg）显著减轻了肺、肾和肝损伤。BN82002（20 mg/kg）还降低了肺水肿和血清丙氨酸转氨酶 (ALT)、天冬氨酸转氨酶 (AST)、TNF-α、IL-1β 和一氧化氮 (NO) 水平。此外，BN82002（20 mg/kg）抑制了肺和肝组织中 TNF-α 的 mRNA 水平。BN82002（20 mg/kg）组肺、肾和肝组织中 IL-1β 和 IL-6 的基因表达水平降低。此外，BN82002（20 mg/kg）降低了 p-AKT2 和 p-IκBα 水平。最后，所有接受 poly(I:C)/LPS 注射的脓毒症小鼠在 7 天后死亡，而 BN82002（20 mg/kg）组的 4 只小鼠存活下来，这强烈表明 BN82002 降低了脓毒症死亡率。总之，我们证实 BN82002 通过抑制 AKT2-NF-κB 信号通路，在脓毒症小鼠中可预防组织损伤并提高存活率。这些结果表明 BN82002 可用于脓毒症的治疗。
