Journal of Natural Medicines

, Volume 73, Issue 1, pp 202–209 | Cite as

Juzentaihoto hot water extract alleviates muscle atrophy and improves motor function in streptozotocin-induced diabetic oxidative stress mice

  • Tomoaki IshidaEmail author
  • Michiro Iizuka
  • Yanglan Ou
  • Shumpei Morisawa
  • Ayumu Hirata
  • Yusuke Yagi
  • Kohei Jobu
  • Yasuyo Morita
  • Mitsuhiko Miyamura
Original Paper


A decrease in skeletal muscle mass and motor function occurs in diabetic patients. In type 1 diabetic patients, in particular, fast-type fiber-dominated muscle atrophy occurs due to increased oxidative stress and inflammation. Juzentaihoto is a herbal medicine that has been found to be effective in reducing oxidative stress. In this study, juzentaihoto hot water extract (JTT) was administered prophylactically to mice with diabetic oxidative stress, which was induced by an injection of streptozotocin, and the effects on skeletal muscle mass, motor function, and antioxidant activity were evaluated. In mice that were administered JTT, skeletal muscle atrophy and loss of motor function were suppressed. Additionally, the administration of JTT increased the mRNA expression level of Sirt1 and the activity of superoxide dismutase in the gastrocnemius. In addition to skeletal muscle atrophy, atrophy of the liver, spleen and thymus gland, and kidney hypertrophy were also suppressed. Furthermore, in order to evaluate the antioxidant activity of 10 constituent crude drugs that comprise juzentaihoto, Sirt1 transcriptional activity in C2C12 cells was evaluated. The Sirt1 transcriptional activity was increased by Cinnamomi Cortex, Astragali Radix, and Glycyrrhizae Radix extracts. These three constituent crude drugs play an important function in the antioxidant action of juzentaihoto, suggesting that juzentaihoto can prevent muscle atrophy by decreasing oxidative stress.


Juzentaihoto Muscle atrophy Diabetes Oxidative stress 


Compliance with ethical standards

Conflict of interest

This research was conducted as a contract research project by Tsumura Co., Ltd.

Supplementary material

11418_2018_1269_MOESM1_ESM.pptx (702 kb)
Supplementary material 1 (PPTX 701 kb)


