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ISSN (Online): 1873-4286

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Research Article

Exploration of the Mechanisms Underlying Yu's Enema Formula in Treating Ulcerative Colitis by Blocking the RhoA/ROCK Pathway based on Network Pharmacology, High-performance Liquid Chromatography Analysis, and Experimental Verification

Author(s): Binbin Liu, Jie Zhang, Xiaoqi Wang, Wei Ye* and Jiaming Yao*

Volume 30, Issue 14, 2024

Published on: 20 March, 2024

Page: [1085 - 1102] Pages: 18

DOI: 10.2174/0113816128290586240315071044

Price: $65

Abstract

Background: The traditional Chinese medicine formula, Yu's Enema Formula (YEF), has demonstrated potential in the treatment of Ulcerative Colitis (UC).

Objective: This study aimed to unveil the anti-UC mechanisms of YEF.

Methods: Utilizing public databases, we obtained YEF and UC-related targets. GO and KEGG analyses were conducted via clusterProfiler and Reactome. The STRING database facilitated the construction of the PPI network, and hub targets were selected using cytoHubba. We used R software for differential expression and correlation analyses, and molecular docking was performed with PyMOL and AutoDock. HPLC analysis identified the compounds in YEF. For in vivo validation, a UC rat model was employed.

Results and Discussion: 495 YEF-UC overlapping targets were identified. GO and KEGG analyses indicated enrichment in exogenous stimuli response, peptide response, positive MAPK cascade regulation, interleukin- related signaling, and the TLR4 cascade. Hub targets included CTNNB1, JUN, MAPK1, MAPK3, SRC, STAT3, TLR4, TP53, and RELA, which were often interconnected. Molecular docking revealed quercetin's strong binding affinity with CTNNB1, MAPK1, MAPK3, SRC, STAT3, TLR4, and TP53, consistent with HPLC analysis. In vivo experiments suggested that YEF has the potential to alleviate UC symptoms and protect the intestinal mucosal barrier by inhibiting the RhoA/ROCK pathway.

Conclusion: YEF may safeguard the intestinal mucosal barrier in UC by targeting CTNNB1, MAPK1, MAPK3, SRC, STAT3, TLR4, and TP53, while blocking the RhoA/ROCK pathway.

