Bioinformatics and Network Pharmacology-Based Approaches to Explore the Potential Mechanism of the Antidepressant Effect of Cyperi Rhizoma through Soothing the Liver

Major depressive disorder (MDD) has become the second most common disease worldwide, making it a threat to human health. Cyperi Rhizoma (CR) is a traditional herbal medicine with antidepressant properties. Traditional Chinese medicine theory states that CR relieves MDD by dispersing stagnated liver qi to soothe the liver, but the material basis and underlying mechanism have not been elucidated. In this study, we identified the active compounds and potential anti-MDD targets of CR by network pharmacology-based approaches. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we hypothesized that the anti-MDD effect of CR may be mediated by an altered response of the liver to lipopolysaccharide (LPS) and glucose metabolism. Through bioinformatics analysis, comparing normal and MDD liver tissue in rats with spontaneous diabetes, we identified differentially expressed genes (DEGs) and selected PAI-1 (SERPINE1) as a target of CR in combating MDD. Molecular docking and molecular dynamics analysis also verified the binding of the active compound quercetin to PAI-1. It can be concluded that quercetin is the active compound of CR that acts against MDD by targeting PAI-1 to enhance the liver response to LPS and glucose metabolism. This study not only reveals the material basis and underlying mechanism of CR against MDD through soothing the liver but also provides evidence for PAI-1 as a potential target and quercetin as a potential agent for MDD treatment.

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Network Pharmacology-Based Strategy for the Investigation of the Anti-Osteoporosis Effects and Underlying Mechanism of Zhuangguguanjie Formulation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.727808 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wang Gong ◽

Xingren Chen ◽

Tianshu Shi ◽

Xiaoyan Shao ◽

Xueying An ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Mass ◽

Signaling Pathway ◽

Osteoclast Differentiation ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Network Pharmacology ◽

Biological Processes

As the society is aging, the increasing prevalence of osteoporosis has generated huge social and economic impact, while the drug therapy for osteoporosis is limited due to multiple targets involved in this disease. Zhuangguguanjie formulation (ZG) is extensively used in the clinical treatment of bone and joint diseases, but the underlying mechanism has not been fully described. This study aimed to examine the therapeutic effect and potential mechanism of ZG on postmenopausal osteoporosis. The ovariectomized (OVX) mice were treated with normal saline or ZG for 4 weeks after ovariectomy following a series of analyses. The bone mass density (BMD) and trabecular parameters were examined by micro-CT. Bone remodeling was evaluated by the bone histomorphometry analysis and ELISA assay of bone turnover biomarkers in serum. The possible drug–disease common targets were analyzed by network pharmacology. To predict the potential biological processes and related pathways, GO/KEGG enrichment analysis was performed. The effects of ZG on the differentiation phenotype of osteoclasts and osteoblasts and the predicted pathway were verified in vitro. The results showed that ZG significantly improved the bone mass and micro-trabecular architecture in OVX mice compared with untreated OVX mice. ZG could promote bone formation and inhibit bone resorption to ameliorate ovariectomy-induced osteoporosis as evidenced by increased number of osteoblast (N.Ob/Tb.Pm) and decreased number of osteoclast (N.Oc/Tb.Pm) in treated group compared with untreated OVX mice. After identifying potential drug–disease common targets by network pharmacology, GO enrichment analysis predicted that ZG might affect various biological processes including osteoblastic differentiation and osteoclast differentiation. The KEGG enrichment analysis suggested that PI3K/Akt and mTOR signaling pathways could be the possible pathways. Furthermore, the experiments in vitro validated our findings. ZG significantly down-regulated the expression of osteoclast differentiation markers, reduced osteoclastic resorption, and inhibited the phosphorylation of PI3K/Akt, while ZG obviously up-regulated the expression of osteogenic biomarkers, promoted the formation of calcium nodules, and hampered the phosphorylation of 70S6K1/mTOR, which can be reversed by the corresponding pathway activator. Thus, our study suggested that ZG could inhibit the PI3K/Akt signaling pathway to reduce osteoclastic bone resorption as well as hamper the mTORC1/S6K1 signaling pathway to promote osteoblastic bone formation.

