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image of Chemical and Mechanistic Prediction Analysis of Anti-obesity Properties of Guang Hawthorn (Malus doumeri) Leaves using Network Analysis

Abstract

Introduction

Obesity is a global health issue linked to metabolic disorders and cardiovascular diseases. Guang hawthorn (Malus doumeri) leaves have been traditionally used for medicinal purposes, but their bioactive compounds and anti-obesity potential remain underexplored.

Methods

This study extracted compounds from M. doumeri leaves using 70% ethanol and ethyl acetate. The extracts were administered to high-fat diet-induced obese rats. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured. The chemical composition of the extracts (HML) was analyzed using chromatography, NMR, and mass spectrometry. Network pharmacology and enrichment analyses were conducted using R and Cytoscape to identify compound-target interactions.

Results

Rats treated with high-dose extracts showed significantly reduced TC, TG, and LDL-C levels and increased HDL-C (all < 0.05). Three major compounds-phlorizin, sieboldin, and kumatakenin β-7-O-glucoside-were identified. A total of 272 overlapping targets and 32 core targets were found between compound-related and obesity-related gene sets. Functional analysis linked these targets to phosphorylation, apoptosis, cell proliferation, and kinase regulation.

Discussion

The anti-obesity effects of M. doumeri may be mediated by modulation of the PI3K-Akt and FoxO signaling pathways, as well as proteoglycan biosynthesis. These pathways are associated with metabolic regulation and obesity-related changes.

Conclusion

M. doumeri leaf extracts demonstrate anti-obesity potential through multi-target and multi-pathway mechanisms, particularly sieboldin and kumatakenin β-7-O-glucoside. These findings support their potential as natural therapeutic agents for obesity management.

This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
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2025-06-18
2025-10-31
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References

