Original Article Utilizing network pharmacology to explore the underlying mechanism of Cinnamomum cassia Presl in treating osteoarthritis

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Int J Clin Exp Med 2019;12(12):13359-13369 www.ijcem.com /ISSN:1940-5901/IJCEM0100310. Original Article Utilizing network pharmacology to explore the underlying mechanism of Cinnamomum cassia Presl in treating osteoarthritis. Guowei Zhou, Ruoqi Li, Tianwei Xia, Chaoqun Ma, Jirong Shen. Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China. Received July 30, 2019; Accepted October 8, 2019; Epub December 15, 2019; Published December 30, 2019. Abstract: Objective: The network pharmacology method was adopted to establish the relationship between “Ingre- dients-Disease Targets-Biological Pathway”, screen the potential target of Cinnamomum cassia Presl in treating osteoarthritis (OA), and explore the underlying mechanism. Methods: Chemical components and selected targets related to Cinnamomum cassia Presl were retrieved from BATMAN-TCM. OA disease targets were searched from TTD, DrugBank, OMIM, GAD, PharmGKB, and DisGeNET databases. Canonical SMILES were obtained from Pub- chem, and targets were obtained from SwissTargetPrediction. We constructed a target interaction network graph by using the STRING database and Cytoscape 3.2.1, and screened key targets by using the MCC algorithm of cytoHubba. Enrichment analysis of the GO function and KEGG pathway was conducted using the DAVID database. Results: Eighteen active compounds derived from Cinnamomum cassia Presl and 40 intersections between Cin- namomum cassia Presl and OA were obtained. Ten key targets were screened by the MCC algorithm, including PTGS2, MAPK8, MMP9, ALB, MMP2, MMP1, SERPINE1, TGFB1, PLAU, and ESR1. The GO analysis consisted of 33 enrichment results, including biological processes (e.g., collagen catabolic process and inflammatory response), cell composition (e.g., extracellular space and extracellular matrix), and molecular function (e.g., heme binding and aromatase activity). A total of 32 pathways were enriched by KEGG, including osteoclast differentiation, arachidonic acid metabolism, hypoxia-inducible factor (HIF)-1, nuclear factor кB (NF-кB), Toll-like receptors (TLRs), and tumor necrosis factor (TNF). Conclusion: This study predicted the main possible mechanism of Cinnamomum cassia Presl in treating OA, including anti-inflammation, regulating cellular proliferation, differentiation and apoptosis, and an- tioxidation, which provided a theoretical basis for exploring active ingredients and experimental research about Cinnamomum cassia Presl against OA.. Keywords: Network pharmacology, Cinnamomum cassia Presl, osteoarthritis, mechanism. Introduction. Osteoarthritis (OA) is a chronic disease that occurs in articular cartilage and impacts the ligaments, synovium, articular capsule and subchondral bone, leading to joint deformity and loss of function [1]. OA is a common dis- ease in middle-aged and elderly patients, and the disability rate is > 50% [2]. The etiology of OA is still unclear [3]. Modern medicine can only relieve symptoms and many of them also have side effects [4]. It is of great value to exca- vate potential active ingredients for the treat- ment of OA from traditional Chinese medicine. OA is often referred to as “bi zheng” in ancient Chinese medical books. Traditional Chinese medicine often used Cinnamomum Cassia to treat OA.. Cinnamomum Cassia is the dry bark of Cin- namomum cassia. Modern pharmacologic stu- dies have found that cinnamaldehyde and other monomers in Cinnamomum Cassia have the following properties: anti-inflammatory; regulat- ing cell proliferation; antioxidant and other ther- apeutic effects on OA [5, 6]. The toxicity is rela- tively small. These studies indicated that Cin- namomum Cassia have the potential ability to