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The Underlying Mechanism of Chinese Herb of Regulating Marrow in the Treatment of Osteonecrosis of the Femoral Head Based on Network Pharmacology and Molecular Docking

10.21203/rs.3.rs-699020/v1 ◽

2021 ◽

Author(s):

Xiaojian Wang ◽

Rui Wang ◽

Ting Xu ◽

Hongting Jin ◽

Peijian Tong ◽

...

Keyword(s):

Molecular Docking ◽

Chinese Medicine ◽

Signaling Pathway ◽

Kegg Pathway ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Chinese Herbs ◽

Network Pharmacology ◽

Active Components ◽

Pathway Enrichment

Abstract Background The lesion of marrow is a crucial factor in orthopedic diseases, which is recognized by orthopedics-traumatology expert from "Zhe-School of Chinese Medicine". The Chinese herbs of regulating marrow has been widely used to treat osteonecrosis of the femoral head (ONFH) in China, while the interaction mechanisms were still elucidated. Thus, we conducted this study to explore the underlying mechanism of the five highest-frequency Chinese herbs of regulating marrow(HF-CHRM) in the treatment of ONFH with the aid of network pharmacology(NP) and molecular docking(MD). Methods The active components and potential targets of HF-CHRM were obtained through several online databases, such as Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), UniProt database. The gene targets related to ONFH were collected with the help of the OMIM and GeneCards disease-related databases. The "drug- component-target-disease" network and protein-protein interaction(PPI) network of the drug and disease intersecting targets were constructed by using Cytoscape software and the STRING database. R software was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The MD of critical components and targets was carried out using Autodock Vina and Pymol to validate the binding affinity. Results A total of 54 active components, 1074 drug targets and 195 gene targets were obtained. There were 1219 ONFH related targets. 39 drug and disease intersection targets(representative genes: IL6, TP53, VEGFA, ESR1, IL1B) were obtained and considered potential therapeutic targets. 1619 items were obtained by the GO enrichment analysis, including 1517 biological processes, 10 cellular components and 92 molecular functions, which is mainly related to angiogenesis, bone and lipid metabolism and inflammatory reaction. The KEGG pathway enrichment analysis revealed 119 pathways, including AGE-RAGE signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway. MD results showed that quercetin, wogonin, and kaempferol active components had good affinity with IL6, TP53, and VEGFA core proteins. Conclusion The HF-CHRM can treat ONFH by multi-component, multi-target, and multi-pathway comprehensive action.

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A System-Level Investigation into the Mechanisms of Apigenin Against Inflammation

Natural Product Communications ◽

10.1177/1934578x19878600 ◽

2019 ◽

Vol 14 (9) ◽

pp. 1934578X1987860 ◽

Cited By ~ 1

Author(s):

Ying Xie ◽

Dongdong Liang ◽

Qingke Wu ◽

Xuemei Chen ◽

Manal Ali Buabeid ◽

...

Keyword(s):

Protein Kinase ◽

Biological Activities ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Mitogen Activated Protein Kinase ◽

System Level ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Biological Processes ◽

Go Terms

Apigenin is a natural flavone that possesses excellent biological activities especially against aging and cancer. However, the underlying mode of its action is not yet revealed. The purpose of this study was to examine the pharmacological mechanisms of apigenin using the knowledge of network pharmacology, protein-protein interaction (PPI) databases and biological processes analysis through Cytoscape. Apigenin targets were retrieved through PASS Prediction and STITCH database and the interactive associations between these targets were studied using STITCH, followed by GO (gene ontology) and pathway enrichment analysis. As a result of target search, 125 protein targets were retrieved. Moreover, 216 GO terms related to various biological processes, 16 GO terms for various molecular processes, 5 GO terms for the cellular components, and 52 Kyoto Encyclopedia of Genes and Genomes pathway terms were achieved by analyzing gene functional annotation clusters and abundance values of these targets. Most of these terms are strongly associated with inflammation through various pathways, for example, FOXO, mammalian target of rapamycin, tumor necrosis factor, p53, AMP-activated protein kinase, p13K-AKT, and mitogen-activated protein kinase, which play an important role in inflammation, aging and cancer. Apigenin can be used to treat inflammation, aging, and cancer with an underlying mechanism of inflammation suppression. This study contributed excellent information for a better understanding of the modes of action of apigenin. However, further studies such as docking and MD simulation are required to understand the therapeutic and toxicological roles of these targets of apigenin.

