Network pharmacology of bioactives from Sorghum bicolor with targets related to diabetes mellitus

Background Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. Methods Compounds in SB were explored through GC-MS and screened by Lipinski’s rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. Results GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski’s rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-β-sitosterol, PPARD-β-sitosterol, and PPARG-β-sitosterol). Conclusion Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.

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Network Pharmacology Study on Morus alba L. Leaves: Pivotal Functions of Bioactives on RAS Signaling Pathway and Its Associated Target Proteins against Gout

International Journal of Molecular Sciences ◽

10.3390/ijms22179372 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9372

Author(s):

Ki-Kwang Oh ◽

Md. Adnan ◽

Dong-Ha Cho

Keyword(s):

Signaling Pathways ◽

Signaling Pathway ◽

Gouty Arthritis ◽

Gene Set Enrichment Analysis ◽

Venn Diagram ◽

Network Pharmacology ◽

Ras Signaling ◽

Target Proteins ◽

Lipinski’S Rule ◽

Ras Signaling Pathway

M. alba L. is a valuable nutraceutical plant rich in potential bioactive compounds with promising anti-gouty arthritis. Here, we have explored bioactives, signaling pathways, and key proteins underlying the anti-gout activity of M. alba L. leaves for the first-time utilizing network pharmacology. Bioactives in M. alba L. leaves were detected through GC-MS (Gas Chromatography-Mass Spectrum) analysis and filtered by Lipinski’s rule. Target proteins connected to the filtered compounds and gout were selected from public databases. The overlapping target proteins between bioactives-interacted target proteins and gout-targeted proteins were identified using a Venn diagram. Bioactives-Proteins interactive networking for gout was analyzed to identify potential ligand-target and visualized the rich factor on the R package via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on STRING. Finally, a molecular docking test (MDT) between bioactives and target proteins was analyzed via AutoDock Vina. Gene Set Enrichment Analysis (GSEA) demonstrated that mechanisms of M. alba L. leaves against gout were connected to 17 signaling pathways on 26 compounds. AKT1 (AKT Serine/Threonine Kinase 1), γ-Tocopherol, and RAS signaling pathway were selected as a hub target, a key bioactive, and a hub signaling pathway, respectively. Furthermore, three main compounds (γ-Tocopherol, 4-Dehydroxy-N-(4,5-methylenedioxy-2-nitrobenzylidene) tyramine, and Lanosterol acetate) and three key target proteins—AKT1, PRKCA, and PLA2G2A associated with the RAS signaling pathway were noted for their highest affinity on MDT. The identified three key bioactives in M. alba L. leaves might contribute to recovering gouty condition by inactivating the RAS signaling pathway.

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Network Pharmacology Identifies the Mechanisms of Sang-Xing-Zhi-Ke-Fang against Pharyngitis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2421916 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yinhe Deng ◽

Quanjiang Li ◽

Menglin Li ◽

Tiantian Han ◽

Guixian Li ◽

...

Keyword(s):

Signaling Pathway ◽

Influenza A ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Venn Diagram ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Ras Signaling ◽

Clinical Effects ◽

Overlapping Genes

Background. Sang-Xing-Zhi-Ke-Fang (SXZKF) demonstrates good therapeutic effect against pharyngitis. Nevertheless, the pharmacological mechanism underlying its effectiveness is still unclear. Objective. To investigate the underlying mechanisms of SXZKF against pharyngitis using network pharmacology method. Methods. Bioactive ingredients of SXZKF were collected and screened using published literature and two public databases. Using four public databases, the overlapping genes between these bioactive compound-related and pharyngitis-related genes were identified by Venn diagram. Protein-protein interaction (PPI) was obtained using “Search Tool for the Retrieval of Interacting Genes (STRING)” database. “Database for Annotation, Visualization, and Integrated Discovery ver. 6.8 (DAVID 6.8)” was used to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the molecular mechanisms of SXZKF against pharyngitis. Finally, Cytoscape 3.7.2 software was used to construct and visualize the networks. Result. A total of 102 bioactive compounds were identified. Among them, 886 compounds-related and 6258 pharyngitis-related genes were identified, including 387 overlapping genes. Sixty-three core targets were obtained, including ALB, PPARγ, MAPK3, EGF, and PTGS2. Signaling pathways closely related to mechanisms of SXZKF for pharyngitis were identified, including serotonergic synapse, VEGF signaling pathway, Fc epsilon RI signaling pathway, Ras signaling pathway, MAPK signaling pathway, and influenza A. Conclusion. This is the first identification of in-depth study of SXZKF against pharyngitis using network pharmacology. This new evidence could be informative in providing new support on the clinical effects of SXZKF on pharyngitis and for the development of personalized medicine for pharyngitis.

