Supercritical Extracts from Arctium lappa as a Potential Inhibitor for the Activation of Complement System 

Abstract

Arctium lappa is a perennial species of the Asteraceae family originally from Europe and Asia. Considered a weed species in the southern region of Brazil, it is popularly used as a natural anti-inflammatory. The complement system is an important component of the innate immune response. However, its exacerbated activation can lead to harmful conditions like autoimmune and inflammatory disorders. Plants that inhibit the activation of complement can be a promising tool in the treatment of inflammatory diseases. Here, we evaluated the effect of A. lappa leaves extracts on the activation of the classical and alternative pathways of complement system. Two extracts were obtained under supercritical conditions using scCO₂ with ethanol as cosolvent, at 313.15K, 15 MPa (E1) and 25 MPa (E2). Classical and alternative activation were evaluated using complement fixation test. Different concentrations of A. lappa extracts E1 and E2 showed an inhibitory effect on both complement pathways, and heparin was used as control. The IC₅₀ of E1, E2, and heparin were 28.26, 20.12 and 92.54 µg/mL for classical and 26.12, 27.70, 27.78 µg/mL for the alternative pathway. Results demonstrate that A. lappa is a promising complementary treatment for diseases associated with complement activation.

Key words

Arctium lappa - Asteraceae - burdock - supercritical extract - classical pathway - alternative pathway - complement system - hemolysis inhibition

• References

• 1 Chan YS, Cheng LN, Wu JH, Chan E, Kwan YW, Lee SM, Leung GP, Yu PH, Chan SW. A review of the pharmacological effects of Arctium lappa (burdock). Inflammopharmacology 2011; 19: 245-254
• 2 Holetz FB, Pessini GL, Sanches NR, Cortez DA, Nakamura CV, Filho BP. Screening of some plants used in the Brazilian folk medicine for the treatment of infectious diseases. Mem Inst Oswaldo Cruz 2002; 97: 1027-1031
• 3 Jeelani S, Khuroo MA. Triterpenoids from Arctium lappa. Nat Prod Res 2012; 26: 654-658
• 4 Taher M, Hussain DAA, Hasan HF, Fahmi ZM, Luaibi OK, Ali MG. Hypolipidemic effect of caffeic acid isolated from Arctium lappa cultivated in Iraq, in hyperlipidemic rat model. Iraqi J Pharm Sci 2015; 24: 7
• 5 Kim YK, Koppula S, Shim DW, In EJ, Kwak SB, Kim MK, Yu SH, Lee KH, Kang TB. Inhibitory effect and mechanism of Arctium lappa extract on NLRP3 inflammasome activation. Evid Based Complement Alternat Med 2018; 2018: 6346734
• 6 Fierascu RC, Georgiev MI, Fierascu I, Ungureanu C, Avramescu SM, Ortan A, Georgescu MI, Sutan AN, Zanfirescu A, Dinu-Pirvu CE. and others Mitodepressive, antioxidant, antifungal and anti-inflammatory effects of wild-growing Romanian native Arctium lappa L. (Asteraceae) and Veronica persica Poiret (Plantaginaceae). Food Chem Toxicol 2018; 111: 44-52
• 7 Lou C, Zhu Z, Zhao Y, Zhu R, Zhao H. Arctigenin, a lignan from Arctium lappa L., inhibits metastasis of human breast cancer cells through the downregulation of MMP-2/-9 and heparanase in MDA-MB-231 cells. Oncol Rep 2017; 37: 179-184
• 8 Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: A key system for immune surveillance and homeostasis. Nat Immunol 2010; 11: 785-797
• 9 Wallis R, Mitchell DA, Schmid R, Schwaeble WJ, Keeble AH. Paths reunited: Initiation of the classical and lectin pathways of complement activation. Immunobiology 2010; 215: 1-11
• 10 Evans-Osses I, de Messias-Reason I, Ramirez MI. The emerging role of complement lectin pathway in trypanosomatids: Molecular bases in activation, genetic deficiencies, susceptibility to infection, and complement system-based therapeutics. Sci World J 2013; 2013: 1-12
• 11 Gasque P. Complement: A unique innate immune sensor for danger signals. Mol Immunol 2004; 41: 1089-1098
• 12 Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: Pathophysiological mechanisms. J Immunol 2013; 190: 3831-3838
• 13 Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov 2010; 9: 43-56
• 14 Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012; 75: 311-335
• 15 Jiang YY, Yu J, Li YB, Wang L, Hu L, Zhang L, Zhou YH. Extraction and antioxidant activities of polysaccharides from roots of Arctium lappa L. Int J Biol Macromol 2019; 123: 531-538
• 16 Zhao J, Evangelopoulos D, Bhakta S, Gray AI, Seidel V. Antitubercular activity of Arctium lappa and Tussilago farfara extracts and constituents. J Ethnopharmacol 2014; 155: 796-800
• 17 Lou Z, Wang H, Zhu S, Chen S, Zhang M, Wang Z. Ionic liquids based simultaneous ultrasonic and microwave assisted extraction of phenolic compounds from burdock leaves. Anal Chim Acta 2012; 716: 28-33
• 18 Sánchez-Camargo AP, Mendiola JA, Ibáñez I, Herrero M. Supercritical fluid extraction. In: Reedijk J. ed. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. Waltham: Elsevier; 2014: 1-17
• 19 de Souza ARC, Guedes AR, Rodriguez JMF, Bombardelli MCM, Corazza ML. Extraction of Arctium lappa leaves using supercritical CO2+ethanol: Kinetics, chemical composition, and bioactivity assessments. J Supercrit Fluids 2018; 140: 137-146
• 20 Souza ARCd, Stefanov S, Bombardelli MCM, Corazza ML, Stateva RP. Assessment of composition and biological activity of Arctium lappa leaves extracts obtained with pressurized liquid and supercritical CO2 extraction. J Supercrit Fluids 2019; 152: 1-10
• 21 Lin CC, Lu JM, Yang JJ, Chuang SC, Ujiie T. Anti-inflammatory and radical scavenge effects of Arctium lappa. Am J Chin Med 1996; 24: 127-137
• 22 Namdar Ahmadabad H, Behnamfar M, Nezafat Firizi M, Saghayan S, Taghasi F, Abbaspur A. Comparison of the immunomodulatory properties of root and leaves of Arctium lappa (Burdock) in vitro. Zahedan J Res Med Sci 2017; 19: e12965
• 23 Sohn EH, Jang SA, Joo H, Park S, Kang SC, Lee CH, Kim SY. Anti-allergic and anti-inflammatory effects of butanol extract from Arctium Lappa L. Clin Mol Allergy 2011; 9: 4
• 24 Harboe M, Mollnes TE. The alternative complement pathway revisited. J Cell Mol Med 2008; 12: 1074-1084
• 25 Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin Exp Immunol 2004; 138: 439-446
• 26 Pérez-González MZ, Siordia-Reyes AG, Damián-Nava P, Hernández-Ortega S, Macías-Rubalcava ML, Jiménez-Arellanes MA. Hepatoprotective and anti-inflammatory activities of the Cnidoscolus chayamansa (Mc Vaugh) leaf extract in chronic models. Evid Based Complement Alternat Med 2018; 2018: 3896517
• 27 Hultqvist M, Olofsson P, Gelderman KA, Holmberg J, Holmdahl R. A new arthritis therapy with oxidative burst inducers. PLoS Med 2006; 3: e348
• 28 Milani GB, Camponogara C, Piana M, Silva CR, Oliveira SM. Cariniana domestica fruit peels present topical anti-inflammatory efficacy in a mouse model of skin inflammation. Naunyn Schmiedebergs Arch Pharmacol 2019; 392: 513-528
• 29 Tatiya AU, Saluja AK, Kalaskar MG, Surana SJ, Patil PH. Evaluation of analgesic and anti-inflammatory activity of Bridelia retusa (Spreng) bark. J Tradit Complement Med 2017; 7: 441-451
• 30 Wang WH, Chuang HY, Chen CH, Chen WK, Hwang JJ. Lupeol acetate ameliorates collagen-induced arthritis and osteoclastogenesis of mice through improvement of microenvironment. Biomed Pharmacother 2016; 79: 231-240
• 31 Okoye NN, Ajaghaku DL, Okeke HN, Ilodigwe EE, Nworu CS, Okoye FB. beta-Amyrin and alpha-amyrin acetate isolated from the stem bark of Alstonia boonei display profound anti-inflammatory activity. Pharm Biol 2014; 52: 1478-1486
• 32 Jin W, Min BS, Lee J, Thuong PT, Lee HK, Song K, Seong YH, Bae K. Isolation of constituents and anti-complement activity from Acer okamotoanum. Arch Pharm Res 2007; 30: 172-176
• 33 McNeil MJ, Porter RBR, Rainford L, Dunbar O, Francis S, Laurieri N, Delgoda R. Chemical composition and biological activities of the essential oil from Cleome rutidosperma DC. Fitoterapia 2018; 129: 191-197
• 34 Silva RO, Sousa FB, Damasceno SR, Carvalho NS, Silva VG, Oliveira FR, Sousa DP, Aragão KS, Barbosa AL, Freitas RM. and others Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress. Fundam Clin Pharmacol 2014; 28: 455-464
• 35 Gao Q, Yang M, Zuo Z. Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L. Acta Pharmacol Sin 2018; 39: 787-801
• 36 Zhao F, Wang L, Liu K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J Ethnopharmacol 2009; 122: 457-462
• 37 Wu X, Yang Y, Dou Y, Ye J, Bian D, Wei Z, Tong B, Kong L, Xia Y, Dai Y. Arctigenin but not arctiin acts as the major effective constituent of Arctium lappa L. fruit for attenuating colonic inflammatory response induced by dextran sulfate sodium in mice. Int Immunopharmacol 2014; 23: 505-515
• 38 Saleem M. Lupeol, a novel anti-inflammatory and anti-cancer dietary triterpene. Cancer Lett 2009; 285: 109-115
• 39 de Melo MMR, Silvestre AJD, Silva CM. Supercritical fluid extraction of vegetable matrices: Applications, trends and future perspectives of a convincing green technology. J Supercrit Fluids 2014; 92: 115-176
• 40 Danh LT, Mammucari R, Truong P, Foster N. Response surface method applied to supercritical carbon dioxide extraction of Vetiveria zizanioides essential oil. Chem Eng J 2009; 155: 617-626
• 41 Ruckenstein E, Shulgin I. Entrainer effect in supercritical mixtures. Fluid Phase Equilib 2001; 180: 345-359
• 42 KHC Baser, Buchbauer G. eds Handbook of Essential Oils: Science, Technology, and Applications. Boca Raton: CRC Press, Taylor & Francis Group, LLC; 2010. 1–994 
• 43 Gaya da Costa M, Poppelaars F, Berger SP, Daha MR, Seelen MA. The lectin pathway in renal disease: Old concept and new insights. Nephrol Dial Transplant 2018; 33: 2073-2079
• 44 Alban S, Classen B, Brunner G, Blaschek W. Differentiation between the complement modulating effects of an arabinogalactan-protein from Echinacea purpurea and heparin. Planta Med 2002; 68: 1118-1124
• 45 Logue GL. Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria (PNH) red cells. Blood 1977; 50: 239-247