Network Analysis of Anti-inflammatory Phytochemicals and Omics Data
for Rheumatoid Arthritis

Bharathi      Nathan; Archana      Prabahar; Sudheer      Mohammed

doi:10.2174/1573409919666230106125058

Abstract

Background: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects the synovial joints. Nearly 1.6 billion patients are affected by RA worldwide and the incidence of RA is about 0.5 to 1%. Recent studies reveal that immune cell responses and secretion of inflammatory factors are important for the control of RA.

Methods: In this study, a set of 402 phytochemicals with anti-inflammatory properties and 16 target proteins related to anti-inflammatory diseases were identified from the literature and they were subjected to network analysis. The protein-protein interaction (PPI) network was constructed using STRING (Search Tool for the Retrieval of Interacting Genes database) database. Visualization of the target gene-phytochemical network and its protein-protein interaction network was conducted using Cytoscape and further analyzed using MCODE (Molecular Complex Detection). The gene ontology and KEGG pathway analysis was performed using DAVID tool.

Results: Our results from the network approach indicate that the phytochemicals such as Withanolide, Diosgenin, and Butulin could act as potential substitute for anti-inflammatory drugs, including DMARDs. Genes such as Mitogen-activated protein kinase (MAPK) and Interleukin were found as hub genes and acted as best inhibitors for the target protein pathways. Curcumin, Catechin was also found to be involved in various signaling pathways such as NF-kappa B signaling pathway, ErbB signaling pathway and acted as the best inhibitor along with other candidate phytochemicals.

Conclusion: In the current study, we were able to identify Withanolide, Diosgenin, and Butulin as potential anti-inflammatory phytochemicals and determine their association with key pathways involved in RA through network analysis. We hypothesized that natural compounds could significantly contribute to the reduction of dosage, improve the treatment and act as a therapeutic agent for more economical and safer treatment of RA.

« Previous Next »

Graphical Abstract

[1]
Gordon, M-M.; Thomson, E.A.; Madhok, R.; Capell, H.A. Can intervention modify adverse lifestyle variables in a rheumatoid population? Results of a pilot study. Ann. Rheum. Dis.,  2002, 61(1), 66-69.
 [http://dx.doi.org/10.1136/ard.61.1.66] [PMID: 11779763]

[2]
Yap, H.Y.; Tee, S.; Wong, M.; Chow, S.K.; Peh, S.C.; Teow, S.Y. Pathogenic role of immune cells in rheumatoid arthritis: Implications in clinical treatment and biomarker development. Cells,  2018, 7(10), 161.
 [http://dx.doi.org/10.3390/cells7100161] [PMID: 30304822]

[3]
Guo, Q.; Wang, Y.; Xu, D.; Nossent, J.; Pavlos, N.J.; Xu, J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res.,  2018, 6(1), 15.
 [http://dx.doi.org/10.1038/s41413-018-0016-9] [PMID: 29736302]

[4]
Cho, S.K.; Kim, D.; Won, S.; Lee, J.; Choi, C.B.; Choe, J.Y.; Hong, S.J.; Jun, J.B.; Kim, T.H.; Koh, E.; Lee, H.S.; Lee, J.; Yoo, D.H.; Yoon, B.Y.; Bae, S.C.; Sung, Y.K. Factors associated with time to diagnosis from symptom onset in patients with early rheumatoid arthritis. Korean J. Intern. Med.,  2019, 34(4), 910-916.
 [http://dx.doi.org/10.3904/kjim.2017.113] [PMID: 29232938]

[5]
Recio, M.C.; Andujar, I.; Rios, J.L. Anti-inflammatory agents from plants: progress and potential. Curr. Med. Chem.,  2012, 19(14), 2088-2103.
 [http://dx.doi.org/10.2174/092986712800229069] [PMID: 22414101]

[6]
Holroyd, C.R.; Seth, R.; Bukhari, M.; Malaviya, A.; Holmes, C.; Curtis, E.; Chan, C.; Yusuf, M.A.; Litwic, A.; Smolen, S.; Topliffe, J.; Bennett, S.; Humphreys, J.; Green, M.; Ledingham, J. The british society for rheumatology biologic dmard safety guidelines in inflammatory arthritis. Rheumatology,  2019, 58(2), 372.
 [http://dx.doi.org/10.1093/rheumatology/key298] [PMID: 30239912]