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Uncovering the Mechanism of Shenlian Capsules in the Treatment of Non-small Cell Lung Cancer by System Pharmacology

10.21203/rs.3.rs-41447/v1 ◽

2020 ◽

Author(s):

Wanjin Fu ◽

Ajuan Gong ◽

Bin Yu ◽

Xin Wei ◽

Yong Chen ◽

...

Keyword(s):

Lung Cancer ◽

Molecular Docking ◽

Small Cell Lung Cancer ◽

Active Compound ◽

Enrichment Analysis ◽

Small Cell ◽

Network Pharmacology ◽

Small Cell Lung ◽

Active Compounds

Abstract Background: Shenlian Capsule is a Chinese medicine compound approved by the China Food and Drug Administration (CFDA) for the treatment of advanced non-small cell lung cancer(NSCLC). However, due to its complex constituents, cause its effective active compounds and main action mechanisms for treating diseases are still not fully clear. The purpose of this work is to explore the active ingredients and mechanisms of Shenlian Capsule treatment NSCLC through a system pharmacological approach. Methods: First, a database of Shenlian Capsule chemical composition was constructed by retrieving Chinese herbal medicine data. Absorption, distribution, metabolism and excretion (ADME) methods were used to screen potential active compounds. Predict active compound targets with a large-scale molecular network target prediction technology. Clustering of active compounds obtained through cluster analysis by MECODE plug-in, each cluster obtains the main pathways through enrichment analysis method. To get all targets related to survival in NSCLC, the survival related targets were intersected with the compounds target (C-T) network to get the survival related targets for Shenlian Capsule. Finally, a batch molecular docking technique was used to verify the effect of active compounds of Shenlian Capsule on survival-related targets.Results: The Shenlian Capsule C-T network was constructed with 117 potential compounds and 47 targets. Treatment of NSCLC with Shenlian Capsule through enrichment analysis may involve multiple pathways such as anti-inflammatory, immune regulation, regulation of cell cycle, apoptosis, antiviral, cell hypoxia, angiogenesis and so on. Shenlian Capsule has eight survival-related genes in non-small cell lung adenocarcinoma (LUAD) and two survival-related genes in non-small cell squamous cell lung carcinoma (LUSC). It is known through molecular docking that the active compound has lower energy after conformation with survival-related genes, and has lower binding energy and stable binding.Conclusion: In this study, the potential compounds of active compounds in Shenlian Capsule were first predicted using network pharmacology technology. Through the enrichment analysis, the main pathways of the role of Shenlian Capsule were outcropped. Secondly, by combining bioinformatics and network pharmacology, Shenlian Capsule can be regulated to target survival-related targets. Finally, the molecular docking technique shows the relationship between active compounds and survival-related targets after docking. This work provided a scientific basis for the clinical role of Shenlian Capsule in the treatment of NSCLC, provided a research basis for further clarifying the active ingredients and mechanism of Shenlian Capsule in the treatment of NSCLC.

