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Effect of Chimpi, dried citrus peel, on aquaporin-3 expression in HaCaT human epidermal keratinocytes

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Abstract

Background

Chimpi, the dried peel of Citrus unshiu or Citrus reticulata, has various pharmacological effects. Chimpi extract was recently shown to affect the skin, including its inhibitory effect against atopic dermatitis. In this study, we analyzed the effects of Chimpi extract on the functional molecule aquaporin-3 (AQP3), which is involved in water transport and cell migration in the skin.

Methods and Results

Chimpi extract was added to HaCaT human skin keratinocytes, and the AQP3 expression level was analyzed. A wound healing assay was performed to evaluate the effect of Chimpi extract on cell migration. The components of Chimpi extract and fractions obtained by liquid–liquid distribution studies were added to HaCaT cells, and AQP3 expression was analyzed. Chimpi extract significantly increased AQP3 expression in HaCaT cells at both the mRNA and protein levels. Immunocytochemical staining revealed that Chimpi extract also promoted the transfer of AQP3 to the cell membrane. Furthermore, Chimpi extract enhanced cell migration. Hesperidin, narirutin, and nobiletin did not increase AQP3 levels. Although the components contained in the fractions obtained from the chloroform, butanol, and water layer increased AQP3, the active components could not be identified.

Conclusions

These results reveal that Chimpi extract may increase AQP3 levels in keratinocytes and increase the dermal water content. Therefore, Chimpi extract may be effective for the management of dry skin.

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References

  1. Kim A, Im M, Gu MJ, Ma JY (2016) Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma. Sci Rep 6:24214. https://doi.org/10.1038/srep24214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ito A, Shin N, Tsuchida T, Okubo T, Norimoto H (2013) Antianxiety-like effects of Chimpi (dried citrus peels) in the elevated open-platform test. Molecules 18:10014–10023. https://doi.org/10.3390/molecules180810014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kang GJ, Han SC, Yi EJ, Kang HK, Yoo ES (2011) The inhibitory effect of premature citrus unshiu extract on atopic dermatitis in vitro and in vivo. Toxicol Res 27:173–180. https://doi.org/10.5487/TR.2011.27.3.173

    Article  PubMed  PubMed Central  Google Scholar 

  4. Park SH, Park EK, Kim DH (2005) Passive cutaneous anaphylaxis-inhibitory activity of flavanones from Citrus unshiu and Poncirus trifoliata. Planta Med 71:24–27. https://doi.org/10.1055/s-2005-837746

    Article  CAS  PubMed  Google Scholar 

  5. Choi SH, Choi SI, Jung TD, Cho BY, Lee JH, Kim SH, Yoon SA, Ham YM, Yoon WJ, Cho JH, Lee OH (2017) Anti-photoaging effect of Jeju putgyul (Unripe Citrus) extracts on human dermal fibroblasts and ultraviolet B-induced hairless mouse skin. Int J Mol Sci. https://doi.org/10.3390/ijms18102052

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bae JT, Ko HJ, Kim GB, Pyo HB, Lee GS (2012) Protective effects of fermented Citrus unshiu peel extract against ultraviolet-A-induced photoageing in human dermal fibrobolasts. Phytother Res 26:1851–1856. https://doi.org/10.1002/ptr.4670

    Article  CAS  PubMed  Google Scholar 

  7. Kim C, Ji J, Ho Baek S, Lee JH, Ha IJ, Lim SS, Yoon HJ, Je Nam Y, Ahn KS (2019) Fermented dried Citrus unshiu peel extracts exert anti-inflammatory activities in LPS-induced RAW264.7 macrophages and improve skin moisturizing efficacy in immortalized human HaCaT keratinocytes. Pharm Biol 57:392–402. https://doi.org/10.1080/13880209.2019.1621353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Oliver N, Sternlicht M, Gerritsen K, Goldschmeding R (2010) Could aging human skin use a connective tissue growth factor boost to increase collagen content? J Invest Dermatol 130:338–341. https://doi.org/10.1038/jid.2009.331

