Anti-inflammatory effects of alkaloid enriched extract from roots of Eurycoma longifolia Jack
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摘要
Objective: To examine the in vitro and in vivo anti-inflammatory effects of the alkaloid enriched extract(ELA) from the roots of Eurycoma longifolia. Methods: The in vitro antiinflammatory effects of ELA were evaluated by examining its inhibitory activities against nitric oxide(NO) production and inducible nitric oxide synthase(iN OS) and cyclooxygenase2(COX-2) expressions in lipopolysaccharide(LPS)-stimulated RAW264.7 cells. The level of NO produced in the culture media was determined by Griess method. The i NOS and COX-2 protein expressions were analyzed by Western blot. The in vivo effect of ELA was evaluated on LPS-induced septic shock in mice model. Mice mortality was monitored for5 days after injection of LPS. The chemical contents of the ELA were determined by using various chromatographic and spectroscopic techniques. Results: The ELA was found to exhibit a significant anti-inflammatory effect in both in vitro and in vivo models. The results demonstrated that ELA dose-dependently inhibited LPS-induced NO production as well as the protein iN OS and COX-2 expressions. In the septic shock model, ELA dose-dependently protected mice from LPS-induced mortality. Further study on the isolated components of ELA indicated that 9,10-dimethoxycanthin-6-one may contribute significantly to the antiinflammatory effects of the extract. Conclusions: These results suggest that ELA exhibits the anti-inflammatory activity via suppression of pro-inflammatory mediators such as NO, iN OS,and COX-2 and protects mice from LPS-induced mortality in septic shock model.
Objective: To examine the in vitro and in vivo anti-inflammatory effects of the alkaloid enriched extract(ELA) from the roots of Eurycoma longifolia. Methods: The in vitro antiinflammatory effects of ELA were evaluated by examining its inhibitory activities against nitric oxide(NO) production and inducible nitric oxide synthase(iN OS) and cyclooxygenase2(COX-2) expressions in lipopolysaccharide(LPS)-stimulated RAW264.7 cells. The level of NO produced in the culture media was determined by Griess method. The i NOS and COX-2 protein expressions were analyzed by Western blot. The in vivo effect of ELA was evaluated on LPS-induced septic shock in mice model. Mice mortality was monitored for5 days after injection of LPS. The chemical contents of the ELA were determined by using various chromatographic and spectroscopic techniques. Results: The ELA was found to exhibit a significant anti-inflammatory effect in both in vitro and in vivo models. The results demonstrated that ELA dose-dependently inhibited LPS-induced NO production as well as the protein iN OS and COX-2 expressions. In the septic shock model, ELA dose-dependently protected mice from LPS-induced mortality. Further study on the isolated components of ELA indicated that 9,10-dimethoxycanthin-6-one may contribute significantly to the antiinflammatory effects of the extract. Conclusions: These results suggest that ELA exhibits the anti-inflammatory activity via suppression of pro-inflammatory mediators such as NO, iN OS,and COX-2 and protects mice from LPS-induced mortality in septic shock model.
Objective: To examine the in vitro and in vivo anti-inflammatory effects of the alkaloid enriched extract(ELA) from the roots of Eurycoma longifolia. Methods: The in vitro antiinflammatory effects of ELA were evaluated by examining its inhibitory activities against nitric oxide(NO) production and inducible nitric oxide synthase(iN OS) and cyclooxygenase2(COX-2) expressions in lipopolysaccharide(LPS)-stimulated RAW264.7 cells. The level of NO produced in the culture media was determined by Griess method. The i NOS and COX-2 protein expressions were analyzed by Western blot. The in vivo effect of ELA was evaluated on LPS-induced septic shock in mice model. Mice mortality was monitored for5 days after injection of LPS. The chemical contents of the ELA were determined by using various chromatographic and spectroscopic techniques. Results: The ELA was found to exhibit a significant anti-inflammatory effect in both in vitro and in vivo models. The results demonstrated that ELA dose-dependently inhibited LPS-induced NO production as well as the protein iN OS and COX-2 expressions. In the septic shock model, ELA dose-dependently protected mice from LPS-induced mortality. Further study on the isolated components of ELA indicated that 9,10-dimethoxycanthin-6-one may contribute significantly to the antiinflammatory effects of the extract. Conclusions: These results suggest that ELA exhibits the anti-inflammatory activity via suppression of pro-inflammatory mediators such as NO, iN OS,and COX-2 and protects mice from LPS-induced mortality in septic shock model.
