The Anti-inflammatory Effects of Isoflavonoids from Radix Astragali in Hepatoprotective Potential against LPS/D-gal-induced Acute Liver Injury

 

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Abstract

Radix Astragali (RA) is an important Traditional Chinese Medicine widely used in the treatment of various diseases, such as pneumonia, atherosclerosis, diabetes, kidney and liver fibrosis. The role of isoflavonoids from RA in the treatment of liver injury remains unclear. The study aimed to explore hepatoprotective and anti-inflammatory effects of isoflavonoids from Astragalus mongholicus. Network pharmacological analysis showed that RA had a multi-target regulating effect on alleviating liver injury and inhibiting inflammation through its active ingredients, among which isoflavones were closely related to its key molecular targets. The anti-inflammatory and liver protection effects of isoflavonoids of RA were investigated using lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro and LPS/D-galactosamine (D-gal)-induced acute liver injury mice in vivo. The experimental results showed that methylnissolin (ML) and methylnissolin-3-O-β-D-glucoside (MLG) presented more notable anti-inflammatory effects. Both of them suppressed the release of pro-inflammatory cytokines, such as iNOS, COX-2, IL-1β, IL-6, and TNF-α in LPS-stimulated RAW 264.7 cells. In vivo investigation demonstrated that ML markedly meliorated liver injury in LPS/D-gal-induced mice. Western blot results revealed that ML and MLG down-regulated the expression of proinflammatory cytokines via NF-κB signaling pathway. The isoflavonoids, methylnissolin (ML), and methylnissolin-3-O-β-D-glucoside (MLG), play a vital role in the hepatoprotective and anti-inflammatory effects of RA.

Publication History

Received: 10 April 2022

Accepted after revision: 12 September 2022

Article published online:
12 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
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• References

