Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Lycium barbarum Ameliorates Oral Mucositis via HIF and TNF Pathways: A Network Pharmacology Approach

In Press, (this is not the final "Version of Record"). Available online 29 July, 2024
Author(s): Xun Chen, Yanhui Wu, Jing Li, Sijing Jiang, Qiang Sun, Li Xiao, Xiliang Jiang, Xun Xiao*, Xianxian Li* and Yandong Mu*
Published on: 29 July, 2024

DOI: 10.2174/0113816128312694240712072959

Price: $95

Abstract

Background: Oral mucositis is the most common and troublesome complication for cancer patients receiving radiotherapy or chemotherapy. Recent research has shown that Lycium barbarum, an important economic crop widely grown in China, has epithelial protective effects in several other organs. However, it is unknown whether or not Lycium barbarum 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 Lycium barbarum on oral mucositis through network pharmacology, molecular docking and experimental validation.

Aim: To explore the biological effects and molecular mechanisms of Lycium barbarum 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 Lycium barbarum 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 Lycium barbarum 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 Lycium barbarum 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, Lycium barbarum significantly promoted healing and reduced inflammation. The experimental verification showed Lycium barbarum 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 Lycium barbarum on oral mucositis through network pharmacology analysis and experimental validation. The results showed that Lycium barbarum could promote healing and reduce the inflammatory response through TNF and HIF signaling pathways.