treat OA; however, Cinnamomum Cassia has multi-component characteristics, and its mech- anism is relatively complex.. As a new research method, network pharmacol- ogy breaks away from the traditional research mode of “one target, one disease, one drug” [7]. The systematism of the strategy resonates well with the holistic view of traditional Chinese. http://www.ijcem.com. Underlying mechanism of Cinnamomum cassia Presl against OA. 13360 Int J Clin Exp Med 2019;12(12):13359-13369. medicine (TCM), as well as the mechanism of multi-ingredient, multi-pathway, and multi-tar- get synergy in TCM [8]. In recent years, many related research reports indicate that exploring the molecular mechanism of TCM efficacy will become possible [9-11]. This study analyzed the active ingredients, targets, and possible mechanisms of Cinnamomum cassia approach network pharmacology to uncover the pharma- cological mechanism of Cinnamomum Cassia acting on OA. The workflow of the study on Cinnamomum Cassia against OA based on net- work pharmacology was shown in Figure 1.. Methods. Active compounds screening of cinnamomum cassia. BATMAN-TCM (http://bionet.ncpsb.org/batman- tcm), an online bioinformatics analysis data-. base, can be used for target prediction of tradi- tional Chinese medicine components, function- al analysis of targets, visualization of related networks, and comparative analysis of tradi- tional Chinese medicine. The active compounds in Cinnamomum Cassia were collected from the BATMAN-TCM (http://bionet.ncpsb.org/ba- tman-tcm) database (with “ROUGUI” as the search term) [12].. Target fishing of cinnamomum cassia. All active compounds in Cinnamomum Cassia were input to the Pubchem database (https:// pubchem.ncbi.nlm.nih.gov/) to obtain the Can- onical SMILES. SwissTargetPrediction (http:// www.swisstargetprediction.ch/) is a network platform that can predict small molecule tar- gets on the basis of the 2D and 3D similarity measurements of ligands [13]. First, the Can-. Figure 1. Flowchart of utilizing net- work pharmacology to explore the un- derlying mechanism of Cinnamomum cassia Presl in treating osteoarthritis.. Underlying mechanism of Cinnamomum cassia Presl against OA. 13361 Int J Clin Exp Med 2019;12(12):13359-13369. onical SMILES of compounds were submitted to the platform. Then, the property was set to “Homo Sapiens” to obtain the predicted tar- gets. The active compounds obtained from BA- TMAN-TCM were uploaded to the GeneCards database (https://www.genecards.org/), the human gene compendium [14], with the prop- erty set to “Homo Sapiens”. The intersections of GeneCards and SwissTargetPrediction were the targets of Cinnamomum Cassia.. Disease targets database building and col- lection of cinnamomum cassia-OA common target. The OA-associated disease targets were sea- rched from TTD (https://db.idrblab.org/ttd/), DrugBank (https://www.drugbank.ca/), OMIM (http://www.omim.org/), GAD (https://geneti- cassociationdb.nih.gov/), PharmGKB (https:// www.pharmgkb.org/), and DisGeNET (http:// www.disgenet.org/web/DisGeNET/menu/home) 6 databases with “osteo-arthritis” as a key word. The common targets of Cinnamomum Cassia and OA were obtained.. Construction of network and analysis. The active compounds and common targets were put into Cytoscape 3.2.1 to draw “Drug- Compounds-Targets Network”. The common targets were also uploaded to the STRING data- base (http://string-db.org/) for building a pro- tein interaction network. Next, the MCC algo- rithm of the cytoHubba plug-in of the Cytoscape 3.2.1 was used to screen key targets [15].. Enrichment analysis of the go function and kegg pathway. Database for Annotation, Visualization and Integrated Discovery (DAVID, https://david.ncif- crf.gov/, v6.8) was used for gene ontology (GO) enrichment analysis. Pathway enrichment anal- ysis was accomplished using Kyoto Ency- clopedia of Genes and Genomes (KEGG, http:// www.kegg.jp/) data obtained from DAVID [16].. Results. Active compounds of cinnamomum cassia. A total of 18 active herbal ingredients were retrieved from the BATMAN-TCM (Table 1). They are cinnamic aldehyde (cinnamaldhyde), pro-. anthocyanidin B2, coumarin, melilotocarpan A, cinnamyl benzoate, cinnamyl alcohol, anethole, procyanidin B1, procyanidin B5, protocatechuic acid, cinnamyl acetate, procyanidin C1, (-)-epi- catechin-3-o-gallate, trans-cinnamic acid, ethyl cinnamate, cinnamic ccid, styrene, and procy- anidin B7.. Prediction and analysis active compound tar- gets of Cinnamomum cassia. Eight hundred twenty-one targets were ob- tained, which were reduced to 335 after dupli- cation removal. A total of 3247 targets were screened from the GeneCards database, and 1396 after banishing duplication. There were 169 targets in GeneCards and SwissTarget- Prediction (Figure 2). Then, the “compound-pre- dicted” network was built by Cytoscape 3.2.1 software (Figure 3).. Collection of OA targets and acquisition of cin- namomum cassia (RG)-OA common targets. Six hundred four targets were obtained from six databases, and the number was reduced to 531 after removing duplication. Forty common targets were obtained that intersected with Cinnamomum Cassia (RG)-associated targets (Figure 4). They are ABCC1, C1R, AKR1C1, CA3, BCHE, CA2, MMP13, CTSK, PLAU, MMP1, SERPINE1, ADAM17, BCL2, TGFB1, MMP2, MM- P9, AR, NFKB1, MAPK8, ALB, PTGS2, ESR1, TLR9, ESR2, NOS2, CYP19A1, CYP1A1, ACHE, CYP1A2, CYP2C19, ABCB1, PTGS1, CES1, AK- R1C3, AKR1B1, PLA2G2A, ALOX5, MPO, TTR, and TDO2.. Forty targets were uploaded to the STRING database to draw the Protein-Protein Interaction (PPI) network (Figure 5A). There were 39 nodes (isolated nodes were removed) and 184 sides (network nodes represent targets, and lines represent the interactions of targets). The aver- age node degree was 9.2. “Cinnamomum Ca- ssia (RG)-Compounds-Targets Network” was drawn by Cytoscape 3.2.1 (Figure 5B). The in- formation on protein interactions was uploaded to the Cytoscape 3.2.1, and the MCC algorithm (the higher the score, the higher the signifi- cance) of the cytoHubba plug-in was used to screen out 10 key targets (Figure 5C). Key tar- gets that rank from more importance-to-less importance are PTGS2, MAPK8, MMP9, ALB,. Underlying mechanism of Cinnamomum cassia Presl against OA. 13362 Int J Clin Exp Med 2019;12(12):13359-13369. Table 1. Basic information of 18 candidate compounds of Cinnamomum cassia Compound Pubchem ID Canonical SMILES Cinnamic Aldehyde/Cinnamaldehyde 637511 C1=CC=C(C=C1)C=CC=O Proanthocyanidin B2 122738 C1C(C(OC2=C1C(=CC(=C2C3C(C(OC4=CC(=CC(=C34)O)O). C5=CC(=C(C=C5)O)O)O)O)O)C6=CC(=C(C=C6)O)O)O Coumarin 323 C1=CC=C2C(=C1)C=CC(=O)O2 Melilotocarpan A 4484393 COC1=CC2=C(C=C1)C3COC4=C(C3O2)C=CC(=C4O)OC Cinnamyl benzoate 5705112 C1=CC=C(C=C1)C=CCOC(=O)C2=CC=CC=C2 Cinnamyl alcohol 5315892 C1=CC=C(C=C1)C=CCO Anethole 637563 CC=CC1=CC=C(C=C1)OC Procyanidin B1 11250133 C1C(C(OC2=C1C(=CC(=C2C3C(C(OC4=CC(=CC(=C34)O)O). C5=CC(=C(C=C5)O)O)O)O)O)C6=CC(=C(C=C6)O)O)O Procyanidin B5 124017 C1C(C(OC2=CC(=C(C(=C21)O)C3C(C(OC4=CC(=CC(=C34)O). O)C5=CC(=C(C=C5)O)O)O)O)C6=CC(=C(C=C6)O)O)O Protocatechuic Acid 72 C1=CC(=C(C=C1C(=O)O)O)O Cinnamyl acetate 5282110 CC(=O)OCC=CC1=CC=CC=C1 Procyanidin C1 169853 C1C(C(OC2=C1C(=CC(=C2C3C(C(OC4=C(C(=CC(=C34)O). O)C5C(C(OC6=CC(=CC(=C56)O)O)C7=CC(=C(C=C7)O)O)O) C8=CC(=C(C=C8)O)O)O)O)O)C9=CC(=C(C=C9)O)O)O. (-)-Epicatechin-3-O-Gallate 107905 C1C(C(OC2=CC(=CC(=C21)O)O)C3=CC(=C(C=C3)O)O) OC(=O)C4=CC(=C(C(=C4)O)O)O. Trans-Cinnamic Acid 444539 C1=CC=C(C=C1)C=CC(=O)O Ethyl cinnamate 637758 CCOC(=O)C=CC1=CC=CC=C1 Cinnamic Acid 444539 C1=CC=C(C=C1)C=CC(=O)O Styrene 7501 C=CC1=CC=CC=C1 Procyanidin B7 474541 C1C(C(OC2=CC(=C(C(=C21)O)C3C(C(OC4=CC(=CC(=C34)O). O)C5=CC(=C(C=C5)O)O)O)O)C6=CC(=C(C=C6)O)O)O. Figure 