引文
[1]Sharma B,Dabur R.Role of pro-inflammatory cytokines in regulation of skeletal muscle metabolism:A systematic review.Curr Med Chem 2018(in press).Doi:10.2174/0929867326666181129095309.
[2]Lind M,Hayes A,Caprnda M,Petrovic D,Rodrigo L,Kruzliak P,et al.Inducible nitric oxide synthase:Good or bad?Biomed Pharmacother2017;93:370-375.
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[5]Mitchell JA,Larkin S,Williams TJ.Cyclooxygenase-2:Regulation and relevance in inflammation.Biochem Pharmacol 1995;50(10):1535-1542.
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[7]Mutschlechner B,Schwaiger S,Tran TVA,Stuppner H.Development of a selective HPLC-DAD/ELSD method for the qualitative and quantitative assessment of commercially available Eurycoma longifolia products and plant extracts.Fitoterapia 2018;124:188-192.
[8]Nguyen HD,Choo YY,Nguyen TD,Nguyen HN,Chau VM,Lee JH.7-Methoxy-(9H-beta-carbolin-1-il)-(E)-1-propenoic acid,a beta-carboline alkaloid from Eurycoma longifolia,exhibits anti-inflammatory effects by activating the Nrf2/Heme Oxygenase-1 pathway.J Cell Biochem 2016;117(3):659-670.
[9]Han YM,Woo SU,Choi MS,Park YN,Kim SH,Yim H,et al.Antiinflammatory and analgesic effects of Eurycoma longifolia extracts.Arch Pharm Res 2016;39(3):421-428.
[10]Mosmann T.Rapid colorimetric assay for cellular growth and survival:Application to proliferation and cytotoxicity assays.J Immunol Methods1983;65(1-2):55-63.
[11]Hatziieremia S,Gray AI,Ferro VA,Paul A,Plevin R.The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappa B signalling pathways in monocytes/macrophages.Br J Pharmacol 2006;149(2):188-198.
[12]Moreira GL,Maria VI,António RJ.An overview on cardamonin.J Med Food 2014;17(6):633-640.
[13]Kardono LB,Angerhofer CK,Tsauri S,Padmawinata K,Pezzuto JM,Kinghorn AD.Cytotoxic and antimalarial constituents of the roots of Eurycoma longifolia.J Nat Prod 1991;54(5):1360-1367.
[14]Miyake K,Tezuka Y,Awale S,Li F,Kadota S.Canthin-6-one alkaloids and a tirucallanoid from Eurycoma longifolia and their cytotoxic activity against a human HT-1080 fibrosarcoma cell line.Nat Prod Commun2010;5(1):17-22.
[15]Readel KE,Seigler DS,Young DA.5-Methoxycanthin-6-one from Leitneria floridana(Simaroubaceae).Biochem Syst Ecol 2003;31(2):167-170.
[16]Lu Z,Huang W,Wang L,Xu N,Ding Q,Cao C.Exhaled nitric oxide in patients with chronic obstructive pulmonary disease:A systematic review and meta-analysis.Int J Chron Obstruct Pulmon Dis 2018;13:2695-2705.
[17]Stuehr DJ,Haque MM.Nitric oxide synthase enzymology in the twenty years after the Nobel prize.Br J Pharmacol 2018(in press).
[18]Garcia-Ortiz A,Serrador JM.Nitric oxide signaling in T cell-mediated immunity.Trends Mol Med 2018;24(4):412-427.