« Previous Next »
[1]
Sun J, Zhao P, Ding X, et al. Cayratia japonica prevents ulcerative colitis by promoting M2 macrophage polarization through blocking the TLR4/MAPK/NF-κB pathway. Mediators Inflamm 2022; 2022: 1-20.
[http://dx.doi.org/10.1155/2022/1108569] [PMID: 36619207]
[2]
You W, Xu Z, Di A, et al. Mechanism by which Tong Xie Yao Fang heals the intestinal mucosa of rats with ulcerative colitis through the Hippo pathway. Evid Based Complement Alternat Med 2021; 2021: 1-11.
[http://dx.doi.org/10.1155/2021/5533914] [PMID: 34504536]
[3]
Yang Y, Song J, Liu N, et al. Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway. Pharmacol Res 2022; 175: 105989.
[http://dx.doi.org/10.1016/j.phrs.2021.105989] [PMID: 34800628]
[4]
Chen J, Shen B, Jiang Z. Traditional Chinese medicine prescription Shenling BaiZhu powder to treat ulcerative colitis: Clinical evidence and potential mechanisms. Front Pharmacol 2022; 13: 978558.
[http://dx.doi.org/10.3389/fphar.2022.978558] [PMID: 36160392]
[5]
Gao H, Liang J, Duan J, et al. A prognosis marker SLC2A3 correlates with EMT and immune signature in colorectal cancer. Front Oncol 2021; 11: 638099.
[http://dx.doi.org/10.3389/fonc.2021.638099] [PMID: 34211835]
[6]
Lai LQ, Ye B. Research of the effect of Yu’s enema on IL-8, IL-10, TNF-α levels to ulcerative colitis rats. Chin J Health Lab Tec 2016; 26: 3221-7.
[7]
Yang YT. Effect of the enema treatment of Yu’s clearing heat and activating blood on β-arrestin 2 signaling pathway in ulcerative colitis. China: Zhejiang Chinese Medical University 2018.
[8]
Jia L, Zhou H, Li W, Lv Z. Network pharmacology integrated molecular docking revealed the mechanism of Jianpi Yiqi Taohua decoction against ulcerative colitis. Med Sci Monit 2022; 28: e933537.
[http://dx.doi.org/10.12659/MSM.933537] [PMID: 35173140]
[9]
Liu BB, Yao JM, Ye W, Wang JL, Yang YT, Wang XQ. Experimental study on the enema treatment of Yu’s clearing heat and activating blood method for ulcerative colitis. Zhejiang J Trad Chin Med 2017; 52: 574-5.
[10]
Song K, Sun Y, Liu H, et al. Network pharmacology and bioinformatics methods reveal the mechanism of berberine in the treatment of ischaemic stroke. Evid Based Complement Alternat Med 2022; 2022: 1-17.
[http://dx.doi.org/10.1155/2022/5160329] [PMID: 35815278]
[11]
Dong Y, Fan H, Zhang Z, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/β-catenin pathway. Int J Biol Sci 2022; 18(4): 1381-97.
[http://dx.doi.org/10.7150/ijbs.65476] [PMID: 35280677]
[12]
Dong Y, Tao B, Xue X, et al. Molecular mechanism of Epicedium treatment for depression based on network pharmacology and molecular docking technology. BMC Complem Med Ther 2021; 21(1): 222.
[http://dx.doi.org/10.1186/s12906-021-03389-w] [PMID: 34479552]
[13]
Yan D, Zheng G, Wang C, et al. HIT 2.0: An enhanced platform for Herbal Ingredients’ Targets. Nucleic Acids Res 2022; 50(D1): D1238-43.
[http://dx.doi.org/10.1093/nar/gkab1011] [PMID: 34986599]
[14]
Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[15]
Huang L, Xie D, Yu Y, et al. TCMID 2.0: A comprehensive resource for TCM. Nucleic Acids Res 2018; 46(D1): D1117-20.
[http://dx.doi.org/10.1093/nar/gkx1028] [PMID: 29106634]
[16]
Safran M, Dalah I, Alexander J, et al. GeneCards Version 3: The human gene integrator. Database (Oxford) 2010; 2010(0): baq020.
[http://dx.doi.org/10.1093/database/baq020] [PMID: 20689021]
[17]
Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res 2020; 48(D1): D845-55.
[PMID: 31680165]
[18]
Kim J, So S, Lee HJ, Park JC, Kim J, Lee H. DigSee: Disease gene search engine with evidence sentences (version cancer). Nucleic Acids Res 2013; 41(W1): W510-7.