2. Venn diagram of Cinnamomum cassia targets. The blue circle rep- resents the targets predicted by the Genecards, and the red circle repre- sents the targets predicted by the SwissTargetPrediction.. Enrichment analysis of the go function and kegg pathway. A total of 48 GO enrichment results were obtained during this study, and 33 results were screened out according to P < 0.05. The top 20 results were shown in Table 2. They are col- lagen catabolic process, he- me binding, extracellular spa- ce, extracellular matrix, aro- matase activity, and so on.. Similarly, 36 KEGG enrich- ment results were obtained in this analysis, and 28 results were collected based on the threshold of P < 0.05. The Top 20 results were shown in Figure 6. They are pathways in cancer, toxoplasmosis, Chag- as disease, MicroRNAs in can-. MMP2, MMP1, SERPINE1, TGFB1, PLAU, and ESR1.. cer, tuberculosis, ovarian steroidogenesis, Lei- shmaniasis, prolactin signaling pathway, hepa-. Underlying mechanism of Cinnamomum cassia Presl against OA. 13363 Int J Clin Exp Med 2019;12(12):13359-13369. Figure 3. Compound-predicted targets network. The square nodes represent the compounds of Cinnamomum Cassia, the round nodes represent the targets. The node color changes from orange-to-blue reflect the degree value changes from low-to-high in the network.. Underlying mechanism of Cinnamomum cassia Presl against OA. 13364 Int J Clin Exp Med 2019;12(12):13359-13369. titis B, small cell lung cancer, NF-kappaB signal- ing pathway, estrogen signaling pathway, HIF-1 signaling pathway, proteoglycans in cancer, toll- like receptor signaling pathway, TNF signaling pathway, bladder cancer, Sphingolipid signaling pathway, tryptophan metabolism, and osteo- clast differentiation.. Discussion. According to the investigations, it was suggest- ed that the global age-standardized prevalence of knee OA is 3.8% [1]. With the development of molecular biology, disease-modifying osteoar- thritis drugs have become a major focus of research. The positive effects and relatively small toxicity of Cinnamomum Cassia in treat- ing OA have attracted the attention of scien- tists and researchers [5, 6].. Eighteen compounds of Cinnamomum Cassia were retrieved from the BATMAN-TCM database in this study. The targets of such compounds were further predicted by Swisstarget predic- tion and were obtained in combination with GeneCards database retrieval, thus 169 Cinna- momum Cassia-associated targets were ob- tained. OA-associated targets were retrieved from the 6 online databases. A total of 40 in- tersection targets between OA targets and Cinnamomum Cassia-associated targets were obtained. It can be seen from the PPI diagram and the “drug-compounds-targets” diagram. stream pathways are included. For example, downstream pathways of cancer signaling pa- thways include the Wnt signaling pathway, Hedgehog signaling pathway, Notch signaling pathway, MAPK signaling pathway, and vas- cular endothelial growth factor signaling pa- thways.. In combination with the common OA signaling pathways and after the exclusion of cancer- associated pathways and other broad path- ways, Cinnamomum Cassia can be predicted to have effects in treating OA by an anti-inflamma- tory effect, and mediate cell proliferation, dif- ferentiation, and apoptosis, thus promoting the balance between osteoblast (OB) and osteo- clast (OC) and the antioxidant effects. . Anti-inflammatory. Enrichment analysis results showed that the inflammation-associated signaling pathways mainly enrich NF-кB, TLRs, TNF, arachidonic acid metabolism-associated signaling path- ways and other signaling pathways. Inflam- matory factors, such as IL-1β, play an important role in the pathogenesis of OA [17]. IL-1β is an important inflammatory factor causing OA and can aggravate OA-associated inflammation by activating NF-κB and other signaling