The Network Pharmacology Study And Molecular Docking To Investigate The Potential Mechanism of Acoritataninowii Rhizoma Against Alzheimer's Disease

Background and objective: Alzheimer's Disease (AD) is considered as a progressively developing neurodegenerative disease with an insidious onset that induces increased cost of social burden and decreased quality of life. Acoritataninowii Rhizoma produced the effects of resuscitating and eliminating phlegm, dispelling dampness and appetizing, refreshing mind and nourishing the mind, and exerted the activities of anti-dementia and improving learning and memory. while little was relevant to its anti-AD mechanism. The present study explored the potential mechanism of Acoritataninowii Rhizoma defend AD by network pharmacology and molecular docking. Methods: The bioactive ingredients of Acoritataninowii Rhizoma were screened by absorption, distribution, metabolism as well as excretion evaluation and obtained from databases retrieval. Genes associated with AD or ingredients were searching by databases, and the overlapping genes between AD and ingredients were analyzed by the Venn diagram. Moreover, the network of Acoritataninowii Rhizoma-ingredients-targets-AD was visualized by cytoscape software. Furthermore, protein-protein interaction, gene ontology, pathway enrichment and molecular docking were conducted to evaluate potential factors of Acoritataninowii Rhizoma against AD. Results: 4 potential compounds were considered as bioactive ingredients after screening ADME. 81 ingredients-related genes and 6765 AD-related genes were screened by databases with 61 overlapping genes. The bioactive ingredients derived from Acoritataninowii Rhizoma (e.g Cycloartenol, (1R,3aS,4R,6aS)-1,4-bis(3,4-dimethoxyphenyl)-1,3,3a,4,6,6a-hexahydrofuro[4,3-c]furan, 8-Isopentenyl-kaempferol, kaempferol) and target proteins (e.g AKT1, JUN, ESR1, CASP3, MAPK14, RELA) with high degree in the network were associated with in mitogen-activated protein kinase (MAPK) of DNA-binding transcription factor. Moreover, Acoritataninowii Rhizoma might play a signicant in the treatment of AD which induced Fluid shear stress and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, Epstein-Barr virus infection, AGE-RAGE signaling pathway in diabetic complications. Conclusion: The bioactive ingredients and potential mechnism of Acoritataninowii Rhizoma defended AD was analyzed by network pharmacology and molecular docking. This study provided a research basis and scientic evidence for supporting the activities of Acoritataninowii Rhizoma against AD. to provide the feasibility of Acoritataninowii Rhizoma for the therapy of AD and reliable information. This research was conducted in the following steps: (1) the ingredients of Acoritataninowii Rhizoma and its corresponding targets and AD-related DPP4, PRSS1, VCAM1, GSTP1, PRKACA, AHR, CYP1A1, KCNMA1, CDK2, PGR, SLC2A4, SLPI, PIK3CG, NR1I2, RXRA, CHEK1, PSMD3, CCNA2, HAS2, HSP90AB1, PIM1, TOP2B, AHSA1, DIO1, PYGM, SCN5A. Overlapping genes accounted for 0.9% of the total genes, indicating that the inuence of Acoritataninowii Rhizoma on AD was possibly associated with above-mentioned multiple overlapping genes. 