[http://dx.doi.org/10.1093/nar/gkt531] [PMID: 23761452]
[19]
Chen H, Boutros PC. VennDiagram: A package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics 2011; 12(1): 35.
[http://dx.doi.org/10.1186/1471-2105-12-35] [PMID: 21269502]
[20]
Legeay M, Doncheva NT, Morris JH, Jensen LJ. Visualize omics data on networks with Omics Visualizer, a Cytoscape App. F1000 Res 2020; 9: 157.
[http://dx.doi.org/10.12688/f1000research.22280.1] [PMID: 32399202]
[21]
Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[22]
Jassal B, Matthews L, Viteri G, et al. The reactome pathway knowledgebase. Nucleic Acids Res 2020; 48(D1): D498-503.
[PMID: 31691815]
[23]
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[24]
Clough E, Barrett T. The gene expression Omnibus database. Methods Mol Biol 2016; 1418: 93-110.
[http://dx.doi.org/10.1007/978-1-4939-3578-9_5] [PMID: 27008011]
[25]
Kim S, Chen J, Cheng T, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021; 49(D1): D1388-95.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[26]
Burley SK, Bhikadiya C, Bi C, et al. RCSB protein data bank: Tools for visualizing and understanding biological macromolecules in 3D. Protein Sci 2022; 31(12): e4482.
[http://dx.doi.org/10.1002/pro.4482] [PMID: 36281733]
[27]
Seeliger D, de Groot BL. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des 2010; 24(5): 417-22.
[http://dx.doi.org/10.1007/s10822-010-9352-6] [PMID: 20401516]
[28]
Feng C, Zhao M, Jiang L, Hu Z, Fan X. Mechanism of modified danggui sini decoction for knee osteoarthritis based on network pharmacology and molecular docking. Evid Based Complement Alternat Med 2021; 2021: 1-11.
[http://dx.doi.org/10.1155/2021/6680637] [PMID: 33628311]
[29]
Elmastaş M, Demir A, Genç N, Dölek Ü, Güneş M. Changes in flavonoid and phenolic acid contents in some Rosa species during ripening. Food Chem 2017; 235: 154-9.
[http://dx.doi.org/10.1016/j.foodchem.2017.05.004] [PMID: 28554620]
[30]
Liu J, Liu J, Tong X, et al. Network Pharmacology prediction and molecular docking-based strategy to discover the potential pharmacological mechanism of Huai Hua San against ulcerative colitis. Drug Des Devel Ther 2021; 15: 3255-76.
[http://dx.doi.org/10.2147/DDDT.S319786] [PMID: 34349502]
[31]
Antoniou E, Margonis GA, Angelou A, et al. The TNBS-induced colitis animal model: An overview. Ann Med Surg (Lond) 2016; 11: 9-15.
[http://dx.doi.org/10.1016/j.amsu.2016.07.019] [PMID: 27656280]
[32]
Yao JM, Liu BB, Ye W, Yang YT, Wang JL, Wang XQ. The influence of Yu’s enema treatment on the expression of β-arrestin1/2, δ-opioid receptor, Bcl-2, and NF-κB in the colonic mucosa of rats with ulcerative colitis models. Zhejiang J Trad Chin Med 2021; 56: 678-9.
[33]
Nan Q, Ye Y, Tao Y, et al. Alterations in metabolome and microbiome signatures provide clues to the role of antimicrobial peptide KT2 in ulcerative colitis. Front Microbiol 2023; 14: 1027658.
[http://dx.doi.org/10.3389/fmicb.2023.1027658] [PMID: 36846795]
[34]
Gao Y, Zhou B, Zhang H, et al. L-Ergothioneine exhibits protective effects against dextran sulfate sodium-induced colitis in mice. ACS Omega 2022; 7(25): 21554-65.
[http://dx.doi.org/10.1021/acsomega.2c01350] [PMID: 35785312]
[35]
Sun Y, Zhang Z, Zheng CQ, Sang LX. Mucosal lesions of the upper gastrointestinal tract in patients with ulcerative colitis: A review. World J Gastroenterol 2021; 27(22): 2963-78.
[http://dx.doi.org/10.3748/wjg.v27.i22.2963] [PMID: 34168401]
[36]
Pravda J. Can ulcerative colitis be cured? Discov Med 2019; 27(149): 197-200.
[PMID: 31361982]
[37]
Gao W, Wang C, Yu L, et al. Chlorogenic acid attenuates dextran sodium sulfate-induced ulcerative colitis in mice through MAPK/ERK/JNK pathway. BioMed Res Int 2019; 2019: 1-13.