  1. 1.
    Seok WP, Bret HG, Elsa SS, Nathalie R, Tamara BH, Ann VS, Frances AT, Anne BN (2006) Decreased muscle strength and quality in older adults with type 2 diabetes. Diabetes 55:1813–1818CrossRefGoogle Scholar
  2. 2.
    Marika L, Lex BV, Lettyvan H, Jos JA, Janneauvan K, RachelN Luc JL (2013) Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging. J Am Med Dir Assoc 14:585–592CrossRefGoogle Scholar
  3. 3.
    Matthew PK, Michael CR, Thomas JH (2010) Effects of type 1 diabetes mellitus on skeletal muscle: clinical observations and physiological mechanisms. Pediatr Diabetes 12:345–364Google Scholar
  4. 4.
    Maritim AC, Sanders RA, Watkins JB (2003) Diabetes, oxidative stress, and antioxidants. J Biochem Mol Toxicol 17:24–38CrossRefGoogle Scholar
  5. 5.
    Paresh D, Thusu K, Cook S, Snyder B, Makowski J, Armstrong D, Nicotera T (1996) Oxidative damage to DNA in diabetes mellitus. Lancet 347:444–445CrossRefGoogle Scholar
  6. 6.
    Ahmed AE, Jennifer CS (2012) Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther 30:49–59CrossRefGoogle Scholar
  7. 7.
    Naik E, Dixit VM (2011) Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 208:417–420CrossRefGoogle Scholar
  8. 8.
    Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 15:481–484CrossRefGoogle Scholar
  9. 9.
    Parola M, Robino G (2001) Oxidative stress-related molecules and liver fibrosis. J Hepatol 35:297–306CrossRefGoogle Scholar
  10. 10.
    Forbes JM, Coughlan MT, Cooper ME (2008) Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57:1446–1454CrossRefGoogle Scholar
  11. 11.
    Saiki I (2000) A Kampo medicine "Juzen-taiho-to"–prevention of malignant progression and metastasis of tumor cells and the mechanism of action. Biol Pharm Bull 23:677–688CrossRefGoogle Scholar
  12. 12.
    The Japanese Pharmacopoeia, Seventeenth Edition (JP17), Ministry of Health, Labour and Welfare, Japan (2016)
  13. 13.
    Tagami K, Niwa K, Lian Z, Gao J, Mori H, Tamaya T (2004) Preventive effect of Juzen-taiho-to on endometrial carcinogenesis in mice is based on Shimotsu-to constituent. Biol Pharm Bull 27:156–161CrossRefGoogle Scholar
  14. 14.
    Hong T, Matsumoto T, Kiyohara H, Yamada H (1998) Enhanced production of hematopoietic growth factors through T cell activation in Peyer’s patches by oral administration of kampo (Japanese herbal) medicine, “Juzen-Taiho-to”. Phytomedicine 5:353–360CrossRefGoogle Scholar
  15. 15.
    Takeno N, Inujima A, Shinohara K, Yamada M, Shibahara N, Sakurai H, Saiki I, Koizumi K (2015) Immune adjuvant effect of Juzentaihoto, a Japanese traditional herbal medicine, on tumor vaccine therapy in a mouse model. Int J Oncol 47:2115–2122CrossRefGoogle Scholar
  16. 16.
    Tsuchiya M, Kono H, Matsuda M, Fujii H, Rusyn I (2008) Protective effect of Juzen-taiho-to on hepatocarcinogenesis is mediated through the inhibition of kupffer cell-induced oxidative stress. Int J Cancer 11:2503–2511CrossRefGoogle Scholar
  17. 17.
    Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:536–546Google Scholar
  18. 18.
    Junod A, Lambert AE, Stauffacher W, Renold AE (1969) Diabetogenic action of streptozocin: relationship of dose to metabolic response. J Clin Invest 48:2129–2139CrossRefGoogle Scholar
  19. 19.
    Raffaella M, Patrizia R, Fabio P, Chiara ET, Giuseppe B, Francesco MB, Manuela A, Paola C (2008) Muscle wasting in diabetic and in tumor bearing rats: role of oxidative stress. Free Radic Biol Med 44:584–593CrossRefGoogle Scholar
  20. 20.
    Manuela A, Raffaella M, Maria GC, Enrico B, Oliviero D, Giuseppe B (2004) Oxidative stress impairs skeletal muscle repair in diabetic rats. Diabetes 53:1082–1088CrossRefGoogle Scholar
  21. 21.
    Zafer M, Naeemhassan S (2010) Effect of STZ-induced diabetes on the relative weights of kidney, liver and pancreas in albino rats: a comparative study. Int J Morphol 28:135–142Google Scholar
  22. 22.
    Rakesh K, Subrahmanyam VM, Jasim R, Kailash P, Jawahar K (1998) Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. Clin Sci 94:623–632CrossRefGoogle Scholar
  23. 23.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247CrossRefGoogle Scholar
  24. 24.
    Takemoto Y, Inaba S, Zhang L, Baba K, Hagihara K, Fukada S (2017) An herbal medicine Go-sha-jinki-gan (GJG), increases muscle weight in severe muscle dystrophy model mice. Clin Nutr Exp 16:13–23CrossRefGoogle Scholar
  25. 25.
    Kishida Y, Kagawa S, Arimitsu J, Nakanishi M, Sakashita N, Otsuka S, Yoshikawa H, Hagihara K (2016) Go-sha-jinki-Gan (GJG), a traditional Japanese herbal medicine, protects against sarcopenia in senescence-accelerated mice. Phytomedicine 22:16–22CrossRefGoogle Scholar
  26. 26.
    Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922CrossRefGoogle Scholar
  27. 27.
    McCord JM, Edeas MA (2005) SOD, oxidative stress and human pathologies: a brief history and a future vision. Biomed Pharmacother 59:139–142CrossRefGoogle Scholar
  28. 28.
    Igor NZ, Thomas JM, Rodney JF (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337–349CrossRefGoogle Scholar
  29. 29.
    Shimizu T, Shirasawa T (2010) Anti-aging research using Mn-SOD conditional knockout mice. Yakugaku Zasshi 130:19–24CrossRefGoogle Scholar
  30. 30.
    Lustgarten MS, Jang YC, Liu Y, Muller FL, Qi W, Steinhelper M, Brooks SV, Larkin L, Shimizu T, Shirasawa T, McManus LM, Bhattacharya A, Richardson A, Van Remmen H (2009) Conditional knockout of Mn-SOD targeted to type B skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity. Am J Physiol 297:1520–1532CrossRefGoogle Scholar
  31. 31.
    Stefano C, Alberto CR, Kenneth AD, Bert B, Stefano S (2013) Muscle type and fiber type specificity in muscle wasting. Int J Biochem Cell Biol 45:2191–2199CrossRefGoogle Scholar
  32. 32.
    Price SR, Bailey JL, Wang X, Jurkovitz C, England BK, Ding X, Phillips LS, Mitch WE (1996) Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription. J Clin Invest 98:1703–1708CrossRefGoogle Scholar
  33. 33.
    Lin W, Hei Z, Nie H, Tang F, Huang H, Li X, Deng Y, Chen S, Guo F, Huang W, Chen F, Liu P (2008) Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase. Chin Med J 121:706–712Google Scholar
  34. 34.
    Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, Washida N, Tokuyama H, Hayashi K, Itoh H (2008) Sirt1 protects against oxidative stress induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem Biophys Res Commun 372:51–56CrossRefGoogle Scholar
  35. 35.
    Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi Y, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T (2010) Adiponectin and AdipoR1 regulate PGC-1a and mitochondria by Ca21 and AMPK/SIRT1. Nature 464:1313–1319CrossRefGoogle Scholar
  36. 36.
    Carles C, Zachary G, Jerome NF, Marie L, Liliana N, Jill CM, Peter JE, Pere P, Johan A (2009) AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature 458:1056–1060CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Tomoaki Ishida
    • 1
    • 2
    Email author
  • Michiro Iizuka
    • 1
  • Yanglan Ou
    • 2
  • Shumpei Morisawa
    • 1
    • 2
  • Ayumu Hirata
    • 1
  • Yusuke Yagi
    • 1
  • Kohei Jobu
    • 1
  • Yasuyo Morita
    • 1
  • Mitsuhiko Miyamura
    • 1
    • 2
  1. 1.Department of PharmacyKochi Medical School HospitalNankokuJapan
  2. 2.Department of Biomedical ScienceKochi Medical Graduate SchoolNankokuJapan

Personalised recommendations