Anti-inflammatory activities of gentiopicroside against iNOS and COX-2 targets
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摘要
Objective: To isolate high-purity gentiopicroside from the Chinese herbal Gentiana officinalis and investigate its anti-inflammatory activity against iNOS and COX-2 targets.Methods: The purity and structures of gentiopicroside were determined by HPLC, IR, NMR, and MS. The anti-inflammatory effects of gentiopicroside were investigated by in vivo, in vitro, and molecular experiments.Results: In vitro experiment results showed that gentiopicroside inhibited nitric oxide(NO), prostaglandin E2(PGE2), and interleukin-6(IL-6) production in mouse macrophages RAW 264.7 stimulated by lipopolysaccharide. In vivo experiment found that xylene-induced mouse ear swelling was inhibited by gentiopicroside with an inhibition rate of 34.17%. Molecular docking of cyclooxygenase-2(COX-2) and inducible nitric oxide synthase(i NOS) with gentiopicroside showed that hydrogen bonds(H-bonds) were formed between the sugar fragments in gentiopicroside structure with Tyr355, Ser353, Leu352, Ser530,Arg120, and His90 of COX-2, and Glu377, Asp382, Tyr373, Tyr347, Gln263, Asn370, and Gly371 of i NOS.Thus, gentiopicroside had a lower docking score and displayed satisfactory anti-inflammatory activities.Conclusion: These results suggested that the mechanism of anti-inflammatory activity of gentiopicroside was associated with the downregulation of inflammatory cytokines, such as NO, PGE2, and IL-6, and the suppression of iNOS and COX-2. Therefore, gentiopicroside is a potential and selective iNOS and COX-2 inhibitor.
Objective: To isolate high-purity gentiopicroside from the Chinese herbal Gentiana officinalis and investigate its anti-inflammatory activity against iNOS and COX-2 targets.Methods: The purity and structures of gentiopicroside were determined by HPLC, IR, NMR, and MS. The anti-inflammatory effects of gentiopicroside were investigated by in vivo, in vitro, and molecular experiments.Results: In vitro experiment results showed that gentiopicroside inhibited nitric oxide(NO), prostaglandin E2(PGE2), and interleukin-6(IL-6) production in mouse macrophages RAW 264.7 stimulated by lipopolysaccharide. In vivo experiment found that xylene-induced mouse ear swelling was inhibited by gentiopicroside with an inhibition rate of 34.17%. Molecular docking of cyclooxygenase-2(COX-2) and inducible nitric oxide synthase(i NOS) with gentiopicroside showed that hydrogen bonds(H-bonds) were formed between the sugar fragments in gentiopicroside structure with Tyr355, Ser353, Leu352, Ser530,Arg120, and His90 of COX-2, and Glu377, Asp382, Tyr373, Tyr347, Gln263, Asn370, and Gly371 of i NOS.Thus, gentiopicroside had a lower docking score and displayed satisfactory anti-inflammatory activities.Conclusion: These results suggested that the mechanism of anti-inflammatory activity of gentiopicroside was associated with the downregulation of inflammatory cytokines, such as NO, PGE2, and IL-6, and the suppression of iNOS and COX-2. Therefore, gentiopicroside is a potential and selective iNOS and COX-2 inhibitor.