[http://dx.doi.org/10.1155/2019/6769789] [PMID: 31139644]
[38]
Ma H, Zhou M, Duan W, Chen L, Wang L, Liu P. Anemoside B4 prevents acute ulcerative colitis through inhibiting of TLR4/NF-κB/MAPK signaling pathway. Int Immunopharmacol 2020; 87: 106794.
[http://dx.doi.org/10.1016/j.intimp.2020.106794] [PMID: 32688280]
[39]
Bai XS, Bai G, Tang LD, Li Y, Huan Y, Wang H. MiR-195 alleviates ulcerative colitis in rats via MAPK signaling pathway. Eur Rev Med Pharmacol Sci 2020; 24(5): 2640-6.
[PMID: 32196614]
[40]
Ma Y, Du Y, Yang J, He Q, Wang H, Lin X. Anti-inflammatory effect of Irisin on LPS-stimulated macrophages through inhibition of MAPK pathway. Physiol Res 2023; 72(2): 235-49.
[http://dx.doi.org/10.33549/physiolres.934937] [PMID: 37159857]
[41]
Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev 2022; 21(3): 103017.
[http://dx.doi.org/10.1016/j.autrev.2021.103017] [PMID: 34902606]
[42]
Shamoun L, Skarstedt M, Andersson RE, Wågsäter D, Dimberg J. Association study on IL-4, IL-4Rα and IL-13 genetic polymorphisms in Swedish patients with colorectal cancer. Clin Chim Acta 2018; 487: 101-6.
[http://dx.doi.org/10.1016/j.cca.2018.09.024] [PMID: 30227113]
[43]
Zhu L, Dai LM, Shen H, et al. Qing Chang Hua Shi granule ameliorate inflammation in experimental rats and cell model of ulcerative colitis through MEK/ERK signaling pathway. Biomed Pharmacother 2019; 116: 108967.
[http://dx.doi.org/10.1016/j.biopha.2019.108967] [PMID: 31102937]
[44]
Yang Q, Ma L, Zhang C, et al. Exploring the mechanism of indigo naturalis in the treatment of ulcerative colitis based on TLR4/MyD88/NF-κB signaling pathway and gut microbiota. Front Pharmacol 2021; 12: 674416.
[http://dx.doi.org/10.3389/fphar.2021.674416] [PMID: 34366843]
[45]
Dai Y, Lu Q, Li P, et al. Xianglian pill attenuates ulcerative colitis through TLR4/MyD88/NF-κB signaling pathway. J Ethnopharmacol 2023; 300: 115690.
[http://dx.doi.org/10.1016/j.jep.2022.115690] [PMID: 36075274]
[46]
Wu X, Wei S, Chen M, et al. P2RY13 exacerbates intestinal inflammation by damaging the intestinal mucosal barrier via activating IL-6/STAT3 pathway. Int J Biol Sci 2022; 18(13): 5056-69.
[http://dx.doi.org/10.7150/ijbs.74304] [PMID: 35982893]
[47]
Wen J, Min X, Shen M, et al. ACLY facilitates colon cancer cell metastasis by CTNNB1. J Exp Clin Cancer Res 2019; 38(1): 401.
[http://dx.doi.org/10.1186/s13046-019-1391-9] [PMID: 31511060]
[48]
Li F, Yan H, Jiang L, Zhao J, Lei X, Ming J. Cherry polyphenol extract ameliorated dextran sodium sulfate-induced ulcerative colitis in mice by suppressing Wnt/β-Catenin signaling pathway. Foods 2021; 11(1): 49.
[http://dx.doi.org/10.3390/foods11010049] [PMID: 35010176]
[49]
Sharma A, Tirpude NV, Kulurkar PM, Sharma R, Padwad Y. Berberis lycium fruit extract attenuates oxi-inflammatory stress and promotes mucosal healing by mitigating NF-κB/c-Jun/MAPKs signalling and augmenting splenic Treg proliferation in a murine model of dextran sulphate sodium-induced ulcerative colitis. Eur J Nutr 2020; 59(6): 2663-81.
[http://dx.doi.org/10.1007/s00394-019-02114-1] [PMID: 31620885]
[50]
Dou B, Hu W, Song M, Lee RJ, Zhang X, Wang D. Anti-inflammation of Erianin in dextran sulphate sodium-induced ulcerative colitis mice model via collaborative regulation of TLR4 and STAT3. Chem Biol Interact 2020; 324: 109089.
[http://dx.doi.org/10.1016/j.cbi.2020.109089] [PMID: 32272095]
[51]
Xue HH, Li JJ, Li SF, et al. Phillygenin attenuated colon inflammation and improved intestinal mucosal barrier in DSS-induced colitis mice via TLR4/Src mediated MAPK and NF-κB signaling pathways. Int J Mol Sci 2023; 24(3): 2238.
[http://dx.doi.org/10.3390/ijms24032238]