pathways, leading to an increase in protease expression in the downstream of inflammatory reaction, accelerating the degradation of proteoglycan. Figure 4. Venn diagram of the common targets both in Cinnamomum Cas- sia (RG) and OA targets network construction and analysis. The blue circle represents the 169 targets with RG, and the yellow circle represents the 531 targets with OA.. that the active compounds of Cinnamomum Cassia have more than one targets. Such targets can also interact with multiple compounds. More- over, 10 key targets can be further obtained from the MCC algorithm of the cytoHub- ba plug-in of Cytoscape 3.2.1. There are PTGS2, MAPK8, MMP9, ALB, MMP2, MMP1, SERPINE1, TGFB1, PLAU, and ESR1. The results of KEGG pathway enrichment showed that pathways in cancer, To- xoplasmosis, Chagas disease, microRNAs in cancer, and tu- berculosis were the most sig- nificant signaling pathways (Figure 3). These pathways are complex and many down-. Underlying mechanism of Cinnamomum cassia Presl against OA. 13365 Int J Clin Exp Med 2019;12(12):13359-13369. Figure 5. A. Protein-protein interaction. B. Drug- Compound-Target Network. The red squares rep- resent the drug, Cinnamomum Cassia (RG); green triangles represent compounds; and yellow rounds represent targets. C. Key Target Proteins. The node color changes from yellow-to-red reflect the MCC value changes from low-to-high in the network.. Underlying mechanism of Cinnamomum cassia Presl against OA. 13366 Int J Clin Exp Med 2019;12(12):13359-13369. and collagen, and damaging articular cartilage [18-23]. The preliminary study of this research group showed that cinnamaldehyde can pro- tect cartilage by mediating signal pathways such as NF-κB to resist IL-1β-induced inflamma- tion on chondrocytes [6]. In addition, type-A procyanidine polyphenols extracted from the bark of Cinnamomum zeylanicum was also reported to have disease-modifying potential in animal models of inflammation and arthritis in rats [24]. Youn et al. have reported that cinnam- aldehyde suppressed the activation of NF-κB and IRF3 induced by LPS, leading to the de- creased expression of target genes, such as cyclooxygenase-2 (COX-2) and Interferon-β (IFN-β), in RAW264.7 macrophages [25]. . Mediate cell proliferation, differentiation, apoptosis, and promote the balance between OB and OC. In the enrichment results, such OC differentia- tion-related pathways, such as HIF-1, and the downstream pathways of cancer signaling pa- thways, such as the Wnt [26] and MAPK signal- ing pathways, are also closely correlated to such effects [27]. Wang et al. found that a high concentration of cinnamaldehyde significantly inhibits the growth of synovial fibroblasts in OA. patients [28]. Wu et al. found that administra- tion of cinnamaldehyde promotes osteogenesis in ovariectomized rats and differentiation of osteoblast in vitro [29]. The results of western blot supported that cinnamaldehyde promotes the maturation and differentiation of osteo- blasts for cinnamaldehyde and apparently en- hances the expression of runx2, ocn and col1a1 [29]. Moreover, with the treatment of cinnamal- dehyde, the number of osteoclasts in ovariecto- mized rats is gradually decreased, so bone resorption activity was inhibited [29]. Zhang et al. found that cinnamaldehyde inhibits prolifer- ation and bone resorption of osteoclast induced by dexamethasone, which may be mediated by down-regulation of receptor activator of NF kappaB (RANK) and nuclear factor of activating T cells 1 (NFATc1) mRNA [30].. Antioxidant effects. Previous studies have shown that the mito- chondrial dysfunction of chondrocytes and synovial cells in patients with OA produces a large amount of NO and reactive oxygen spe- cies, which can cause oxidative damage. Accor- ding to the previous study, cinnamaldehyde can increase the activity of catalase, superox- ide