  1. Lin Y. Ren N. Li S. Chen M. Pu P. Novel anti-obesity effect of scutellarein and potential underlying mechanism of actions. Biomed. Pharmacother. 2019 117 109042 10.1016/j.biopha.2019.109042 31228804
    [Google Scholar]
  2. Obesity and overweight 2024 Available from:https://www.who.int/news-room/factsheets/detail/obesity-and-overweight
  3. Hosseini B. Saedisomeolia A. Allman-Farinelli M. Association between antioxidant intake/status and obesity: A systematic review of observational studies. Biol. Trace Elem. Res. 2017 175 2 287 297 10.1007/s12011‑016‑0785‑1 27334437
    [Google Scholar]
  4. Jaacks L.M. Vandevijvere S. Pan A. McGowan C.J. Wallace C. Imamura F. Mozaffarian D. Swinburn B. Ezzati M. The obesity transition: Stages of the global epidemic. Lancet Diabetes Endocrinol. 2019 7 3 231 240 10.1016/S2213‑8587(19)30026‑9 30704950
    [Google Scholar]
  5. Wu T. Guo A. Shu Q. Qi Y. Kong Y. Sun Z. Sun S. Fu Z. l-Carnitine intake prevents irregular feeding-induced obesity and lipid metabolism disorder. Gene 2015 554 2 148 154 10.1016/j.gene.2014.10.040 25445284
    [Google Scholar]
  6. Qureshi K. Abrams G.A. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 2007 13 26 3540 3553 10.3748/wjg.v13.i26.3540 17659704
    [Google Scholar]
  7. Chen J. Leong P.K. Leung H.Y. Chan W.M. Wong H.S. Ko K.M. 48Biochemical mechanisms of the anti-obesity effect of a triterpenoid-enriched extract of Cynomorium songaricum in mice with high-fat-diet-induced obesity. Phytomedicine 2020 73 153038 10.1016/j.phymed.2019.153038 31378503
    [Google Scholar]
  8. Tada A. Misawa E. Tanaka M. Saito M. Nabeshima K. Yamauchi K. Abe F. Goto T. Kawada T. Investigating anti-obesity effects by oral administration of aloe vera gel extract (AVGE): Possible involvement in activation of brown adipose tissue (BAT). J. Nutr. Sci. Vitaminol. 2020 66 2 176 184 10.3177/jnsv.66.176 32350179
    [Google Scholar]
  9. Zheng Y. Lee J. Lee E. In, G.; Kim, J.; Lee, M.H.; Lee, O.H.; Kang, I.J. A combination of korean red ginseng extract and Glycyrrhiza glabra L. extract enhances their individual anti-obesity properties in 3T3-L1 adipocytes and C57BL/6J obese mice. J. Med. Food 2020 23 3 215 223 10.1089/jmf.2019.4660 32191576
    [Google Scholar]
  10. Vickers S.P. Jackson H.C. Cheetham S.C. The utility of animal models to evaluate novel antiobesity agents. Br. J. Pharmacol. 2011 164 4 1248 1262 10.1111/j.1476‑5381.2011.01245.x 21265828
    [Google Scholar]
  11. Hussain H.T. Parker J.L. Sharma A.M. Clinical trial success rates of antiobesity agents: The importance of combination therapies. Obes. Rev. 2015 16 9 707 714 10.1111/obr.12299 26222385
    [Google Scholar]
  12. Wan-Loy C. Siew-Moi P. Marine algae as a potential source for anti-obesity agents. Mar. Drugs 2016 14 12 222 10.3390/md14120222 27941599
    [Google Scholar]
  13. Karri S. Sharma S. Hatware K. Patil K. Natural anti-obesity agents and their therapeutic role in management of obesity: A future trend perspective. Biomed. Pharmacother. 2019 110 224 238 10.1016/j.biopha.2018.11.076 30481727
    [Google Scholar]
  14. Rahman H.A. Sahib N.G. Saari N. Abas F. Ismail A. Mumtaz M.W. Hamid A.A. Anti-obesity effect of ethanolic extract from Cosmos caudatus Kunth leaf in lean rats fed a high fat diet. BMC Complement. Altern. Med. 2017 17 1 122 10.1186/s12906‑017‑1640‑4 28228098
    [Google Scholar]
  15. Gao D. Wang D.D. Fu Q.F. Wang L.J. Zhang K.L. Yang F.Q. Xia Z.N. Preparation and evaluation of magnetic molecularly imprinted polymers for the specific enrichment of phloridzin. Talanta 2018 178 299 307 10.1016/j.talanta.2017.09.058 29136826
    [Google Scholar]
  16. Wen L. Guo R. You L. Abbasi A.M. Li T. Fu X. Liu R.H. Major triterpenoids in Chinese hawthorn “Crataegus pinnatifida” and their effects on cell proliferation and apoptosis induction in MDA-MB-231 cancer cells. Food Chem. Toxicol. 2017 100 149 160 10.1016/j.fct.2016.12.032 28025124
    [Google Scholar]
  17. Li H. Liu Y. Jin H. Liu S. Fang S. Wang C. Xia C. Separation of vitexin-4-O-glucoside and vitexin-2-O-rhamnoside from hawthorn leaves extracts using macroporous resins. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2015 1007 23 29 10.1016/j.jchromb.2015.10.043 26562804
    [Google Scholar]
  18. Jouyandeh M. Tavakoli O. Sarkhanpour R. Sajadi S.M. Zarrintaj P. Rabiee N. Green products from herbal medicine wastes by subcritical water treatment J Hazard Mater 2022 424 (Part A) 127294 10.1016/j.jhazmat.2021.127294
    [Google Scholar]
  19. Bagade S.B. Patil M. Recent advances in microwave assisted extraction of bioactive compounds from complex herbal samples: A review. Crit. Rev. Anal. Chem. 2021 51 2 138 149 10.1080/10408347.2019.1686966 31729248
    [Google Scholar]
  20. Lv G.P. Hu D.J. Zhou Y.Q. Zhang Q.W. Zhao J. Li S.P. Preparation and application of standardized typical volatile components fraction from turmeric (Curcuma longa L.) by supercritical fluid extraction and step molecular distillation. Molecules 2018 23 7 1831 10.3390/molecules23071831 30041445
    [Google Scholar]
  21. Fotakis C. Tsigrimani D. Tsiaka T. Lantzouraki D.Z. Strati I.F. Makris C. Tagkouli D. Proestos C. Sinanoglou V.J. Zoumpoulakis P. Metabolic and antioxidant profiles of herbal infusions and decoctions. Food Chem. 2016 211 963 971 10.1016/j.foodchem.2016.05.124 27283718
    [Google Scholar]
  22. Hu Y.H. Peng L.Q. Wang Q.Y. Yang J. Dong X. Wang S.L. Cao J. Liu F.M. Ecofriendly microwaveassisted reaction and extraction of bioactive compounds from hawthorn leaf. Phytochem. Anal. 2019 30 6 710 719 10.1002/pca.2849 31264752
    [Google Scholar]
  23. Dahmer S. Scott E. Health effects of hawthorn. Am. Fam. Physician 2010 81 4 465 468 [PMID: 20148500
    [Google Scholar]
  24. Gosch C. Halbwirth H. Stich K. Phloridzin: Biosynthesis, distribution and physiological relevance in plants. Phytochemistry 2010 71 8-9 838 843 10.1016/j.phytochem.2010.03.003 20356611
    [Google Scholar]
  25. Ehrenkranz J.R.L. Lewis N.G. Ronald Kahn C. Roth J. Phlorizin: A review. Diabetes Metab. Res. Rev. 2005 21 1 31 38 10.1002/dmrr.532 15624123
    [Google Scholar]
  26. Maghsoudi S. Taghavi Shahraki B. Rameh F. Nazarabi M. Fatahi Y. Akhavan O. Rabiee M. Mostafavi E. Lima E.C. Saeb M.R. Rabiee N. A review on computeraided chemogenomics and drug repositioning for rational COVID 19 drug discovery. Chem. Biol. Drug Des. 2022 100 5 699 721 10.1111/cbdd.14136 36002440
    [Google Scholar]
  27. Fang J. Wang L. Wu T. Yang C. Gao L. Cai H. Liu J. Fang S. Chen Y. Tan W. Wang Q. Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment. J. Ethnopharmacol. 2017 196 281 292 10.1016/j.jep.2016.11.034 27888133
    [Google Scholar]
  28. Guo S. Wu J. Zhou W. Liu X. Zhang J. Jia S. Meng Z. Liu S. Ni M. Liu Y. Investigating the multi-target pharmacological mechanism of danhong injection acting on unstable angina by combined network pharmacology and molecular docking. BMC Complement. Med. Ther. 2020 20 1 66 10.1186/s12906‑020‑2853‑5 32122353
    [Google Scholar]
  29. Li N.N. Xiang S.Y. Huang X.X. Li Y.T. Luo C. Ju P.J. Xu Y.F. Chen J.H. Network pharmacology-based exploration of therapeutic mechanism of Liu-Yu-Tang in atypical antipsychotic drug-induced metabolic syndrome. Comput. Biol. Med. 2021 134 104452 10.1016/j.compbiomed.2021.104452 33984751
    [Google Scholar]
  30. Zhang M. Liu C. Hu M. Zhang J. Xu P. Li F. Zhong Z. Liu L. Liu X. High-fat diet enhanced retinal dehydrogenase activity, but suppressed retinol dehydrogenase activity in liver of rats. J. Pharmacol. Sci. 2015 127 4 430 438 10.1016/j.jphs.2015.03.001 25953270
    [Google Scholar]
  31. Yin L. Lu C. Yu L. Meng L. Fang X. Lan M. Preliminary study on the long-term toxicity of the extract of large-fruited hawthorn leaves in rats. Chin J Ethnomed Ethnopharm. 2017 26 15 62 65