[52]
Zheng L, Wen XL, Dai YC. Mechanism of Jianpi Qingchang Huashi Recipe in treating ulcerative colitis: A study based on network pharmacology and molecular docking. World J Clin Cases 2021; 9(26): 7653-70.
[http://dx.doi.org/10.12998/wjcc.v9.i26.7653] [PMID: 34621817]
[53]
Ioannou I, Chatziantoniou A, Drenios C, Christodoulou P, Kourti M, Zaravinos A. Signatures of co-deregulated genes and their transcriptional regulators in kidney cancers. Int J Mol Sci 2023; 24(7): 6577.
[http://dx.doi.org/10.3390/ijms24076577] [PMID: 37047552]
[54]
Luo Y, Yu MH, Yan YR, et al. Rab27A promotes cellular apoptosis and ROS production by regulating the miRNA-124-3p/STAT3/RelA signalling pathway in ulcerative colitis. J Cell Mol Med 2020; 24(19): 11330-42.
[http://dx.doi.org/10.1111/jcmm.15726] [PMID: 32815642]
[55]
Di Petrillo A, Orrù G, Fais A, Fantini MC. Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytother Res 2022; 36(1): 266-78.
[http://dx.doi.org/10.1002/ptr.7309] [PMID: 34709675]
[56]
Zhou H, Yang C, Li J, et al. Quercetin serves as the major component of Xiang-lian pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARγ and dictating the alternative activation of macrophage. J Ethnopharmacol 2023; 313: 116557.
[http://dx.doi.org/10.1016/j.jep.2023.116557] [PMID: 37142141]
[57]
Dicarlo M, Teti G, Verna G, et al. Quercetin exposure suppresses the inflammatory pathway in intestinal organoids from winnie mice. Int J Mol Sci 2019; 20(22): 5771.
[http://dx.doi.org/10.3390/ijms20225771] [PMID: 31744123]
[58]
Zhao Y, Luan H, Jiang H, et al. Gegen Qinlian decoction relieved DSS-induced ulcerative colitis in mice by modulating Th17/Treg cell homeostasis via suppressing IL-6/JAK2/STAT3 signaling. Phytomedicine 2021; 84: 153519.
[http://dx.doi.org/10.1016/j.phymed.2021.153519] [PMID: 33640781]
[59]
Yao D, Dai W, Dong M, Dai C, Wu S. MUC2 and related bacterial factors: Therapeutic targets for ulcerative colitis. EBioMedicine 2021; 74: 103751.
[http://dx.doi.org/10.1016/j.ebiom.2021.103751] [PMID: 34902790]
[60]
Vancamelbeke M, Laeremans T, Vanhove W, et al. Butyrate does not protect against inflammation-induced loss of epithelial barrier function and cytokine production in primary cell monolayers from patients with ulcerative colitis. J Crohn’s Colitis 2019; 13(10): 1351-61.
[http://dx.doi.org/10.1093/ecco-jcc/jjz064] [PMID: 30919886]
[61]
Wang Y, Shou Z, Fan H, et al. Protective effects of oxymatrine against DSS-induced acute intestinal inflammation in mice via blocking the RhoA/ROCK signaling pathway. Biosci Rep 2019; 39(7): BSR20182297.
[http://dx.doi.org/10.1042/BSR20182297] [PMID: 31262973]
[62]
Wang J, Zhang C, Guo C, Li X. Chitosan ameliorates DSS-induced ulcerative colitis mice by enhancing intestinal barrier function and improving microflora. Int J Mol Sci 2019; 20(22): 5751.
[http://dx.doi.org/10.3390/ijms20225751] [PMID: 31731793]
[63]
Yang W, Zhou G, Yu T, et al. Critical role of ROCK2 activity in facilitating mucosal CD4 + T cell activation in inflammatory bowel disease. J Autoimmun 2018; 89: 125-38.
[http://dx.doi.org/10.1016/j.jaut.2017.12.009] [PMID: 29269245]
[64]
Li Z, Gao M, Yang B, et al. Naringin attenuates MLC phosphorylation and NF-κB activation to protect sepsis-induced intestinal injury via RhoA/ROCK pathway. Biomed Pharmacother 2018; 103: 50-8.
[http://dx.doi.org/10.1016/j.biopha.2018.03.163] [PMID: 29635128]
[65]
Guan G, Cannon RD, Coates DE, Mei L. Effect of the Rho-Kinase/ROCK signaling pathway on cytoskeleton components. Genes (Basel) 2023; 14(2): 272.
[http://dx.doi.org/10.3390/genes14020272] [PMID: 36833199]

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