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Mechanism of Youguiyin in the Treatment of Osteoporosis Based on Network Pharmacology and Molecular Docking

10.21203/rs.3.rs-798949/v1 ◽

2021 ◽

Author(s):

Yi Pan ◽

Wanlu Zhao ◽

Luping Qin ◽

Lu Zhang

Keyword(s):

Molecular Docking ◽

Signaling Pathway ◽

Enrichment Analysis ◽

Network Pharmacology ◽

Transcriptional Gene Silencing ◽

Pathway Enrichment Analysis ◽

Signal Pathways ◽

Biological Processes ◽

The Core ◽

Material Basis

Abstract Background: Youguiyin (YGY) has been confirmed to treat osteoporosis (OP) in clinical trials, but its specific pharmacological mechanism remains unclear. This study aimed to explore the material basis and potential mechanism of YGY in the treatment of OP based on network pharmacology and molecular docking.Methods: Databases including TCMSP, SwissTargetPrediction database, OMIM, and TTD were used to predict the effective ingredients and relevant targets of YGY in the treatment of OP. The STRING database was used to reveal the relationship between each intersection target protein. Metascape database was used to perform GO enrichment analysis and KEGG pathway enrichment analysis on the intersection targets. Cytoscape 3.6.0 software was used to show the complex network relationship of YGY in the treatment of OP. According to the results of network characteristics analysis, the core effective ingredients and the core targets were screened out. Autodock 4.0 was used for molecular docking and Pymol was used to visualize the docking results.Results: 290 effective ingredients, 1127 targets of the effective ingredients, 273 relevant targets of OP and 17 intersection targets were screened out in total by searching literature and databases. Intersection targets could affect biological processes including regulation of inflammatory response, ossification, negative regulation of post-transcriptional gene silencing, positive regulation of cytokine biosynthetic process and regulation of hormone levels by regulating signal pathways including TNF signaling pathway, osteoclast differentiation, apoptosis, MAPK signaling pathway and PI3K/Akt signaling pathway. Through screening, 14 core effective ingredients and 6 core targets were confirmed. The results of molecular docking showed that most of the core effective ingredients including α-humulene, cinnamaldehyde, denudatine, benzoylhypaconine and quercetin had good binding activity with the core targets including TNF-α, IL-1β and IL-6.Conclusion: Based on network pharmacology and molecular docking, the critical effective ingredients, key targets, important signal pathways and main biological processes of YGY in the treatment of OP were successfully screened out. This study revealed the material basis and the mechanism of YGY in the treatment of OP and provided a theoretical basis for follow-up experimental research and clinical application of YGY.

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Pharmacological Mechanisms of Tinglizi against Chronic Heart Failure Determined by Network Pharmacology and Molecular Docking

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2022/2152399 ◽

2022 ◽

Vol 2022 ◽

pp. 1-11

Author(s):

Liangtao Luo ◽

Haowen Wang ◽

Guowei Huang ◽

Lu Zhang ◽

Xiuwei Li ◽

...

Keyword(s):

