Home Food & Medicine Homology Article
PDF (976.1 KB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Figures (5)

Tables (1)
Table 1
Research Article | Open Access | Online First

Characteristic components from Rehmannia radix and their effects on insulin resistance through PI-3K/AKT signaling pathway in HepG2 Cells

Zhen-Hua Liu1,2, Bei-Bei Yu1,3, Hui-Hui Zhou1,2, Shi-Shi Zhang1,3, Xu Yang1,3, Zhi-Fei Chen4, Chang-Tong Lu4, Qiu-Ling Wang4, Dong-Xu Cheng4, Yi-Bo Ning4, Yan-Xia Xiong5, Guang-Ping Lv6(), Wen-Yi Kang1,3()
National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China
Functional Food Engineering Technology Research Center, Henan, Kaifeng 475004, China
Joint International Research Laboratory of Food & Medicine Resource Function, Kaifeng 475004, China
China Tobacco Henan Industrial Company Ltd., Zhengzhou 450000, China
Jiangzhong Pharmaceutical Co. Ltd, Nanchang 330004, China
School of Food and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210046, China
Show Author Information

Highlights

(1) Thirteen compounds were identified from Rehmannia radix, a kind of food and medicinal herb, including a new iridoid.

(2) Seven compounds could promote glucose uptake of IR-HepG2 cells.

(3) The mechanism of compound 6 improved insulin resistance in HepG2 cells probably by activating PI-3K/AKT signaling pathway and inhibiting gluconeogenesis.

Graphical Abstract

View original image Download original image
Thirteen compounds were identified from 75% ethanol extract of Rehmannia radix, including a new iridoid, among which seven compounds could promote glucose uptake by IR-HepG2 cells. Furthermore, compound 6 could improve insulin resistance of HepG2 cells by activating the PI-3K/AKT signaling pathway, promoting the synthesis of glycogen, and inhibiting gluconeogenesis.

Abstract

Rehmannia radix is a kind of food and medicinal material, riched in monoterpenoids, phenylethanol glycosides, triterpenes, flavonoids, and other kinds of chemical compounds, among which monoterpenoids such as iridoids and ionones, and phenylethanol glycosides are the characteristic components of R. radix, with various biological activities. To excavate more characteristic active ingredients, the chemical compositions were identified from the 75% ethanol extract by v a variety of column methods and their hypoglycemic activities were evaluated in HepG2 cells. As a consequence, 13 compounds (1-13) were identified, including 4 iridoid compounds, 3 ionones, and 6 phenylethanol compounds, among them compound 3 was a new iridoid. The hypoglycemic activity showed that 7 compounds (1~2, 4~7 and 13) could promote glucose uptake of IR-HepG2 cells. And compound 6 could significantly upregulate protein levels of PI-3K, p-GSK3β, p-AKT and GLUT4, and significantly downregulated protein levels of PEPCK and G6Pase. These results revealed that compound 6 improved insulin resistance in HepG2 cells probably by activating PI-3K/AKT signaling pathway and inhibiting gluconeogenesis. These results succeeded in enriching the chemical composition of R. radix and provided an important scientific basis for the application of Rehmannia in the treatment of diabetes.

Keywords

Rehmannia radixiridoidsiononesphenylethanolinsulin resistanceHepG2 cells

References

[1]

Lee, S., Park, S., & Choi, C. S. Insulin resistance: from mechanisms to therapeutic strategies. diabetes & metabolism journal, 2022, 46: 15–37. https://doi.org/10.4093/dmj.2021.0280

Crossref Google Scholar
[2]

Dong, Z. H., Pan, R. Y., Ren, G. Y., et al. A novel antidiabetic peptide GPAGAP from Andrias davidianus collagen hydrolysates: screening, action mechanism prediction and improving insulin resistance in HepG2 cells. Food & Medicine Homology, 2024, 1: 9420010. https://doi.org/10.26599/FMH.2024.9420010

Crossref Google Scholar
[3]

Wang, T., Wang, Y. Y., Shi, M. Y., et al. Mechanisms of action of natural products on type 2 diabetes. World Journal of Diabetes, 2023, 14: 1603–1620. https://doi.org/10.4239/wjd.v14.i11.1603

Crossref Google Scholar
[4]

