Skip to content
2000
Volume 30, Issue 34
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Background

Oral mucositis is the most common and troublesome complication for cancer patients receiving radiotherapy or chemotherapy. Recent research has shown that , an important economic crop widely grown in China, has epithelial protective effects in several other organs. However, it is unknown whether or not can exert a beneficial effect on oral mucositis. Network pharmacology has been suggested to be applied in “multi-component-multi-target” functional food studies. The purpose of this study is to evaluate the effect of on oral mucositis through network pharmacology, molecular docking and experimental validation.

Aims

To explore the biological effects and molecular mechanisms of in the treatment of oral mucositis through network pharmacology and molecular docking combined with experimental validation.

Methods

Based on network pharmacology methods, we collected the active components and related targets of from public databases, as well as the targets related to oral mucositis. We mapped protein-protein interaction (PPI) networks, performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment, and constructed a 'components-disease-targets' network and 'components-pathways-targets' network using Cytoscape to further analyse the intrinsic molecular mechanisms of against oral mucositis. The affinity and stability predictions were performed using molecular docking strategies, and experiments were conducted to demonstrate the biological effects and possible mechanisms of against oral mucositis.

Results

A network was established between 49 components and 61 OM targets. The main active compounds were quercetin, beta-carotene, palmatine, and cyanin. The predicted core targets were IL-6, RELA, TP53, TNF, IL10, CTNNB1, AKT1, CDKN1A, HIF1A and MYC. The enrichment analysis predicted that the therapeutic effect was mainly through the regulation of inflammation, apoptosis, and hypoxia response with the involvement of TNF and HIF pathways. Molecular docking results showed that key components bind well to the core targets. In both chemically and radiation-induced OM models, significantly promoted healing and reduced inflammation. The experimental verification showed targeted the key genes (IL-6, RELA, TP53, TNF, IL10, CTNNB1, AKT1, CDKN1A, HIF1A, and MYC) through regulating the HIF and TNF signaling pathways, which were validated using the RT-qPCR, immunofluorescence staining and western blotting assays.

Conclusion

In conclusion, the present study systematically demonstrated the possible therapeutic effects and mechanisms of on oral mucositis through network pharmacology analysis and experimental validation. The results showed that could promote healing and reduce the inflammatory response through TNF and HIF signaling pathways.

Loading

Article metrics loading...

/content/journals/cpd/10.2174/0113816128312694240712072959
2024-07-29
2025-01-09
Loading full text...

Full text loading...

