Chen Xin, Ding Hai-Wen, Li Hai-Di, Huang Hui-Min, Li Xiao-Feng, Yang Yang, Zhang Yi-Long, Pan Xue-Yin, Huang Cheng, Meng Xiao-Ming, Li Jun
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory of Immune medicines, Ministry of Education, China; Institute for Liver Diseases of Anhui Medical University, China.
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; The Key Laboratory of Anti-inflammatory of Immune medicines, Ministry of Education, China; Institute for Liver Diseases of Anhui Medical University, China.
Toxicol Lett. 2017 May 15;274:51-63. doi: 10.1016/j.toxlet.2017.04.008. Epub 2017 Apr 18.
Hesperetin is a flavanone glycoside compound naturally occurring in the fruit peel of Citrusaurantium L. (Rutaceae). Previous studies revealed that hesperetin possesses various pharmacological effects, including anti-inflammation, anti-tumor, anti-oxidant and neuroprotective properties. Hesperetin derivative-14 (HD-14) is a derivative of hesperetin improved in water solubility and bioavailability. In this study, we indicated that HD-14 (2μM) significantly attenuated inflammation in LPS-treated RAW264.7 cells, besides, HD-14 (100mg/kg) exhibited hepato-protective effects and anti-inflammatory effects on C57BL/6J mice with CCl-induced acute liver injury. In addition, it was demonstrated that HD-14 dramatically up-regulated the expression of PPAR-γ in vivo and in vitro. Interestingly, over-expression of PPAR-γ had anti-inflammatory effects on the expressions of TNF-α, IL-6, and IL-1β, whereas, knockdown of PPAR-γ with small interfering RNA had pro-inflammatory effects in LPS-treated RAW264.7 cells. Thus, our findings demonstrated that HD-14 alleviated inflammation by activating PPAR-γ expression at least in part. Further studies founded that HD-14 remarkably inhibited the expression of p-JAK1 and p-STAT1 through up-regulating PPAR-γ. Together, these results suggested that HD-14 served as an activator of PPAR-γ and the JAK1/STAT1 signaling pathway may be involved in the progress of inflammation. Collectively, HD-14 may be utilized as a potential anti-inflammation monomeric compound in the treatment of acute liver injury.
橙皮素是一种天然存在于芸香科酸橙果实果皮中的黄烷酮糖苷化合物。先前的研究表明，橙皮素具有多种药理作用，包括抗炎、抗肿瘤、抗氧化和神经保护特性。橙皮素衍生物-14（HD-14）是一种在水溶性和生物利用度方面得到改善的橙皮素衍生物。在本研究中，我们表明HD-14（2μM）显著减轻了脂多糖处理的RAW264.7细胞中的炎症，此外，HD-14（100mg/kg）对四氯化碳诱导的急性肝损伤的C57BL/6J小鼠具有肝保护作用和抗炎作用。此外，还证明HD-14在体内和体外均显著上调PPAR-γ的表达。有趣的是，PPAR-γ的过表达对TNF-α、IL-6和IL-1β的表达具有抗炎作用，而用小干扰RNA敲低PPAR-γ在脂多糖处理的RAW264.7细胞中具有促炎作用。因此，我们的研究结果表明，HD-14至少部分通过激活PPAR-γ表达来减轻炎症。进一步的研究发现，HD-14通过上调PPAR-γ显著抑制p-JAK1和p-STAT1的表达。总之，这些结果表明HD-14作为PPAR-γ的激活剂，JAK1/STAT1信号通路可能参与炎症的进展。总体而言，HD-14可能作为一种潜在的抗炎单体化合物用于治疗急性肝损伤。