[7]
Kourakis, S.; Timpani, C.A.; Campelj, D.G.; Hafner, P.; Gueven, N.; Fischer, D.; Rybalka, E. Standard of care versus new-wave corticosteroids in the treatment of duchenne muscular dystrophy: Can we do better? Orphanet J. Rare Dis.,  2021, 16(1), 117.
 [http://dx.doi.org/10.1186/s13023-021-01758-9] [PMID: 33663533]

[8]
Carbone, F.; Bonaventura, A.; Liberale, L.; Paolino, S.; Torre, F.; Dallegri, F.; Montecucco, F.; Cutolo, M. Atherosclerosis in rheumatoid arthritis: Promoters and opponents. Clin. Rev. Allergy Immunol.,  2020, 58(1), 1-14.
 [http://dx.doi.org/10.1007/s12016-018-8714-z] [PMID: 30259381]

[9]
Voigt, A.; Seipelt, E.; Bastian, H.; Juche, A.; Krause, A. Improved early diagnostics of rheumatic diseases. Z. Rheumatol.,  2018, 77(9), 844-849.
 [http://dx.doi.org/10.1007/s00393-018-0540-4] [PMID: 30255411]

[10]
Iqbal, M.; Verpoorte, R.; Korthout, H.A.A.J.; Mustafa, N.R. Phytochemicals as a potential source for TNF-α inhibitors. Phytochem. Rev.,  2013, 12(1), 65-93.
 [http://dx.doi.org/10.1007/s11101-012-9251-7]

[11]
Murakami, A.; Nishizawa, T.; Egawa, K.; Kawada, T.; Nishikawa, Y.; Uenakai, K.; Ohigashi, H. New class of linoleic acid metabolites biosynthesized by corn and rice lipoxygenases: Suppression of proinflammatory mediator expression via attenuation of mapk- and akt-, but not pparγ-, dependent pathways in stimulated macrophages. Biochem. Pharmacol.,  2005, 70(9), 1330-1342.
 [http://dx.doi.org/10.1016/j.bcp.2005.07.032] [PMID: 16143312]

[12]
Jakovljevic, V.; Veselinovic, M.; Vasiljevic, D.; Jakovljevic, B.; Vucic, V.; Arsic, A.; Petrovic, S. Clinical benefits of n-3-PUFA and gama-linolenic acid in patients with rheumatoid arthritis. Atherosclerosis,  2017, 263, e168-e169.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.537]

[13]
Xagorari, A.; Papapetropoulos, A.; Mauromatis, A.; Economou, M.; Fotsis, T.; Roussos, C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J. Pharmacol. Exp. Ther.,  2001, 296(1), 181-187.
 [PMID: 11123379]

[14]
Javadi, F.; Ahmadzadeh, A.; Eghtesadi, S.; Aryaeian, N.; Zabihiyeganeh, M.; Rahimi Foroushani, A.; Jazayeri, S. The effect of quercetin on inflammatory factors and clinical symptoms in women with rheumatoid arthritis: A double-blind, randomized controlled trial. J. Am. Coll. Nutr.,  2017, 36(1), 9-15.
 [http://dx.doi.org/10.1080/07315724.2016.1140093] [PMID: 27710596]

[15]
Shamekhi, Z.; Amani, R.; Habibagahi, Z.; Namjoyan, F.; Ghadiri, A.; Saki, M.A. A randomized, double-blind, placebo-controlled clinical trial examining the effects of green tea extract on systemic lupus erythematosus disease activity and quality of life. Phytother. Res.,  2017, 31(7), 1063-1071.
 [http://dx.doi.org/10.1002/ptr.5827] [PMID: 28585735]

[16]
Liang, G.; Zhou, H.; Wang, Y.; Gurley, E.C.; Feng, B.; Chen, L.; Xiao, J.; Yang, S.; Li, X. Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin. J. Cell. Mol. Med.,  2009, 13(9b), 3370-3379.
 [http://dx.doi.org/10.1111/j.1582-4934.2009.00711.x] [PMID: 19243473]