7B), it could be known that the number of nodes is 57 and the number of edges is 131. Other meaningful parameters were further tested, such as network density (0.082), network centralization (0.174), average number of neighbors (4.596), network heterogeneity (0.690). The cellular components and target gene with maximum degree were GO:0045121 (14) and SCN5A (10), respectively. The results showed that the pharmacological effects of bioactive ingredients of Acoritataninowii Rhizoma on were closely linked to MAPK-coupled receptor activity or signal pathways. In addition, the transcription factors have a signicant impact on signal transduction. was as followed: AKT1 (-6.04 to -9.07 kcal/mol), CASP3 (-6.14 to -7.9 kcal/mol), ESR1 (-5.65 to -10.85 kcal/mol), JUN (-6.31 to -8.98) and MAPK14 (-6.63 to -9.29 kcal/mol). Additionally, the highest binding anity of each biologically active ingredient was as followed: MOL00042 (ESR1: -6.92 kcal/mol), MOL003542 (CASP3: -6.96 kcal/mol), MOL003576 (CASP3: -7.9 kcal/mol), and MOL003578 (ESR1: -10.85 kcal/mol). The results show that these bioactive ingredients and core target proteins were of great signicance to the possible mechanism of Acoritataninowii Rhizoma defensive against AD. Moreover, ESR1 and MAPK14 were shown higher anity for these biologically active ingredients. most promising group of substances with potential activity against AD are the avonoids, including myricetin, morin, rutin, quercetin, setin, kaempferol, apigenin and glycerin, which have been shown, in vitro, to possess antiamyloidogenic and bril-destabilization activity, as well as being able to act as metal chelators and to suppressing oxidative stress. Cycloartenol is a plant sterol compounds, is made up of 2, 3 - oxidized squalene (OS) in cycloartenol synthase (CAS) catalyzed by cycloartenol synthase, and biosynthesis of many kinds of one of the key precursor substance of sterol compounds, exert many pharmacological activities, such as anti-inammatory, anti-tumor, antioxidant, biological activity and resistance against alzheimer's disease 29 . Jung HA et al. evaluated the anti-Alzheimer's disease effect of Cycloartenol by inhibition of AChE, BChE and beta amyloid precursor protein (APP) lyase 1 (BACE1), suggesting Cycloartenol may play a major role as AChE inhibitor against Alzheimer's disease. To sum up, the above three active ingredients have anti-inammatory, anti-oxidant and anti-dementia effects. EAR1, JUN, CASP3, PPARG, CDK1, BCL2. Cellular oxidative stress generates DNA damage and activates the important mitogen-activated protein kinase 14 (p38MAPK) that is involved in pathology like Alzheimer's disease. mitogen-activated protein kinase (MAPK) leads to increased production of proinammatory cytokines and neurodegeneration. Mitogen-activated protein kinase 14 (MAPK14),MiR-22-3p overexpression reduced Aβ deposit and alleviated AD symptoms by targeting and regulating MAPK14 expression, which ameliorated AD symptoms. Secondly, it may decrease tau protein phosphorylation through down-regulating the phosphorylation level of MAPK14. Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinammation-synaptic dysfunction cycle of pathophysiology progression, provides an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for ecacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. pathways and regulating a multi-target and multi-pathway model. The active ingredients of Acoritataninowii Rhizoma could regulate target genes/proteins that were related to signal pathways, play a role in stabilizing the signal pathway, and reveal the mode of action of multi- ingredient-multi-target-multi-pathway in TCM. Further analysis of the pharmacological effects of Acoritataninowii Rhizoma on AD, as well as the targets and signal pathways that interact with active ingredients still need further verication.

