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The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice

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Abstract

Purpose

Rikkunshito is a traditional Japanese medicine that is widely used for treating upper gastrointestinal symptoms. Our purpose is to clarify the effect of Rikkunshito on the levels of peptide hormones and cytokines in healthy humans and mice.

Methods

We administered Rikkunshito, 7.5 g per day, to 21 healthy volunteers for 2 weeks and examined the changes in plasma peptide and hormone levels. In mice, we administered free access to water containing 0, 0.7, 1.1, and 1.4% Rikkunshito for 2 weeks and examined the changes in plasma peptide levels and ghrelin mRNA expression levels in the stomach.

Results

Plasma acylated ghrelin levels at 0, 2, and 6 weeks after the start of administration were 6.7 ± 2.8, 11.7 ± 4.0, and 10.5 ± 4.4 fmol/ml, respectively. The levels at 2 and 6 weeks were significantly higher than that at 0 time (p < 0.01, paired t test). The levels of interleukin 4, interferon γ, and granulocyte colony-stimulating factor in plasma decreased significantly (p < 0.01) after the administration of Rikkunshito. In mice, the levels of plasma acylated ghrelin changed in proportion to the concentration of Rikkunshito in drinking water, and it was revealed by quantitative RT-PCR that the ghrelin mRNA expression level in the stomach was up-regulated.

Conclusion

Rikkunshito increased the plasma acylated ghrelin level in healthy volunteers and normal mice. Additionally, this change was maintained for at least 4 weeks after the end of administration. In mice, Rikkunshito increased the ghrelin mRNA expression level in the stomach.

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Abbreviations

GH:

Growth hormone

FD:

Functional dyspepsia

GHRL:

Ghrelin prepropeptide

GOAT:

Ghrelin o-acyltransferase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

References

  1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–60.

    Article  CAS  PubMed  Google Scholar 

  2. Nakazato M, Murakami N, Kojima M, Matuo H, Kangawa K, Matsukura S, et al. A role of ghrelin in the central regulation of feeding. Nature. 2001;409:194–8.

    Article  CAS  PubMed  Google Scholar 

  3. Wren AM, Seal LJ, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992.

    Article  CAS  PubMed  Google Scholar 

  4. Tack J, Depoortere I, Coulie B, Meulemans A, Janssens J, Peeters T, et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut. 2006;55(3):327–33.

    Article  CAS  PubMed  Google Scholar 

  5. Strassburg S, Anker SD, Dong JZ, Culler MD, Datta R, Tschöp MH, et al. Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats. Am J Physiol Endocrinol Metab. 2008;295(1):E78–84.

    Article  CAS  PubMed  Google Scholar 

  6. Tatsuta M, Iishi H. Effect of treatment with Liu-Jun-Zi-Tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther. 1993;7:459–62.

    CAS  PubMed  Google Scholar 

  7. Tomono H, Ito Y, Watanabe T. Successful antiemetic treatment of Tsumura rikkunshi-to extract granules for ethical use in addition to other antiemetic agents in neoadjuvant chemotherapy for an advanced breast cancer patient. Jpn J Cancer Chemother. 2006;33:1129–31.

    Google Scholar 

  8. Oka T, Tamagawa Y, Tamagawa Y, Hayashida S, Kaneda Y, Kodama N, et al. Rikkunshi-to attenuates adverse gastrointestinal symptoms induced by fluvoxamine. Biopsychosoc Med. 2007;15:1–21.

    Google Scholar 

  9. Takeda H, Sadakane C, Katsurada T, Ohkawara T, Nagai K, Asaka M, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008;134:2004–13.

    Article  PubMed  Google Scholar 

  10. Arai M, Yokosuka O, Takiguchi M, Saisho H, Muramatsu M, Seki N, et al. Gene expression profiling reveals the mechanism and pathophysiology of mouse liver regeneration. J Biol Chem. 2003;278:29813–8.

    Article  CAS  PubMed  Google Scholar 

  11. Arvat E, Gianotti L, Papotti M, Graziani A, Ghigo E, Deghenghi R, et al. Growth hormone-releasing hormone and growth hormone secretagogue-receptor ligands: focus on reproductive system. Endocrine. 2001;14:35–43.

    Article  CAS  PubMed  Google Scholar 

  12. Yoshihara F, Kojima M, Hosoda H, Nakazato M, Kangawa K. Ghrelin: a novel peptide for growth hormone release and feeding regulation. Curr Opin Clin Nutr Metab Care. 2002;5:391–5.

