# Network Pharmacology-Based Study on the Efficacy and Mechanism of _Lonicera japonica_ Thunberg
## 4 Discussion  
This study was designed to discover and predict the potential efficacy and mechanisms of LJ based on network pharmacology. Network pharmacology is known to be an analytical method which enables target genes to be gathered and network analyses to be performed to identify features of elements in a gene set. In the present study, 26 compounds of LJ were collected from the literature via open databases. Through public databases, such as PubChem, target genes of the compounds were used to build the network for LJ, which consists of genes and their connections. On the basis of the LJ network, the main target genes and potential pathways of LJ were investigated and 'AGE-RAGE signaling pathway in diabetic complications' emerged as the most relevant pathway for LJ with the lowest \(p\)-value and the highest combined score, both indicating confidence in the correlated pathway. In addition, 'IL-17 signaling pathway', 'Bladder cancer', 'Pancreatic cancer', 'Hepatitis B', 'HIIF-1 signaling pathway', 'Prostate cancer', 'Chagens disease', 'FoxO signaling pathway' and 'Colorectal cancer' can also be predicted as potential mechanisms of LJ. Among the targets of the LJ network, the top 10 targets with the highest edges were presented in order of high edge degrees. _AKT1_ was the node with the highest number of edges, associating with 99 other genes in the network. GO Biological Process is a database which provides computational analyses of large-scale molecular biology and genetics experiments in biomedical research. Based on GO Biological Process, known functions of _AKT1_ were derived. As _AKT1_ was the node with the highest edges, 'negative regulation of cell size' and 'negative regulation of protein kinase activity' functions of _AKT1_ can be predicted as functions of LJ. Through functional enrichment analysis, the gene set for LJ was analyzed to predict potential pathways of LJ. 'AGE-RAGE signaling pathway in diabetic complications' was identified as the pathway most highly correlated with the LJ network based on functional enrichment analysis. This result suggests that the AGE-RAGE pathway might be a potential mechanism of LJ and that LJ might have therapeutic efficacy in relation to diabetic complications. Genes including _AKT1_, _IL6_, _STAT3_ and _MAPK1_ were associated with the  
Figure 4: A diagram of the AGE-RAGE signaling pathway in diabetic complications. KEGG pathway: hsa04933. Matched genes are marked in red boxes. AGE-RAGE signaling pathway, which implies that the top 10 edge degree genes of the network are highly related to the main pathway of LJ. Not only 'AGE-RAGE signaling pathway in diabetic complications' but also other pathways, including 'IL-17 signaling pathway', can be predicted as related mechanisms of LJ. The 34 genes in common between the LJ network and 'AGE-RAGE signaling pathway in diabetic complications' were extracted. Among the common genes, _ERK1/2_, _P38_, _AP1_, _P21 RAS_, _JNK_, _NFKB_, _MCP1_, _PAII_, _VCAM1_, _MMP2_, _IL1_, _IL6_, _IL8_, _TNFA_ and _THBD_ belonged to 'MAPK signaling pathway'. _NADPH_, _PI3K_, _AKT_, _NOS_, _JNK_, _P38_, _FOX01_ and _CASP3_ belonged to 'PI3K-AKT signaling pathway'. _JAK2_, _STAT3_, _STAT1_, _NETC1_, _COL1_, _CYCD1_ and _CDK4_ belonged to 'JAK-STAT signaling pathway'. The results demonstrated that LJ might affect the 'AGE-RAGE signaling pathway in diabetic complications' pathway in humans through 'MAPK signaling pathway', 'PI3K-AKT signaling pathway' and 'JAK-STAT signaling pathway'. In order to confirm whether the results were reliable, the relevance of LJ to 'MAPK', 'PI3K-AKT' and 'JAK-STAT' was investigated based on literature studies. LJ attenuated H2O2-induced apoptosis by blocking the phosphorylation of PI3K/Akt and MAPKs [17]. LJ down-regulated the production of pro-inflammatory mediators, including nitric oxide (NO), as well as pro-inflammatory cytokines (IL-1B and TNF-\(\alpha\)) by suppressing nuclear factor-kappa B (NF-kB) activity at least through inhibition of the PI3K-Akt signaling pathway [26].