hydrogenation, and Gasteiger charges calculation. The minimal energy conformation requires the structure of the ligand. Protein ligand with the lowest binding energy is considered the most likely target.

Potential targets in Acoritataninowii Rhizoma and AD
Through searching TCMSP, TCMID and BATMAN-TCM, detailed information of 4 active ingredients with 81 target genes in Acoritataninowii Rhizoma was obtained, as shown in Table 1. In addition, the topological properties of the network construction based on the Acoritataninowii Rhizoma-ingredients-targets show that the number of nodes is 85 and the number of edges is 106 (Fig. 2). The network centralization is 0.738 and the network density is 0.029. The ingredient and target with maximum degree are kaempferol (64) and NCOA2 (3) PGH2(3) CALM1(3), respectively. By searching database such as DrugBank, GeneCards, OMIM, DisGeNET, TTD and PharmGKB, a total of 6765 target genes were found to be AD-spec c target genes. The result show that the pharmacological characteristics of Acoritataninowii Rhizoma involve a variety of biologically active ingredients and target genes. Similarly, the pathology of AD is also related to many target genes. Overlapping genes accounted for 0.9% of the total genes, indicating that the in uence of Acoritataninowii Rhizoma on AD was possibly associated with above-mentioned multiple overlapping genes.

Network of medicine-ingredients-targets-disease construction
As is indicated in Fig. 3B and table 2, the network construction of medicine-ingredients-targets-disease including 67 nodes and 140 edges. In the Venn diagram, the network contains 4 biologically active ingredients and 61 overlapping genes. The cytoscape3.72 software analyze other critical parameters, such as network density (0.063), network centralization (0.888), average number of neighbors (4.149), network heterogeneity (2.218). The pharmacological effects of Acoritataninowii Rhizoma on AD were carried out through active ingredients and targets genes as indicated in mapping. Figure 4B -a PPI network was constructed by STRING because provided 61 overlapping proteins and that analyze their interaction that looks like this. 59 proteins except two: HAS2, DIO1, which had been established the connection. The main parameters of the network were analyzed through the STRING database: the number of nodes (61), the number of edges (355), the average node degree (11.6), and the average local clustering coe cient (0.555).

Network of PPI
Additionally, the degree of each node was constructed by GraphPad Prism 5.0 (version 2.0; GraphPad Software Inc., San Diego, CA) (Fig. 4A). Top 10 protein node degrees were AKT1, JUN, CASP3, AR, ESR1, MAPK8, RELA, MAPK14, NOS3, HSP90AB1. The results shown that the pharmacological effects of active ingredients of Acoritataninowii Rhizoma on AD might be associated with the interaction of these core proteins.

GO enrichment analysis for target genes
The GO enrichment analysis further evaluates the functions of overlapping target genes from three aspects: molecular function, biological process and cellular components. Threshold value based on p < 0.05 and from the above three aspects, it was constructed that GO enrichment was in the top 30. The molecular function results indicated that the top 5 (generatio) term were protein serine/threonine kinase activity, ubiquitin-like protein ligase binding, RNA polymerase II-speci c DNA-binding transcription factor binding, ubiquitin protein ligase binding and DNA-binding transcription factor binding (Fig. 5A and  table 3). In addition, the number of nodes is 59 and the number of edges is 122 was illustrated in Fig. 5B, which was the topological properties of network construction. More meaningful parameters were tested, such as network centralization (0.123), network heterogeneity (0.581), average number of neighbors (4.136), network density (0.071). The molecular function and target gene with maximum degree were GO:0004674 (11) and ESR1 (8), respectively.
Top 5 (generatio) in the Biological process were response to metal ion, response to lipopolysaccharide, response to molecule of bacterial origin, cellular response to chemical stress and response to oxygen levels ( Fig. 6A and table 4). Moreover, from the topological properties of network construction (Fig. 6B), it could be known that the number of nodes is 65 and the number of edges is 256. Other meaningful parameters were further tested, such as network density (0.123), network centralization (0.131), average number of neighbors (7.877), network heterogeneity (0.602). The biological process and target gene with maximum degree were GO:0010038 (15) and ICAM1 (16), respectively.
As shown in Fig. 7A and table 5, membrane raft, membrane microdomain, membrane region, plasma membrane raft and ion channel complex were the top 5 (generatio) of cellular components. Moreover, from the topological properties of network construction (Fig. 7B), it could be known that the number of nodes is 57 and the number of edges is 131. Other meaningful parameters were further tested, such as network density (0.082), network centralization (0.174), average number of neighbors (4.596), network heterogeneity (0.690). The cellular components and target gene with maximum degree were GO:0045121 (14) and SCN5A (10), respectively. The results showed that the pharmacological effects of bioactive ingredients of Acoritataninowii Rhizoma on were closely linked to MAPK-coupled receptor activity or signal pathways. In addition, the transcription factors have a signi cant impact on signal transduction.  Fig. 8A -KEGG results showed that 61 overlapping genes in 20 signaling pathways were signi cantly enriched, as showed here. Top 5 (generatio) signaling pathways were Fluid shear stress and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, Epstein-Barr virus infection AGE-RAGE signaling pathway in diabetic complications and Human immunode ciency virus 1 infection. In addition, the number of nodes is 57 and the number of edges is 218 were illustrated in Fig. 8B, which was the topological properties of network construction. Other parameters including network density (0.137), network centralization (0.210), average number of neighbors (7.649), network heterogeneity (0.691) were tested, also. The signaling pathway and target protein with maximum degree were hsa05418 (15) and RELA (19), respectively. Top 3 mapping signaling pathways were Fluid shear stress and atherosclerosis ( Fig. 9), Kaposi sarcoma-associated herpesvirus infection Fig. 10) and Epstein-Barr virus infection (Fig. 11), indicating that these signaling pathways play an important role in the pharmacological effects of bioactive ingredients originate from Acoritataninowii Rhizoma on AD.