Yan, F., Dai, G., & Zheng, X. Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/ db mice. Journal of Nutritional Biochemistry, 2016, 36: 68–80. https://doi.org/10.1016/j.jnutbio.2016.07.004

Crossref Google Scholar
[5]

Gandhi, G. R., Jothi, G., Antony, P. J., et al. Gallic acid attenuates high-fat diet fed streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-AKT signaling pathway. European Journal of Pharmacology, 2014, 745: 201–216. https://doi.org/10.1016/j.ejphar.2014.10.044

Crossref Google Scholar
[6]

Pu, P., Wang, X. A., Salim, M., et al. Baicalein, a natural product, selectively activating AMPKα(2) and ameliorates metabolic disorder in diet-induced mice. Molecular And Cellular Endocrinology, 2012, 362: 128–138. https://doi.org/10.1016/j.mce.2012.06.002

Crossref Google Scholar
[7]
National Pharmacopoeia Committee. Pharmacopoeia of the People’s Republic of China. Beijing: China Med Sci Press, 2020 , 129.
[8]

Feng, W. S., Li, M., Zheng, X. K., et al. Study on chemical constituents of lmmunosuppressive parts from the roots of Rehmannia glutinosa. Chinese Pharmaceutical Journal, 2014, 49: 1496–1502.

Google Scholar
[9]
Li, M. M., Jiang, H. J., & Hao, Y. A. systematic review on botany, processing, application, phytochemistry and pharmacological action of Radix Rehmnniae. Journal of Ethnopharmacology, 2021 , 285, 114820. https://doi.org/10.1016/j.jep.2021.114820
Crossref
[10]

Chao, C.H., Hsu, J.L., Chen, M.F., et al. Anti-hypertensive effects of Radix Rehmanniae and its active ingredients. Natural Product Research, 2020, 34: 1547–1552. https://doi.org/10.1080/14786419.2018.1516660

Crossref Google Scholar
[11]

Sung, Y. Y., Yoon, T., Jang, J. Y., et al. Topical application of Rehmannia glutinosa extract inhibits mite allergen-induced atopic dermatitis in NC/Nga mice. Journal of Ethnopharmacology, 2011, 134: 37–44. https://doi.org/10.1016/j.jep.2010.11.050

Crossref Google Scholar
[12]
Zhang, Z., Meng, Y., Guo, Y., et al. Rehmannia glutinosa polysaccharide induces maturation of murine bone marrow derived Dendritic cells (BMDCs). International Journal of Biological Macromolecules, 2013 , 54: 136–143. https://doi.org/10.1016/j.ijbiomac.2012.12.005
Crossref
[13]
Xu, L., Zhang, W., Zeng, L., et al. Rehmannia glutinosa polysaccharide induced an anti-cancer effect by activating natural killer cells. International Journal of Biological Macromolecules, 2017 , 105: 680–685. https://doi.org/10.1016/j.ijbiomac.2017.07.090
Crossref
[14]
Lee, B. C., Choi, J. B., Cho, H. J., et al. Rehmannia glutinosa ameliorates the progressive renal failure induced by 5/6 nephrectomy. Journal of Ethnopharmacoloogy, 2009 , 122: 131–135. https://doi.org/10.1016/j.jep.2008.12.015
Crossref
[15]

Zhu, D., Wang, Y., Du, Q., et al. Cichoric acid reverses insulin resistance and suppresses inflammatory responses in the glucosamine-induced HepG2 cells. Journal Of Agricultural And Food Chemistry, 2016, 63: 10903–10913. https://doi.org/10.1021/acs.jafc.5b04533

Crossref Google Scholar
[16]

Liu, J. J., Lu, J. J., Zhang, J. K., et al. Chemical constituents from the Rehmanniae Radix Preparata. Chinese Pharmaceutical Journal, 2021, 56: 449–456.

Google Scholar
[17]

Tran, T. H. H., Pham, T. M. H., Pham, T. C., et al. Iridoids from the aerial parts of adenosma caeruleum with their nitric oxide inhibitory effects. Journal of Molecular Structure, 2024, 1299: 137–149. https://doi.org/10.1016/j.molstruc.2023.137149

Crossref Google Scholar
[18]

Wang, H., Wu, F. H., Xiong, F., et al. Iridoids from Neopicrorhiza scrophulariiflora and their hepatoprotective activities in vitro. Chemical & Pharmaceutical Bulletin, 2006, 54: 1144–1149. https://doi.org/10.1248/cpb.54.1144

Crossref Google Scholar
[19]

Wang, H., Ye, W. C., Jiang, R. W., et al. Three new cyclopentanoid monoterpenes from Picrorhizascrophulariiflora. Planta Medica, 2004, 70: 382–384. https://doi.org/10.1055/s-2004-818957

Crossref Google Scholar
[20]

Wei, S. F., Meng, L., Xiao, K. Z., et al. Two new ionone glycosides from the roots of Rehmannia glutinosa Libosch. Natural Product Research, 2015, 29: 59–63. https://doi.org/10.1080/14786419.2014.958735

Crossref Google Scholar
[21]
Zhang, L., Wen, K., Zhang, Z. Q., et al, et al. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model. Open Life Sciences, 2021 , 16: 1313–1320. https://doi.org/10.1515/biol-2021-0125
Crossref
[22]

Zhang, J. K., Lu, J. J., Li, M., et al. Ionones from the "nine steaming nine sun-drying" Rehmanniae Radix Praeparata. Natural Product Research and Development, 2021, 33: 767–772. https://doi.org/10.16333/j.1001-6880.2021.5.007

Crossref Google Scholar
[23]
Li, C. Y., Gao, H., Jiao, W. H., et al. lsolation and identification of quinones constituents from root cortex of Morinda officinalis. Journal of Shenyang Pharmaceutical University, 2011 , 28: 30–36+60. https://doi.org/10.14066/j.cnki.cn21-1349/r.2011.01.004
[24]

Gao, Y., Peng, C. Y., Chen, Y. Y., et al. Studies on the phenylethanoid glycosides from the fresh roots of Rehmannia glutinosa. Journal of Chinese Medicinal Materials, 2017, 40: 2073–2076. https://doi.org/10.13863/j.issn1001-4454.2017.09.017

Crossref Google Scholar
[25]

Hong, M. Y., Du, Y. S., Chen, D. D., et al. Martynoside rescues 5-fluorouracil-impaired ribosome biogenesis by stabilizing RPL27A. Science Bulletin, 2023, 68: 15.

Crossref Google Scholar
[26]
Lee, H. D., Kim, J. H., Pang, Q. Q., et al. Antioxidant Activity and acteoside analysis of Abeliophyllum distichum. Antioxidants (Basel ). 2020 , 9: 1148. https://doi.org/10.3390/antiox9111148
Crossref
[27]

Anna B., & Jaromir B. A new flavonoid, a new phenylethanoid glycoside and related compounds isolated from the inflorescences of Plantago lanceolata L. Natural Product Research, 2022, 36: 3813–3824. https://doi.org/10.1080/14786419.2021.1888289

Crossref Google Scholar
[28]

Tripetch, K., & Ryoji, K. Phenolic glycosides from Markhamia stipulata. Phytochemistry, 2002, 59: 557–563. https://doi.org/10.1016/S0031-9422(01)00466-6

Crossref Google Scholar
[29]

Liu, Y. F., Shi, G. R., Wang, X., et al. Nine new compounds from the whole plants of Rehmannia chingii. Journal of Asian Natural Products Research, 2016, 18: 509–519. https://doi.org/10.1080/10286020.2016.1173680

Crossref Google Scholar
[30]

Yan, J., Wang, C., Jin, Y., et al. Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway. Pharmacological Research, 2018, 130: 466–480. https://doi.org/10.1016/j.phrs.2017.12.026

Crossref Google Scholar
[31]

Xu, D. Q., Huang, X. F., Hassan, H. M., et al. Hypoglycaemic effect of catalpol in a mouse model of high-fat diet-induced prediabetes. Applied Physiology Nutrition and Metabolism, 2020, 45: 1127–1137. https://doi.org/10.1139/apnm-2020-0075

Crossref Google Scholar
[32]

Xu, D. Q., Wang, L., Jiang, Z., et al. A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis. Life Sciences, 2018, 209: 313–323. https://doi.org/10.1016/j.lfs.2018.08.028

Crossref Google Scholar
[33]