[19]Yun HY,Dawson VL,Dawson TM.Neurobiology of nitric oxide.Critical Rev Neurobiol 1996;10(3-4):291-316.
[20]Robinson MA,Baumgardner JE,Otto CM.Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase.Free Rad Biol Med 2011;51(11):1952-1965.
[21]Pautz A,Art J,Hahn S,Nowag S,Voss C,Kleinert H.Regulation of the expression of inducible nitric oxide synthase.Nitric Oxide 2010;23(2):75-93.
[22]Smith WL,Garavito RM,De Witt DL.Prostaglandin endoperoxide H synthases(cyclooxygenases)-1 and-2.J Biol Chem 1996;271(52):33157-33160.
[23]Ricciotti E,Fitz Gerald GA.Prostaglandins and inflammation.Arterioscler Thromb Vasc Biol 2011;31(5):986-1000.
[24]Lee JH,Jung NH,Lee BH,Kim SH,Jun JH.Suppression of heme oxygenase-1 by prostaglandin E2-protein kinase A-A-kinase anchoring protein signaling is central for augmented Cyclooxygenase-2 expression in lipopolysaccharide-atimulated RAW 264.7 macrophages.Allergy Asthma Immunol Res 2013;5(5):329-336.
[25]Yan L,Wang S,Rafferty SP,Wesley RA,Danner RL.Endogenously produced nitric oxide increases tumor necrosis factor-毩production in transfected human U937 cells.Blood 1997;90(3):1160-1167.
[26]Wu CH,Chen TL,Chen TG,Ho WP,Chiu WT,Chen RM.Nitric oxide modulates pro-and anti-inflammatory cytokines in lipopolysaccharideactivated macrophages.J Trauma 2003;55(3):540-545.
[27]Jung WK,Choi I,Lee DY,Yea SS,Choi YH,Kim MM,et al.Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappa B pathways.Int J Biochem Cell Bio 2008;40(11):2572-2582.
[28]Guo LY,Hung TM,Bae KH,Shin EM,Zhou HY,Hong YN,et al.Antiinflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill.Eur J Pharmacol 2008;591(1-3):293-299.
[29]Saba E,Shafeeq T,Irfan M,Lee YY,Kwon HW,Seo MG,et al.Antiinflammatory activity of crude venom isolated from parasitoid wasp,Bracon hebetor Say.Mediators Inflamm 2017;2017:6978194.
[30]Okunrobo LO,Usifoh CO,Uwaya JO.Anti-inflammatory and gastroprotective properties of some chalcones.Acta Pol Pharm 2006;63(3):195-199.
[31]Yang H,Du Z,Wang W,Song M,Sanidad K,Sukamtoh E,et al.Structure-activity relationship of curcumin:Role of the methoxy group in anti-inflammatory and anticolitis effects of curcumin.J Agric Food Chem2017;65(22):4509-4515.
[32]Ngoc PB,Pham TB,Nguyen HD,Tran TT,Chu HH,Chau VM,et al.A new anti-inflammatory beta-carboline alkaloid from the hairy-root cultures of Eurycoma longifolia.Nat Prod Res 2016;30(12):1360-1365.
[33]Tran TV,Malainer C,Schwaiger S,Atanasov AG,Heiss EH,Dirsch VM,et al.NF-kappa B inhibitors from Eurycoma longifolia.J Nat Prod 2014;77(3):483-488.
[34]Kim HM,Lee JS,Sezirahiga J,Kwon J,Jeong M,Lee D,et al.A new canthinone-type alkaloid isolated from Ailanthus altissima Swingle.Molecules 2016;21(5):E642.Doi:10.3390/molecules21050642..
[35]Cho SK,Jeong M,Jang DS,Choi JH.Anti-inflammatory effects of canthin-6-one alkaloids from Ailanthus altissima.Planta Med 2018;84(8):527-535.
[36]Rehman SU,Choe K,Yoo HH.Review on a traditional herbal medicine,Eurycoma longifolia Jack(Tongkat Ali):Its traditional uses,chemistry,evidence-based pharmacology and toxicology.Molecules 2016;21(3):331.