[1]
Peterson DE, Bensadoun RJ, Roila F. Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol 2009; 20 (Suppl. 4): iv174-7.
[http://dx.doi.org/10.1093/annonc/mdp165] [PMID: 19454447]
[2]
McGowan D. Chemotherapy-induced oral dysfunction: A literature review. Br J Nurs 2008; 17(22): 1422-6.
[http://dx.doi.org/10.12968/bjon.2008.17.22.31870] [PMID: 19057504]
[3]
Sonis ST. Treatment for oral mucositis-current options and an update of small molecules under development. Curr Treat Options Oncol 2021; 22(3): 25.
[http://dx.doi.org/10.1007/s11864-021-00823-6] [PMID: 33595722]
[4]
Xing X, Liu F, Xiao J, So KF. Neuro-protective Mechanisms of Lycium barbarum. Neuromolecular Med 2016; 18(3): 253-63.
[http://dx.doi.org/10.1007/s12017-016-8393-y] [PMID: 27033360]
[5]
Liu H, Cui B, Zhang Z. Mechanism of glycometabolism regulation by bioactive compounds from the fruits of Lycium barbarum: A review. Food Res Int 2022; 159: 111408.
[http://dx.doi.org/10.1016/j.foodres.2022.111408] [PMID: 35940747]
[6]
Zhou B, Xia H, Yang L, Wang S, Sun G. The effect of Lycium barbarum polysaccharide on the glucose and lipid metabolism: A systematic review and meta-analysis. J Am Nutr Assoc 2022; 41(6): 617-25.
[http://dx.doi.org/10.1080/07315724.2021.1925996] [PMID: 34213407]
[7]
Xu T, Liu R, Lu X, et al. Lycium barbarum polysaccharides alleviate LPS-induced inflammatory responses through PPARγ/MAPK/NF-κB pathway in bovine mammary epithelial cells. J Anim Sci 2022; 100(1): skab345.
[http://dx.doi.org/10.1093/jas/skab345] [PMID: 34791267]
[8]
Wong HL, Bu Y, Chan YK, Shih KC. Lycium barbarum polysaccharide promotes corneal Re-epithelialization after alkaline injury. Exp Eye Res 2022; 221: 109151.
[http://dx.doi.org/10.1016/j.exer.2022.109151] [PMID: 35714698]
[9]
Yang YJ, Wang Y, Deng Y, et al. Lycium barbarum polysaccharides regulating mir-181/bcl-2 decreased autophagy of retinal pigment epithelium with oxidative stress. Oxid Med Cell Longev 2023; 2023: 1-18.
[http://dx.doi.org/10.1155/2023/9554457] [PMID: 36644575]
[10]
Cao C, Zhu B, Liu Z, et al. 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 2021; 12(20): 9829-43.
[http://dx.doi.org/10.1039/D1FO01200B] [PMID: 34664587]
[11]
Wang J, Wei L, Liu C, et al. Taurine treatment alleviates intestinal mucositis induced by 5-fluorouracil in mice. Plant Foods Hum Nutr 2022; 77(3): 399-404.
[http://dx.doi.org/10.1007/s11130-022-00980-5] [PMID: 35788942]
[12]
Wang X, Wang ZY, Zheng JH, Li S. TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med 2021; 19(1): 1-11.
[http://dx.doi.org/10.1016/S1875-5364(21)60001-8] [PMID: 33516447]
[13]
Su Y, Bai Q, Tao H, Xu B. Prospects for the application of traditional Chinese medicine network pharmacology in food science research. J Sci Food Agric 2023; 103(11): 5183-200.
[http://dx.doi.org/10.1002/jsfa.12541] [PMID: 36882903]
[14]
Nicolatou-Galitis O, Bossi P, Orlandi E, René-Jean B. The role of benzydamine in prevention and treatment of chemoradiotherapy-induced mucositis. Support Care Cancer 2021; 29(10): 5701-9.
[http://dx.doi.org/10.1007/s00520-021-06048-5] [PMID: 33649918]
[15]
Jiang SJ, Xiao X, Li , Mu Y. Lycium barbarum polysaccharide-glycoprotein ameliorates ionizing radiation-induced epithelial injury by regulating oxidative stress and ferroptosis via the Nrf2 pathway. Free Radic Biol Med 2023; 204: 84-94.
[http://dx.doi.org/10.1016/j.freeradbiomed.2023.04.020] [PMID: 37119863]
[16]
Shi XQ, Yue SJ, Tang YP, et al. A network pharmacology approach to investigate the blood enriching mechanism of Danggui buxue Decoction. J Ethnopharmacol 2019; 235: 227-42.
[http://dx.doi.org/10.1016/j.jep.2019.01.027] [PMID: 30703496]
[17]
Sun T, Quan W, Peng S, et al. 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 2022; 16: 1621-45.
[http://dx.doi.org/10.2147/DDDT.S357483] [PMID: 35669282]
[18]