    [Google Scholar]
  32. Xiang S.Y. Zhao J. Lu Y. Chen R.M. Wang Y. Chen Y. Long B. Zhu L.P. Yao P.F. Xu Y.F. Chen J.H. Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs. Comput. Biol. Med. 2019 110 1 7 10.1016/j.compbiomed.2019.05.007 31085379
    [Google Scholar]
  33. Nebeg H. Benarous K. Serseg T. Lazreg A. Hassani H. Yousfi M. Seeds, leaves and roots of thapsia garganica as a source of new potent lipases inhibitors: In vitro and in silico studies. Endocr. Metab. Immune Disord. Drug Targets 2019 19 5 683 696 10.2174/1871530319666190128122211 30706829
    [Google Scholar]
  34. Hilt P. Schieber A. Yildirim C. Arnold G. Klaiber I. Conrad J. Beifuss U. Carle R. Detection of phloridzin in strawberries (Fragaria x ananassa Duch.) by HPLC-PDA-MS/MS and NMR spectroscopy. J. Agric. Food Chem. 2003 51 10 2896 2899 10.1021/jf021115k 12720368
    [Google Scholar]
  35. Le Guernevé C. Sanoner P. Drilleau J.F. Guyot S. New compounds obtained by enzymatic oxidation of phloridzin. Tetrahedron Lett. 2004 45 35 6673 6677 10.1016/j.tetlet.2004.06.096
    [Google Scholar]
  36. Feng J. Zhang P. Cui Y. Li K. Qiao X. Zhang Y.T. Li S-M. Cox R.J. Wu B. Ye M. Yin W-B. Regio and stereospecific o glycosylation of phenolic compounds catalyzed by a fungal Glycosyltransferase from Mucor hiemalis. Adv. Synth. Catal. 2017 359 6 995 1006 10.1002/adsc.201601317
    [Google Scholar]
  37. Diane A. Borthwick F. Wu S. Lee J. Brown P.N. Dickinson T.A. Croft K.D. Vine D.F. Proctor S.D. Hypolipidemic and cardioprotective benefits of a novel fireberry hawthorn fruit extract in the JCR:LA-cp rodent model of dyslipidemia and cardiac dysfunction. Food Funct. 2016 7 9 3943 3952 10.1039/C6FO01023G 27538786
    [Google Scholar]
  38. Chapman M.J. Ginsberg H.N. Amarenco P. Andreotti F. Borén J. Catapano A.L. Descamps O.S. Fisher E. Kovanen P.T. Kuivenhoven J.A. Lesnik P. Masana L. Nordestgaard B.G. Ray K.K. Reiner Z. Taskinen M.R. Tokgözoglu L. Tybjærg-Hansen A. Watts G.F. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: Evidence and guidance for management. Eur. Heart J. 2011 32 11 1345 1361 10.1093/eurheartj/ehr112 21531743
    [Google Scholar]
  39. Guo W.L. Shi F.F. Li L. Xu J.X. Chen M. Wu L. Hong J.L. Qian M. Bai W.D. Liu B. Zhang Y.Y. Ni L. Rao P.F. Lv X.C. Preparation of a novel Grifola frondosa polysaccharide-chromium (III) complex and its hypoglycemic and hypolipidemic activities in high fat diet and streptozotocin-induced diabetic mice. Int. J. Biol. Macromol. 2019 131 81 88 10.1016/j.ijbiomac.2019.03.042 30851330
    [Google Scholar]
  40. Li T.T. Huang Z.R. Jia R.B. Lv X.C. Zhao C. Liu B. Spirulina platensis polysaccharides attenuate lipid and carbohydrate metabolism disorder in high-sucrose and high-fat diet-fed rats in association with intestinal microbiota. Food Res. Int. 2021 147 110530 10.1016/j.foodres.2021.110530 34399508
    [Google Scholar]
  41. Hu J.N. Shen J.R. Xiong C.Y. Zhu X.M. Deng Z.Y. Investigation of lipid metabolism by a new structured lipid with medium- and long-chain triacylglycerols from Cinnamomum camphora seed oil in healthy C57BL/6J mice. J. Agric. Food Chem. 2018 66 8 1990 1998 10.1021/acs.jafc.7b05659 29429331
    [Google Scholar]
  42. Chumphoochai K. Manohong P. Niamnont N. Tamtin M. Sobhon P. Meemon K. Anti-obesity effects of marine macroalgae extract Caulerpa lentillifera in a Caenorhabditis elegans model. Mar. Drugs 2023 21 11 577 10.3390/md21110577 37999401
    [Google Scholar]
  43. Li Y. Li Y. Fang Z. Huang D. Yang Y. Zhao D. Hang M. Wang J. The effect of Malus doumeri leaf flavonoids on oxidative stress injury induced by hydrogen peroxide (H2O2) in human embryonic kidney 293 T cells. BMC Complement. Med. Ther. 2020 20 1 276 10.1186/s12906‑020‑03072‑6 32917204
    [Google Scholar]