[17]
Sen, S.; Chakraborty, R. Toward the integration and advancement of herbal medicine: A focus on traditional Indian medicine. Botanics,  2015, 5, 33-44.
 [http://dx.doi.org/10.2147/BTAT.S66308]

[18]
White, P.T.; Subramanian, C.; Motiwala, H.F.; Cohen, M.S. Natural withanolides in the treatment of chronic diseases. In: Gupta, S.; Prasad, S.; Aggarwal, B.; (eds) Anti-inflammatory Nutraceuticals and Chronic Diseases. Advances in Experimental Medicine and Biology,  2016, 928, 329-373.
 [http://dx.doi.org/10.1007/978-3-319-41334-1_14]

[19]
Khanna, D.; Sethi, G.; Ahn, K.; Pandey, M.; Kunnumakkara, A.; Sung, B.; Aggarwal, A.; Aggarwal, B. Natural products as a gold mine for arthritis treatment. Curr. Opin. Pharmacol.,  2007, 7(3), 344-351.
 [http://dx.doi.org/10.1016/j.coph.2007.03.002] [PMID: 17475558]

[20]
Del Grossi Moura, M.; Cruz Lopes, L.; Silva, M.T.; Barberato-Filho, S.; Motta, R.H.L.; Bergamaschi, C.C. Use of steroid and nonsteroidal anti-inflammatories in the treatment of rheumatoid arthritis. Medicine,  2018, 97(41), e12658.
 [http://dx.doi.org/10.1097/MD.0000000000012658] [PMID: 30313057]

[21]
Bertin, P.; Carpentier, N.; Vergne, P.; Bonnet, C.; Bannwarth, B.; Dehais, J.; Treves, R. Methotrexate and non-steroidal anti-inflammatory agent combination in rheumatoid arthritis. Therapie,  1997, 52(2), 133-137.
 [PMID: 9231508]

[22]
Parra-Izquierdo, V.; Cubides, H.; Rivillas, V.; Frías-Ordoñez, J.S.; Mora, S.; Ermann, J. SAPHO-a diagnosis to consider in patients with refractory costochondritis. Egypt. Rheumatol. Rehabil.,  2022, 49(1), 44.
 [http://dx.doi.org/10.1186/s43166-022-00144-y]

[23]
Zhang, X.; Xu, D.; Chen, M.; Wang, Y.; He, L.; Wang, L.; Wu, J.; Yin, J. Impacts of selected dietary nutrient intakes on skeletal muscle insulin sensitivity and applications to early prevention of type 2 diabetes. Adv. Nutr.,  2021, 12(4), 1305-1316.
 [http://dx.doi.org/10.1093/advances/nmaa161] [PMID: 33418570]

[24]
Ballestar, E. Epigenetic alterations in autoimmune rheumatic diseases. Nat. Rev. Rheumatol.,  2011, 7(5), 263-271.
 [http://dx.doi.org/10.1038/nrrheum.2011.16] [PMID: 21343899]

[25]
Glant, T.T.; Mikecz, K.; Rauch, T.A. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med.,  2014, 12(1), 35.
 [http://dx.doi.org/10.1186/1741-7015-12-35] [PMID: 24568138]

[26]
Saito, Y.; Saito, H.; Liang, G.; Friedman, J.M. Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: A critical review. Clin. Rev. Allergy Immunol.,  2014, 47(2), 128-135.
 [http://dx.doi.org/10.1007/s12016-013-8401-z] [PMID: 24362548]

[27]
Chatzikyriakidou, A.; Voulgari, P.V.; Georgiou, I.; Drosos, A.A. miRNAs and related polymorphisms in rheumatoid arthritis susceptibility. Autoimmun. Rev.,  2012, 11(9), 636-641.
 [http://dx.doi.org/10.1016/j.autrev.2011.11.004] [PMID: 22100329]

