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Article Special Issue Open Access

Evaluation of the effects of ursolic acid/γ‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells

This article is part of the special Issue: Artificial Intelligence in Personalized Functional Food Nutrition
  • Authors:
    • Ryosuke Kuwashima
    • Mao Ishizuka
    • Takashi Tanikawa
    • Yoshiyuki Ishida
    • Daisuke Nakata
    • Keiji Terao
    • Yutaka Inoue
  • View Affiliations / Copyright

    Affiliations: Laboratory of Nutri‑Pharmacotherapeutics Management, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Sakado, Saitama 350‑0295, Japan, CycloChem Bio Co., Ltd., Chuo‑ku, Kobe 6500047, Japan
    Copyright: © Kuwashima et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 6
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    Published online on: July 4, 2025
       https://doi.org/10.3892/ijfn.2025.47
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Abstract

The present study aimed to evaluate the effects of ursolic acid (UA), a compound found in apple peels and other fruits and known for its biological activities on the improvement of muscle atrophy. The present study also examined γ‑cyclodextrin (γ‑CD) and cyclodextrin‑based metal‑organic framework‑1 (CD‑MOF‑1) complexes for their effects on the proliferation of C2C12 myotube cells, which are derived from mouse skeletal muscle. Cell viability under proliferative and differentiation conditions was assessed using the 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. Cell viability was reduced at 20 µM in intact UA, at 40 µM in UA/γ‑CD, and at 20 µM in UA/CD‑MOF‑1 cells under proliferative conditions. Under differentiation conditions, cell viability was decreased at 20 µM in intact UA, at 40 µM in UA/γ‑CD, and at 10 µM in UA/CD‑MOF‑1. The reduced viability of C2C12 cells under proliferative and differentiation conditions was not observed in UA/γ‑CD concentrations up to and higher than those of intact UA, suggesting that the cytotoxic effect of UA was mitigated. Under both proliferative and differentiation conditions, encapsulation with CD‑MOF‑1 did not reduce the cytotoxic effect of UA, suggesting that UA/CD‑MOF‑1 enhanced the intracellular release of UA. The myotube diameters of the C2C12 cells were measured to evaluate muscle atrophy. The addition of dexamethasone (DEX) decreased the myotube diameter; however, UA + DEX, UA/γ‑CD + DEX, and UA/CD‑MOF‑1 + DEX exhibited no difference compared with the control, suggesting that UA ameliorated muscle atrophy induced by DEX. On the whole, the present study confirms that UA myotubular cells can act even when UA/γ‑CD and UA/CD‑MOF‑1 form inclusion complexes, and that muscle atrophy is sustained in UA myotubular cells.
View Figures

Figure 1

Chemical structures of (A) UA, (B)
γ-CD, and (C) γ-CD(KOH)2:(CD-MOF-1). UA, ursolic acid;
γ-CD, γ-cyclodextrin; CD-MOF-1, cyclodextrin-based metal-organic
frameworks-1.

Figure 2

Effects of UA, γ-CD, UA/γ-CD, CD-MOF-1
and UA/CD-MOF-1 on the proliferation of C2C12 cells. The ‘control’
represents the control configured vehicle (CCV: UA at 0 µM). Data
are expressed as the mean ± SD. **P<0.01 (n=3) in the
control vs. sample. Data were analyzed using one-way ANOVA with
Dunnett's post hoc test. UA, ursolic acid; γ-CD, γ-cyclodextrin;
CD-MOF-1, cyclodextrin-based metal-organic frameworks-1.

Figure 3

Effects of UA, γ-CD, UA/γ-CD,
CD-MOF-1, and UA/CD-MOF-1 on the differentiation of C2C12 cells.
The ‘control’ represents the control configured vehicle (CCV: UA at
0 µM). The results are expressed as the mean ± SD (n=3).
*P<0.05 and **P<0.01, compared with the
control. Data were analyzed using one-way ANOVA with Dunnett's post
hoc test. UA, ursolic acid; γ-CD, γ-cyclodextrin; CD-MOF-1,
cyclodextrin-based metal-organic frameworks-1.

Figure 4

Effect of UA, γ-CD, UA/γ-CD, CD-MOF-1
and UA/CD-MOF-1 on DEX-induced atrophy in C2C12 myotubes. The
results are expressed as the mean ± SD (n=5).
**P<0.01, compared with the control. Data were
analyzed using one-way ANOVA with Dunnett's post hoc test. UA,
ursolic acid; γ-CD, γ-cyclodextrin; CD-MOF-1, cyclodextrin-based
metal-organic frameworks-1; DEX, dexamethasone.

Figure 5

Morphological observation of the
control, DEX, UA + DEX, UA/γ-CD + DEX and UA/CD-MOF-1 + DEX under
differentiation conditions of C2C12 cells. Magnification, x20. UA,
ursolic acid; γ-CD, γ-cyclodextrin; CD-MOF-1, cyclodextrin-based
metal-organic frameworks-1; DEX, dexamethasone. Red arrows indicate
myotube diameter.
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Spandidos Publications style
Kuwashima R, Ishizuka M, Tanikawa T, Ishida Y, Nakata D, Terao K and Inoue Y: Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells. Int J Funct Nutr 6: 6, 2025.
APA
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., & Inoue, Y. (2025). Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells. International Journal of Functional Nutrition, 6, 6. https://doi.org/10.3892/ijfn.2025.47
MLA
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., Inoue, Y."Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells". International Journal of Functional Nutrition 6.1 (2025): 6.
Chicago
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., Inoue, Y."Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells". International Journal of Functional Nutrition 6, no. 1 (2025): 6. https://doi.org/10.3892/ijfn.2025.47
Copy and paste a formatted citation
x
Spandidos Publications style
Kuwashima R, Ishizuka M, Tanikawa T, Ishida Y, Nakata D, Terao K and Inoue Y: Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells. Int J Funct Nutr 6: 6, 2025.
APA
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., & Inoue, Y. (2025). Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells. International Journal of Functional Nutrition, 6, 6. https://doi.org/10.3892/ijfn.2025.47
MLA
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., Inoue, Y."Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells". International Journal of Functional Nutrition 6.1 (2025): 6.
Chicago
Kuwashima, R., Ishizuka, M., Tanikawa, T., Ishida, Y., Nakata, D., Terao, K., Inoue, Y."Evaluation of the effects of ursolic acid/&gamma;‑cyclodextrin or cyclodextrin‑based metal‑organic framework‑1 complexes on reducing cytotoxicity and improving muscle atrophy in C2C12 cells". International Journal of Functional Nutrition 6, no. 1 (2025): 6. https://doi.org/10.3892/ijfn.2025.47
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