  44. Yang Y. van der Klaauw A.A. Zhu L. Cacciottolo T.M. He Y. Stadler L.K.J. Wang C. Xu P. Saito K. Hinton A. Jr Yan X. Keogh J.M. Henning E. Banton M.C. Hendricks A.E. Bochukova E.G. Mistry V. Lawler K.L. Liao L. Xu J. O’Rahilly S. Tong Q. Inês Barroso; O’Malley, B.W.; Farooqi, I.S.; Xu, Y. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nat. Commun. 2019 10 1 1718 10.1038/s41467‑019‑08737‑6 30979869
    [Google Scholar]
  45. Holzer R.G. Park E.J. Li N. Tran H. Chen M. Choi C. Solinas G. Karin M. Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 2011 147 1 173 184 10.1016/j.cell.2011.08.034 21962514
    [Google Scholar]
  46. Oba D. Inoue S. Miyagawa-Tomita S. Nakashima Y. Niihori T. Yamaguchi S. Matsubara Y. Aoki Y. Mice with an oncogenic HRAS mutation are resistant to high-fat diet-induced obesity and exhibit impaired hepatic energy homeostasis. EBioMedicine 2018 27 138 150 10.1016/j.ebiom.2017.11.029 29254681
    [Google Scholar]
  47. Chen K. He H. Xie Y. Zhao L. Zhao S. Wan X. Yang W. Mo Z. miR-125a-3p and miR-483-5p promote adipogenesis via suppressing the RhoA/ROCK1/ERK1/2 pathway in multiple symmetric lipomatosis. Sci. Rep. 2015 5 1 11909 10.1038/srep11909 26148871
    [Google Scholar]
  48. Sanchez-Gurmaches J. Martinez Calejman C. Jung S.M. Li H. Guertin D.A. Brown fat organogenesis and maintenance requires AKT1 and AKT2. Mol. Metab. 2019 23 60 74 10.1016/j.molmet.2019.02.004 30833219
    [Google Scholar]
  49. Jun H.S. Hwang K. Kim Y. Park T. High-fat diet alters PP2A, TC10, and CIP4 expression in visceral adipose tissue of rats. Obesity 2008 16 6 1226 1231 10.1038/oby.2008.220 18388891
    [Google Scholar]
  50. Wu R. Yao Y. Jiang Q. Cai M. Liu Q. Wang Y. Wang X. Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner. Int. J. Obes. 2018 42 7 1378 1388 10.1038/s41366‑018‑0082‑5 29795461
    [Google Scholar]
  51. Lee S. Dong H.H. FoxO integration of insulin signaling with glucose and lipid metabolism. J. Endocrinol. 2017 233 2 R67 R79 10.1530/JOE‑17‑0002 28213398
    [Google Scholar]
  52. Song N.J. Chang S.H. Kim S. Panic V. Jang B.H. Yun U.J. Choi J.H. Li Z. Park K.M. Yoon J.H. Kim S. Yoo J.H. Ling J. Thomas K. Villanueva C.J. Li D.Y. Ahn J.Y. Ku J.M. Park K.W. PI3Ka-Akt1-mediated Prdm4 induction in adipose tissue increases energy expenditure, inhibits weight gain, and improves insulin resistance in diet-induced obese mice. Cell Death Dis. 2018 9 9 876 10.1038/s41419‑018‑0904‑3 30158592
    [Google Scholar]
  53. Wang J. Hu X. Ai W. Zhang F. Yang K. Wang L. Zhu X. Gao P. Shu G. Jiang Q. Wang S. Phytol increases adipocyte number and glucose tolerance through activation of PI3K/Akt signaling pathway in mice fed high-fat and high-fructose diet. Biochem. Biophys. Res. Commun. 2017 489 4 432 438 10.1016/j.bbrc.2017.05.160 28571740
    [Google Scholar]
  54. Li M. Gao S. Kang M. Zhang X. Lan P. Wu X. Yan X. Dang H. Zheng J. Quercitrin alleviates lipid metabolism disorder in polycystic ovary syndrome-insulin resistance by upregulating PM20D1 in the PI3K/Akt pathway. Phytomedicine 2023 117 154908 10.1016/j.phymed.2023.154908 37321077
    [Google Scholar]
  55. Qiu Y. Yu H. Zeng R. Guo S. Daniyal M. Deng Z. Wang A. Wang W. Recent development on anti-obesity compounds and their mechanisms of action: A review. Curr. Med. Chem. 2020 27 21 3577 3597 10.2174/0929867326666190215114359 30767730
    [Google Scholar]
  56. Rodríguez-Pérez C. Segura-Carretero A. del Mar Contreras M. Phenolic compounds as natural and multifunctional anti-obesity agents: A review. Crit. Rev. Food Sci. Nutr. 2019 59 8 1212 1229 10.1080/10408398.2017.1399859 29156939
    [Google Scholar]
  57. Chang Y.H. Hung H.Y. Recent advances in natural anti-obesity compounds and derivatives based on in vivo evidence: A mini-review. Eur. J. Med. Chem. 2022 237 114405 10.1016/j.ejmech.2022.114405 35489224
    [Google Scholar]
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