    Article  CAS  PubMed  Google Scholar 

  9. Liu T, Li N, Yan YQ, Liu Y, Xiong K, Liu Y, Xia QM, Zhang H, Liu ZD (2020) Recent advances in the anti-aging effects of phytoestrogens on collagen, water content, and oxidative stress. Phytother Res 34:435–447. https://doi.org/10.1002/ptr.6538

    Article  CAS  PubMed  Google Scholar 

  10. Ghersetich I, Lotti T, Campanile G, Grappone C, Dini G (1994) Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol 33:119–122. https://doi.org/10.1111/j.1365-4362.1994.tb01540.x

    Article  CAS  PubMed  Google Scholar 

  11. Papakonstantinou E, Roth M, Karakiulakis G (2012) Hyaluronic acid: a key molecule in skin aging. Dermatoendocrinol 4:253–258. https://doi.org/10.4161/derm.21923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li Q, Fang H, Dang E, Wang G (2020) The role of ceramides in skin homeostasis and inflammatory skin diseases. J Dermatol Sci 97:2–8. https://doi.org/10.1016/j.jdermsci.2019.12.002

    Article  CAS  PubMed  Google Scholar 

  13. Bollag WB, Aitkens L, White J, Hyndman KA (2020) Aquaporin-3 in the epidermis: more than skin deep. Am J Physiol Cell Physiol 318:C1144–C1153. https://doi.org/10.1152/ajpcell.00075.2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fujiyoshi Y, Mitsuoka K, de Groot BL, Philippsen A, Grubmuller H, Agre P, Engel A (2002) Structure and function of water channels. Curr Opin Struct Biol 12:509–515. https://doi.org/10.1016/s0959-440x(02)00355-x

    Article  CAS  PubMed  Google Scholar 

  15. Ma T, Hara M, Sougrat R, Verbavatz JM, Verkman AS (2002) Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3. J Biol Chem 277:17147–17153. https://doi.org/10.1074/jbc.M200925200

    Article  CAS  PubMed  Google Scholar 

  16. Hara M, Ma T, Verkman AS (2002) Selectively reduced glycerol in skin of aquaporin-3-deficient mice may account for impaired skin hydration, elasticity, and barrier recovery. J Biol Chem 277:46616–46621. https://doi.org/10.1074/jbc.M209003200

    Article  CAS  PubMed  Google Scholar 

  17. Hara-Chikuma M, Verkman AS (2008) Aquaporin-3 facilitates epidermal cell migration and proliferation during wound healing. J Mol Med (Berl) 86:221–231. https://doi.org/10.1007/s00109-007-0272-4

    Article  CAS  Google Scholar 

  18. Spector DA, Wade JB, Dillow R, Steplock DA, Weinman EJ (2002) Expression, localization, and regulation of aquaporin-1 to -3 in rat urothelia. Am J Physiol Renal Physiol 282:F1034-1042. https://doi.org/10.1152/ajprenal.00136.2001

    Article  CAS  PubMed  Google Scholar 

  19. Umenishi F, Narikiyo T, Schrier RW (2005) Effect on stability, degradation, expression, and targeting of aquaporin-2 water channel by hyperosmolality in renal epithelial cells. Biochem Biophys Res Commun 338:1593–1599. https://doi.org/10.1016/j.bbrc.2005.10.127

    Article  CAS  PubMed  Google Scholar 

  20. Hendriks G, Koudijs M, van Balkom BW, Oorschot V, Klumperman J, Deen PM, van der Sluijs P (2004) Glycosylation is important for cell surface expression of the water channel aquaporin-2 but is not essential for tetramerization in the endoplasmic reticulum. J Biol Chem 279:2975–2983. https://doi.org/10.1074/jbc.M310767200