dismutase and glutathione peroxidase, and. Table 2. GO entries of targets (P < 0.05) Category GO ID Discription Genes P Value BP GO:0030574 collagen catabolic process 5 8.18E-09 MF GO:0020037 heme binding 8 4.07E-08 CC GO:0005615 extracellular space 12 1.23E-06 CC GO:0031012 extracellular matrix 5 7.00E-05 MF GO:0070330 aromatase activity 3 1.54E-04 MF GO:0004222 metalloendopeptidase activity 5 2.26E-04 MF GO:0004601 peroxidase activity 3 6.68E-04 BP GO:0045893 positive regulation of transcription, DNA-templated 5 0.001653109 MF GO:0005496 steroid binding 3 0.001704889 MF GO:0008270 zinc ion binding 9 0.003388197 MF GO:0005506 iron ion binding 4 0.005819584 MF GO:0003990 acetylcholinesterase activity 2 0.006506693 BP GO:0010469 regulation of receptor activity 2 0.007896778 MF GO:0004497 monooxygenase activity 3 0.008190211 BP GO:0006979 response to oxidative stress 3 0.008534181 CC GO:0072562 blood microparticle 3 0.009127845 BP GO:0001666 response to hypoxia 3 0.009166887 MF GO:0004666 prostaglandin-endoperoxide synthase activity 2 0.009744585 BP GO:0019371 cyclooxygenase pathway 2 0.010515617 BP GO:0006954 inflammatory response 4 0.012832271. Underlying mechanism of Cinnamomum cassia Presl against OA. 13367 Int J Clin Exp Med 2019;12(12):13359-13369. inhibit the oxidation of chondrocytes. Cinna- momum Cassia polyphenols also have strong reducibility [31]; and the higher the content, the stronger the antioxidant ability [32]. In addition, enrichment analysis results showed that the estrogen, prolactin, sphingolipid, and other sig- naling pathways indirectly affect the growth and repair of articular cartilage, thus playing a role in treating OA.. Conclusion. In conclusion, the complex mechanism of Cin- namomum Cassia in treating OA with multiple components, targets, and pathways was stud- ied with a theoretical approach in this study by. network pharmacology to provide thoughts and a basis for future studies. Due to the limitation of certain conditions, this study had the follow- ing shortcomings. First, TCM often uses Cin- namomum Cassia as a decoction, but this study did not consider the absorption and metabolism of monomers in the body. Second, the content of different compounds in Cin- namomum Cassia and the interactions (syner- gism or antagonism) between monomers after oral administration were not taken into account. Third, the number of Cinnamomum Cassia-OA intersection targets obtained was small. We believe that with the development of technolo- gy and in-depth study, the underlying mecha-. Figure 6. KEGG pathway entries of targets.. Underlying mechanism of Cinnamomum cassia Presl against OA. 13368 Int J Clin Exp Med 2019;12(12):13359-13369. nisms of Cinnamomum Cassia in treating OA will be more adequately revealed.. Acknowledgements. We are grateful to all the coworkers and part- ners in this study. This work was supported by Jiangsu Province Hospital of Chinese Medicine Project (Y2018CX54).. Disclosure of conflict of interest. None.. Abbreviations. OA, Osteoarthritis; TCM, traditional Chinese me- dicine; NF-Κb, nuclear factor-kappa B; MAPKs, mitogen-activated protein kinase; HIF, hypoxia- inducible factor-1; NF-кB, nuclear factor кB; TLRs, Toll-like receptors; TNF, tumor necrosis factor; LPS, lipopolysaccharide; COX-2, cyclo- oxygenase-2; IFN-β, interferon-β; OB, osteo- blast; OC, osteoclast; RANK, receptor activator of NF kappaB; NFATc1, nuclear factor of activat- ing T cells 1.. Address correspondence to: Chaoqun Ma and Jirong Shen, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China. E-mail: mcq_1964@sina.com (CQM); joint- 66118@sina.com (JRS). References. [1] Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A and March L. The global burden of hip and knee osteoarthri- tis: estimates from the global burden of dis- ease 2010 study. 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