[28]
Ceribelli, A.; Yao, B.; Dominguez-Gutierrez, P.R.; Nahid, M.A.; Satoh, M.; Chan, E.K.L. MicroRNAs in systemic rheumatic diseases. Arthritis Res. Ther.,  2011, 13(4), 229.
 [http://dx.doi.org/10.1186/ar3377] [PMID: 21787439]

[29]
Birlea, S.A.; Gowan, K.; Fain, P.R.; Spritz, R.A. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J. Invest. Dermatol.,  2010, 130(3), 798-803.
 [http://dx.doi.org/10.1038/jid.2009.347] [PMID: 19890347]

[30]
Bharathi, N.; Kavinkumar, N.K.; Mohammed, S.M. Aip base-a comprehensive database on anti-inflammatory plants. Res. J. Life Sci. Bioinform. Pharm. Chem. Sci.,  2019, 5(6), 49-63.

[31]
Nathan, B.; Mohammed, S.M.M. An insight into anti-arthritic property of phytochemicals against rheumatoid arthritis using molecular modelling and docking approach. Res. J. Biotechnol.,  2021, 16(12), 185-195.
 [http://dx.doi.org/10.25303/1612rjbt185195]

[32]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res.,  2003, 13(11), 2498-2504.
 [http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]

[33]
Maere, S.; Heymans, K.; Kuiper, M. BiNGO: A cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics,  2005, 21(16), 3448-3449.
 [http://dx.doi.org/10.1093/bioinformatics/bti551] [PMID: 15972284]

[34]
Bindea, G.; Mlecnik, B.; Hackl, H.; Charoentong, P.; Tosolini, M.; Kirilovsky, A.; Fridman, W.H.; Pagès, F.; Trajanoski, Z.; Galon, J.; Clue, G.O. A cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics,  2009, 25(8), 1091-1093.
 [http://dx.doi.org/10.1093/bioinformatics/btp101] [PMID: 19237447]

[35]
Dennis, G., Jr; Sherman, B.T.; Hosack, D.A.; Yang, J.; Gao, W.; Lane, H.C.; Lempicki, R.A. DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol.,  2003, 4(5), 3.
 [http://dx.doi.org/10.1186/gb-2003-4-5-p3] [PMID: 12734009]

[36]
Bader, G.D.; Hogue, C.W.V. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics,  2003, 4(1), 2.
 [http://dx.doi.org/10.1186/1471-2105-4-2] [PMID: 12525261]

[37]
Prabahar, A.; Natarajan, J. MicroRNA mediated network motifs in autoimmune diseases and its crosstalk between genes, functions and pathways. J. Immunol. Methods,  2017, 440, 19-26.
 [http://dx.doi.org/10.1016/j.jim.2016.10.002] [PMID: 27729225]

[38]
Prabahar, A.; Natarajan, J. Prediction of microRNAs involved in immune system diseases through network based features. J. Biomed. Inform.,  2017, 65, 34-45.
 [http://dx.doi.org/10.1016/j.jbi.2016.11.003] [PMID: 27871823]

[39]
Seo, E.J.; Efferth, T.; Panossian, A. Curcumin downregulates expression of opioid-related nociceptin receptor gene (OPRL1) in isolated neuroglia cells. Phytomedicine,  2018, 50, 285-299.

[40]
Kim, C.S.; Kawada, T.; Kim, B.S.; Han, I.S.; Choe, S.Y.; Kurata, T.; and Yu, R. 2003. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell. Signal.,  2003, 15(3), 299-306.
 [http://dx.doi.org/10.1016/50898-6568(02)00086-4] [PMID: 12531428]

[41]
Filippi, A.; Ciolac, O.A.; Ganea, C.; Mocanu, M.M.; Erb, B. Proteins as Molecular Target of Dietary Phytochemicals in Malignant Diseases. J. Oncol.,  2017, 2017, 1532534.

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1573409919666230106125058	Print ISSN 1573-4099
Publisher Name Bentham Science Publisher	Online ISSN 1875-6697

Current Computer-Aided Drug Design

Network Analysis of Anti-inflammatory Phytochemicals and Omics Data for Rheumatoid Arthritis

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract