Planta Med
DOI: 10.1055/a-2615-7291
Original Papers

Compositional Analysis of Glycyrrhiza uralensis, G. inflata, and G. glabra after Honey Processing, and the Cardioprotective Effects in Zebrafish Embryos

Jiayi Wang
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Wenxin Wang
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Binghan Liu
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Xiaoyu Fan
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Shucen Liu
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Guangchao Yang
2   Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, China
,
Jining Liu
2   Advanced Institute of Natural Sciences, Beijing Normal University, Zhuhai, China
,
Tulin Lu
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Lihong Chen
1   School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
› Author Affiliations

This work was financially supported by National Key R&D Program of China (2023YFC3504200, 2023YFC3905100).

Abstract

The “Shang Han Lun” indicates that honey-processed licorice protects the heart better than raw licorice. Ten major constituents in honey-processed licorice samples were quantified. Protective effects of honey-processed licorices against doxorubicin-induced cardiotoxicity were assessed in zebrafish larvae. Network pharmacology analysis based on the ten target constituents was conducted. Results showed glabridin was lowest in honey-processed Gg, while total content of six components (such as liquiritin) was highest in honey-processed Gu, followed by honey-processed Gi, and lowest in honey-processed Gg. Pharmacological results indicated that honey-processed Gu and Gi significantly improved doxorubicin-induced abnormal pericardial edema and increased venous sinus-arterial bulb distance in larvae. The pericardial area was reduced by 23% and 20%, respectively compared to the model group, and the distances reduced to 81% and 83.3% of the model group, respectively. Although improvements in pericardial edema were rare in the honey-processed Gg group, it reversed venous sinus-arterial bulb distance increase. These results indicate that honey-processed Gu and honey-processed Gi can significantly protect zebrafish embryos against the effects of doxorubicin-induced cardiotoxicity, namely, abnormal heart rate, pericardial edema, and elongation of the venous sinus-arterial bulb distance, whereas honey-processed Gg can only significantly reverse the doxorubicin-induced increase in the venous sinus-arterial bulb distance. Network pharmacology analysis predicted that these constituents have potential for the treatment of metabolic abnormalities and cellular senescence related diseases caused by reactive oxygen species induction, linking to Rap1 pathways. Honey-processed Gu and honey-processed Gi had stronger cardioprotective effects on zebrafish embryos than honey-processed Gg possibly because of differences in composition.

Supporting Information



Publication History

Received: 29 November 2024

Accepted after revision: 09 May 2025

Article published online:
10 June 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 
  • References