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A network pharmacology analysis on drug-like compounds from Ganoderma lucidum for alleviation of Atherosclerosis

10.21203/rs.3.rs-236410/v1 ◽

2021 ◽

Author(s):

Ki Kwang Oh ◽

Md. Adnan ◽

Dong Ha Cho

Keyword(s):

Signaling Pathways ◽

Signaling Pathway ◽

Ganoderma Lucidum ◽

Mapk Signaling ◽

Mendelian Inheritance ◽

Chronic Inflammatory Disease ◽

Mapk Signaling Pathway ◽

Venn Diagram ◽

Network Pharmacology ◽

Overlapping Genes

Abstract Background: Ganoderma lucidum (GL) is known as a potent alleviator against chronic inflammatory disease like atherosclerosis (AS), but its critical bioactive compounds and their mechanisms against AS have not been unveiled. This research aimed to identify the key compounds(s) and mechanism(s) of GL against AS through network pharmacology.Methods: The compounds from GL were identified by gas chromatography-mass spectrum (GC-MS), and SwissADME screened their physicochemical properties. Then, the gene(s) associated with the screened compound(s) or AS related genes were identified by public databases, and we selected the overlapping genes using a Venn diagram. The networks between overlapping genes and compounds were visualized, constructed, and analyzed by RStudio. Finally, we performed molecular docking test (MDT) to identify key gene(s), compound(s) on AutoDockVina.Results: A total of 35 compounds in GL was detected via GC-MS, and 34 compounds (accepted by the Lipinski's rule) were selected as drug-like compounds (DLCs). A total of 34 compounds were connected to the number of 785 genes and 2,606 AS-related genes were identified by DisGeNET and Online Mendelian Inheritance in Man (OMIM). The final 98 overlapping genes were extracted between the compounds-genes network and AS-related genes. On Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, the number of 27 signaling pathways were sorted out, and a hub signaling pathway (MAPK signaling pathway), a core gene (PRKCA), and a key compound (Benzamide, 4-acetyl-N-(2,6-dimethylphenyl)) were selected among the 27 signaling pathways via MDT. Conclusion: Overall, we found that the identified 3 DLCs from GL have potent anti-inflammatory efficacy, improving AS by inactivating the MAPK signaling pathway.

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SARS-CoV-2 intervened by NSAIDs: A network pharmacology approach to decipher signaling pathway and interactive genes

10.21203/rs.3.rs-111615/v1 ◽

2020 ◽

Author(s):

Ki Kwang Oh ◽

Md. Adnan ◽

Dong Ha Cho

Keyword(s):

Signaling Pathway ◽

Binding Affinity ◽

Target Genes ◽

Enrichment Analysis ◽

Venn Diagram ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Ras Signaling ◽

Overlapping Genes ◽

Anti Inflammatory

Abstract Background: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 patients as painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most potent NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology.Method: FDA (U.S. Food & Drug Administration) approved twenty NSAIDs were used for this study. Genes related to selected NSAIDs and COVID-19 related genes were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases. Venn diagram identified overlapping genes between NSAIDs and COVID-19 related genes. The interactive networking between NSAIDs and overlapping genes was analyzed by STRING. RStudio plotted the bubble chart of KEGG pathway enrichment analysis of overlapping genes. Finally, the binding affinity of NSAIDs against target genes was determined through molecular docking analysis.Results: Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD genes were explored as the associated genes of the RAS. Among twenty NSAIDs, 6MNA, rofecoxib, and indomethacin revealed promising binding affinity with the highest docking score against three identified genes, respectively.Conclusions: Overall, our proposed three NSAIDs (6MNA, rofecoxib, and indomethacin) might block the RAS by inactivating its associated genes, thus may alleviate excessive inflammation induced by SARS-CoV-2.

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Studies on the Mechanism of Gegen Qinlian Decoction in Treating Diabetes Mellitus Based on Network Pharmacology

Natural Product Communications ◽

10.1177/1934578x20982138 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1934578X2098213

Author(s):

Xiaodong Deng ◽

Yuhua Liang ◽

Jianmei Hu ◽

Yuhui Yang

Keyword(s):

Diabetes Mellitus ◽

Molecular Docking ◽

Protein Interaction ◽

Protein Interaction Network ◽

Interaction Network ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Network Pharmacology ◽

