Journal of Natural Medicines

, Volume 73, Issue 2, pp 339–352 | Cite as

Gastroprotective effect of araloside A on ethanol- and aspirin-induced gastric ulcer in mice: involvement of H+/K+-ATPase and mitochondrial-mediated signaling pathway

  • Haibo He
  • Xiaomei Li
  • Haili Yu
  • Shu Zhu
  • Yumin He
  • Katsuko Komatsu
  • Dongyan GuoEmail author
  • Xiaoqin Li
  • Junzhi WangEmail author
  • Huajun Luo
  • Daoxiang Xu
  • Kun Zou
Original Paper


The aim of this study was to elucidate the gastroprotective activity and possible mechanism of involvement of araloside A (ARA) against ethanol- and aspirin-induced gastric ulcer in mice. The experimental mice were randomly divided into control, model, omeprazole (20 mg/kg, orally) and ARA (10, 20 and 40 mg/kg, orally). Gastric ulcer in mice was induced by intragastric administration of 80% ethanol (10 mL/kg) containing 15 mg/mL aspirin 4 h after drug administration on day 7. The results indicated that ARA could significantly raise gastric juice volume and acidity; ameliorate gastric mucosal blood flow, gastric binding mucus volume, ulcer index and ulcer inhibition rate; suppress H+/K+-ATPase activity, which was confirmed by computer-aided docking simulations; inhibit the release of mitochondrial cytochrome c into the cytoplasm; inhibit caspase-9 and caspase-3 activities and down-regulate mRNA expression levels; down-regulate the mRNA and protein expressions of apoptosis protease-activating factor-1 and protein expression of cleaved poly(ADP ribose) polymerase-1; and up-regulate Bcl-2 mRNA and protein expressions and down-regulate Bax mRNA and protein expressions, thus elevating the Bcl-2/Bax ratio in a dose-dependent manner. Histopathological observations further provided supportive evidence for the aforementioned results. The results demonstrated that ARA exerted beneficial gastroprotective effects on alcohol- and aspirin-induced gastric ulcer in mice, which was related to suppressing H+/K+-ATPase activity as well as pro-apoptotic protein expression, and promoting anti-apoptotic protein expression, thus alleviating gastric mucosal injury and cell death.


Araloside A Gastric ulcer H+/K+-ATPase Mitochondrial-mediated signaling pathway Apoptosis 



This work was financially supported by the National Natural Science Foundation of China (No: 81202905, 31370373).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest in this article.