Molecular Docking ◽

Signaling Pathway ◽

Kegg Pathway ◽

Enrichment Analysis ◽

Network Pharmacology ◽

Advanced Glycation ◽

Pathway Enrichment ◽

Material Basis ◽

Glycation End Products ◽

End Products

Objective. Tinglizi has been extensively used to treat chronic heart failure (CHF) in modern times, but the material basis and pharmacological mechanisms are still unclear. To explore the material basis and corresponding potential targets and to elucidate the mechanism of Tinglizi, network pharmacology and molecular docking methods were utilized. Methods. The main chemical compounds and potential targets of Tinglizi were collected from the pharmacological database analysis platform (TCMSP). The corresponding genes of related action targets were queried through gene cards and UniProt database. The corresponding genes of CHF-related targets were searched through Disgenet database, and the intersection targets were obtained by drawing Venn map with the target genes related to pharmacodynamic components. Then, drug targets and disease targets were intersected and put into STRING database to establish a protein interaction network. The “active ingredient-CHF target” network was constructed with Cytoscape 3.8.2. Finally, Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of intersection targets were analyzed using metascape. With the aid of SYBYL software, the key active ingredients and core targets were docked at molecular level, and the results were visualized by PyMOL software. Molecular docking was carried out to investigate interactions between active compounds and potential targets. Results. A total of 12 active components in Tinglizi were chosen from the TCMSP database, and 193 corresponding targets were predicted. Twenty-nine potential targets of Tinglizi on CHF were obtained, of which nine were the core targets of this study. Twenty GO items were obtained by GO function enrichment analysis ( P < 0.05 ), and 10 signal pathways were screened by KEGG pathway enrichment analysis ( P < 0.05 ), which is closely related to the treatment of CHF by Tinglizi. The constructed drug compound composition action target disease network shows that quercetin, kaempferol, and other active compounds play a key role in the whole network. The results of molecular docking showed that all the key active ingredients, such as quercetin and isorhamnetin, were able to successfully dock with ADRB2 and HMOX1 with a total score above 5.0, suggesting that these key components have a strong binding force with the targets. Conclusion. Through network pharmacology and molecular docking technology, we found that the main components of Tinglizi in the treatment of CHF are quercetin, kaempferol, β-sitosterol, isorhamnetin, and so on. The action targets are beta 2-adrenergic receptor (ADRB2), heme oxygenase 1 (HMOX1), and so on. The main pathways are advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor (HIF-1) signaling pathway, estrogen signaling pathway, and so on. They play an integrated role in the treatment of CHF.

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A Network Pharmacology Approach to Explore the Underlying Mechanism of Tufuling Qiwei Tangsan in Treating Psoriasis

Current Bioinformatics ◽

10.2174/1574893616666210315093639 ◽

2021 ◽

Vol 16 ◽

Author(s):

Xiaolei Ma ◽

Yinan Lu ◽

Yang Lu ◽

Zhili Pei

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Mechanism Of Action ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Mapk Signaling ◽

Binding Activity ◽

Network Pharmacology ◽

Active Components ◽

Active Compounds

Background: Tufuling Qiwei Tangsan (TQTS) is a commonly used Mongolian medicine preparation against psoriasis in China. However, its mechanism of action and molecular targets for the treatment of psoriasis is still unclear. Network pharmacology can reveal the synergistic mechanism of drugs at the molecular, target and pathway levels, and is suitable for the complex study of traditional Chinese medicine formulations. However, it is rarely involved in the application of Mongolian medicine with the same holistic concept of traditional Chinese medicine. Method: In this paper, the active compounds of TQTS were collected and their targets were identified. Psoriasis-related targets were obtained by analyzing the differential expressed genes between psoriasis patients and healthy individuals. Then, the network concerning the interactions of potential targets of TQTS with well-known psoriasis-related targets was built. The core targets were selected according to topological parameters. And the enrichment analysis was carried out to explore the mechanism of action of TQTS. Moreover, molecular docking was performed to study the interaction between the selected ligands and receptors related to psoriasis. Result and Conclusion: Eighty-five active compounds of TQTS were screened, with corresponding 270 targets, and 313 differentially expressed genes were identified. Additionally, enrichment analysis showed that the targets of TQTS for treating psoriasis were mainly concentrated in multiple biological processes, including apoptosis, growth factor response,etc., and related pathways including PI3K-Akt and MAPK signaling pathway, and so on. Genes such as NFKB1, TP53 and MAPK1 are the key genes in the gene pathway network of TQTS against psoriasis. The 4 main active components of TQTS have certain binding activity with 13 potential targets, and the stability of interaction with AKT1 is the best, which indicate the potential mechanism of TQTS on psoriasis.

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Deciphering the Underlying Mechanism of Eucommiae Cortex against Osteoporotic Fracture by Network Pharmacology

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7049812 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yongming Shuai ◽

Zhili Jiang ◽

Qiuwen Yuan ◽

Shuqiang Tu ◽

Fanhui Zeng

Keyword(s):

Osteoporotic Fractures ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Ovariectomized Rats ◽

