Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2  

作　　者：Li-jiao Sun Xin Chen Sai Zhu Jin-jin Xu Xiao-feng Li Shao-xi Diao Ying-li Yang Jin-yu Liu Jia-nan Wang Ying-yin Sun Cheng Huang Xiao-ming Meng Hua Wang Xiong-wen Lv Jun Li 

机构地区：[1]Inflammation and Immune Mediated Diseases Laboratory of Anhui Province,Anhui Institute of Innovative Drugs,School of Pharmacy,Anhui Medical University,Hefei 230032,China [2]The Key Laboratory of Anti-inflammatory and Immune Medicines,Anhui Medical University,Ministry of Education,Hefei 230032,China [3]Institute for Liver Diseases of Anhui Medical University,ILD-AMU,Anhui Medical University,Hefei 230032,China [4]Department of Nephropathy,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [5]Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei 230032,China

出　　处：《Acta Pharmacologica Sinica》2024年第2期354-365,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.U19A2001,82070628,82300722);funds from the University Synergy Innovation Programme of Anhui Province(GXXT-2020-063 and GXXT-2020-025);the China Postdoctoral Science Foundation(2022M710178).

摘　　要：Acute liver injury(ALI)is a complex,life-threatening inflammatory liver disease,and persistent liver damage leads to rapid decline and even failure of liver function.However,the pathogenesis of ALI is still not fully understood,and no effective treatment has been discovered.Recent evidence shows that many circular RNAs(circRNAs)are associated with the occurrence of liver diseases.In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide(LPS)-induced ALI mice.We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells.Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells.We designed and synthesized a series of hesperidin derivatives for circDcbld2,and found that hesperetin derivative 2a(HD-2a)at the concentrations of 2,4,8μM effectively inhibited circDcbld2 expression in RAW264.7 cells.Administration of HD-2a(50,100,200 mg/kg.i.g.,once 24 h in advance)effectively relieved LPS-induced liver dysfunction and inflammatory responses.RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway.We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway,thereby inhibiting the inflammatory responses in ALI.The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI,and HD-2a may have potential as a drug for the treatment of ALI.

关 键 词：acute liver injury CircDcbld2 hesperetin derivatives HD-2a inflammation JAK2/STAT3 

分 类 号：R575[医药卫生—消化系统]