Objective: To isolate high-purity gentiopicroside from the Chinese herbal Gentiana officinalis and investigate its anti-inflammatory activity against iNOS and COX-2 targets.Methods: The purity and structures of gentiopicroside were determined by HPLC, IR, NMR, and MS. The anti-inflammatory effects of gentiopicroside were investigated by in vivo, in vitro, and molecular experiments.Results: In vitro experiment results showed that gentiopicroside inhibited nitric oxide(NO), prostaglandin E2(PGE2), and interleukin-6(IL-6) production in mouse macrophages RAW 264.7 stimulated by lipopolysaccharide. In vivo experiment found that xylene-induced mouse ear swelling was inhibited by gentiopicroside with an inhibition rate of 34.17%. Molecular docking of cyclooxygenase-2(COX-2) and inducible nitric oxide synthase(i NOS) with gentiopicroside showed that hydrogen bonds(H-bonds) were formed between the sugar fragments in gentiopicroside structure with Tyr355, Ser353, Leu352, Ser530,Arg120, and His90 of COX-2, and Glu377, Asp382, Tyr373, Tyr347, Gln263, Asn370, and Gly371 of i NOS.Thus, gentiopicroside had a lower docking score and displayed satisfactory anti-inflammatory activities.Conclusion: These results suggested that the mechanism of anti-inflammatory activity of gentiopicroside was associated with the downregulation of inflammatory cytokines, such as NO, PGE2, and IL-6, and the suppression of iNOS and COX-2. Therefore, gentiopicroside is a potential and selective iNOS and COX-2 inhibitor.
引文
Abdelall,E.K.A.,&Abdelhamid,A.O.(2017).Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids.Bioorganic&Medicinal Chemistry Letters,27(18),4358-4369.
An,J.Y.,Lee,H.H.,Shin,J.S.,Yoo,H.S.,Park,J.S.,Son,S.H.,&Kim,N.J.(2017).Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE 2 in LPS-induced RAW 264.7 cells.Bioorganic&Medicinal Chemistry Letters,27(11),2613-2616.
Bist,G.,Pun,N.T.,Magar,T.B.T.,Shrestha,A.,Oh,H.J.,Khakurel,A.,&Lee,E.S.(2017).Inhibition of LPS-stimulated ROS production by fluorinated and hydroxylated chalcones in RAW 264.7 macrophages with structure-activity relationship study.Bioorganic&Medicinal Chemistry Letters,27(5),1205-1209.
Dirsch,V.,Stuppner,H.,&Vollmar,A.(1998).The griess assay:Suitable for a bio-Guided fractionation of anti-inflammatory plant extracts?Planta Medica,64(05),423-426.
Guo,R.,Guo,C.,He,D.,Zhao,D.,&Shen,Y.(2017).Two new C19-diterpenoid alkaloids with anti-inflammatory activity from Aconitum iochanicum.Chinese Journal of Chemistry,35(10),1644-1647.
Khatri,C.K.,Indalkar,K.S.,Patil,C.R.,Goyal,S.N.,&Chaturbhuj,G.U.(2017).Novel2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene analogues as selective COX-2 inhibitors:Design,synthesis,anti-inflammatory evaluation,and molecular docking studies.Bioorganic&Medicinal Chemistry Letters,27(8),1721-1726.
Kiem,P.V.,Huyen,L.T.,&Hang,D.T.(2017).Sesquiterpene derivatives from marine sponge Smenospongia cerebriformis and their anti-inflammatory activity.Bioorganic&Medicinal Chemistry Letters,27(7),1525-1529.
Jo,A.,Han,H.,Seo,S.,Shin,J.S.,Lee,J.Y.,Kim,H.J.,&Lee,K.T.(2017).Inhibitory effect of moschamine isolated from Carthamus tinctorius on LPS-induced inflammatory mediators via AP-1 and STAT1/3 inactivation in RAW 264.7macrophages.Bioorganic&Medicinal Chemistry Letters,27(23),5245-5251.
Lee,S.,Kim,D.C.,Park,J.S.,Son,J.Y.,Hak Sohn,J.,Liu,L.,&Oh,H.(2017).Penicillospirone from a marine isolate of Penicillium sp.(SF-5292)with anti-inflammatory activity.Bioorganic&Medicinal Chemistry Letters,27(15),3516-3520.
Li,J.,Li,D.,Xu,Y.,Guo,Z.,Liu,X.,Yang,H.,&Wang,L.(2017).Design,synthesis,biological evaluation,and molecular docking of chalcone derivatives as anti-inflammatory agents.Bioorganic&Medicinal Chemistry Letters,27(3),602-606.