Network Pharmacology ◽

Future Research ◽

Ppi Network ◽

Hub Genes ◽

Traditional Chinese Herbal Medicine ◽

Kegg Pathways

Background. Du Zhong (DZ), or Eucommiae Cortex, a traditional Chinese herbal medicine, has been used to treat osteoporosis. Although it has been reported that DZ can improve bone mass in ovariectomized rats, its pharmacological mechanisms in treating osteoporotic fractures (OPF) remain unclear. Methods. In this study, we used a network pharmacological manner to explore its potential complicated mechanism in treating OPF. We obtained DZ compounds from TCMSP and BATMAN-TCM databases and collected potential targets of these compounds through target fishing based on TCMSP and BATMAN-TCM databases. Next, we collected the OPF targets by using CTD, GeneCards, OMIM, HPO, and GenCLiP 3 databases. And then the overlapping genes between DZ potential targets and OPF targets were used to build up the protein-protein interaction (PPI) network and to analyze their interactions and find out the big hub genes in this network. Subsequently, clusterProfiler package in R language was utilized to conduct the enrichment of Gene Ontology biological process and KEGG pathways. Results. There were totally 93 active compounds and 916 related targets in DZ. After the enrichment analysis, we collected top 25 cellular biological processes and top 25 pathways based on the adjusted P value and found that the DZ anti-OPF effect was mainly associated with the regulation of ROS and inflammatory response. Furthermore, 64 hub genes in PPI network, such as MAPK1 (degree = 41), SRC (degree = 39), PIK3R1 (degree = 36), VEGFA (degree = 31), TP53 (degree = 29), EGFR (degree = 29), JUN (degree = 29), AGT (degree = 29), MAPK1, SRC, PIK3R1, VEGFA, and TP53, were considered as potential therapeutic targets, implying the underlying mechanisms of DZ acting on OPF. Conclusion. We investigated the possible therapeutic mechanisms of DZ from a systemic perspective. These key targets and pathways provided promising directions for the future research to reveal the exact regulating mechanisms of DZ in treating OPF.

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Network Pharmacology Integrated Molecular Docking Reveals the Mechanism of Zhongfeng Xingnao Formula against Intracerebral Hemorrhage

10.21203/rs.3.rs-117791/v1 ◽

2020 ◽

Author(s):

Can Wan ◽

Ziyi Zhou ◽

Yun Lu ◽

Guangyao Zhang ◽

Yefeng Cai ◽

...

Keyword(s):

Molecular Docking ◽

Intracerebral Hemorrhage ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Interaction Network ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Network Pharmacology ◽

Pathway Network ◽

Drug Compound

Abstract Background: Previous studies have shown that Zhongfeng Xingnao Formula (ZXF) can effectively reduce the mortality of intracerebral hemorrhage (ICH), but the underlying mechanism of the treatment remained still unexplored. This study aimed to expound the potential mechanism of ZXF in the treatment of ICH through network pharmacology and molecular docking.Methods: The putative targets of ZXF were obtained from the TCMSP and Uniprot database, while the potential targets of ICH received from Drugbank, Genecards and OMIM database. Then through the Venn 2.1, the overlapping targets of disease and drug were gotten for the further study. The GO and KEGG enrichment analyses were performed by R version 4.0.2 software so that the signaling pathway was acquired to the subsequent analysis. Cytoscape was used to construct the drug-compound-target-pathway network and String was utilized for the protein-protein interaction network. What’s more, the interaction between compound and target was verified by the AutoDockTools and Autodock Vina. Results: There were a total of 166 ZXF-related targets and 1258 ICH-related targets obtained from the public databases. And 87 potential targets were both related to drug and disease. The GO enrichment analysis mainly involved receptor ligand activity, signaling receptor activator activity, and cytokine receptor binding, while the signaling pathway, such as Fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, were significantly enriched in the KEGG enrichment analysis. The molecular docking elucidated that the aloe-emodin, beta-sitosterol, quercetin could bound well to the top five targets sorted by degree value.Conclusions: ZXF treated ICH through multiple compounds, multiple targets, and multiple pathways. The underlying mechanism of the treatment may be promoting angiogenesis, anti-inflammatory, anti-oxidative stress, and reversing atherosclerosis, which is of great significance for the treatment of ICH.

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