  1. 1.
    Zhang QY, Huang NY, Wang JZ, Luo HJ, He HB, Ding MR, Deng WQ, Zou K (2013) The H+/K+-ATPase inhibitory activities of Trametenolic acid B from Trametes lactinea (Berk.) Pat, and its effects on gastric cancer cells. Fitoterapia 89:210–217CrossRefGoogle Scholar
  2. 2.
    Shin JM, Vagin O, Munson K, Kidd M, Modlin IM, Sachs G (2008) Molecular mechanisms in therapy of acid-related diseases. Cell Mol Life Sci 65:264–281CrossRefGoogle Scholar
  3. 3.
    Shin JM, Munson K, Vagin O, Sachs G (2009) The gastric H+/K+-ATPase: structure, function, and inhibition. Pflugers Arch 457:609–622CrossRefGoogle Scholar
  4. 4.
    Weidemüller C, Hauser K (2009) Ion transport and energy transduction of P-type ATPases: implications from electrostatic calculations. Biochim Biophys Acta 1787:721–729CrossRefGoogle Scholar
  5. 5.
    Chakraborty S, Stalin S, Das N, Choudhury ST, Ghosh S, Swarnakar S (2012) The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 33:2991–3001CrossRefGoogle Scholar
  6. 6.
    Lee GJ, Chae SJ, Jeong JH, Lee SR, Ha SJ, Pak YK, Kim W, Park HK (2011) Characterization of mitochondria isolated from normal and ischemic hearts in rats utilizing atomic force microscopy. Micron 42:299–304CrossRefGoogle Scholar
  7. 7.
    Lee MJ, Chen HM, Tzang BS, Lin CW, Wang CJ, Liu JY, Kao SH (2011) Ocimum gratissimum aqueous extract protects H9c2 myocardiac cells from H(2)O(2)-induced cell apoptosis through Akt signalling. Evid Based Complement Alternat Med. Google Scholar
  8. 8.
    Orsucci D, Mancuso M, Siciliano G (2008) Mitochondria, oxidative stress and PARP-1 network: a new target for neuroprotective effects of tetracyclines? J Physiol 586:2427–2428CrossRefGoogle Scholar
  9. 9.
    Tjandrawinata RR, Nailufar F, Arifin PF (2013) Hydrogen potassium adenosine triphosphatase activity inhibition and downregulation of its expression by bioactive fraction DLBS2411 from Cinnamomum burmannii in gastric parietal cells. Int J Gen Med 6:807–815CrossRefGoogle Scholar
  10. 10.
    Yang ZF, Tang HF, Jia YY, Xi MM, Wen AD (2008) The effect of total saponin of Aralia Taibaiensison Glycemia Lipidan antioxidation in hyperglyce mice. Pharm J Chin PLA 24:110–113Google Scholar
  11. 11.
    Yook CS (1981) Medicinal plants of Korea. Jinmyung Publishing Co., Ltd, SeoulGoogle Scholar
  12. 12.
    Namba T (1980) The encyclopedia of Wakan-Yaku with color pictures, vol Vol II. Hoikusha Publishing Co., Ltd, OsakaGoogle Scholar
  13. 13.
    Munwha Broadcast Corporation (ed.) (1987) Korean folk medicinal therapeutics. Keumbak Publishing. Co., Ltd, SeoulGoogle Scholar
  14. 14.
    Lee EB, Kim OJ, Kang SS, Jeong C (2005) Araloside A, an antiulcer constituent from the root bark of Aralia elata. Biol Pharm Bull 28:523–526CrossRefGoogle Scholar
  15. 15.
    He HB, Zhang YF, Li XM, Li XQ, Qin HL, Liu CX, Tang HB, Wang JZ, Zou K (2017) Effect of triterpene from Chaenomeles speciose (Sweet) Nakai on gastric acid secretion and gastric mucosal barrier function in indomethacin induced mice. Biotic Resour 39:211–216Google Scholar
  16. 16.
    Martín MJ, Marhuenda E, Pérez-Guerrero C, Franco JM (1994) Antiulcer effect of naringin on gastric lesions induced by ethanol in rats. Pharmacology 49:144–150CrossRefGoogle Scholar
  17. 17.
    Shinoda T, Ogawa H, Cornelius F, Toyoshima C (2009) Crystal structure of the sodium-potassium pump at 2.4 A resolution. Nature 459:446–450CrossRefGoogle Scholar
  18. 18.
    Berman HM, Westbrook J, Feng Z (2000) The protein data bank. Anhui Med Pharma J 28:235–242Google Scholar
  19. 19.
    Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680CrossRefGoogle Scholar
  20. 20.
    Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815CrossRefGoogle Scholar
  21. 21.
    Schrödinger LLC (2010) (New York). Accessed 30 Dec 2017
  22. 22.
    Vaguine AA, Richelle J, Wodak SJ (1999) SFCHECK: a unified set of procedures for evaluating the quality of macromolecular structure-factor data and their agreement with the atomic model. Acta Crystallogr D Biol Crystallogr 55:191–205CrossRefGoogle Scholar
  23. 23.
    DeLano WL (2004) The PyMOL molecular graphics system. DeLano Scientific, San CarlosGoogle Scholar
  24. 24.