Hub Genes ◽

Topological Parameters

Diabetes mellitus (DM) is a chronic disease that is very common and seriously threatens patient health. Gegen Qinlian decoction (GQD) has long been applied clinically, but its mechanism in pharmacology has not been extensively and systematically studied. A GQD protein interaction network and diabetes protein interaction network were constructed based on the methods of system biology. Functional module analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Gene Ontology (GO) enrichment analysis were carried out on the 2 networks. The hub nodes were filtered by comparative analysis. The topological parameters, interactions, and biological functions of the 2 networks were analyzed in multiple ways. By applying GEO-based external datasets to verify the results of our analysis that the Gene Set Enrichment Analysis (GSEA) displayed metabolic pathways in which hub genes played roles in regulating different expression states. Molecular docking is used to verify the effective components that can be combined with hub nodes. By comparing the 2 networks, 24 hub targets were filtered. There were 7 complex relationships between the networks. The results showed 4 topological parameters of the 24 selected hub targets that were much higher than the median values, suggesting that these hub targets show specific involvement in the network. The hub genes were verified in the GEO database, and these genes were closely related to the biological processes involved in glucose metabolism. Molecular docking results showed that 5,7,2', 6'-tetrahydroxyflavone, magnograndiolide, gancaonin I, isoglycyrol, gancaonin A, worenine, and glyzaglabrin produced the strongest binding effect with 10 hub nodes. This compound–target mode of interaction may be the main mechanism of action of GQD. This study reflected the synergistic characteristics of multiple targets and multiple pathways of traditional Chinese medicine and discussed the mechanism of GQD in the treatment of DM at the molecular pharmacological level.

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Use of Network Pharmacology to Explore the Mechanism of Gegen (Puerariae lobatae Radix) in the Treatment of Type 2 Diabetes Mellitus Associated with Hyperlipidemia

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6633402 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Guozhen Yuan ◽

Shuai Shi ◽

Qiulei Jia ◽

Jingjing Shi ◽

Shuqing Shi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Chinese Herbs ◽

Network Pharmacology ◽

Biological Processes ◽

Active Ingredients

Rapid increases in metabolic disorders, such as type 2 diabetes mellitus (T2DM) and hyperlipidemia, are becoming a substantial challenge to worldwide public health. Traditional Chinese medicine has a long history and abundant experience in the treatment of diabetes and hyperlipidemia, and Puerariae lobatae Radix (known as Gegen in Chinese) is one of the most prevalent Chinese herbs applied to treat these diseases. The underlying mechanism by which Gegen simultaneously treats diabetes and hyperlipidemia, however, has not been clearly elucidated to date. Therefore, we systematically explored the potential mechanism of Gegen in the treatment of T2DM complicated with hyperlipidemia based on network pharmacology. We screened the potential targets of Gegen, T2DM, and hyperlipidemia in several online databases. Then, the hub targets were analyzed by performing protein-protein interaction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays, and finally, the complicated connections among compounds, targets, and pathways were visualized in Cytoscape. We found that isoflavones, including daidzein, genistein, and puerarin, as well as β-sitosterol, are the key active ingredients of Gegen responsible for its antidiabetic and antihyperlipidemia effects, which mainly target AKR1B1, EGFR, ESR, TNF, NOS3, MAPK3, PPAR, CYP19A1, INS, IL6, and SORD and multiple pathways, such as the PI3K-Akt signaling pathway; the AGE-RAGE signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis; the PPAR signaling pathway; insulin resistance; the HIF-1 signaling pathway; the TNF signaling pathway; and others. These active ingredients also target multiple biological processes, including the regulation of glucose and lipid metabolism, the maintenance of metabolic homeostasis, and anti-inflammatory and antioxidant pathways. In conclusion, Gegen is a promising therapeutic phytomedicine for T2DM with hyperlipidemia that targets multiple proteins, biological processes, and pathways.

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Discussing the Mechanism of Dahuang Huanglian Xiexin Decoction in the Treatment of Type 2 Diabetes Mellitus via Network Pharmacology and Molecular Docking

10.21203/rs.3.rs-531851/v1 ◽

2021 ◽

Author(s):