Liu Y, Li S, Liu D, Wei H, Wang X, Yan F. Exploration of the potential mechanism of Pushen capsule in the treatment of vascular dementia based on network pharmacology and experimental verification. J Ethnopharmacol 2022; 298: 115632.
[http://dx.doi.org/10.1016/j.jep.2022.115632] [PMID: 35964821]
[19]
Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: Protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43(D1): D447-52.
[http://dx.doi.org/10.1093/nar/gku1003] [PMID: 25352553]
[20]
Zhao R, He Y. 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 2018; 210: 287-95.
[http://dx.doi.org/10.1016/j.jep.2017.08.041] [PMID: 28882624]
[21]
Wang J, Bao B, Meng F, et al. To study the mechanism of Cuscuta chinensis Lam. and Lycium barbarum L. in the treatment of asthenospermia based on network pharmacology. J Ethnopharmacol 2021; 270: 113790.
[http://dx.doi.org/10.1016/j.jep.2021.113790] [PMID: 33460759]
[22]
Zhao Y, Cao Y, Yang X, et al. Network pharmacology-based prediction and verification of the active ingredients and potential targets of Huagan decoction for reflux esophagitis. J Ethnopharmacol 2022; 298: 115629.
[http://dx.doi.org/10.1016/j.jep.2022.115629] [PMID: 35988839]
[23]
Picciolo G, Mannino F, Irrera N, et al. PDRN, a natural bioactive compound, blunts inflammation and positively reprograms healing genes in an “in vitro” model of oral mucositis. Biomed Pharmacother 2021; 138: 111538.
[http://dx.doi.org/10.1016/j.biopha.2021.111538] [PMID: 34311536]
[24]
Pinzi L, Rastelli G. Molecular docking: Shifting paradigms in drug discovery. Int J Mol Sci 2019; 20(18): 4331.
[http://dx.doi.org/10.3390/ijms20184331] [PMID: 31487867]
[25]
Zhang J, Hong Y, Liuyang Z, et al. Quercetin prevents radiation-induced oral mucositis by upregulating BMI-1. Oxid Med Cell Longev 2021; 2021: 1-16.
[http://dx.doi.org/10.1155/2021/2231680] [PMID: 34873428]
[26]
Miazek K, Beton K, Śliwińska A, Brożek-Płuska B. 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. Biomolecules 2022; 12(8): 1087.
[http://dx.doi.org/10.3390/biom12081087] [PMID: 36008981]
[27]
Telfer A. Singlet oxygen production by PSII under light stress: Mechanism, detection and the protective role of β-carotene. Plant Cell Physiol 2014; 55(7): 1216-23.
[http://dx.doi.org/10.1093/pcp/pcu040] [PMID: 24566536]
[28]
Dodda D, Chhajed R, Mishra J, Padhy M. Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: Role of quercetin. Indian J Pharmacol 2014; 46(3): 286-91.
[http://dx.doi.org/10.4103/0253-7613.132160] [PMID: 24987175]
[29]
Tarabasz D, Kukula-Koch W. Palmatine: A review of pharmacological properties and pharmacokinetics. Phytother Res 2020; 34(1): 33-50.
[http://dx.doi.org/10.1002/ptr.6504] [PMID: 31496018]
[30]
Jeong JW, Lee W, Shin S, Kim GY, Choi B, Choi Y. Anthocyanins downregulate lipopolysaccharide-induced inflammatory responses in BV2 microglial cells by suppressing the NF-κB and Akt/MAPKs signaling pathways. Int J Mol Sci 2013; 14(1): 1502-15.
[http://dx.doi.org/10.3390/ijms14011502] [PMID: 23344054]
[31]
Medda R, Lyros O, Schmidt JL, et al. Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells. Microvasc Res 2015; 97: 167-80.
[http://dx.doi.org/10.1016/j.mvr.2014.10.008] [PMID: 25446010]
[32]
Almoiliqy M, Wen J, Xu B, et al. Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53. Acta Pharmacol Sin 2020; 41(9): 1208-22.
[http://dx.doi.org/10.1038/s41401-020-0359-9] [PMID: 32238887]
[33]
Alyoussef A, Taha M. Blocking Wnt as a therapeutic target in mice model of skin cancer. Arch Dermatol Res 2019; 311(8): 595-605.
[http://dx.doi.org/10.1007/s00403-019-01939-4] [PMID: 31165240]
[34]
Chen H, Shen Y, Gong F, Jiang Y, Zhang R. HIF-α promotes chronic myelogenous leukemia cell proliferation by upregulating p21 expression. Cell Biochem Biophys 2015; 72(1): 179-83.
[http://dx.doi.org/10.1007/s12013-014-0434-2] [PMID: 25596666]
[35]
Deben C, Deschoolmeester V, De Waele J, et al. 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. Cancers 2018; 10(4): 126.