[2]Lind M,Hayes A,Caprnda M,Petrovic D,Rodrigo L,Kruzliak P,et al.Inducible nitric oxide synthase:Good or bad?Biomed Pharmacother2017;93:370-375.
[3]Rankin JA.Biological mediators of acute inflammation.AACN Clin Issues2004;15(1):3-17.
[4]Isomaki P,Punnonen J.Pro-and anti-inflammatory cytokines in rheumatoid arthritis.Ann Med 1997;29(6):499-507.
[5]Mitchell JA,Larkin S,Williams TJ.Cyclooxygenase-2:Regulation and relevance in inflammation.Biochem Pharmacol 1995;50(10):1535-1542.
[6]Rehman SU,Choe K,Yoo HH.Review on a traditional herbal medicine,Eurycoma longifolia Jack(Tongkat Ali):Its traditional uses,chemistry,evidence-based pharmacology and toxicology.Molecules 2016;21(3):331.
[7]Mutschlechner B,Schwaiger S,Tran TVA,Stuppner H.Development of a selective HPLC-DAD/ELSD method for the qualitative and quantitative assessment of commercially available Eurycoma longifolia products and plant extracts.Fitoterapia 2018;124:188-192.
[8]Nguyen HD,Choo YY,Nguyen TD,Nguyen HN,Chau VM,Lee JH.7-Methoxy-(9H-beta-carbolin-1-il)-(E)-1-propenoic acid,a beta-carboline alkaloid from Eurycoma longifolia,exhibits anti-inflammatory effects by activating the Nrf2/Heme Oxygenase-1 pathway.J Cell Biochem 2016;117(3):659-670.
[9]Han YM,Woo SU,Choi MS,Park YN,Kim SH,Yim H,et al.Antiinflammatory and analgesic effects of Eurycoma longifolia extracts.Arch Pharm Res 2016;39(3):421-428.
[10]Mosmann T.Rapid colorimetric assay for cellular growth and survival:Application to proliferation and cytotoxicity assays.J Immunol Methods1983;65(1-2):55-63.
[11]Hatziieremia S,Gray AI,Ferro VA,Paul A,Plevin R.The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappa B signalling pathways in monocytes/macrophages.Br J Pharmacol 2006;149(2):188-198.
[12]Moreira GL,Maria VI,António RJ.An overview on cardamonin.J Med Food 2014;17(6):633-640.
[13]Kardono LB,Angerhofer CK,Tsauri S,Padmawinata K,Pezzuto JM,Kinghorn AD.Cytotoxic and antimalarial constituents of the roots of Eurycoma longifolia.J Nat Prod 1991;54(5):1360-1367.
[14]Miyake K,Tezuka Y,Awale S,Li F,Kadota S.Canthin-6-one alkaloids and a tirucallanoid from Eurycoma longifolia and their cytotoxic activity against a human HT-1080 fibrosarcoma cell line.Nat Prod Commun2010;5(1):17-22.
[15]Readel KE,Seigler DS,Young DA.5-Methoxycanthin-6-one from Leitneria floridana(Simaroubaceae).Biochem Syst Ecol 2003;31(2):167-170.
[16]Lu Z,Huang W,Wang L,Xu N,Ding Q,Cao C.Exhaled nitric oxide in patients with chronic obstructive pulmonary disease:A systematic review and meta-analysis.Int J Chron Obstruct Pulmon Dis 2018;13:2695-2705.
[17]Stuehr DJ,Haque MM.Nitric oxide synthase enzymology in the twenty years after the Nobel prize.Br J Pharmacol 2018(in press).
[18]Garcia-Ortiz A,Serrador JM.Nitric oxide signaling in T cell-mediated immunity.Trends Mol Med 2018;24(4):412-427.
[19]Yun HY,Dawson VL,Dawson TM.Neurobiology of nitric oxide.Critical Rev Neurobiol 1996;10(3-4):291-316.