  • 1 Jiang L, Akram W, Luo B, Hu S, Faruque MO, Ahmad S, Yasin NA, Khan WU, Ahmad A, Shikov AN, Chen J, Hu X. Metabolomic and pharmacologic insights of aerial and underground parts of Glycyrrhiza uralensis Fisch. ex DC. for maximum utilization of medicinal resources. Front Pharmacol 2021; 12: 658670
  • 2 Jiang M, Zhao S, Yang S, Lin X, He X, Wei X, Song Q, Li R, Fu C, Zhang J, Zhang Z. An “essential herbal medicine”–Licorice: A review of phytochemicals and its effects in combination preparations. J Ethnopharmacol 2020; 249: 112439
  • 3 Ding Y, Brand E, Wang W, Zhao Z. Licorice: Resources, applications in ancient and modern times. J Ethnopharmacol 2022; 298: 115594
  • 4 Ota M, Xu F, Li YL, Shang MY, Makino T, Cai SQ. Comparison of chemical constituents among licorice, roasted licorice, and roasted licorice with honey. J Nat Med 2018; 72: 80-95
  • 5 Aiyasiding X, Liao HH, Feng H, Zhang N, Lin Z, Ding W, Yan H, Zhou ZY, Tang QZ. Liquiritin attenuates pathological cardiac hypertrophy by activating the PKA/LKB1/AMPK pathway. Front Pharmacol 2022; 13: 870699
  • 6 Han X, Yang Y, Zhang M, Li L, Xue Y, Jia Q, Wang X, Guan S. Liquiritin protects against cardiac fibrosis after myocardial infarction by inhibiting CCL5 expression and the NF-kappaB signaling pathway. Drug Des Devel Ther 2022; 16: 4111-4125
  • 7 Li L, Fang H, Yu YH, Liu SX, Yang ZQ. Liquiritigenin attenuates isoprenaline-induced myocardial fibrosis in mice through the TGF-β1/Smad2 and AKT/ERK signaling pathways. Mol Med Rep 2021; 24: 686
  • 8 Heidari S, Mehri S, Hosseinzadeh H. The genus Glycyrrhiza (Fabaceae family) and its active constituents as protective agents against natural or chemical toxicities. Phytother Res 2021; 35: 6552-6571
  • 9 Wang W, Li H, Shi Y, Zhou J, Khan GJ, Zhu J, Liu F, Duan H, Li L, Zhai K. Targeted intervention of natural medicinal active ingredients and traditional Chinese medicine on epigenetic modification: Possible strategies for prevention and treatment of atherosclerosis. Phytomedicine 2024; 122: 155139
  • 10 Song Z, Zhang Y, Zhang H, Rajendran RS, Wang R, Hsiao CD, Li J, Xia Q, Liu K. Isoliquiritigenin triggers developmental toxicity and oxidative stress-mediated apoptosis in zebrafish embryos/larvae via Nrf2-HO1/JNK-ERK/mitochondrion pathway. Chemosphere 2020; 246: 125727
  • 11 Wang W, Yu Y, Chen H, Sun P, Lu L, Yan S, Liu X, Lu T, Li W, Liu J, Chen L. Anti-arrhythmia potential of honey-processed licorice in zebrafish model: Antioxidant, histopathological and tissue distribution. J Ethnopharmacol 2023; 316: 116724
  • 12 Duan H, Wang W, Shi Y, Wang L, Khan GJ, Luo M, Zhou J, Yang J, He C, Li F, Hu H, Zhai K. Anti-colorectal cancer actions of Glycyrrhiza uralensis Fisch. and its underlying mechanism via HPLC integration and network pharmacological approaches. Phytomedicine 2025; 138: 156370
  • 13 Duan H, Li H, Liu T, Chen Y, Luo M, Shi Y, Zhou J, Rashed MMA, Zhai K, Li L, Wei Z. Exploring the molecular mechanism of Schisandrin C for the treatment of atherosclerosis via the PI3K/AKT/mTOR autophagy pathway. ACS Omega 2024; 9: 32920-32930
  • 14 Yang G, Yang Q, Beta T, Liu Q, Zhu Z, Shen F. Protective effects of melanoidins from black garlic on zearalenone-induced toxicity in zebrafish embryonic developmental model. Comp Biochem Physiol C Toxicol Pharmacol 2024; 276: 109789
  • 15 Lin JH, Yang KT, Ting PC, Lee WS, Lin DJ, Chang JC. Licochalcone a improves cardiac functions after ischemia-reperfusion via reduction of ferroptosis in rats. Eur J Pharmacol 2023; 957: 176031
  • 16 Yang Z, Kirton HM, Al-Owais M, Thireau J, Richard S, Peers C, Steele DS. Epac2-Rap1 signaling regulates reactive oxygen species production and susceptibility to cardiac arrhythmias. Antioxid Redox Signal 2017; 27: 117-132
  • 17 Kitakata H, Endo J, Ikura H, Moriyama H, Shirakawa K, Katsumata Y, Sano M. Therapeutic targets for DOX-induced cardiomyopathy: Role of apoptosis vs. ferroptosis. Int J Mol Sci 2022; 23: 1414
  • 18 Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother 2021; 139: 111708
  • 19 Zhang X, Hu C, Kong CY, Song P, Wu HM, Xu SC, Yuan YP, Deng W, Ma ZG, Tang QZ. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT. Cell Death Differ 2020; 27: 540-555
  • 20 Zhou Q, Zhang S, Geng X, Jiang H, Dai Y, Wang P, Hua M, Gao Q, Lang S, Hou L, Shi D, Zhou M. Antioxidant effects of roasted licorice in a zebrafish model and its mechanisms. Molecules 2022; 27: 7743
  • 21 Wang Y, Ning Y, He T, Chen Y, Han W, Yang Y, Zhang CX. Explore the potential ingredients for detoxification of honey-fired licorice (ZGC) Based on the metabolic profile by UPLC-Q-TOF-MS. Front Chem 2022; 10: 924685
  • 22 Zhai K, Deng L, Wu Y, Li H, Zhou J, Shi Y, Jia J, Wang W, Nian S, Jilany Khan G, El-Seedi HR, Duan H, Li L, Wei Z. Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4. J Adv Res 2024; [Epub ahead of Print] + doi:10.1016/j.jare.2024.08.012
  • 23 Kong S, Li P, Verpoorte R, Li M, Dai Y. Chemical and pharmacological difference between honey-fried licorice and fried licorice. J Ethnopharmacol 2023; 302: 115841
  • 24 Sun P, Chen H, Fan X, Wang J, Lu L, Yang G, Liu J, Yao W, Ding F, Ding J, Liu J, Lu T, Chen L. Exploring the effective components of honey-processed licorice (Glycyrrhiza uralensis Fisch.) in attenuating Doxorubicin-induced myocardial cytotoxicity by combining network pharmacology and in vitro experiments. J Ethnopharmacol 2024; 329: 118178
  • 25 Jeon HJ, Kim C, Kim K, Lee SE. Piperlongumine treatment impacts heart and liver development and causes developmental delay in zebrafish (Danio rerio) embryos. Ecotoxicol Environ Saf 2023; 258: 114995
  • 26 Cheng Y, Wu X, Nie X, Wu Y, Zhang C, Lee SMY, Lv K, Leung GPH, Fu C, Zhang J, Li J. Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway. Phytomedicine 2022; 106: 154407
  • 27 Sun X, Sun P, Zhen D, Xu X, Yang L, Fu D, Wei C, Niu X, Tian J, Li H. Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression. Toxicol Appl Pharmacol 2022; 437: 115902
  • 28 Tan H, Chen J, Li Y, Li Y, Zhong Y, Li G, Liu L, Li Y. Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Mol Med 2022; 28: 58