Discussion
TCM is a complicated system with multiple components and multiple targets, and each ingredient produces a synergistic effect. The composition of TCM is complex, it is di cult to study its effect from the perspective of mixture, and it is also hard to explain its mechanism from the perspective of modern medicine. Network Pharmacology supplied new perspectives for research on complex TCM system. The pharmacology of traditional Chinese medicine system has established a model of the interaction of drug molecules, protein targets, tissues, organs and other elements to clarify and predict the e cacy and toxicity of traditional Chinese medicine. This study evaluated the possibility of Acoritataninowii Rhizoma's pharmacological characteristics in the treatment of AD with network pharmacology study and molecular docking. In order to explore the multi-ingredients and multi-targets research mode of TCM, network pharmacology research provided an innovative way for the study of traditional Chinese medicine ingredients. The results showed that the biologically active components and target proteins with prominent nodes occupy a pivotal position in the network and play an important role in the pharmacological effects of Acoritataninowii Rhizoma.
Acoritataninowii Rhizoma not only has the functions recorded in the Pharmacopoeia of the People's Republic of China, but also has regulatory and therapeutic effects on the nervous system, cardiovascular system, immune system, and reproductive system, while little was known about its mechanism of action on AD. Through the search of the database and the screening of MW, OB, DL, it was determined that these ingredients were four biologically active in Acoritataninowii Rhizoma. The genes accounted for 0.9% in total were shown in medicine-ingredients-targets-disease interaction network. It was indicated that might be at the core genes for the pharmacological pro le of Acoritataninowii Rhizoma suggesting the effects of Acoritataninowii Rhizoma on AD was possibly associated with multiple overlapping genes.

Active ingredients
Among the 4 bioactive ingredients of Acoritataninowii Rhizoma have been passed the ADME screening. It is a natural avonol present in different plant species, Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), which has been described to possess potent anti-in ammatory properties. Some epidemiological studies have found a positive association between consumption of food containing kaempferol and a reduced risk of developing several disorders such as cancer and cardiovascular diseases. Numerous preclinical studies have shown that kaempferol and some glycosides of kaempferol have a wide range of pharmacological activities, including antioxidant, anti-in ammatory, antimicrobial, anticancer, cardioprotective, neuroprotective, antidiabetic, anti-osteoporotic, estrogenic/antiestrogenic, anxiolytic, analgesic and anti allergic activities. Beg et al. found that Kaempferol could be used as a possible drug to ght the development of Alzheimer's disease through animal experiments, Exposure to Kaempferol in AD patients could delay climbing ability, memory loss, reduce oxidative stress and acetylcholinesterase activity. Among the most promising group of substances with potential activity against AD are the avonoids, including myricetin, morin, rutin, quercetin, setin, kaempferol, apigenin and glycerin, which have been shown, in vitro, to possess antiamyloidogenic and bril-destabilization activity, as well as being able to act as metal chelators and to suppressing oxidative stress. Cycloartenol is a plant sterol compounds, is made up of 2, 3 -oxidized squalene (OS) in cycloartenol synthase (CAS) catalyzed by cycloartenol synthase, and biosynthesis of many kinds of one of the key precursor substance of sterol compounds, exert many pharmacological activities, such as anti-in ammatory, anti-tumor, antioxidant, biological activity and resistance against alzheimer's disease 29

