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Hydrophobic constituents of Polygonum multiflorum roots promote renal erythropoietin expression in healthy mice

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Abstract

The roots of Polygonum multiflorum Thunberg (Polygonaceae) are used as a crude drug Kashu that is considered to improve blood deficiency based on a Kampo concept. Kashu has been included in Kampo formulas, such as Tokiinshi, which is used to treat eczema and dermatitis with itchiness by inhibiting inflammation and facilitating blood circulation in the skin. However, the effects of P. multiflorum roots on erythropoiesis are unclear. Previously, we isolated six phenolic constituents from an ethyl acetate (EtOAc)-soluble fraction of P. multiflorum root extract and identified them as (E)-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside [(E)-THSG], emodin, emodin-8-O-β-D-glucopyranoside, physcion, physcion-8-O-β-D-glucopyranoside, and catechin. To examine whether P. multiflorum roots facilitate erythropoiesis, the EtOAc-soluble fraction was orally administered to healthy ICR mice. When compared with mice fed a standard diet alone (Controls), the mice fed a diet including the EtOAc-soluble fraction exhibited significantly higher serum erythropoietin (Epo) levels. The renal Epo mRNA levels in EtOAc-soluble fraction-administered mice were significantly higher than those in the control mice. Then, we administered roxadustat, which is a drug to treat the patient suffering with renal anemia by specifically inhibiting hypoxia-inducible factor prolyl hydroxylases. Roxadustat slightly increased renal Epo mRNA levels in healthy mice. Administration of (E)-THSG, a major constituent, significantly increased serum Epo levels. It is likely that (E)-THSG may facilitate the process to convert inactive renal Epo-producing cells to active Epo-producing cells. Collectively, it is implied that (E)-THSG in the EtOAc-soluble fraction of P. multiflorum roots may primarily improve blood deficiency of Kampo concept by promoting erythropoiesis.

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Abbreviations

EtOAc:

Ethyl acetate

THSG:

2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucopyranoside

Epo:

Erythropoietin

REP:

Renal erythropoietin-producing

HIF:

Hypoxia-inducible factor

PHD2:

Prolyl hydroxylase domain protein 2

pVHL:

Von Hippel‒Lindau protein

RBC:

Red blood cell

ELISA:

Enzyme-linked immunosorbent assay

RT‒PCR:

Reverse transcription–polymerase chain reaction

EF:

Elongation factor 1α

SD:

Standard deviation

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Acknowledgements

We thank Ms. Noriko Kanazawa for her secretarial assistance and Springer Nature Author Services (https://authorservices.springernature.com) for editing a draft of this manuscript. S.M.U. performed this study as an affiliate assistant professor under support from the Asia-Japan Research Institute, Ritsumeikan University. Y.N. was supported by the JSPS Research Fellowships for Young Scientists. This work was partly supported by the Asia-Japan Research Institute, Ritsumeikan Asia-Japan Research Organization.

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Author notes

  1. Saki Shirako and Siti Mariyah Ulfa equally contributed to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan

    Saki Shirako & Mikio Nishizawa

  2. Department of Chemistry, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, East Jawa, 65145, Indonesia

    Siti Mariyah Ulfa

  3. Asia-Japan Research Institute, Ritsumeikan Asia-Japan Research Organization, Ritsumeikan University, Iwakura-cho, Ibaraki, Osaka, 567-8570, Japan

    Siti Mariyah Ulfa & Yukinobu Ikeya

  4. College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan

    Yuto Nishidono & Ken Tanaka

  5. Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan

    Yuto Nishidono

  6. Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, East Jawa, 65145, Indonesia

    Dinia Rizqi Dwijayanti

  7. Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan

    Tetsuya Okuyama & Richi Nakatake

  8. Center for Supporting Pharmaceutical Education, Faculty of Pharmacy, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan

    Yukinobu Ikeya

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  1. Saki Shirako
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Correspondence to Yukinobu Ikeya.

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Shirako, S., Ulfa, S.M., Nishidono, Y. et al. Hydrophobic constituents of Polygonum multiflorum roots promote renal erythropoietin expression in healthy mice. J Nat Med 77, 880–890 (2023). https://doi.org/10.1007/s11418-023-01737-3

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