[http://dx.doi.org/10.3390/cancers10040126] [PMID: 29690507]
[36]
Li Q, Liu Y, Xia X, et al. 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 2021; 35(5): e21609.
[http://dx.doi.org/10.1096/fj.202100086RR]
[37]
Petrenko O, Li J, Cimica V, et al. IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3. PLoS One 2021; 16(3): e0247394.
[http://dx.doi.org/10.1371/journal.pone.0247394] [PMID: 33651821]
[38]
Ong ZY, Gibson RJ, Bowen JM, et al. Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis. Radiat Oncol 2010; 5(1): 22.
[http://dx.doi.org/10.1186/1748-717X-5-22] [PMID: 20233440]
[39]
Basso FG, Soares DG, Pansani TN, et al. 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 2016; 48(10): 1006-14.
[http://dx.doi.org/10.1002/lsm.22553] [PMID: 27416953]
[40]
Kiyomi A, Yoshida K, Arai C, et al. Salivary inflammatory mediators as biomarkers for oral mucositis and oral mucosal dryness in cancer patients: A pilot study. PLoS One 2022; 17(4): e0267092.
[http://dx.doi.org/10.1371/journal.pone.0267092] [PMID: 35476641]
[41]
Ramírez-Amador V, Zambrano JG, Anaya-Saavedra G, et al. TNF as marker of oral candidiasis, HSV infection, and mucositis onset during chemotherapy in leukemia patients. Oral Dis 2017; 23(7): 941-8.
[http://dx.doi.org/10.1111/odi.12677] [PMID: 28403570]
[42]
Günther C, Martini E, Wittkopf N, et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 2011; 477(7364): 335-9.
[http://dx.doi.org/10.1038/nature10400] [PMID: 21921917]
[43]
Yang JH, Le WD, Basinger SF. Mechanisms of apoptosis in human retinal pigment epithelium induced by TNF-alpha in conditions of heavy metal ion deficiency. Invest Ophthalmol Vis Sci 2005; 46(3): 1039-46.
[http://dx.doi.org/10.1167/iovs.04-0325]
[44]
Linker-Israeli M, Honda M, Nand R, et al. Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC. Clin Immunol 1999; 91(1): 6-16.
[http://dx.doi.org/10.1006/clim.1998.4680] [PMID: 10219249]
[45]
Rossato M, Curtale G, Tamassia N, et al. IL-10–induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci 2012; 109(45): E3101-10.
[http://dx.doi.org/10.1073/pnas.1209100109] [PMID: 23071313]
[46]
Fang D, Zhu J. Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells. Cell Mol Life Sci 2020; 77(2): 289-303.
[http://dx.doi.org/10.1007/s00018-019-03277-0] [PMID: 31432236]
[47]
Freitas MO, Fonseca APR, de Aguiar MT, et al. Tumor necrosis factor alpha (TNF-α) blockage reduces acute inflammation and delayed wound healing in oral ulcer of rats. Inflammopharmacology 2022; 30(5): 1781-98.
[http://dx.doi.org/10.1007/s10787-022-01046-3] [PMID: 35948810]
[48]
Feng CJ, Guo JB, Jiang HW, et al. Spatio-temporal localization of HIF-1α and COX-2 during irradiation-induced oral mucositis in a rat model system. Int J Radiat Biol 2008; 84(1): 35-45.
[http://dx.doi.org/10.1080/09553000701616080] [PMID: 17885826]
[49]
Chen LJ, Xu W, Li YP, et al. Lycium barbarum polysaccharide inhibited hypoxia-inducible factor 1 in COPD patients. Int J Chron Obstruct Pulmon Dis 2020; 15: 1997-2004.
[http://dx.doi.org/10.2147/COPD.S254172] [PMID: 32921997]
[50]
Wang Y, Liu M, Jafari M, Tang J. A critical assessment of traditional Chinese medicine databases as a source for drug discovery. Front Pharmacol 2024; 15: 1303693.
[http://dx.doi.org/10.3389/fphar.2024.1303693] [PMID: 38738181]
[51]
Wang Y, Yang H, Chen L, Jafari M, Tang J. Network-based modeling of herb combinations in traditional Chinese medicine. Brief Bioinform 2021; 22(5): bbab106.
[http://dx.doi.org/10.1093/bib/bbab106] [PMID: 33834186]
[52]
Jafari M, Wang Y, Amiryousefi A, Tang J. Unsupervised learning and multipartite network models: A promising approach for understanding traditional medicine. Front Pharmacol 2020; 11: 1319.
[http://dx.doi.org/10.3389/fphar.2020.01319] [PMID: 32982738]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy