|
|
1.INTRODUCTIONDepression is a common health issue prevalent in the general population. Latest data released by the World Health Organization (WHO) shows that the global prevalence of depression is approximately 4.4%, with a patient population reaching up to 322 million people, making it the leading cause of disability worldwide [1]. In contrast to short-term non-pathological depression, pathological depression can last longer and may severely affect individual function and daily activities, troubling many patients suffering from chronic diseases such as heart disease and diabetes [2]. Currently, commonly used anti-depressants in clinical practice mainly work by regulating the level of neurotransmitters in the brain, such as selective serotonin reuptake inhibitors (SSRIs), dopamine and norepinephrine reuptake inhibitors, etc. [3] However, these drugs may cause a series of side effects, including weight gain, sexual dysfunction and sleep disorders. In traditional Chinese medicine, depression is classified as Yu syndrome, which is mainly caused by emotional injury and Qi-blood imbalance [4]. The treatment principle is to soothe the liver and relieve depression, regulating Qi and the blood. Bazhen decoction is a classic Chinese herbal formula, the main effect of which is invigorating Qi and nourishing blood. Its potential effects in regulating immune function, improving chronic fatigue, and enhancing quality of life also provide a theoretical basis for exploring its application in the field of anti-depression [5]. This study aims to explore the potential mechanism of Bazhen decoction and its ingredients in the treatment of depression from the perspective of network pharmacology to provide a more scientific theoretical basis for its clinical application. 2.MATERIALS AND METHODS2.1Selection of active ingredients in Bazhen decoction and collection of target informationTo explore the potentiality of Bazhen decoction in treating depression, the research first focused on identifying its inherent effective compounds and their corresponding biological targets. (1) Identification of effective compounds: Search on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), keywords including the components of Bazhen decoction: ginseng, atractylodes, poria, licorice, angelica, chuanxiong, rehmannia, and paeonia were used, and specific screening criteria adopted, i.e., oral bioavailability (OB) must be greater than or equal to 30%, and drug-likeness (DL) must be greater than or equal to 0.18. (2) Determination of biological targets: Relevant targets of these herbs were searched on TCMSP, which were matched with corresponding gene codes through The UniProt database (https://www.uniprot.org/). These genes were further annotated with Perl software (https://www.perl.org/get.html). 2.2Screening of depression targets, Bazhen decoction action targets, and intersection of depression targetsTo screen out the target genes related to depression and determine the action targets of Bazhen decoction in anti-depression, we first used the GeneCards database (https://www.genecards.org/) and DrugBank database (https://go.drugbank.com/) for searching, with “depression” and “anti-depression” as keywords to retrieve related target genes, and thus established a gene dataset for depression (Data with a relevance of less than 5% in the GeneCards database were deleted). Subsequently, we visited the UniProt database to standardize the screened drug and disease targets. Then the candidate target genes corresponding to the main active ingredients in Bazhen decoction were compared and analyzed with the target genes related to depression disease. Through this comparison, a series of common target genes were successfully screened out, which are considered to be potential targets for the anti-depressive effect of Bazhen decoction. 2.3Construction of target interaction network2.3.1Construction of Bazhen decoction active ingredient-action target networkTo reveal the relationship between the active ingredients and action targets of Bazhen decoction in anti-depression, Cytoscape 3.8.0 software (https://cytoscape.org/) was used to construct the active ingredient-action target network of Bazhen decoction for anti-depression. In this network, nodes represent the active ingredients in Bazhen decoction and their action target proteins for depression, while edges represent the interaction. Using the “Analyze Network” function of Cytoscape, we analyzed the topological structure parameters of the network. The degree of connection (Degree) of the nodes in the network helps identify the most important active ingredients in Bazhen decoction for anti-depression. 2.3.2Construction of Chinese medicine-disease target protein interaction network and screening of core genesUsing the STRING database (https://string-db.org), we imported the potential action targets of Bazhen decoction in the treatment of depression and set the screening criteria as “homo sapiens” to establish a protein-protein interaction (PPI) network. We downloaded the corresponding target gene PPI information tsv. file from the database and used Cytoscape to visualize this information, creating a PPI network diagram. By using the CytoNCA plugin in Cytoscape, we conducted a detailed analysis of key network parameters such as Betweenness (BC), Closeness (CC), Degree (DC), Eigenvector (EC), Local Average Connectivity-based method (LAC), Network (NC), etc., and screened out those nodes that reached or exceeded the median in the above parameters, and identified them as core genes for Bazhen decoction’s anti-depressive effect. Finally, these identified core genes were imported into Cytoscape 3.8.0 software again for graphical display, helping us to understand more clearly the potential mechanism of Bazhen decoction in the treatment of depression. 2.4GO and KEGG pathway enrichment analysisThe obtained intersection targets were imported into the Metascape database (https://metascape.org), the species type was set as “homo sapiens”, “Custom Analysis” was selected, and the default settings were used as screening criteria to perform GO function and KEGG pathway enrichment analysis. GO function enrichment analysis includes analysis of biological processes (BP), molecular functions (MF), and cellular components (CC). 3.RESULTS3.1Screening of effective components in Bazhen decoctionBy screening all effective components and their related targets of Bazhen Decoction in TCMSP, a total of 160 effective components and 4775 drug targets were obtained. Table 1 shows the statistics of effective components and drug targets. Table 1.Statistics of Effective Components and Drug Targets of Bazhen Tang (Count)
3.2Action targets of Bazhen decoction in anti-depressionAfter the de-duplication of the targets corresponding to the main effective components of Bazhen Decoction obtained from the databases, a total of 827 potential action targets and 1964 depression targets were retrieved. The intersection of the two yielded 270 targets (see Figure 1), which are the potential target genes for Bazhen Decoction’s anti-depression effect. 3.3Network analysis3.3.1Drug-target gene network analysisBased on the 270 target genes in 3.2, a drug-target gene network map of Bazhen Decoction for anti-depression is established. (see Figure 2). 3.3.2PPI network analysis and key target screeningTo further understand the pharmacological mechanism of Bazhen Decoction on depression, the 270 intersection targets were imported into the STRING online database to create a PPI network, as in Figure 3. The screened PPI network had 391 nodes and 2866 edges. The larger and darker the node, the larger the Degree value, and the more important the gene. These are the key target genes for Bazhen Decoction’s anti-depression effect. After screening, the core target was obtained by sorting by the Degree value, with TP53 (degree=37) being the largest. 3.4GO function and KEGG pathway enrichment analysisThe results of GO function enrichment analysis (Figure 4) show that biological processes are mainly concentrated in response to lipopolysaccharide, aging, positive regulation of apoptotic process, response to cocaine, phospholipase C-activating G-protein coupled receptor signaling pathway, signal transduction, positive regulation of protein phosphorylation, positive regulation of peptidyl-serine phosphorylation, positive regulation of ERK1 and ERK2 cascade, positive regulation of MAP kinase activity, and chemical synaptic transmission. Molecular functions are mainly concentrated in kinase binding, DNA-binding transcription factor binding, and protein domain-specific binding. KEGG pathway enrichment analysis (Figure 5) shows that the pathways are mainly enriched in Neuroactive ligand-receptor interaction, cAMP signaling pathway, Pathways in cancer, Calcium signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, HIF-1 signaling pathway, Proteoglycans in cancer, Serotonergic synapse, Prostate cancer, Endocrine resistance, and Colorectal cancer. 3.5Molecular dockingThe network graph of the active components corresponding to the targets in Bazhen Decoction shows that kaempferol, quercetin, licochalcone a, etc., are likely to be the main active components exerting their pharmacological effects. The PPI network graph of the intersection targets obtained from Bazhen Decoction and depression was then obtained using the CytoNCA plugin in Cytoscape 3.7.2 software, and the core targets were obtained. Autodock software was used for molecular docking. The smaller the binding energy, the more stable the ligand and receptor binding, and the more likely the interaction will occur. Then, Pymol software was used to visualize the docking results. The results show that quercetin has a good binding with the core target, and then Pymol and Ligplus software were used for visualization. The molecular docking model and visualization model of TP53 and quercetin are shown (Figure 6). 4.DISCUSSIONTraditional Chinese medicine, with its multi-component, multi-target, and systemic regulation characteristics, has shown unique advantages in treating various diseases including depression [6]. The core idea of network pharmacology is highly consistent with these characteristics of traditional Chinese medicine. By introducing network pharmacology methods into traditional Chinese medicine research, it can effectively predict and identify the action targets and active component groups of traditional Chinese medicine, clarify its mechanism of action, scientifically explain the rules of prescription, discover new indications and active compounds, thereby promoting the research and design of new drugs. The etiology and pathogenesis of depression are complex and diverse, including various hypotheses such as neurotransmitter imbalance, neuroinflammation, oxidative stress, and hormone imbalance [7]. This study screened out the core compounds in Bazhen Decoction, such as flavonoids, saponins, polysaccharides, etc., through network pharmacology methods. These compounds have shown a variety of pharmacological effects such as regulating neurotransmitters, anti-oxidation, anti-inflammation, and regulating hormone levels. For example, flavonoid compounds can exert anti-depressant effects by regulating the levels of neurotransmitters such as serotonin and norepinephrine. Saponin compounds reduce the level of inflammation in the brain through anti-inflammatory pathways, thus making Bazhen Decoction have a therapeutic effect on depression [8]. Through network pharmacology method analysis, 827 targets corresponding to the components of each drug in the Bazhen Decoction, and 1964 depression-related genes were obtained, and 270 intersection targets of drugs and diseases were obtained, indicating that Bazhen Decoction treats depression through multiple components, multiple targets, and multiple pathways. Then, the main active components of the drug in Bazhen Decoction and the core targets were docked to better explore the mechanism of Bazhen Decoction in the treatment of depression. Through PPI network analysis, the key target genes of Bazhen Decoction’s anti-depression were obtained, mainly including serotonin receptors, norepinephrine receptors, etc. The regulation of these targets is closely related to the treatment of depression, suggesting that Bazhen Decoction may exert anti-depressant effects through multiple pathways and multiple targets [9]. The KEGG pathway analysis of Bazhen Decoction’s anti-depression shows that the involved pathways include serotonin signaling pathway, norepinephrine signaling pathway, inflammation signaling pathway, etc. The regulation of these pathways is of great significance for the treatment of depression, especially the serotonin and norepinephrine signaling pathways, which are the main pathways of current anti-depressant drugs [10]. In summary, this study explored the potential mechanism of Bazhen Decoction’s anti-depression through network pharmacology methods and molecular docking technology, determined its key targets, main biological processes, and main pathways, and provided a theoretical basis and scientific evidence for the application of Bazhen Decoction in the treatment of depression. These findings not only provide a direction for basic research, but also provide theoretical support for the clinical use of Bazhen Decoction in the treatment of depression, demonstrating the great potential and value of traditional Chinese medicine in modern medicine. ACKNOWLEDGEMENTSThis work is supported by National Level Project of Jilin Province University Student Science and Technology Innovation and Entrepreneurship Training Program 202311439023. REFERENCESZhang Tengyue,
“The Changes of Amplitude of Low Frequency Fluctuation in Patients with Major Depressive Disorder after Antidepressant Treatment: A Resting-State fMRI Study [D],”
China Medical University,
(2021). Google Scholar
Lin Hengzhen,
“Behavioral Effects of Antidepressant Drugs in Mice [J],”
Chinese Journal of Traditional Veterinary Science,
(12), 4
–6+9
(2023). Google Scholar
Liu Chen,
“The Literature Study on to Treat Depression Syndrome from the Respect of the Lungs [D],”
Beijing University of Chinese Medicine,
(2013). Google Scholar
Li Xia, Wang Yuanbo, Li Xin, et al,
“Pharmacological Study and Key Target Validation of the Mechanism of Difference between Kaixin San for Depression, and Depression Combined with Myocardial Infarction [J],”
Western Journal of Traditional Chinese Medicine, 37
(05), 24
–36
(2024). Google Scholar
Zuo Lihua, Shi Yingying, Liu Liwei, et al,
“Study on the Mechanism of Shugan Jieyu Capsule in the Treatment of Depression Based on Network Pharmacology [J],”
Chinese Journal of Hospital Pharmacy, 40
(12), 1320
–1329
(2020). Google Scholar
Niu Zeji,
“Clinical Observation and Network Pharmacology of Modified Eight-gem Decoction in Treating Advanced Colorectal Cancer with Deficiency of Qi and Blood [D],”
Heilongjiang University of Chinese Medicine,
(2023). Google Scholar
Yu Debo, Lin Zhixiong, Lin Juda,
“Related Research on rs6295 Polymorphism of 5-HTR1A Gene and Depression with Self-injury Behavior [J],”
Journal of Medical Information, 37
(09), 179
–183
(2024). Google Scholar
Liu Liting,
“Clinical Study of Bazhen Decoction Combined with Ganoderma lucidum Extract Tablet in the Treatment of Insomnia with Deficiency of Qi and Blood [D],”
Jiangxi University of Chinese Medicine,
(2021). Google Scholar
Huang Jianyi,
“Clinical Study on the Treatment of Breast Cancer with Anxiety and Depression of Liver Depression and Blood Deficiency Type by Magnetic Bead Auricular Point Combined with Chinese Medicine [D],”
Beijing University of Chinese Medicine,
(2022). Google Scholar
Wang Ruolan, Han Zucheng, Wang Pei,
“Mechanism of Action of the Anti-fatigue Effect of Bazhen Decoction Based on Network Pharmacology and Molecular Docking [J],”
Hunan Journal of Traditional Chinese Medicine, 38
(08), 151
–159
(2022). Google Scholar
|