Li,S.,Sun,X.,Li,Y.,Liu,F.,Ma,J.,Tong,L.,&Guo,Y.(2017).Natural NO inhibitors from the leaves of Callicarpa kwangtungensis:Structures,activities,and interactions with iNOS.Bioorganic&Medicinal Chemistry Letters,27(3),670-674.
Niu,Y.T.,Zhao,Y.P.,Jiao,Y.F.,Zheng,J.,Yang,W.L.,Zhou,R.,&Yu,J.Q.(2016).Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice.International Immunopharmacology,39,16-22.
Qin,N.B.,Li,S.G.,Yang,X.Y.,Gong,C.,Zhang,X.Y.,Wang,J.,&Hua,H.M.(2017).Bioactive terpenoids from Silybum marianum and their suppression on NO release in LPS-induced BV-2 cells and interaction with iNOS.Bioorganic&Medicinal Chemistry Letters,27(10),2161-2165.
Wang,Z.,Tang,S.,Jin,Y.,Zhang,Y.,Hattori,M.,Zhang,H.,&Zhang,N.(2015).Two main metabolites of gentiopicroside detected in rat plasma by LC-TOF-MS following 2,4-dinitrophenylhydrazine derivatization.Journal of Pharmaceutical and Biomedical Analysis,107(3),1-6.
Wu,S.,Yang,L.,Sun,W.,Si,L.,Xiao,S.,Wang,Q.,&Zhang,Y.(2017).Design,synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors.European Journal of Medicinal Chemistry,130,308-319.
Xiong,K.,Gao,T.,Zhang,T.,Wang,Z.,&Han,H.(2017).Simultaneous determination of gentiopicroside and its two active metabolites in rat plasma by LC-MS/MSand its application in pharmacokinetic studies.Journal of Chromatography B,1065-1066,1-7.
Feng,X.,Cheng,G.,Chen,S.,Yang,H.,&Huang,W.(2010).Evaluation of the burn healing properties of oil extraction from housefly larva in mice.Journal of Ethnopharmacology,130(3),586-592.
Zhang,X.,Sun,J.,Xin,W.,Li,Y.,Ni,L.,&Du,G.(2015).Anti-inflammation effect of methyl salicylate 2-O-β-D-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide(LPS)-treated murine macrophages RAW264.7 cells.International Immunopharmacology,25(1),88-95.
Zhao,L.,Ye,J.,Wu,G.T.,Peng,X.J.,Xia,P.F.,&Ren,Y.(2015).Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte.Journal of Ethnopharmacology,172,100-107.
An,J.Y.,Lee,H.H.,Shin,J.S.,Yoo,H.S.,Park,J.S.,Son,S.H.,&Kim,N.J.(2017).Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE 2 in LPS-induced RAW 264.7 cells.Bioorganic&Medicinal Chemistry Letters,27(11),2613-2616.
Bist,G.,Pun,N.T.,Magar,T.B.T.,Shrestha,A.,Oh,H.J.,Khakurel,A.,&Lee,E.S.(2017).Inhibition of LPS-stimulated ROS production by fluorinated and hydroxylated chalcones in RAW 264.7 macrophages with structure-activity relationship study.Bioorganic&Medicinal Chemistry Letters,27(5),1205-1209.
Dirsch,V.,Stuppner,H.,&Vollmar,A.(1998).The griess assay:Suitable for a bio-Guided fractionation of anti-inflammatory plant extracts?Planta Medica,64(05),423-426.
Guo,R.,Guo,C.,He,D.,Zhao,D.,&Shen,Y.(2017).Two new C19-diterpenoid alkaloids with anti-inflammatory activity from Aconitum iochanicum.Chinese Journal of Chemistry,35(10),1644-1647.
Khatri,C.K.,Indalkar,K.S.,Patil,C.R.,Goyal,S.N.,&Chaturbhuj,G.U.(2017).Novel2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene analogues as selective COX-2 inhibitors:Design,synthesis,anti-inflammatory evaluation,and molecular docking studies.Bioorganic&Medicinal Chemistry Letters,27(8),1721-1726.
