Stauntonia hexaphylla leaf extract (YRA-1909) suppresses inflammation by modulating Akt/NF-κB signaling in lipopolysaccharide-activated peritoneal macrophages and rodent models of inflammation
Abstract
Background: Inflammation is emerging as a key contributor to many vascular diseases and furthermore plays a major role in autoimmune diseases, arthritis, allergic reactions, and cancer. Lipopolysaccharide (LPS), which is a component constituting the outer membrane of Gram-negative bacteria, is commonly used for an inflammatory stimuli to mimic inflammatory diseases. Nuclear factor-kappa B (NF-κB) is a transcription factor and regulates gene expression particularly related to the inflammatory process. Stauntonia hexaphylla (Lardizabalaceae) is widely used as a traditional herbal medicine for rheumatism and osteoporosis and as an analgesic, sedative, and diuretic in Korea, Japan, and China.
Objective: The purpose of this study was to investigate the anti-inflammatory activity of YRA-1909, the leaf aqueous extract of Stauntonia hexaphylla using LPS-activated rat peritoneal macrophages and rodent inflammation models.
Results: YRA-1909 inhibited the LPS-induced nitric oxide (NO) and proinflammatory cytokine production in rat peritoneal macrophages without causing cytotoxicity and reduced inducible NO synthase and prostaglandin E2 levels without affecting the cyclooxygenase-2 expression. YRA-1909 also prevented the LPS-stimulated Akt and NF-κB phosphorylation and reduced the carrageenan-induced hind paw edema, xylene-induced ear edema, acetic acid-induced vascular permeation, and cotton pellet-induced granuloma formation in a dose-dependent manner in mice and rats.
Conclusions: S. hexaphylla leaf extract YRA-1909 had anti-inflammatory activity in vitro and in vivo that involves modulation of Akt/NF-κB signaling. Thus, YRA-1909 is safe and effective for the treatment of inflammation.
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- Masresha B, Makonnen E, Debella A. In vivo anti-inflammatory activities of Ocimum suave in mice. J Ethnopharmacol 2012; 142: 201–5. doi: 10.1016/j.jep.2012.04.041
- Talwar S, Nandakumar K, Nayak PG, Bansal P, Mudgal J, Mor V. Anti-inflammatory activity of Terminalia paniculata bark extract against acute and chronic inflammation in rats. J Ethnopharmacol 2011; 134: 323–8. doi: 10.1016/j.jep.2010.12.015
- Huang GJ, Pan CH, Liu FC, Wu TS, Wu CH. Anti-inflammatory effects of ethanolic extract of Antrodia salmonea in the lipopolysaccharide-stimulated RAW246.7 macrophages and the λ-carrageenan-induced paw edema model. Food Chem Toxicol 2012; 50: 1485–93. doi: 10.1016/j.fct.2012.01.041
- Posadas I, Terencio MC, Guillén I, Ferrándiz ML, Coloma J, Payá M. Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 98–106. doi: 10.1007/s002109900150
- Zhang CX, Dai ZR, Cai QX. Anti-inflammatory and anti-nociceptive activities of Sipunculus nudus L. extract. J Ethnopharmacol 2011; 137: 1177–82. doi: 10.1016/j.jep.2011.07.039
- Brüne B, Dehne N, Grossmann N, Jung M, Namgaladze D, Schmid T. Redox control of inflammation in macrophages. Antioxid Redox Signal 2013; 19: 595–637. doi: 10.1089/ars.2012.4785
- Sakamoto T, Ohashi W, Tomita K, Hattori K, Matsuda N, Hattori Y. Anti-inflammatory properties of cilostazol: its interruption of DNA binding activity of NF-κB from the Toll-like receptor signaling pathways. Int Immunopharmacol 2018; 62: 120–31. doi: 10.1016/j.intimp.2018.06.021
- Schmitz ML, Bacher S, Kracht M. IκB-independent control of NF-κB activity by modulatory phosphorylations. Trends Biochem Sci 2001; 26: 186–90. doi: 10.1016/s0968-0004(00)01753-9
