Ha Yoon-Su, Kim Taek-Kyong, Heo Jun, Oh Jintaek, Kim Seung-Kyoon, Kim Jeongkyu, Lee Jeonghyung, Yang Se-Ran, Hwang Seonghwan, Kim Seung-Jin
Department of Biochemistry, College of Natural Sciences, Kangwon National University, 24341 Chuncheon, Republic of Korea.
Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, 24341 Chuncheon, Republic of Korea.
Toxicol Res. 2024 Sep 27;41(1):47-59. doi: 10.1007/s43188-024-00263-y. eCollection 2025 Jan.
Lipopolysaccharide (LPS), a gut-derived endotoxin, is a recognized risk factor for both Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Rocaglamide-A (Roc-A), a natural compound derived from the genus Aglaia, is known for its pharmacological and immunosuppressive effects on various cell types. Although our recent investigations have unveiled Roc-A's anti-adipogenic role in adipocytes, its mechanism in hepatic inflammation remains elusive. This study delves into Roc-A's protective effects on LPS-induced hepatic inflammation. Our results demonstrated that Roc-A treatment significantly reduced the LPS-induced production of inflammatory cytokines in hepatocytes. Intriguingly, Roc-A decreased LPS-induced production of reactive oxygen species (ROS), upregulated antioxidant gene expression, and downregulated endoplasmic reticulum (ER) stress-related gene expression. Mechanistically, Roc-A significantly attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). Notably, this effect was abolished by the JNK activator Anisomycin, while the JNK inhibitor SP600125 enhanced it. Furthermore, Roc-A suppressed the expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), thereby alleviating iNOS-derived nitric oxide (NO) production. These findings collectively indicate that Roc-A has the potential to alleviate LPS-induced nitrosative/oxidative stress and hepatic inflammation by inhibiting JNK phosphorylation. Thus, Roc-A emerges as a promising anti-inflammatory intervention for LPS-induced hepatic inflammation.
The online version contains supplementary material available at 10.1007/s43188-024-00263-y.
脂多糖（LPS）是一种源自肠道的内毒素，是公认的非酒精性脂肪性肝病（NAFLD）和酒精性肝病（ALD）的危险因素。罗卡酰胺-A（Roc-A）是一种从米仔兰属植物中提取的天然化合物，以其对多种细胞类型的药理和免疫抑制作用而闻名。尽管我们最近的研究揭示了Roc-A在脂肪细胞中的抗脂肪生成作用，但其在肝脏炎症中的机制仍不清楚。本研究深入探讨了Roc-A对LPS诱导的肝脏炎症的保护作用。我们的结果表明，Roc-A处理显著降低了LPS诱导的肝细胞中炎性细胞因子的产生。有趣的是，Roc-A降低了LPS诱导的活性氧（ROS）的产生，上调了抗氧化基因的表达，并下调了内质网（ER）应激相关基因的表达。机制上，Roc-A显著减弱了LPS诱导的c-Jun氨基末端激酶（JNK）和活化蛋白-1（AP-1）的磷酸化。值得注意的是，JNK激活剂茴香霉素消除了这种作用，而JNK抑制剂SP600125增强了这种作用。此外，Roc-A抑制了NF-κB靶基因的表达，包括诱导型一氧化氮合酶（iNOS），从而减轻了iNOS衍生的一氧化氮（NO）的产生。这些发现共同表明，Roc-A有可能通过抑制JNK磷酸化来减轻LPS诱导的亚硝化/氧化应激和肝脏炎症。因此，Roc-A成为一种有前途的针对LPS诱导的肝脏炎症的抗炎干预措施。
在线版本包含可在10.1007/s43188-024-00263-y获取的补充材料。