Yap, K. H., Yee, G. S., Candasamy, M., et al. Catalpol ameliorates insulin sensitivity andmitochondrial respiration in skeletal muscle of type-2 diabetic mice through insulin signaling pathway and AMPK/SIRT1/PGC-1 α/PPAR- γ activation. Biomolecules, 2020, 10: 1360. https://doi.org/10.3390/biom10101360

Crossref Google Scholar
[34]

Liu, Z. H., Xu, L. T., Xu, X. Q., et al. Effects and mechanisms of iridoid glycosides from Patrinia scabiosaefolia on improving insulin resistance in 3T3-L1 adipocytes. Food And Chemical Toxicology, 2019, 134: 110806. https://doi.org/10.1016/j.fct.2019.110806

Crossref Google Scholar
[35]
Liu, Z. H., Wang, M. K., Liu, Y. H., et al. Patrinoside and Patrinoside A from Patrinia scabiosaefolia improve insulin resistance by inhibiting NF-κB, MAPK pathways and oxidative stress in RAW264.7 and 3T3-L1 cells. Oxidative Medicine and Cellular Longevity, 2023 , 9069645. https://doi.org/10.1155/2023/9069645
Crossref
[36]

Liu, Z. H., Meng, L. J., Wang, M. K., et al. New iridoids from Patrinia scabiosaefolia and their hypoglycemic effects by activating PI3K/AKT signaling pathway. Fitoterapia, 2023, 165: 105423. https://doi.org/10.1016/j.fitote.2022.105423

Crossref Google Scholar
[37]

Cao, R., Tian, H., Zhang, Y., et al. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm, 2020, 4: e283. https://doi.org/10.1002/mco2.283

Crossref Google Scholar
[38]

Thu, V. K., Thoa, N. T., Hien, N. T. T., et al. Iridoid glycosides link with phenylpropanoids from Rehmannia glutinosa. Natural Product Research, 2022, 36: 5370–5375. https://doi.org/10.1080/14786419.2021.1931189

Crossref Google Scholar
[39]

Uddin, M. J., Russo, D., Haque, M. A., et al. Bioactive abietane-type diterpenoid glycosides from leaves of Clerodendrum infortunatum (Lamiaceae ). Molecules, 2021, 26: 4121. https://doi.org/10.3390/molecules26144121

Crossref Google Scholar
[40]

Ivanka, K. K., Liliya, V. M., Monika, N. T., et al. Leucosceptoside A from devil’s claw modulates psoriasis-like inflammation via suppression of the PI3K/AKT signaling pathway in keratinocyte. Molecules, 2021, 26: 7014. https://doi.org/10.3390/molecules26227014

Crossref Google Scholar
[41]
Hong, M., Chen, D., Hong, Z., et al. Ex vivo and in vivo chemoprotective activity and potential mechanism of martynoside against 5-fluorouracil-induced bone marrow cytotoxicity. Biomed Pharmacother, 2021 , 138: 111501. https://doi.org/10.1016/j.biopha.2021.111501
Crossref
Food & Medicine Homology
DOI: 10.26599/FMH.2025.9420073
Cite this article:
Liu Z-H, Yu B-B, Zhou H-H, et al. Characteristic components from Rehmannia radix and their effects on insulin resistance through PI-3K/AKT signaling pathway in HepG2 Cells. Food & Medicine Homology, 2025, https://doi.org/10.26599/FMH.2025.9420073
Metrics & Citations  
Article History
Copyright
Rights and Permissions
Return

The 1H and 13C-NMR data of compound 3 (CD3OD, δ in ppm, J in 500MHz)

PositionδHδC
15.30(1H, s)96.3
33.58 (1H, m)3.79 (1H, t, J = 11.2 Hz)59.4
41.38(1H, ddd, J = 4.6,12.6,25.0 Hz)2.07(1H, dd, J = 6.0,1.3 Hz)32.9
52.72 (1H, s)46.0
63.63 (1H, t, J = 5.9 Hz)79.6
74.35（1H, d, J = 6.0 Hz）74.5
8138.3
9137.6
104.24 (1H, d, J = 13.3 Hz)4.09 (1H, dd, J = 2.7,13.3 Hz)56.7
113.33(3H, s)54.8