PPI network and proteins
Not only the overlapping genes were investigated, the interaction among the overlapping proteins was also explored. 59 shared target proteins regulated by Acoritataninowii Rhizoma and AD, including AKT1,JUN, CASP3, ESR1, AR, MAPK8, RELA, NOS3, MAPK14 were the key target proteins with high node degree by analyzing PPI network. Through experiments in APP/PS1 mice, Ahmad F et al. proved that Akt1 oxidative modi cation mediated by reactive oxygen ROS led to synaptic dysfunction in AD, which was considered to be the loss of activity-dependent protein translation that was crucial for synaptic plasticity and maintenance. Liu SY reported that Alzheimer's disease (AD) was closely related to type 2 diabetes mellitus (T2D), in which V-Akt murine thymoma viral oncogene homologue 1 (AKT1) play an important role in protein synthesis pathway and cell apoptosis. The interaction among the JUN, CASP3, ESR1 in PPI network indicated the proteins interacted each other were involved in the pharmacological pro le of Acoritataninowii Rhizoma and pathologists of AD.
CASP (cysteinyl aspartate speci c proteinases) is the speci c mediator and executor of apoptosis. Caspase-3 not only re ects the level of apoptosis, but also indicates the existence of apoptosis factors. Caspase-3 is an important factor of apoptosis and a common pathway of apoptosis signal transmission . Animal experiments conducted by Mao et al. showed that the expression of CASP3 protein in hippocampus CA1 region of rats in the VD group increased with time, and the over expression of CASP3 protein could lead to the apoptosis of neurons in hippocampus CA1 region of rats. MAPK8 (mitogen-activated protein kinase 8) is a group of protein kinases that can be stimulated by different extracellular processes and is mainly concentrated in the TNF signaling pathway. The AR (androgen receptor) plays an important role in the pathogenesis of castration-resistant prostate cancer, involving gene ampli cation and mutation, regulatory factor changes, apoptosis resistance, tumor immunity and so on.

GO
On the basis of GO functional analysis, it was evaluated that in molecular function, biological process and cellular components, the common target genes were involved in more than 30 signal transduction functions. The following functions were of signi cance to the pharmacological effects of Acoritataninowii Rhizoma on AD: molecular function and biological process were associated with several receptors or signal pathways, like lipopolysaccharide, metal ion, protein serine/threonine kinase, which were relevant to MAPK. The functions/process were correlated with the synaptic or postsynaptic membrane in the cells of the following target genes including AKT1, EAR1, JUN, CASP3, PPARG, CDK1, BCL2. Cellular oxidative stress generates DNA damage and activates the important mitogen-activated protein kinase 14 (p38MAPK) that is involved in pathology like Alzheimer's disease. mitogen-activated protein kinase (MAPK) leads to increased production of proin ammatory cytokines and neurodegeneration. Mitogen-activated protein kinase 14 (MAPK14),MiR-22-3p overexpression reduced Aβ deposit and alleviated AD symptoms by targeting and regulating MAPK14 expression, which ameliorated AD symptoms. Secondly, it may decrease tau protein phosphorylation through down-regulating the phosphorylation level of MAPK14. Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroin ammation-synaptic dysfunction cycle of pathophysiology progression, provides an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for e cacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates.
AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. It blocked that the activation of nuclear factor (NF)-kB and mitogen-activated protein kinases (MAPKs) e.g., JNK (mitogen-activated protein kinase 8) and p38 MAPK, thereby attenuated the nuclear translocation of NF-kB subunit, p65, and activator protein-1 (AP-1) proteins (c-Fos and c-Jun). activation of p38MAPK and JNK, resulting in the increased production of NO. activate the NF-kB, p38MAPK and JNK pathways to induce a prolonged microglial activation which may downregulate the neuroprotective events in the brain of neurodegenerative diseases. In addition, Zhu T et al. suggested that NMB-induced COX-2 and IL-6 expression were mediated via p65 and c-Jun activation. Thus, MAPK play an important role in three biological functions. KEGG Furthermore, the possible pathways of Acoritataninowii Rhizoma on AD were analyzed by KEGG enrichment. The results indicated that pharmacological effects of Acoritataninowii Rhizoma involve multiple signaling pathways, like Fluid shear stress and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, Epstein-Barr virus infection, AGE-RAGE signaling pathway in diabetic complications, Human immunode ciency virus 1 infection, Hepatitis B, Human T-cell leukemia virus 1 infection, IL-17 signaling pathway, TNF signaling pathway. The Fluid shear stress and atherosclerosis of signal pathway induces the expression of Fractalkine mRNA in endothelial cells to increase, which makes blood vessels harden to produce plaques, which in turn affects hemodynamics and causes cardiovascular and cerebrovascular diseases. The AGE-RAGE (advanced glycosylation end product-receptor of AGE) signaling pathway, which RAGE acts as a pro-in ammatory mediator, AGEs is an important ligand of RAGE and it can activate RAGE receptors, activate the transcription factor NF-κB, cause in ammation and oxidative stress, damage the structure and function of brain neurons and hippocampus, and lead to decreased learning and memory functions. TNF-α (Tumor Necrosis Factor-α) is a pro-in ammatory cytokine, which participates in cell differentiation, apoptosis and induce in ammation through up-regulation of signalling pathways such as MAPK and NF-κB. The signal pathway composed of PI3K and AKT is an anti-apoptotic and pro-survival signal pathway. PI3K/AKT pathway has been shown to play a critical role on the neuroprotection and inhibiting apoptosis via enhancing expression of the SODs. This pathway appears to be crucial in Alzheimer's disease because it is related to the tau protein hyper-phosphorylation. A number of studies showed that Chinese medicine play an anti-AD effect by regulating the PI3K/AKT signaling pathway .