    Article  CAS  PubMed  Google Scholar 

  21. Baumgarten R, Van De Pol MH, Wetzels JF, Van Os CH, Deen PM (1998) Glycosylation is not essential for vasopressin-dependent routing of aquaporin-2 in transfected Madin-Darby canine kidney cells. J Am Soc Nephrol 9:1553–1559. https://doi.org/10.1681/ASN.V991553

    Article  CAS  PubMed  Google Scholar 

  22. Cao C, Sun Y, Healey S, Bi Z, Hu G, Wan S, Kouttab N, Chu W, Wan Y (2017) Correction: EGFR-mediated expression of aquaporin-3 is involved in human skin fibroblast migration. Biochem J 474:2901–2902. https://doi.org/10.1042/BCJ-2006-0816_COR

    Article  CAS  PubMed  Google Scholar 

  23. Sakaki M, Harai K, Takahashi R, Amitani M, Amitani H, Takimoto Y, Inui A (2021) Medicine and food with particular reference to chinpi, dried citrus peel, and a component of Ninjin’yoeito. Neuropeptides 89:102166. https://doi.org/10.1016/j.npep.2021.102166

    Article  CAS  PubMed  Google Scholar 

  24. Tsujimoto T, Arai R, Yoshitomi T, Yamamoto Y, Ozeki Y, Hakamatsuka T, Uchiyama N (2021) UHPLC/MS and NMR-based metabolomic analysis of dried water extract of Citrus-type crude drugs. Chem Pharm Bull (Tokyo) 69:741–746. https://doi.org/10.1248/cpb.c21-00180

    Article  CAS  Google Scholar 

  25. Itoh K, Hirata N, Masuda M, Naruto S, Murata K, Wakabayashi K, Matsuda H (2009) Inhibitory effects of Citrus hassaku extract and its flavanone glycosides on melanogenesis. Biol Pharm Bull 32:410–415. https://doi.org/10.1248/bpb.32.410

    Article  CAS  PubMed  Google Scholar 

  26. Sasaki K, Yoshizaki F (2002) Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit. Biol Pharm Bull 25:806–808. https://doi.org/10.1248/bpb.25.806

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka S, Sato T, Akimoto N, Yano M, Ito A (2004) Prevention of UVB-induced photoinflammation and photoaging by a polymethoxy flavonoid, nobiletin, in human keratinocytes in vivo and in vitro. Biochem Pharmacol 68:433–439. https://doi.org/10.1016/j.bcp.2004.04.006

    Article  CAS  PubMed  Google Scholar 

  28. Man G, Mauro TM, Zhai Y, Kim PL, Cheung C, Hupe M, Crumrine D, Elias PM, Man MQ (2015) Topical hesperidin enhances epidermal function in an aged murine model. J Invest Dermatol 135:1184–1187. https://doi.org/10.1038/jid.2014.486

    Article  CAS  PubMed  Google Scholar 

  29. Hou M, Man M, Man W, Zhu W, Hupe M, Park K, Crumrine D, Elias PM, Man MQ (2012) Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol 21:337–340. https://doi.org/10.1111/j.1600-0625.2012.01455.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yoshizaki N, Fujii T, Masaki H, Okubo T, Shimada K, Hashizume R (2014) Orange peel extract, containing high levels of polymethoxyflavonoid, suppressed UVB-induced COX-2 expression and PGE2 production in HaCaT cells through PPAR-gamma activation. Exp Dermatol 23(Suppl 1):18–22. https://doi.org/10.1111/exd.12394

    Article  CAS  PubMed  Google Scholar 

  31. Jiang YJ, Kim P, Lu YF, Feingold KR (2011) PPARgamma activators stimulate aquaporin 3 expression in keratinocytes/epidermis. Exp Dermatol 20:595–599. https://doi.org/10.1111/j.1600-0625.2011.01269.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ikarashi N, Kon R, Kaneko M, Mizukami N, Kusunoki Y, Sugiyama K (2017) Relationship between Aging-related skin dryness and aquaporins. Int J Mol Sci. https://doi.org/10.3390/ijms18071559