    Article  CAS  PubMed  Google Scholar 

  13. Wolf I, Sadetzki S, Oberman B, Catane R, Kaufman B, Shimon I. Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients. Cancer. 2006;15(106):966–73.

    Article  CAS  Google Scholar 

  14. Ataseven H, Bahcecioglu I, Yalniz M, Celebi S, Erensoy A, Ustundag B, et al. The levels of ghrelin, leptin, TNF-alpha, and IL-6 in liver cirrhosis and hepatocellular carcinoma due to HBV and HDV infection. Mediators Inflamm. 2006;2006:78380.

    Article  PubMed  CAS  Google Scholar 

  15. Shinomiya T, Fukunaga M, Yokode M, Kangawa K, Nakai Y, Nakai Y, et al. Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol. 2005;40:648–53.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia JM, Garcia-Touza M, Mann D, Smith RG, Cunningham GR, Marcelli M, et al. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J Clin Endocrinol Metab. 2005;90:2920–6.

    Article  CAS  PubMed  Google Scholar 

  17. Soriano-Guillén L, Barrios V, Campos-Barros A, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr. 2004;144:36–42.

    Article  PubMed  CAS  Google Scholar 

  18. Dostálová V, Haluzík M. The role of ghrelin in the regulation of food intake in patients with obesity and anorexia nervosa. Physiol Res. 2008;58:159–70.

    PubMed  Google Scholar 

  19. Takamori K, Mizuta Y, Ohba K, Omagari K, Shikuwa S, Kohno S, et al. Relation among plasma ghrelin level, gastric emptying, and psychological condition in patients with functional dyspepsia. J Clin Gastroenterol. 2007;41:477–83.

    Article  CAS  PubMed  Google Scholar 

  20. Pilichiewicz AN, Feltrin KL, Wishart JM, Jones KL, Talley NJ, Feinle-Bisset C, et al. Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY. Am J Gastroenterol. 2008;103(10):2613–23.

    Article  CAS  PubMed  Google Scholar 

  21. Akamizu T, Iwakura H, Fukunaga M, Nakai Y, Kangawa K, Clinical Study Team FD, et al. Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur J Endocrinol. 2008;158:491–8.

    Article  CAS  PubMed  Google Scholar 

  22. Shindo T, Futagami S, Hiratsuka T, Horie A, Hamamoto T, Ueki N, et al. Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease. Digestion. 2009;79:65–72.

    Article  CAS  PubMed  Google Scholar 

  23. Ringel Y. Brain research in functional gastrointestinal disorders. J Clin Gastroenterol. 2002;35:23–5.

    Article  Google Scholar 

  24. Konturek SJ, Konturek JW, Pawlik T, Brzozowski T. Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol. 2004;55:137–54.

    CAS  PubMed  Google Scholar 

  25. Itoh Z. Motilin and clinical application. Peptides. 1997;18:593–608.

    Article  CAS  PubMed  Google Scholar 

  26. Sanger GJ. Motilin, ghrelin and related neuropeptides as targets for the treatment of GI diseases. Drug Discov Today. 2008;13:234–9.

    Article  CAS  PubMed  Google Scholar 

  27. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132(3):387–96.

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez-Rey E, Chorny A, Delgado M. Therapeutic action of ghrelin in a mouse model of colitis. Gastroenterology. 2006;130:1707–20.

    Article  CAS  PubMed  Google Scholar 

  29. Dixit VD, Schaffer EM, Sakthivel SK, Palaniappan R, Lillard JW Jr, Taub DD, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest. 2004;114:57–66.

    CAS  PubMed  Google Scholar 

  30. Zhang M, Yuan F, Chen H, Qiu X, Fang W. Effect of exogenous ghrelin on cell differentiation antigen 40 expression in endothelial cells. Acta Biochim Biophys Sin. 2007;39:974–81.

    CAS  PubMed  Google Scholar 

  31. Kodama T, Ashitani J, Matsumoto N, Kangawa K, Nakazato M. Ghrelin treatment suppresses neutrophil-dominant inflammation in airways of patients with chronic respiratory infection. Pulm Pharmacol Ther. 2008;21:774–9.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Makoto Arai.

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Matsumura, T., Arai, M., Yonemitsu, Y. et al. The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J Gastroenterol 45, 300–307 (2010). https://doi.org/10.1007/s00535-009-0166-z

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  • DOI: https://doi.org/10.1007/s00535-009-0166-z

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