CAY10594 is an effective inhibitor of phospholipase D2 (PLD2) (IC50 140 nm in vitro and 110 nm in cells). Cay10594 highly inhibits the invasive migration of breast cancer cells in vitro and regulates the phosphorylation of GSK-3 β/ JNK axis ameliorates paracetamol induced acute liver injury.
CAY10594 significantly improved intestinal mucosal inflammation, which was characterized by higher survival rate, slight decrease in body weight, less or no bloody stool and lower pathological score level,compared with the control group. RNA was extracted from colon tissue to detect the expression of cytokines, as well as proinflammatory cytokines, such as TNF- α?￠ IL-6, IL-23 and IL-1 β It was found that PLD2 was significantly decreased after blocking in DSS induced colitis, while anti-inflammatory cytokines were significantly increased after inhibiting PLD2. In addition, fresh colon samples were also obtained and cultured in vitro for 24 hours; The supernatant was collected to detect cytokines by ELISA. Proinflammatory cytokines (e.g., IL-17A, TNF- α and IL-1 β) [1] While anti-inflammatory cytokines (for example, IL-10 was found to increase after PLD2 blockade), indicating that PLD2 blockade can improve intestinal mucosal inflammation [2].
CAY10594 induced a strong therapeutic effect in APAP challenged mice. The results show that PLD2 plays an important role in mediating APAP induced liver injury [3]. Because PLD2 has basic activity, the administration of cay10594 will block the production of PLD2 enzyme active product PA in an experimental acute liver injury model. Therefore, it is reasonable to assume that the protective and therapeutic effects of cay10594 in the acute liver injury model will be mediated by blocking the production of PA. Cay10594 may regulate early liver pathology to prevent APAP induced liver injury by rapidly restoring GSH levels without affecting antioxidant gene expression [4].
References:
[1] Lee S K, Kim S D, Kook M, et al. Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2[J]. Journal of Experimental Medicine, 2015, 212(9): 1381-1390.
[2] Zhou G, Yu L, Yang W, et al. Blockade of PLD2 ameliorates intestinal mucosal inflammation of inflammatory bowel disease[J]. Mediators of inflammation, 2016, 2016.
[3] Mitchell J R, Jollow D J, Potter W Z, et al. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism[J]. Journal of Pharmacology and Experimental Therapeutics, 1973, 187(1): 185-194.
[4] Lee S K, Bae G H, Kim Y S, et al. A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis[J]. Scientific Reports, 2019, 9(1): 1-10.
CAY10594 是一种有效的磷脂酶 D2 (PLD2) 抑制剂（体外 IC50 为 140 nm，细胞内为 110 nm）。 Cay10594在体外高度抑制乳腺癌细胞的侵袭性迁移并调节GSK-3的磷酸化 β/JNK轴改善对乙酰氨基酚诱导的急性肝损伤。
CAY10594显着改善肠粘膜炎症，其特征是与对照组相比,存活率较高,体重轻度下降,血便较少或无,病理评分水平较低。从结肠组织中提取RNA，检测细胞因子的表达，以及促炎细胞因子，如TNF- α；. IL-6、IL-23和IL-1 β；发现在DSS诱导的结肠炎中阻断后PLD2显着降低，而抑制PLD2后抗炎细胞因子显着增加。此外，还取新鲜结肠标本，体外培养24小时；收集上清液以通过ELISA检测细胞因子。促炎细胞因子（例如，IL-17A、TNF-α；和 IL-1 β；）[1] 而抗炎细胞因子（例如，IL-10 在 PLD2 阻断后被发现增加） , 表明 PLD2 阻断可以改善肠粘膜炎症 [2]。
CAY10594 在 APAP 攻击的小鼠中诱导了强烈的治疗效果。结果表明PLD2在介导APAP诱导的肝损伤中起重要作用[3]。因为 PLD2 具有基本活性，cay10594 的给药将阻断实验性急性肝损伤模型中 PLD2 酶活性产物 PA 的产生。因此，可以合理地假设 cay10594 在急性肝损伤模型中的保护和治疗作用将通过阻断 PA 的产生来介导。 Cay10594 可能通过快速恢复 GSH 水平而不影响抗氧化基因表达来调节早期肝脏病理，从而预防 APAP 诱导的肝损伤[4]。