Ginsenoside Rb1 promotes intestinal epithelial wound healing through extracellular signal-regulated kinase and Rho signaling
Yuki Toyokawa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorCorresponding Author
Tomohisa Takagi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Correspondence
Dr Tomohisa Takagi, Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Email: [email protected]
Search for more papers by this authorKazuhiko Uchiyama
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKatsura Mizushima
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKen Inoue
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorChihiro Ushiroda
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorSaori Kashiwagi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTakahiro Nakano
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYuma Hotta
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorMakoto Tanaka
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorOsamu Dohi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTetsuya Okayama
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorNaohisa Yoshida
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKazuhiro Katada
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKazuhiro Kamada
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTakeshi Ishikawa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorOsamu Handa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorHideyuki Konishi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYuji Naito
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYoshito Itoh
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYuki Toyokawa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorCorresponding Author
Tomohisa Takagi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Correspondence
Dr Tomohisa Takagi, Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Email: [email protected]
Search for more papers by this authorKazuhiko Uchiyama
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKatsura Mizushima
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKen Inoue
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorChihiro Ushiroda
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorSaori Kashiwagi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTakahiro Nakano
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYuma Hotta
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorMakoto Tanaka
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorOsamu Dohi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTetsuya Okayama
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorNaohisa Yoshida
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKazuhiro Katada
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorKazuhiro Kamada
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorTakeshi Ishikawa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorOsamu Handa
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorHideyuki Konishi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYuji Naito
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorYoshito Itoh
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Search for more papers by this authorAbstract
Background and Aim
Daikenchuto, a traditional Japanese herbal medicine, has been reported to exhibit anti-inflammatory effects against intestinal inflammation. However, whether daikenchuto has a therapeutic effect against intestinal mucosal injuries remains unclear. Thus, the aim of this study was to determine the effect of daikenchuto on intestinal mucosal healing.
Methods
Colitis was induced in male Wistar rats by using trinitrobenzenesulfonic acid. Daikenchuto (900 mg/kg/day) was administered for 7 days after the induction of colitis. Thereafter, intestinal mucosal injuries were evaluated by determining the colonic epithelial regeneration ratio ([area of epithelial regeneration/area of ulcer] × 100). Restoration of rat intestinal epithelial cells treated with daikenchuto and its constituent herbs (Zanthoxylum fruit, processed ginger, and ginseng) and ginsenoside Rb1, which is a ginseng ingredient, was evaluated using a wound-healing assay.
Results
The colon epithelial regeneration ratio in the daikenchuto-treated rats was significantly higher than that in the control rats. Daikenchuto, ginseng, and ginsenoside Rb1 enhanced wound healing, and the ginsenoside Rb1-induced enhancement was inhibited by extracellular signal-regulated kinase and Rho inhibitors.
Conclusions
Daikenchuto and its constituent, ginsenoside Rb1, promoted wound healing. Because mucosal healing is one of the most important therapeutic targets in patients with inflammatory bowel disease, ginsenoside Rb1 may be a novel therapeutic agent against intestinal mucosal damage such as that occurring in intestinal bowel disease.
References
- 1Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet 2012; 380: 1606–1619.
- 2Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am. J. Gastroenterol. 2010; 105: 501–523 quiz 24.
- 3Probert CS, Dignass AU, Lindgren S, Oudkerk Pool M, Marteau P. Combined oral and rectal mesalazine for the treatment of mild-to-moderately active ulcerative colitis: rapid symptom resolution and improvements in quality of life. J. Crohns Colitis 2014; 8: 200–207.
- 4Kane S, Lu F, Kornbluth A, Awais D, Higgins PD. Controversies in mucosal healing in ulcerative colitis. Inflamm. Bowel Dis. 2009; 15: 796–800.
- 5Peyrin-Biroulet L, Panes J, Sandborn WJ et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin. Gastroenterol. Hepatol. 2016; 14: 348–354.e17.
- 6Mazzuoli S, Guglielmi FW, Antonelli E, Salemme M, Bassotti G, Villanacci V. Definition and evaluation of mucosal healing in clinical practice. Dig. Liver Dis. 2013; 45: 969–977.
- 7Nakarai A, Kato J, Hiraoka S et al. Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count. World J. Gastroenterol. 2014; 20: 18367–18374.
- 8Colombel JF, Rutgeerts P, Reinisch W et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141: 1194–1201.
- 9Froslie KF, Jahnsen J, Moum BA, Vatn MH, Group I. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007; 133: 412–422.
- 10Laharie D, Filippi J, Roblin X et al. Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a multicenter experience. Aliment. Pharmacol. Ther. 2013; 37: 998–1004.
- 11Theede K, Kiszka-Kanowitz M, Nordgaard-Lassen I, Mertz NA. The impact of endoscopic inflammation and mucosal healing on health-related quality of life in ulcerative colitis patients. J. Crohns Colitis 2015; 9: 625–632.
- 12Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment. Pharmacol. Ther. 2007; 26: 205–215.
- 13Panaccione R, Ghosh S, Middleton S et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146: 392–400 e3.
- 14Reinisch W, Sandborn WJ, Hommes DW et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011; 60: 780–787.
- 15Colombel JF, Sandborn WJ, Reinisch W et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N. Engl. J. Med. 2010; 362: 1383–1395.
- 16Kono T, Kaneko A, Hira Y et al. Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model. J. Crohns Colitis 2010; 4: 161–170.
- 17Matsunaga T, Hashimoto S, Yamamoto N et al. Protective effect of daikenchuto on dextran sulfate sodium-induced colitis in mice. Gastroenterol Res Pract 2017; 2017: 1298263.
- 18Inoue K, Naito Y, Takagi T et al. Daikenchuto, a Kampo medicine, regulates intestinal fibrosis associated with decreasing expression of heat shock protein 47 and collagen content in a rat colitis model. Biol. Pharm. Bull. 2011; 34: 1659–1665.
- 19Isozaki Y, Yoshida N, Kuroda M et al. Anti-tryptase treatment using nafamostat mesilate has a therapeutic effect on experimental colitis. Scand. J. Gastroenterol. 2006; 41: 944–953.
- 20Isozaki Y, Yoshida N, Kuroda M et al. Effect of a novel water-soluble vitamin E derivative as a cure for TNBS-induced colitis in rats. Int. J. Mol. Med. 2006; 17: 497–502.
- 21Takagi T, Naito Y, Okuda T et al. Ecabet sodium promotes the healing of trinitrobenzene-sulfonic-acid-induced ulceration by enhanced restitution of intestinal epithelial cells. J. Gastroenterol. Hepatol. 2010; 25: 1259–1265.
- 22Petit V, Boyer B, Lentz D, Turner CE, Thiery JP, Valles AM. Phosphorylation of tyrosine residues 31 and 118 on paxillin regulates cell migration through an association with CRK in NBT-II cells. J. Cell Biol. 2000; 148: 957–970.
- 23Horii Y, Uchiyama K, Toyokawa Y et al. Partially hydrolyzed guar gum enhances colonic epithelial wound healing via activation of RhoA and ERK1/2. Food Funct. 2016; 7: 3176–3183.
- 24Watanabe J, Kaifuchi N, Kushida H et al. Intestinal, portal, and peripheral profiles of daikenchuto (TU-100)'s active ingredients after oral administration. Pharmacol. Res. Perspect. 2015; 3: e00165.
- 25Bi X, Xia X, Mou T et al. Anti-tumor activity of three ginsenoside derivatives in lung cancer is associated with Wnt/beta-catenin signaling inhibition. Eur. J. Pharmacol. 2014; 742: 145–152.
- 26Hasebe T, Matsukawa J, Ringus D et al. Daikenchuto (TU-100) suppresses tumor development in the azoxymethane and APCmin/+ mouse models of experimental colon cancer. Phytother. Res. 2017; 31: 90–99.
- 27Jeong CS, Hyun JE, Kim YS. Ginsenoside Rb1: the anti-ulcer constituent from the head of Panax ginseng. Arch. Pharm. Res. 2003; 26: 906–911.
- 28Kimura Y, Sumiyoshi M, Kawahira K, Sakanaka M. Effects of ginseng saponins isolated from Red Ginseng roots on burn wound healing in mice. Br. J. Pharmacol. 2006; 148: 860–870.
- 29Tan S, Yu W, Lin Z et al. Anti-inflammatory effect of ginsenoside Rb1 contributes to the recovery of gastrointestinal motility in the rat model of postoperative ileus. Biol. Pharm. Bull. 2014; 37: 1788–1794.
- 30Wang Y, Dong J, Liu P et al. Ginsenoside Rb3 attenuates oxidative stress and preserves endothelial function in renal arteries from hypertensive rats. Br. J. Pharmacol. 2014; 171: 3171–3181.
- 31Watanabe S, Suemaru K, Yamaguchi T, Hidaka N, Sakanaka M, Araki H. Effect of oral mucosal adhesive films containing ginsenoside Rb1 on 5-fluorouracil-induced oral mucositis in hamsters. Eur. J. Pharmacol. 2009; 616: 281–286.
- 32Zhang Y, Sun K, Liu YY et al. Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 2014; 306: G289–G300.
- 33Kawahira K, Sumiyoshi M, Sakanaka M, Kimura Y. Effects of ginsenoside Rb1 at low doses on histamine, substance P, and monocyte chemoattractant protein 1 in the burn wound areas during the process of acute burn wound repair. J. Ethnopharmacol. 2008; 117: 278–284.
- 34Rausch S, Das T, Soine JR et al. Polarizing cytoskeletal tension to induce leader cell formation during collective cell migration. Biointerphases 2013; 8: 32.
- 35Hall A. Rho GTPases and the actin cytoskeleton. Science 1998; 279: 509–514.
- 36Begum R, Nur EKMS, Zaman MA. The role of Rho GTPases in the regulation of the rearrangement of actin cytoskeleton and cell movement. Exp. Mol. Med. 2004; 36: 358–366.
- 37Sit ST, Manser E. Rho GTPases and their role in organizing the actin cytoskeleton. J. Cell Sci. 2011; 124: 679–683.
- 38Zimmerman NP, Vongsa RA, Faherty SL, Salzman NH, Dwinell MB. Targeted intestinal epithelial deletion of the chemokine receptor CXCR4 reveals important roles for extracellular-regulated kinase-1/2 in restitution. Lab. Invest. 2011; 91: 1040–1055.
- 39Pai R, Ohta M, Itani RM, Sarfeh IJ, Tarnawski AS. Induction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats. Gastroenterology 1998; 114: 706–713.
- 40Jones MK, Tomikawa M, Mohajer B, Tarnawski AS. Gastrointestinal mucosal regeneration: role of growth factors. Front. Biosci. 1999; 4: D303–D309.
- 41Tarnawski AS, Jones MK. The role of epidermal growth factor (EGF) and its receptor in mucosal protection, adaptation to injury, and ulcer healing: involvement of EGF-R signal transduction pathways. J. Clin. Gastroenterol. 1998; 27: S12–S20.
- 42Zheng X, Wang S, Zou X et al. Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp. Anim. 2017; 66: 217–228.
- 43Hashimoto R, Yu J, Koizumi H, Ouchi Y, Okabe T. Ginsenoside Rb1 prevents MPP(+)-induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK. Evid. Based Complement. Alternat. Med. 2012; 2012: 693717.