- Wu PS, Ding HY, Yen JH, Chen SF, Lee KH, Wu MJ. Anti-inflammatory activity of 8-hydroxydaidzein in LPS-stimulated BV2 microglial cells via activation of Nrf2-antioxidant and attenuation of Akt/NF-κB-inflammatory signaling pathways, as well as inhibition of COX-2 activity. J Agric Food Chem 2018; 66: 5790–801. doi: 10.1021/acs.jafc.8b00437
- Bacchi S, Palumbo P, Sponta A, Coppolino MF. Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Antiinflamm Antiallergy Agents Med Chem 2012; 11: 52–64. doi: 10.2174/187152312803476255
- Lin DL, Chang HC, Huang SH. Characterization of allegedly musk-containing medicinal products in Taiwan. J Forensic Sci 2004; 49: 1187–93. doi: 10.1520/JFS2003381
- Darshan S, Doreswamy R. Patented antiinflammatory plant drug development from traditional medicine. Phytother Res 2004; 18: 343–57. doi: 10.1002/ptr.1475
- De las Heras B, Slowing K, Benedı J, Carretero E, Ortega T, Toledo C. Antiinflammatory and antioxidant activity of plants used in traditional medicine in Ecuador. J Ethnopharmacol 1998; 61: 161–6. doi: 10.1016/s0378-8741(98)00029-4
- Krishnaswamy K. Traditional Indian spices and their health significance. Asia Pac J Clin Nutr 2008; 17: 265–8. doi: 10.6133/APJCN.2008.17.S1.63
- Talhouk R, Karam C, Fostok S, El-Jouni W, Barbour E. Anti-inflammatory bioactivities in plant extracts. J Med Food 2007; 10: 1–10. doi: 10.1089/jmf.2005.055
- Asongalem EA, Foyet HS, Ngogang J, Folefoc GN, Dimo T, Kamtchouing P. Analgesic and antiinflammatory activities of Erigeron floribundus. J Ethnopharmacol 2004; 91: 301–8. doi: 10.1016/j.jep.2004.01.010
- Choi JH, Cha DS, Jeon H. Anti-inflammatory and anti-nociceptive properties of Prunus padus. J Ethnopharmacol 2012; 144: 379–86. doi: 10.1016/j.jep.2012.09.023
- Zhang GQ, Huang XD, Wang H, Leung AKN, Chan CL, Fong DW. Anti-inflammatory and analgesic effects of the ethanol extract of Rosa multiflora Thunb. Hips. J Ethnopharmacol 2008; 118: 290–4. doi: 10.1016/j.jep.2008.04.014
- Li YC, Xian YF, Ip SP, Su ZR, Su JY, He JJ. Anti-inflammatory activity of patchouli alcohol isolated from Pogostemonis Herba in animal models. Fitoterapia 2011; 82: 1295–301. doi: 10.1016/j.fitote.2011.09.003
- Park YJ, Park YS, Towantakavanit K, Park JO, Kim YM, Jung KJ. Chemical components and biological activity of Stauntonia hexaphylla. Korean J Plant Res 2009; 22: 403–11.
- Wang HB, Mayer R, Rücker G, Yang JJ, Matteson DS. A phenolic glycoside and triterpenoids from Stauntonia hexaphylla. Phytochemistry 1998; 47: 467–70. doi: 10.1016/s0031-9422(97)00588-8
- Cheon YH, Baek JM, Park SH, Ahn SJ, Lee MS, Oh J. Stauntonia hexaphylla (Lardizabalaceae) leaf methanol extract inhibits osteoclastogenesis and bone resorption activity via proteasome-mediated degradation of c-Fos protein and suppression of NFATc1 expression. BMC Complement Alter Med 2015; 15: 280–9. doi: 10.1186/s12906-015-0801-6
- Hwang SH, Kwon SH, Kim SB, Lim SS. Inhibitory activities of Stauntonia hexaphylla leaf constituents on rat lens aldose reductase and formation of advanced glycation end products and antioxidant. Biomed Res Int 2017; 2017: 1–8. doi: 10.1155/2017/4273257
- Ikuta A, Morikawa A, Kubota K. A saponin from callus tissue of Stauntonia hexaphylla. Phytochemistry 1991; 30: 2425–7. doi: 10.1016/0031-9422(91)83672-8
- Yoo HJ, Kim JY, Kang SE, Yoo JS, Lee YN, Lee DG. 2017. Yra-1909 suppresses production of pro-inflammatory mediators and MMPs through downregulating Akt, p38, JNK and NF-kappab activation in rheumatoid arthritis fibroblast-like synoviocytes. Hoboken, NJ: Wiley.