    Wang S, He HB, Xiao SZ, Wang JZ, Bai CH, Wei N, Zou K (2014) Comparison of cardioprotective effects of labeled and unlabeled oleanoic acids with new BOPIM dye on primary neonatal rat cardiomyocytes following hypoxia/reoxygenation injury. Pharmacol Rep 66:677–685CrossRefGoogle Scholar
  25. 25.
    Sohn YA, Hwang SA, Lee SY, Hwang IY, Kim SW, Kim SY, Moon A, Lee YS, Kim YH, Kang KJ, Jeong CS (2015) Protective effect of liriodendrin isolated from Kalopanax pictus against gastric injury. Biomol Ther (Seoul) 23:53–59CrossRefGoogle Scholar
  26. 26.
    Bhattacharya S, Banerjee D, Bauri AK, Chattopadhyay S, Bandyopadhyay SK (2007) Healing property of the Piper betel phenol, allylpyrocatechol against indomethacin-induced stomach ulceration and mechanism of action. World J Gastroenterol 13:3705–3713CrossRefGoogle Scholar
  27. 27.
    Lv RX, Du LL, Lu CW, Wu JH, Ding MC, Wang C, Mao NF, Shi ZC (2017) Allicin protects against H2O2- induced apoptosis of PC12 cells via the mitochondrial pathway. Exp Ther Med 14:2053–2059CrossRefGoogle Scholar
  28. 28.
    Huang SL, He HB, Zou K, Bai CH, Xue YH, Wang JZ, Chen JF (2014) Protective effect of tomatine against hydrogen peroxide-induced neurotoxicity in neuroblastoma (SH-SY5Y) cells. J Pharm Pharmacol 66:844–854CrossRefGoogle Scholar
  29. 29.
    Zhao HG, Zhou SL, Lin YY, Dai HF, Huang FY (2017) Toxicarioside N induces apoptosis in human gastric cancer SGC-7901 cell by activating the p38MAPK pathway. Arch Pharm Res. Google Scholar
  30. 30.
    Namulema J, Nansunga M, Kato CD, Kalange M, Olaleye SB (2018) Thyroid hormones increase stomach goblet cell numbers and mucin expression during indomethacin induced ulcer healing in Wistar rats. Thyroid Res 11:1–8CrossRefGoogle Scholar
  31. 31.
    Lamers CB, Biemond I, Masclee AA, Veenendaal RA (1996) Therapy and prevention of gastric ulcer. Yale J Biol Med 69:265–270Google Scholar
  32. 32.
    Higuchi K, Watanabe T, Tanigawa T, Tominaga K, Fujiwara Y, Arakawa T (2010) Sofalcone, a gastroprotective drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori: a randomized controlled comparative trial with cimetidine, an H2-receptor antagonist. J Gastroenterol Hepatol Suppl 1:S155–S160CrossRefGoogle Scholar
  33. 33.
    Walker J, Hell J, Liszt KI, Dresel M, Pignitter M, Hofmann T, Somoza V (2012) Identification of beer bitter acids regulating mechanisms of gastric acid secretion. J Agric Food Chem 60:1405–1412CrossRefGoogle Scholar
  34. 34.
    Lewin MJ (1999) Cellular mechanisms and inhibitors of gastric acid secretion. Drugs Today (Barc) 35:743–752CrossRefGoogle Scholar
  35. 35.
    Bienia A, Sodolski W, Luchowska E (2002) The effect of chronic alcohol abuse on gastric and duodenal mucosa. Ann Univ Mariae Curie Sklodowska Med 57:570–582Google Scholar
  36. 36.
    O’Connor HJ, Dixon MF, Wyatt JI, Axon AT, Dewar EP, Johnston D (1987) Campylobacter pylori and peptic ulcer disease. Lancet 2:633–634CrossRefGoogle Scholar
  37. 37.
    Tsai HF, Hsu PN (2017) Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage. J Microbiol Immunol Infect 50:4–9CrossRefGoogle Scholar
  38. 38.
    Luo X, Kraus WL (2012) On PAR with PARP: cellular stress signaling through poly (ADP-ribose) and PARP-1. Genes Dev 26:417–432CrossRefGoogle Scholar
  39. 39.
    Krishnakumar R, Kraus WL (2010) The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 39:8–24CrossRefGoogle Scholar
  40. 40.
    Cregan SP, Dawson VL, Slack RS (2004) Role of AIF in caspase-dependent and caspase- independent cell death. Oncogene 23:2785–2796CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Haibo He
    • 1
  • Xiaomei Li
    • 1
  • Haili Yu
    • 1
  • Shu Zhu
    • 2
  • Yumin He
    • 1
  • Katsuko Komatsu
    • 2
  • Dongyan Guo
    • 3
    Email author
  • Xiaoqin Li
    • 1
  • Junzhi Wang
    • 1
    Email author
  • Huajun Luo
    • 1
  • Daoxiang Xu
    • 4
  • Kun Zou
    • 1
  1. 1.Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical SciencesChina Three Gorges UniversityYichangChina
  2. 2.Division of Pharmacognosy, Department of Medicinal Resources, Institute of Natural MedicineUniversity of ToyamaToyamaJapan
  3. 3.Shaanxi Key Laboratory of Traditional Chinese Medicine Foundation and New Drug ResearchShaanxi University of Chinese MedicineXianyangChina
  4. 4.Seventh People’s Hospital of WenzhouWenzhouChina

Personalised recommendations