• 1 Patil KR, Mahajan UB, Unger BS, Goyal SN, Belemkar S, Surana SJ, Ojha S, Patil CR. Animal models of inflammation for screening of anti-inflammatory drugs: implications for the discovery and development of phytopharmaceuticals. Int J Mol Sci 2019; 20: 4367 DOI: 10.3390/ijms20184367.
  CrossrefPubMedGoogle Scholar
• 2 Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Crit Care Clin 2017; 33: 167-191 DOI: 10.1016/j.ccc.2016.08.006.
  CrossrefPubMedGoogle Scholar
• 3 Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369: 2525-2534 DOI: 10.1056/NEJMra1208937.
  CrossrefPubMedGoogle Scholar
• 4 Stravitz RT, Lee WM. Acute liver failure. Lancet 2019; 394: 869-881 DOI: 10.1016/s0140-6736(19)31894-x.
  CrossrefPubMedGoogle Scholar
• 5 Breu AC, Patwardhan VR, Nayor J, Ringwala JN, Devore ZG, Ganatra RB, Hathorn KE, Horton L, Iriana S, Tapper EB. A multicenter study into causes of severe acute liver injury. Clin Gastroenterol Hepatol 2019; 17: 1201-1203 DOI: 10.1016/j.cgh.2018.08.016.
  CrossrefPubMedGoogle Scholar
• 6 Yan T, Huang J, Nisar MF, Wan C, Huang W. The beneficial roles of SIRT1 in drug-induced liver injury. Oxid Med Cell Longev 2019; 2019: 1-14 DOI: 10.1155/2019/8506195.
  CrossrefPubMedGoogle Scholar
• 7 Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2020; 18: 40-55 DOI: 10.1038/s41575-020-0342-4.
  CrossrefPubMedGoogle Scholar
• 8 Zhao L, Tan S, Zhang H, Liu P, Tan YZ, Li JC, Jia D, Shen XF. Astragalus polysaccharides exerts anti-infective activity by inducing human cathelicidin antimicrobial peptide LL-37 in respiratory epithelial cells. Phytother Res 2018; 32: 1521-1529 DOI: 10.1002/ptr.6080.
  CrossrefPubMedGoogle Scholar
• 9 Ma C, Zhang J, Yang S, Hua Y, Su J, Shang Y, Wang Z, Feng K, Zhang J, Yang X, Zhang H, Mao J, Fan G. Astragalus flavone ameliorates atherosclerosis and hepatic steatosis via inhibiting lipid-disorder and inflammation in apoE^−/− Mice. Front Pharmacol 2020; 11: 610550 DOI: 10.3389/fphar.2020.610550.
  CrossrefPubMedGoogle Scholar
• 10 Tian H, Lu J, He H, Zhang L, Dong Y, Yao H, Feng W, Wang S. The effect of Astragalus as an adjuvant treatment in type 2 diabetes mellitus: A (preliminary) meta-analysis. J Ethnopharmacol 2016; 191: 206-215 DOI: 10.1016/j.jep.2016.05.062.
  CrossrefPubMedGoogle Scholar
• 11 Yuan H, Wu X, Wang X, Yuan C. Chinese herbal decoction Astragalus and Angelica exerts its therapeutic effect on renal interstitial fibrosis through the inhibition of MAPK, PI3K-Akt and TNF signaling pathways. Genes Dis 2022; 9: 510-521 DOI: 10.1016/j.gendis.2020.06.001.
  CrossrefPubMedGoogle Scholar
• 12 Gui SY, Wei W, Wang H, Wu L, Sun WY, Chen WB, Wu CY. Effects and mechanisms of crude astragalosides fraction on liver fibrosis in rats. J Ethnopharmacol 2006; 103: 154-159 DOI: 10.1016/j.jep.2005.07.025.
  CrossrefPubMedGoogle Scholar
• 13 Shahzad M, Shabbir A, Wojcikowski K, Wohlmuth H, Gobe GC. The antioxidant effects of Radix Astragali (Astragalus membranaceus and related species) in protecting tissues from injury and disease. Curr Drug Targets 2016; 17: 1331-1340 DOI: 10.2174/1389450116666150907104742.
  CrossrefPubMedGoogle Scholar
• 14 Zou J, Li W, Wang G, Fang S, Cai J, Wang T, Zhang H, Liu P, Wu J, Ma Y. Hepatoprotective effects of Huangqi decoction (Astragali Radix and Glycyrrhizae Radix et Rhizoma) on cholestatic liver injury in mice: involvement of alleviating intestinal microbiota dysbiosis. J Ethnopharmacol 2021; 267: 113544 DOI: 10.1016/j.jep.2020.113544.
  CrossrefPubMedGoogle Scholar
• 15 Zhou J, Zhang N, Zhao L, Wu W, Zhang L, Zhou F, Li J. Astragalus polysaccharides and saponins alleviate liver injury and regulate gut microbiota in alcohol liver disease mice. Foods 2021; 10: 2688 DOI: 10.3390/foods10112688.
  CrossrefPubMedGoogle Scholar