- Kim J, Kim H, Choi H, Jo A, Kang H, Yun H. Anti-inflammatory effects of a Stauntonia hexaphylla fruit extract in lipopolysaccharide-activated RAW264.7 macrophages and rats by carrageenan-induced hind paw swelling. Nutrients 2018; 10: 1–10. doi: 10.3390/nu10010110
- Sato Y, Itagaki S, Kurokawa T, Ogura J. Kobayashi M, Hirano T. In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 2011; 403: 136–38. doi: 10.1016/j.ijpharm.2010.09.035
- Kurata R, Adachi M, Yamakawa O, Yoshimoto M. Growth suppression of human cancer cells by polyphenolics from sweetpotato (Ipomoea batatas L.) leaves. J Agric Food Chem 2007; 55: 1851–90. doi: 10.1021/jf0620259
- Ooi LS, Wang H, He Z, Ooi, VE. Antiviral activities of purified compounds from Youngia japonica (L.) DC (Asteraceae, Compositae). J Ethnopharmacol 2006; 106: 187–91. doi: 10.1016/j.jep.2005.12.028
- Choi WG, Kim JH, Kim D, Lee Y, Yoo J, Shin D. Simultaneous Determination of chlorogenic acid isomers and metabolites in rat plasma using LC-MS/MS and its application to a pharmacokinetic study following oral administration of Stauntonia hexaphylla leaf extract (YRA-1909) to rats. Pharmaceutics 2018; 10: 143. doi: 10.3390/pharmaceutics10030143
- Zhen J, Villani TS, Guo Y, Qi Y, Chin K, Pan MH. Phytochemistry, antioxidant capacity, total phenolic content and anti-inflammatory activity of Hibiscus sabdariffa leaves. Food Chem 2016; 190: 673–80. doi: 10.1016/j.foodchem.2015.06.006
- Choi JH, Kim S. Investigation of the anticoagulant and antithrombotic effects of chlorogenic acid. J Biochem Mol Toxicol 2017; 31: e21865. doi: 10.1002/jbt.21865
- Choi CY, Kim JY, Kim YS, Chung YC, Hahm KS, Jeong HG. Augmentation of macrophage functions by an aqueous extract isolated from Platycodon grandiflorum. Cancer Lett 2001; 166: 17–25. doi: 10.1016/s0304-3835(01)00440-2
- Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002; 2: 7. doi: 10.1186/1471-2210-2-7
- Winter CA, Risley EA, Nuss GW. Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 1962; 111: 544–7. doi: 10.3181/00379727-111-27849
- Verma S, Ojha S, Raish M. Anti-inflammatory activity of aconitum heterophyllum on cotton pellet-induced granuloma in rats. J Med Plant Res 2010; 4: 1566–9. doi: 10.5897/JMPR09.502
- MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997; 15: 323–50. doi: 10.1146/annurev.immunol.15.1.323
- Kim KN, Ko YJ, Kang MC, Yang HM, Roh SW, Oda T. Anti-inflammatory effects of trans-1, 3-diphenyl-2, 3-epoxypropane-1-one mediated by suppression of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Food Chem. Toxicol 2013; 53: 371–5. doi: 10.1016/j.fct.2012.12.021
- Lee MY, Lee JA, Seo CS, Ha H, Lee H, Son JK, et al. Anti-inflammatory activity of Angelica dahurica ethanolic extract on RAW264.7 cells via upregulation of heme oxygenase-1. Food Chem Toxicol 2011; 49: 1047–55. doi: 10.1016/j.fct.2011.01.010
- Kang CH, Jayasooriya RGPT, Dilshara MG, Choi YH, Jeong YK, Kim ND. Caffeine suppresses lipopolysaccharide-stimulated BV2 microglial cells by suppressing Akt-mediated NF-κB activation and ERK phosphorylation. Food Chem Toxicol 2012; 50: 4270–6. doi: 10.1016/j.fct.2012.08.041
- Liu W, Huang S, Li Y, Li Y, Li D, Wu P. Glycyrrhizic acid from licorice down-regulates inflammatory responses via blocking MAPK and PI3K/Akt-dependent NF-κB signalling pathways in TPA-induced skin inflammation. Medchemcomm 2018; 9: 1502–10. doi: 10.1039/c8md00288f
- Dilshara MG, Jayasooriya RGPT, Lee S, Jeong JB, Seo YT, Choi YH. Water extract of processed Hydrangea macrophylla (Thunb.) Ser. leaf attenuates the expression of pro-inflammatory mediators by suppressing Akt-mediated NF-κB activation. Environ Toxicol Pharmacol 2013; 35: 311–9. doi: 10.1016/j.etap.2012.12.012
- Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008; 22: 1490–500. doi: 10.1101/gad.1662308
- Guo D, Xu L, Cao X, Guo Y, Ye Y, Chan CO. Anti-inflammatory activities and mechanisms of action of the petroleum ether fraction of Rosa multiflora Thunb. hips. J Ethnopharmacol 2011; 138: 717–22. doi: 10.1016/j.jep.2011.10.010
- Shah AS, Alagawadi KR. Anti-inflammatory, analgesic and antipyretic properties of Thespesia populnea Soland ex. Correa seed extracts and its fractions in animal models. J Ethnopharmacol 2011; 137: 1504–9. doi: 10.1016/j.jep.2011.08.038
- Mothana RA. Anti-inflammatory, antinociceptive and antioxidant activities of the endemic Soqotraen Boswellia elongata Balf. f. and Jatropha unicostata Balf. f. in different experimental models. Food Chem Toxicol 2011; 49: 2594–9. doi: 10.1016/j.fct.2011.06.079
- Vinegar R, Schreiber W, Hugo R. Biphasic development of carrageenin edema in rats. J Pharmacol Exp Ther 1969; 166: 96–103.
- Babu NP, Pandikumar P, Ignacimuthu S. Anti-inflammatory activity of Albizia lebbeck Benth., an ethnomedicinal plant, in acute and chronic animal models of inflammation. J Ethnopharmacol 2009; 125: 356–60. doi: 10.1016/j.jep.2009.02.041
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