Kiem,P.V.,Huyen,L.T.,&Hang,D.T.(2017).Sesquiterpene derivatives from marine sponge Smenospongia cerebriformis and their anti-inflammatory activity.Bioorganic&Medicinal Chemistry Letters,27(7),1525-1529.
Jo,A.,Han,H.,Seo,S.,Shin,J.S.,Lee,J.Y.,Kim,H.J.,&Lee,K.T.(2017).Inhibitory effect of moschamine isolated from Carthamus tinctorius on LPS-induced inflammatory mediators via AP-1 and STAT1/3 inactivation in RAW 264.7macrophages.Bioorganic&Medicinal Chemistry Letters,27(23),5245-5251.
Lee,S.,Kim,D.C.,Park,J.S.,Son,J.Y.,Hak Sohn,J.,Liu,L.,&Oh,H.(2017).Penicillospirone from a marine isolate of Penicillium sp.(SF-5292)with anti-inflammatory activity.Bioorganic&Medicinal Chemistry Letters,27(15),3516-3520.
Li,J.,Li,D.,Xu,Y.,Guo,Z.,Liu,X.,Yang,H.,&Wang,L.(2017).Design,synthesis,biological evaluation,and molecular docking of chalcone derivatives as anti-inflammatory agents.Bioorganic&Medicinal Chemistry Letters,27(3),602-606.
Li,S.,Sun,X.,Li,Y.,Liu,F.,Ma,J.,Tong,L.,&Guo,Y.(2017).Natural NO inhibitors from the leaves of Callicarpa kwangtungensis:Structures,activities,and interactions with iNOS.Bioorganic&Medicinal Chemistry Letters,27(3),670-674.
Niu,Y.T.,Zhao,Y.P.,Jiao,Y.F.,Zheng,J.,Yang,W.L.,Zhou,R.,&Yu,J.Q.(2016).Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice.International Immunopharmacology,39,16-22.
Qin,N.B.,Li,S.G.,Yang,X.Y.,Gong,C.,Zhang,X.Y.,Wang,J.,&Hua,H.M.(2017).Bioactive terpenoids from Silybum marianum and their suppression on NO release in LPS-induced BV-2 cells and interaction with iNOS.Bioorganic&Medicinal Chemistry Letters,27(10),2161-2165.
Wang,Z.,Tang,S.,Jin,Y.,Zhang,Y.,Hattori,M.,Zhang,H.,&Zhang,N.(2015).Two main metabolites of gentiopicroside detected in rat plasma by LC-TOF-MS following 2,4-dinitrophenylhydrazine derivatization.Journal of Pharmaceutical and Biomedical Analysis,107(3),1-6.
Wu,S.,Yang,L.,Sun,W.,Si,L.,Xiao,S.,Wang,Q.,&Zhang,Y.(2017).Design,synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors.European Journal of Medicinal Chemistry,130,308-319.
Xiong,K.,Gao,T.,Zhang,T.,Wang,Z.,&Han,H.(2017).Simultaneous determination of gentiopicroside and its two active metabolites in rat plasma by LC-MS/MSand its application in pharmacokinetic studies.Journal of Chromatography B,1065-1066,1-7.
Feng,X.,Cheng,G.,Chen,S.,Yang,H.,&Huang,W.(2010).Evaluation of the burn healing properties of oil extraction from housefly larva in mice.Journal of Ethnopharmacology,130(3),586-592.
Zhang,X.,Sun,J.,Xin,W.,Li,Y.,Ni,L.,&Du,G.(2015).Anti-inflammation effect of methyl salicylate 2-O-β-D-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide(LPS)-treated murine macrophages RAW264.7 cells.International Immunopharmacology,25(1),88-95.
Zhao,L.,Ye,J.,Wu,G.T.,Peng,X.J.,Xia,P.F.,&Ren,Y.(2015).Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte.Journal of Ethnopharmacology,172,100-107.