[20]Robinson MA,Baumgardner JE,Otto CM.Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase.Free Rad Biol Med 2011;51(11):1952-1965.
[21]Pautz A,Art J,Hahn S,Nowag S,Voss C,Kleinert H.Regulation of the expression of inducible nitric oxide synthase.Nitric Oxide 2010;23(2):75-93.
[22]Smith WL,Garavito RM,De Witt DL.Prostaglandin endoperoxide H synthases(cyclooxygenases)-1 and-2.J Biol Chem 1996;271(52):33157-33160.
[23]Ricciotti E,Fitz Gerald GA.Prostaglandins and inflammation.Arterioscler Thromb Vasc Biol 2011;31(5):986-1000.
[24]Lee JH,Jung NH,Lee BH,Kim SH,Jun JH.Suppression of heme oxygenase-1 by prostaglandin E2-protein kinase A-A-kinase anchoring protein signaling is central for augmented Cyclooxygenase-2 expression in lipopolysaccharide-atimulated RAW 264.7 macrophages.Allergy Asthma Immunol Res 2013;5(5):329-336.
[25]Yan L,Wang S,Rafferty SP,Wesley RA,Danner RL.Endogenously produced nitric oxide increases tumor necrosis factor-毩production in transfected human U937 cells.Blood 1997;90(3):1160-1167.
[26]Wu CH,Chen TL,Chen TG,Ho WP,Chiu WT,Chen RM.Nitric oxide modulates pro-and anti-inflammatory cytokines in lipopolysaccharideactivated macrophages.J Trauma 2003;55(3):540-545.
[27]Jung WK,Choi I,Lee DY,Yea SS,Choi YH,Kim MM,et al.Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappa B pathways.Int J Biochem Cell Bio 2008;40(11):2572-2582.
[28]Guo LY,Hung TM,Bae KH,Shin EM,Zhou HY,Hong YN,et al.Antiinflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill.Eur J Pharmacol 2008;591(1-3):293-299.
[29]Saba E,Shafeeq T,Irfan M,Lee YY,Kwon HW,Seo MG,et al.Antiinflammatory activity of crude venom isolated from parasitoid wasp,Bracon hebetor Say.Mediators Inflamm 2017;2017:6978194.
[30]Okunrobo LO,Usifoh CO,Uwaya JO.Anti-inflammatory and gastroprotective properties of some chalcones.Acta Pol Pharm 2006;63(3):195-199.
[31]Yang H,Du Z,Wang W,Song M,Sanidad K,Sukamtoh E,et al.Structure-activity relationship of curcumin:Role of the methoxy group in anti-inflammatory and anticolitis effects of curcumin.J Agric Food Chem2017;65(22):4509-4515.
[32]Ngoc PB,Pham TB,Nguyen HD,Tran TT,Chu HH,Chau VM,et al.A new anti-inflammatory beta-carboline alkaloid from the hairy-root cultures of Eurycoma longifolia.Nat Prod Res 2016;30(12):1360-1365.
[33]Tran TV,Malainer C,Schwaiger S,Atanasov AG,Heiss EH,Dirsch VM,et al.NF-kappa B inhibitors from Eurycoma longifolia.J Nat Prod 2014;77(3):483-488.
[34]Kim HM,Lee JS,Sezirahiga J,Kwon J,Jeong M,Lee D,et al.A new canthinone-type alkaloid isolated from Ailanthus altissima Swingle.Molecules 2016;21(5):E642.Doi:10.3390/molecules21050642..
[35]Cho SK,Jeong M,Jang DS,Choi JH.Anti-inflammatory effects of canthin-6-one alkaloids from Ailanthus altissima.Planta Med 2018;84(8):527-535.
[36]Rehman SU,Choe K,Yoo HH.Review on a traditional herbal medicine,Eurycoma longifolia Jack(Tongkat Ali):Its traditional uses,chemistry,evidence-based pharmacology and toxicology.Molecules 2016;21(3):331.