References

  1. PetersonD.E. BensadounR.J. RoilaF. ESMO Guidelines Working Group Management of oral and gastrointestinal mucositis: ESMO clinical recommendations.Ann. Oncol.200920Suppl. 4iv174iv17710.1093/annonc/mdp16519454447
    [Google Scholar]
  2. McGowanD. Chemotherapy-induced oral dysfunction: A literature review.Br. J. Nurs.200817221422142610.12968/bjon.2008.17.22.3187019057504
    [Google Scholar]
  3. SonisS.T. Treatment for oral mucositis-current options and an update of small molecules under development.Curr. Treat. Options Oncol.20212232510.1007/s11864‑021‑00823‑633595722
    [Google Scholar]
  4. XingX. LiuF. XiaoJ. SoK.F. Neuro-protective Mechanisms of Lycium barbarum.Neuromolecular Med.201618325326310.1007/s12017‑016‑8393‑y27033360
    [Google Scholar]
  5. LiuH. CuiB. ZhangZ. Mechanism of glycometabolism regulation by bioactive compounds from the fruits of Lycium barbarum: A review.Food Res. Int.202215911140810.1016/j.foodres.2022.11140835940747
    [Google Scholar]
  6. ZhouB. XiaH. YangL. WangS. SunG. The effect of Lycium barbarum polysaccharide on the glucose and lipid metabolism: A systematic review and meta-analysis.J. Am. Nutr. Assoc.202241661762510.1080/07315724.2021.192599634213407
    [Google Scholar]
  7. XuT. LiuR. LuX. WuX. HenebergP. MaoY. JiangQ. LoorJ. YangZ. Lycium barbarum polysaccharides alleviate LPS-induced inflammatory responses through PPARγ/MAPK/NF-κB pathway in bovine mammary epithelial cells.J. Anim. Sci.20221001skab34510.1093/jas/skab34534791267
    [Google Scholar]
  8. WongH.L. BuY. ChanY.K. ShihK.C. Lycium barbarum polysaccharide promotes corneal Re-epithelialization after alkaline injury.Exp. Eye Res.202222110915110.1016/j.exer.2022.10915135714698
    [Google Scholar]
  9. YangY.J. WangY. DengY. LiuX.Q. LuJ. PengJ. LiJ. ZhouY.S. ZhuH.A. LiB. QinY.H. PengQ.H. Lycium barbarum polysaccharides regulating mir-181/bcl-2 decreased autophagy of retinal pigment epithelium with oxidative stress.Oxid. Med. Cell. Longev.2023202311810.1155/2023/955445736644575
    [Google Scholar]
  10. CaoC. ZhuB. LiuZ. WangX. AiC. GongG. HuM. HuangL. SongS. An arabinogalactan from Lycium barbarum attenuates DSS-induced chronic colitis in C57BL/6J mice associated with the modulation of intestinal barrier function and gut microbiota.Food Funct.202112209829984310.1039/D1FO01200B34664587
    [Google Scholar]
  11. WangJ. WeiL. LiuC. WangL. ZhengW. LiuS. YanL. ZhengL. Taurine treatment alleviates intestinal mucositis induced by 5-fluorouracil in mice.Plant Foods Hum. Nutr.202277339940410.1007/s11130‑022‑00980‑535788942
    [Google Scholar]
  12. WangX. WangZ.Y. ZhengJ.H. LiS. TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches.Chin. J. Nat. Med.202119111110.1016/S1875‑5364(21)60001‑833516447
    [Google Scholar]
  13. SuY. BaiQ. TaoH. XuB. Prospects for the application of traditional Chinese medicine network pharmacology in food science research.J. Sci. Food Agric.2023103115183520010.1002/jsfa.1254136882903
    [Google Scholar]
  14. Nicolatou-GalitisO. BossiP. OrlandiE. René-JeanB The role of benzydamine in prevention and treatment of chemoradiotherapy-induced mucositis.Support. Care Cancer202129105701570910.1007/s00520‑021‑06048‑533649918
    [Google Scholar]
  15. JiangS.J. XiaoX. Li MuY. Lycium barbarum polysaccharide-glycoprotein ameliorates ionizing radiation-induced epithelial injury by regulating oxidative stress and ferroptosis via the Nrf2 pathway.Free Radic. Biol. Med.2023204849410.1016/j.freeradbiomed.2023.04.02037119863
    [Google Scholar]
  16. ShiX.Q. YueS.J. TangY.P. ChenY.Y. ZhouG.S. ZhangJ. ZhuZ.H. LiuP. DuanJ.A. A network pharmacology approach to investigate the blood enriching mechanism of Danggui buxue Decoction.J. Ethnopharmacol.201923522724210.1016/j.jep.2019.01.02730703496
    [Google Scholar]
  17. SunT. QuanW. PengS. YangD. LiuJ. HeC. ChenY. HuB. TuoQ. Network pharmacology-based strategy combined with molecular docking and in vitro validation study to explore the underlying mechanism of Huo Luo Xiao Ling Dan in treating atherosclerosis.Drug Des. Devel. Ther.2022161621164510.2147/DDDT.S35748335669282
    [Google Scholar]
  18. LiuY. LiS. LiuD. WeiH. WangX. YanF. Exploration of the potential mechanism of Pushen capsule in the treatment of vascular dementia based on network pharmacology and experimental verification.J. Ethnopharmacol.202229811563210.1016/j.jep.2022.11563235964821
    [Google Scholar]
  19. SzklarczykD. FranceschiniA. WyderS. ForslundK. HellerD. Huerta-CepasJ. SimonovicM. RothA. SantosA. TsafouK.P. KuhnM. BorkP. JensenL.J. von MeringC. STRING v10: Protein–protein interaction networks, integrated over the tree of life.Nucleic Acids Res.201543D1D447D45210.1093/nar/gku100325352553
    [Google Scholar]
  20. ZhaoR. HeY. Network pharmacology analysis of the anti-cancer pharmacological mechanisms of Ganoderma lucidum extract with experimental support using Hepa1-6-bearing C57 BL/6 mice.J. Ethnopharmacol.201821028729510.1016/j.jep.2017.08.04128882624
    [Google Scholar]
  21. WangJ. BaoB. MengF. DengS. DaiH. FengJ. LiH. WangB. To study the mechanism of Cuscuta chinensis Lam. and Lycium barbarum L. in the treatment of asthenospermia based on network pharmacology.J. Ethnopharmacol.202127011379010.1016/j.jep.2021.11379033460759
    [Google Scholar]
  22. ZhaoY. CaoY. YangX. GuoM. WangC. ZhangZ. ZhangQ. HuangX. SunM. XiC. TangthianchaichanaJ. BaiJ. DuS. LuY. Network pharmacology-based prediction and verification of the active ingredients and potential targets of Huagan decoction for reflux esophagitis.J. Ethnopharmacol.202229811562910.1016/j.jep.2022.11562935988839
    [Google Scholar]
  23. PiccioloG. ManninoF. IrreraN. AltavillaD. MinutoliL. VaccaroM. ArcoraciV. SquadritoV. PiccioloG. SquadritoF. PallioG. PDRN, a natural bioactive compound, blunts inflammation and positively reprograms healing genes in an “in vitro” model of oral mucositis.Biomed. Pharmacother.202113811153810.1016/j.biopha.2021.11153834311536
    [Google Scholar]
  24. PinziL. RastelliG. Molecular docking: Shifting paradigms in drug discovery.Int. J. Mol. Sci.20192018433110.3390/ijms2018433131487867
    [Google Scholar]
  25. ZhangJ. HongY. LiuyangZ. LiH. JiangZ. TaoJ. LiuH. XieA. FengY. DongX. WangY. DongQ. WangG. Quercetin prevents radiation-induced oral mucositis by upregulating BMI-1.Oxid. Med. Cell. Longev.2021202111610.1155/2021/223168034873428
    [Google Scholar]
  26. MiazekK. BetonK. ŚliwińskaA. Brożek-PłuskaB. The effect of β-carotene, tocopherols and ascorbic acid as anti-oxidant molecules on human and animal in vitro/in vivo studies: A review of research design and analytical techniques used.Biomolecules2022128108710.3390/biom1208108736008981
    [Google Scholar]
  27. TelferA. Singlet oxygen production by PSII under light stress: Mechanism, detection and the protective role of β-carotene.Plant Cell Physiol.20145571216122310.1093/pcp/pcu04024566536
    [Google Scholar]
  28. DoddaD. ChhajedR. MishraJ. PadhyM. Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: Role of quercetin.Indian J. Pharmacol.201446328629110.4103/0253‑7613.13216024987175
    [Google Scholar]
  29. TarabaszD. Kukula-KochW. Palmatine: A review of pharmacological properties and pharmacokinetics.Phytother. Res.2020341335010.1002/ptr.650431496018
    [Google Scholar]
  30. JeongJ.W. LeeW. ShinS. KimG.Y. ChoiB. ChoiY. Anthocyanins downregulate lipopolysaccharide-induced inflammatory responses in BV2 microglial cells by suppressing the NF-κB and Akt/MAPKs signaling pathways.Int. J. Mol. Sci.20131411502151510.3390/ijms1401150223344054
    [Google Scholar]
  31. MeddaR. LyrosO. SchmidtJ.L. JovanovicN. NieL. LinkB.J. OttersonM.F. StonerG.D. ShakerR. RafieeP. Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells.Microvasc. Res.20159716718010.1016/j.mvr.2014.10.00825446010
    [Google Scholar]
  32. AlmoiliqyM. WenJ. XuB. SunY. LianM. LiY. QaedE. Al-AzabM. ChenD. ShopitA. WangL. SunP. LinY. Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.Acta Pharmacol. Sin.20204191208122210.1038/s41401‑020‑0359‑932238887
    [Google Scholar]
  33. AlyoussefA. TahaM. Blocking Wnt as a therapeutic target in mice model of skin cancer.Arch. Dermatol. Res.2019311859560510.1007/s00403‑019‑01939‑431165240
    [Google Scholar]
  34. ChenH. ShenY. GongF. JiangY. ZhangR. HIF-α promotes chronic myelogenous leukemia cell proliferation by upregulating p21 expression.Cell Biochem. Biophys.201572117918310.1007/s12013‑014‑0434‑225596666
    [Google Scholar]
  35. DebenC. DeschoolmeesterV. De WaeleJ. JacobsJ. Van den BosscheJ. WoutersA. PeetersM. RolfoC. SmitsE. LardonF. PauwelsP. Hypoxia-induced cisplatin resistance in non-small cell lung cancer cells is mediated by hif-1α and mutant p53 and can be overcome by induction of oxidative stress.Cancers201810412610.3390/cancers1004012629690507
    [Google Scholar]
  36. LiQ. LiuY. XiaX. SunH. GaoJ. RenQ. ZhouT. MaC. XiaJ. YinC. Activation of macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling by hyperglycemia aggravates the complexity of coronary atherosclerosis: An in vivo and in vitro study.FASEB J.2021355e2160910.1096/fj.202100086RR
    [Google Scholar]
  37. PetrenkoO. LiJ. CimicaV. Mena-TaboadaP. ShinH.Y. D’AmicoS. ReichN.C. IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3.PLoS One2021163e024739410.1371/journal.pone.024739433651821
    [Google Scholar]
  38. OngZ.Y. GibsonR.J. BowenJ.M. StringerA.M. DarbyJ.M. LoganR.M. YeohA.S.J. KeefeD.M. Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis.Radiat. Oncol.2010512210.1186/1748‑717X‑5‑2220233440
    [Google Scholar]
  39. BassoF.G. SoaresD.G. PansaniT.N. CardosoL.M. ScheffelD.L. de Souza CostaC.A. HeblingJ. Proliferation, migration, and expression of oral-mucosal-healing-related genes by oral fibroblasts receiving low-level laser therapy after inflammatory cytokines challenge.Lasers Surg. Med.201648101006101410.1002/lsm.2255327416953
    [Google Scholar]
  40. KiyomiA. YoshidaK. AraiC. UsukiR. YamazakiK. HoshinoN. KurokawaA. ImaiS. SuzukiN. ToyamaA. SugiuraM. Salivary inflammatory mediators as biomarkers for oral mucositis and oral mucosal dryness in cancer patients: A pilot study.PLoS One2022174e026709210.1371/journal.pone.026709235476641
    [Google Scholar]
  41. Ramírez-AmadorV. ZambranoJ.G. Anaya-SaavedraG. Zentella-DehesaA. Irigoyen-CamachoE. Meráz-CruzN. Ponce de León-RosalesS. TNF as marker of oral candidiasis, HSV infection, and mucositis onset during chemotherapy in leukemia patients.Oral Dis.201723794194810.1111/odi.1267728403570
    [Google Scholar]
  42. GüntherC. MartiniE. WittkopfN. AmannK. WeigmannB. NeumannH. WaldnerM.J. HedrickS.M. TenzerS. NeurathM.F. BeckerC. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.Nature2011477736433533910.1038/nature1040021921917
    [Google Scholar]
  43. YangJ.H. LeW.D. BasingerS.F. Mechanisms of apoptosis in human retinal pigment epithelium induced by TNF-alpha in conditions of heavy metal ion deficiency.Invest Ophthalmol Vis Sci.20054631039104610.1167/iovs.04‑0325
    [Google Scholar]
  44. Linker-IsraeliM. HondaM. NandR. MandyamR. MengeshaE. WallaceD.J. MetzgerA. BeharierB. KlinenbergJ.R. Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC.Clin. Immunol.199991161610.1006/clim.1998.468010219249
    [Google Scholar]
  45. RossatoM. CurtaleG. TamassiaN. CastellucciM. MoriL. GasperiniS. MariottiB. De LucaM. MiroloM. CassatellaM.A. LocatiM. BazzoniF. IL-10–induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes.Proc. Natl. Acad. Sci.201210945E3101E311010.1073/pnas.120910010923071313
    [Google Scholar]
  46. FangD. ZhuJ. Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells.Cell. Mol. Life Sci.202077228930310.1007/s00018‑019‑03277‑031432236
    [Google Scholar]
  47. FreitasM.O. FonsecaA.P.R. de AguiarM.T. DiasC.C. AvelarR.L. SousaF.B. AlvesA.P.N.N. de Barros SilvaP.G. Tumor necrosis factor alpha (TNF-α) blockage reduces acute inflammation and delayed wound healing in oral ulcer of rats.Inflammopharmacology20223051781179810.1007/s10787‑022‑01046‑335948810
    [Google Scholar]
  48. FengC.J. GuoJ.B. JiangH.W. ZhuS.X. LiC.Y. ChengB. ChenY. WangH.Y. Spatio-temporal localization of HIF-1α and COX-2 during irradiation-induced oral mucositis in a rat model system.Int. J. Radiat. Biol.2008841354510.1080/0955300070161608017885826
    [Google Scholar]
  49. ChenL.J. XuW. LiY.P. MaL.T. ZhangH.F. HuangX.B. YuG.G. MaX.Q. ChenC. LiuY.H. WuJ. WangL.J. XuY. Lycium barbarum polysaccharide inhibited hypoxia-inducible factor 1 in COPD patients.Int. J. Chron. Obstruct. Pulmon. Dis.2020151997200410.2147/COPD.S25417232921997
    [Google Scholar]
  50. WangY. LiuM. JafariM. TangJ. A critical assessment of traditional Chinese medicine databases as a source for drug discovery.Front. Pharmacol.202415130369310.3389/fphar.2024.130369338738181
    [Google Scholar]
  51. WangY. YangH. ChenL. JafariM. TangJ. Network-based modeling of herb combinations in traditional Chinese medicine.Brief. Bioinform.2021225bbab10610.1093/bib/bbab10633834186
    [Google Scholar]
  52. JafariM. WangY. AmiryousefiA. TangJ. Unsupervised learning and multipartite network models: A promising approach for understanding traditional medicine.Front. Pharmacol.202011131910.3389/fphar.2020.0131932982738
    [Google Scholar]
/content/journals/cpd/10.2174/0113816128312694240712072959
Loading
/content/journals/cpd/10.2174/0113816128312694240712072959
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test