• 16 Auyeung KK, Han QB, Ko JK. Astragalus membranaceus: A review of its protection against inflammation and gastrointestinal cancers. Am J Chin Med 2016; 44: 1-22 DOI: 10.1142/s0192415x16500014.
  CrossrefPubMedGoogle Scholar
• 17 Li L, Huang W, Wang S, Sun K, Zhang W, Ding Y, Zhang L, Tumen B, Ji L, Liu C. Astragaloside IV attenuates acetaminophen-induced liver injuries in mice by activating the Nrf2 signaling pathway. Molecules 2018; 23: 2032 DOI: 10.3390/molecules23082032.
  CrossrefPubMedGoogle Scholar
• 18 Krasteva I, Bratkov V, Shkondrov A, Zdraveva P. Flavonoids from the genus Astragalus: Phytochemistry and biological activity. Pharmacogn Rev 2016; 10: 11 DOI: 10.4103/0973-7847.176550.
  CrossrefPubMedGoogle Scholar
• 19 Pu W, Wang D, Zhou D. Structural characterization and evaluation of the antioxidant activity of phenolic compounds from Astragalus taipaishanensis and their structure-activity relationship. Sci Rep 2015; 5 DOI: 10.1038/srep13914.
  CrossrefPubMedGoogle Scholar
• 20 Li W, Sun YN, Yan XT, Yang SY, Kim S, Lee YM, Koh YS, Kim YH. Flavonoids from Astragalus membranaceus and their inhibitory effects on LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells. Arch Pharm Res 2013; 37: 186-192 DOI: 10.1007/s12272-013-0174-7.
  CrossrefPubMedGoogle Scholar
• 21 Zhang LJ, Liu HK, Hsiao PC, Kuo LM, Lee IJ, Wu TS, Chiou WF, Kuo YH. New isoflavonoid glycosides and related constituents from Astragali Radix (Astragalus membranaceus) and their inhibitory activity on nitric oxide production. J Agric Food Chem 2011; 59: 1131-1137 DOI: 10.1021/jf103610j.
  CrossrefPubMedGoogle Scholar
• 22 Spencer GF, Jones BE, Plattner RD, Barnekow DE, Brinen LS, Clardy J. A pterocarpan and two isoflavans from alfalfa. Phytochemistry 1991; 30: 4147-4149 DOI: 10.1016/0031-9422(91)83483-2.
  CrossrefPubMedGoogle Scholar
• 23 Wang YF, Lu CH, Lai GF, Cao JX, Luo SD. A new indolizinone from Polygonatum kingianum. Planta Med 2003; 69: 1066-1068 DOI: 10.1055/s-2003-45160.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Ma X, Tu P, Chen Y, Zhang T, Wei Y, Ito Y. Preparative isolation and purification of isoflavan and pterocarpan glycosides from Astragalus membranaceus Bge. var. mongholicus (Bge.) Hsiao by high-speed counter-current chromatography. J Chromatogr A 2004; 1023: 311-315 DOI: 10.1016/j.chroma.2003.10.014.
  CrossrefPubMedGoogle Scholar
• 25 Li W, Koike K, Asada Y, Hirotani M, Rui H, Yoshikawa T, Nikaido T. Flavonoids from Glycyrrhiza pallidiflora hairy root cultures. Phytochemistry 2002; 60: 351-355 DOI: 10.1016/s0031-9422(02)00093-6.
  CrossrefPubMedGoogle Scholar
• 26 Subarnas A, Oshima Y, Hikino H. Isoflavans and a pterocarpan from Astragalus mongholicus . Phytochemistry 1991; 30: 2777-2780 DOI: 10.1016/0031-9422(91)85143-N.
  CrossrefPubMedGoogle Scholar
• 27 Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008; 4: 682-690 DOI: 10.1038/nchembio.118.
  CrossrefPubMedGoogle Scholar
• 28 Lan S, Duan J, Zeng N, Yu B, Yang X, Ning H, Huang Y, Rao Y. Network pharmacology-based screening of the active ingredients and mechanisms of Huangqi against aging. Medicine 2021; 100: e25660 DOI: 10.1097/md.0000000000025660.
  CrossrefPubMedGoogle Scholar
• 29 Hu Q, Wei S, Wen J, Zhang W, Jiang Y, Qu C, Xiang J, Zhao Y, Peng X, Ma X. Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease. BioData Min 2020; 13: 11 DOI: 10.1186/s13040-020-00224-9.
  CrossrefPubMedGoogle Scholar
• 30 Liu X, Wu J, Tian R, Su S, Deng S, Meng X. Targeting foam cell formation and macrophage polarization in atherosclerosis: The therapeutic potential of rhubarb. Biomed Pharmacother 2020; 129: 110433 DOI: 10.1016/j.biopha.2020.110433.
  CrossrefPubMedGoogle Scholar
• 31 de Oliveira RG, Mahon CP, Ascêncio PG, Ascêncio SD, Balogun SO, de Oliveira Martins DT. Evaluation of anti-inflammatory activity of hydroethanolic extract of Dilodendron bipinnatum Radlk. J Ethnopharmacol 2014; 155: 387-395 DOI: 10.1016/j.jep.2014.05.041.
  CrossrefPubMedGoogle Scholar
• 32 Keklikoglu N, Koray M, Kocaelli H, Akinci S. iNOS expression in oral and gastrointestinal tract mucosa. Dig Dis Sci 2007; 53: 1437-1442 DOI: 10.1007/s10620-007-0061-5.
  CrossrefPubMedGoogle Scholar
• 33 Lind M, Hayes A, Caprnda M, Petrovic D, Rodrigo L, Kruzliak P, Zulli A. Inducible nitric oxide synthase: Good or bad?. Biomed Pharmacother 2017; 93: 370-375 DOI: 10.1016/j.biopha.2017.06.036.
  CrossrefPubMedGoogle Scholar
• 34 Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 2004; 63: 901-910 DOI: 10.1093/jnen/63.9.901.
  CrossrefPubMedGoogle Scholar
• 35 Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019; 124: 315-327 DOI: 10.1161/circresaha.118.313591.
  CrossrefPubMedGoogle Scholar
• 36 Isomäki P, Punnonen J. Pro-and anti-inflammatory cytokines in rheumatoid arthritis. Ann Med 2010; 29: 499-507 DOI: 10.3109/07853899709007474.
  CrossrefPubMedGoogle Scholar
• 37 de las Heras B, Hortelano S. Molecular basis of the anti-inflammatory effects of terpenoids. Inflamm Allergy Drug Targets 2009; 8: 28-39 DOI: 10.2174/187152809787582534.
  CrossrefPubMedGoogle Scholar
• 38 Lee JH, Choi JK, Noh MS, Hwang BY, Hong YS, Lee JJ. Anti-inflammatory effect of kamebakaurin in vivo animal models. Planta Med 2004; 70: 526-530 DOI: 10.1055/s-2004-827152.
  Article in Thieme ConnectPubMedGoogle Scholar
• 39 Vallabhapurapu S, Karin M. Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 2009; 27: 693-733 DOI: 10.1146/annurev.immunol.021908.132641.
  CrossrefPubMedGoogle Scholar
• 40 Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-κB and IκB proteins: Implications in cancer and inflammation. Trends Biochem Sci 2005; 30: 43-52 DOI: 10.1016/j.tibs.2004.11.009.
  CrossrefPubMedGoogle Scholar
• 41 Oh WJ, Jung U, Eom HS, Shin HJ, Park HR. Inhibition of lipopolysaccharide-induced proinflammatory responses by buddleja officinalis extract in BV-2 microglial cells via negative regulation of NF-kB and ERK1/2 signaling. Molecules 2013; 18: 9195-9206 DOI: 10.3390/molecules18089195.
  CrossrefPubMedGoogle Scholar
• 42 Freudenberg MA, Galanos C. Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages. Infect Immun 1988; 56: 1352-1357 DOI: 10.1128/iai.56.5.1352-1357.1988.
  CrossrefPubMedGoogle Scholar
• 43 Noworyta-Sokołowska K, Górska A, Gołembiowska K. LPS-induced oxidative stress and inflammatory reaction in the rat striatum. Pharmacol Rep 2013; 65: 863-869 DOI: 10.1016/s1734-1140(13)71067-3.
  CrossrefPubMedGoogle Scholar
• 44 Kitazawa T, Tsujimoto T, Kawaratani H, Fukui H. Therapeutic approach to regulate innate immune response by Toll-like receptor 4 antagonist E5564 in rats with D-galactosamine-induced acute severe liver injury. J Gastroenterol Hepatol 2009; 24: 1089-1094 DOI: 10.1111/j.1440-1746.2008.05770.x.
  CrossrefPubMedGoogle Scholar
• 45 Wen Y, Cheng L, Zheng D, Han L, Huang X. Chemical constituents of Astragalus membrane var. mongholicus . Pract Pharm Clin Remed 2010; 13: 115-118 DOI: 10.14053/j.cnki.ppcr.2010.02.007.
  CrossrefPubMedGoogle Scholar
• 46 Wang M, Liu F, Yao Y, Zhang Q, Lu Z, Zhang R, Liu C, Lin C, Zhu C. Network pharmacology-based mechanism prediction and pharmacological validation of Xiaoyan Lidan formula on attenuating alpha-naphthylisothiocyanate induced cholestatic hepatic injury in rats. J Ethnopharmacol 2021; 270: 113816 DOI: 10.1016/j.jep.2021.113816.
  CrossrefPubMedGoogle Scholar
• 47 Bi X, Wang P, Ma Q, Han L, Wang X, Mu Y, Guan P, Qu X, Wang Z, Huang X. Anti-inflammatory activities and liver protection of Alisol F and 25-Anhydroalisol F through the inhibition of MAPK, STAT3, and NF-κB activation in vitro and in vivo . Molecules 2017; 22: 951 DOI: 10.3390/molecules22060951.
  CrossrefPubMedGoogle Scholar

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