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lee Y, Je YJ, Lee SS, Li ZJ, Choi DK, Kwon YB, Sohn KC, Im M, Seo YJ, Lee JH (2012) Changes in transepidermal water loss and skin hydration according to expression of aquaporin-3 in psoriasis. Ann Dermatol 24:168–174. https://doi.org/10.5021/ad.2012.24.2.168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ikarashi N, Mizukami N, Pei C, Uchino R, Fujisawa I, Fukuda N, Kon R, Sakai H, Kamei J (2021) Role of cutaneous aquaporins in the development of xeroderma in type 2 diabetes. Biomedicines. https://doi.org/10.3390/biomedicines9020104

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ikarashi N, Mizukami N, Kon R, Kaneko M, Uchino R, Fujisawa I, Fukuda N, Sakai H, Kamei J (2019) Study of the mechanism underlying the onset of diabetic xeroderma focusing on an aquaporin-3 in a streptozotocin-induced diabetic mouse model. Int J Mol Sci. https://doi.org/10.3390/ijms20153782

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ikarashi N, Kaneko M, Watanabe T, Kon R, Yoshino M, Yokoyama T, Tanaka R, Takayama N, Sakai H, Kamei J (2020) Epidermal growth factor receptor tyrosine kinase inhibitor erlotinib induces dry skin via decreased in aquaporin-3 expression. Biomolecules. https://doi.org/10.3390/biom10040545

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ikarashi N, Kon R, Nagoya C, Ishikura A, Sugiyama Y, Takahashi J, Sugiyama K (2020) Effect of astaxanthin on the expression and activity of aquaporin-3 in skin in an in-vitro study. Life (Basel). https://doi.org/10.3390/life10090193

    Article  Google Scholar 

  38. Ikarashi N, Shiseki M, Yoshida R, Tabata K, Kimura R, Watanabe T, Kon R, Sakai H, Kamei J (2021) Cannabidiol application increases cutaneous aquaporin-3 and exerts a skin moisturizing effect. Pharmaceuticals (Basel). https://doi.org/10.3390/ph14090879

    Article  Google Scholar 

  39. Ikarashi N, Kaneko M, Fujisawa I, Fukuda N, Yoshida R, Kon R, Sakai H, Sugiyama K, Kamei J (2021) Wound-healing and skin-moisturizing effects of sasa veitchii extract. Healthcare (Basel). https://doi.org/10.3390/healthcare9060761

    Article  Google Scholar 

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Acknowledgements

This research was funded by the following grants; Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science, grant number 22K11838. We would like to thank Tsumura and Co. for supply HPLC profile of Chimpi extract.

Funding

Japan Society for the Promotion of Science, 22K11838, Nobutomo Ikarashi

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Authors and Affiliations

  1. Department of Biomolecular Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Nobutomo Ikarashi, Miho Kaneko, Yui Shinozaki, Keito Tabata, Yui Nishinaka, Ryotaro Yoshida, Tomofumi Watanabe, Risako Kon, Hiroyasu Sakai & Tomoo Hosoe

  2. Department of Bioregulatory Science, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Daigo Wakana

  3. Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Nobuyuki Wakui

  4. Advanced Research Institute for Health Science, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Junzo Kamei

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  1. Nobutomo Ikarashi
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Contributions

All authors contributed to the study conception and design. Data collection and analysis were performed by NI, MK, DW, YS, KT, RY, YN, and NW. The first draft of the manuscript was written by MK. The review and editing were performed by NI, RK, HS, JK, and TH. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Nobutomo Ikarashi.

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Ikarashi, N., Kaneko, M., Wakana, D. et al. Effect of Chimpi, dried citrus peel, on aquaporin-3 expression in HaCaT human epidermal keratinocytes. Mol Biol Rep 49, 10175–10181 (2022). https://doi.org/10.1007/s11033-022-07892-2

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