Molecular Docking
Moreover, this study also proposes network pharmacology, molecular docking and other widely used research methods for protein-ligand interactions, supplementing the pharmacological effects of Acoritataninowii Rhizoma on AD. Based on their high degree in the network of Acoritataninowii Rhizomaingredients-targets-AD, Several target genes (ESR1, PTSG2, NOS2, and ADRB2) and bioactive ingredients (MOL002565, MOL003896, MOL004891, MOL000392 and MOL000497) were selected to conduct molecular docking. The docking results indicated that accord with the network, these biologically active ingredients and core target genes might be the potential key to the pharmacological effects of Acoritataninowii Rhizoma on AD. NOS2 and ESR1 were shown high a nity for these active ingredients. Combining with the analysis results of network pharmacology study, it seems that the pharmacological effects of biologically active ingredients (MOL002565 and MOL004891) originated from Acoritataninowii Rhizoma on AD were related to NOS2 and ESR1, respectively. However, the docking results need to be con rmed via more studies.

Conclusion
Above all, the pathogenesis of AD is complex, with signalling pathways intersecting and regulating each other, presenting a multi-target and multi-pathway model. The active ingredients of Acoritataninowii Rhizoma could regulate target genes/proteins that were related to signal pathways, play a role in stabilizing the signal pathway, and reveal the mode of action of multi-ingredient-multi-target-multi-pathway in TCM. Further analysis of the pharmacological effects of Acoritataninowii Rhizoma on AD, as well as the targets and signal pathways that interact with active ingredients still need further veri cation. Tables   Table 1 Information  The schedule in the present study was outlined as followed: (1) the ingredients of Acoritataninowii Rhizoma along with their corresponding targets and AD associated targets were searched and screened from databases; (2) The network of medicine-ingredients-targets-disease was constructed, visualized, and analyzed; (3) key ingredients, core targets, top functions and signal pathways were analyzed by PPI, GO, KEGG and the networks were constructed; (4) the valuable targets were obtained and validated via molecular docking with corresponding ingredients and the top targets.

Figure 2
The network of medicine-ingredients-targets. The gene targets were described as green oval. yellow octagon represents ingredients. pastel pink diamond was employed to stand for Acoritataninowii Rhizoma. The edges stand for the association between the nodes.

Figure 7
The cellular components from GO enrichment analysis for target genes. The edges stand for the association between the nodes. In addition, GO enrichment in the top 30 from the molecular function had been obtained based on the threshold value of p < 0.05 (A). The network construction was shown as followed: the gene targets (blue rectangle) and molecular functions (green oval) (B). KEGG enrichment analysis for target genes. The edges stand for the association between the nodes. In addition, signaling pathways from KEGG enrichment had been obtained based on the threshold value of p < 0.05 (A). The network construction was shown as followed: the gene targets (purple rectangle) and signaling pathways (pink oval) (B).

Figure 9
Fluid shear stress and atherosclerosis  Epstein-Barr virus infection