Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor

Sheng Kuo Hsieh, Tse Yu Chung, Yue Chiun Li, Yuan Hao Lo, Nan Hei Lin, Ping Chung Kuo, Wen Ying Chen, Jason T.C. Tzen

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Ethnopharmacological relevance Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin. Materials and methods Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. Results Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. Conclusion The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.

Original languageEnglish
Pages (from-to)237-247
Number of pages11
JournalJournal of Ethnopharmacology
Volume193
DOIs
Publication statusPublished - 2016 Dec 4

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Ghrelin Receptor
Ginkgo biloba
Flavonoids
Growth Hormone
Ghrelin
Therapeutic Uses
Bile
Intravenous Injections
Growth Hormone-Releasing Hormone
Pharmacopoeias
Herbal Medicine
Chinese Traditional Medicine
Substance P
Methylation
Methanol
China
Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

Hsieh, Sheng Kuo ; Chung, Tse Yu ; Li, Yue Chiun ; Lo, Yuan Hao ; Lin, Nan Hei ; Kuo, Ping Chung ; Chen, Wen Ying ; Tzen, Jason T.C. / Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor. In: Journal of Ethnopharmacology. 2016 ; Vol. 193. pp. 237-247.
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title = "Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor",
abstract = "Ethnopharmacological relevance Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin. Materials and methods Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. Results Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. Conclusion The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.",
author = "Hsieh, {Sheng Kuo} and Chung, {Tse Yu} and Li, {Yue Chiun} and Lo, {Yuan Hao} and Lin, {Nan Hei} and Kuo, {Ping Chung} and Chen, {Wen Ying} and Tzen, {Jason T.C.}",
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Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor. / Hsieh, Sheng Kuo; Chung, Tse Yu; Li, Yue Chiun; Lo, Yuan Hao; Lin, Nan Hei; Kuo, Ping Chung; Chen, Wen Ying; Tzen, Jason T.C.

In: Journal of Ethnopharmacology, Vol. 193, 04.12.2016, p. 237-247.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor

AU - Hsieh, Sheng Kuo

AU - Chung, Tse Yu

AU - Li, Yue Chiun

AU - Lo, Yuan Hao

AU - Lin, Nan Hei

AU - Kuo, Ping Chung

AU - Chen, Wen Ying

AU - Tzen, Jason T.C.

PY - 2016/12/4

Y1 - 2016/12/4

N2 - Ethnopharmacological relevance Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin. Materials and methods Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. Results Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. Conclusion The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.

AB - Ethnopharmacological relevance Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin. Materials and methods Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. Results Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. Conclusion The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.

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