Xi Cen ◽

Yan Wang ◽

LeiLei Zhang ◽

XiaoXiao Xue ◽

Yan Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Molecular Docking ◽

Target Genes ◽

Enrichment Analysis ◽

Network Pharmacology ◽

Overlapping Genes ◽

Potential Mechanism ◽

Active Components ◽

The Core ◽

Core Genes

Abstract BackgroundType 2 diabetes mellitus (T2DM) is regarded as Pi Dan disease in traditional Chinese medicine (TCM). Dahuang Huanglian Xiexin Decoction (DHXD), a classical TCM formula, has been used for treating Pi Dan disease in clinic, its pharmacological mechanism has not been elucidated. MethodsThis study used network pharmacological analysis and molecular docking approach to explore the mechanism of DHXD on T2DM. Firstly, the compounds in DHXD were obtained from TCMSP and TCMID databases, the potential targets were determined based on TCMSP and UniProt databases. Next, Genecards, Digenet and UniProt databases were used to identify the targets of T2DM. Then, the protein-protein interaction (PPI) network was established with overlapping genes of T2DM and compounds, and the core targets in the network were identified and analyzed. Then, the David database was used for GO and KEGG enrichment analysis. Finally, the target genes were selected and the molecular docking was completed by Autodock software to observe the binding level of active components with target genes.ResultsA total of 397 related components and 128 overlapping genes were identified. After enrichment analysis, it was found that HIF-1, TNF, IL-17 and other signaling pathways, as well as DNA transcription, gene expression, apoptosis and other cellular biological processes had the strongest correlation with the treatment of T2DM by DHXD, and most of them occurred in the extracellular space, plasma membrane and other places, which were related to enzyme binding and protein binding. In addition, 42 core genes of DHXD, such as VEGFA, TP53 and MAPK1, were considered as potential therapeutic targets, indicating the potential mechanism of DHXD on T2DM. Finally, the results of molecular docking showed that HIF-1 pathway had strong correlation with the target genes INSR and GLUT4, quercetin and berberine had the strongest binding power with them respectively.ConclusionThis study summarized the main components of DHXD in the treatment of T2DM, identified the core genes and pathways, and systematically analyzed the interaction of related targets, trying to lay the foundation for clarifying the potential mechanism of DHXD on T2DM, so as to carry out further research in the future.

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A Network Pharmacology Approach to Explore Mechanism of Action of Longzuan Tongbi Formula on Rheumatoid Arthritis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/5191362 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 5

Author(s):

An Huang ◽

Gang Fang ◽

Yuzhou Pang ◽

Zongran Pang

Keyword(s):

Rheumatoid Arthritis ◽

Signaling Pathway ◽

Active Rheumatoid Arthritis ◽

Trp Channels ◽

Network Pharmacology ◽

Mtor Signaling Pathway ◽

Active Ingredients ◽

Major Pathway ◽

Pharmacological Mechanism ◽

Ppar Signaling

Longzuan Tongbi Formula (LZTB) is an effective proved prescription in Zhuang medicine for treating active rheumatoid arthritis (RA). However, its active ingredients, underlying targets, and pharmacological mechanism are still not clear in treating RA. We have applied network pharmacology to study LZTB and found that 8 herbs in LZTB and 67 compounds in the 8 herbs are involved in the regulation of RA-related genes; we have conducted pathway analysis of overlapping genes and found that 7 herbs participate in the regulations of 24 pathways associated with RA and that 5 herbs in the 7 herbs and 25 compounds in the 5 herbs participate in the regulation of hsa05323 (rheumatoid arthritis). The results indicated that all herbs in LZTB and some compounds in those herbs participate in the treatment of RA; 25 compounds are main active ingredients and hsa05323 (rheumatoid arthritis) is the major pathway in the treatment of RA. We have also found that three pathways (inflammatory mediator regulation of TRP channels, PPAR signaling pathway, and mTOR signaling pathway) might have some effect on the treatment of RA.

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The Study of Yin-Chen-Hao-Tang Preventing and Treating Alcoholic Fatty Liver Disease Through PPAR Signaling Pathway Based on Network Pharmacology and RNA-Seq Transcriptomics

10.21203/rs.3.rs-818720/v1 ◽

2021 ◽

Author(s):

Yi-Wei Zhu ◽

Du Li ◽

Ting-Jie Ye ◽

Feng-Jun Qiu ◽

Xiao-Ling Wang ◽

...

Keyword(s):

Liver Disease ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Liver Tissue ◽

Network Pharmacology ◽

Rna Seq ◽

Alcoholic Fatty Liver ◽

Ppar Signaling ◽

Alcoholic Fatty Liver Disease ◽

Alt Activity

Abstract Background: Alcoholic fatty liver disease (AFLD) is the first stage of the alcoholic liver disease course. Yin-Chen-Hao-Tang (YCHT) has a good clinical effect on the treatment of AFLD, but its molecular mechanism has not been elucidated. In this study, we tried to explore the molecular mechanism of YCHT in improving hepatocyte steatosis in AFLD mice through network pharmacology and RNA sequencing (RNA-Seq) transcriptomics. Methods: Network pharmacological methods were used to analyze the potential therapeutic signaling pathways and targets of YCHT on AFLD. Then, the AFLD mice model was induced and YCHT was administered concurrently. Liver injury was measured by serum alanine aminotransferase (ALT) activity and liver tissue H&E staining, and liver steatosis was determined by serum triglyceride (TG) level and liver tissue Oil Red staining. The molecular mechanism of YCHT on prevention and treatment of mice AFLD was investigated according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differential expression genes data obtained by liver tissue RNA-Seq. Finally, the key signaling pathway and targets of YCHT on AFLD were verified in the ethanol-induced AFLD hepatocyte model by pathway inhibition experiments.Results: The results of network pharmacology analysis showed that YCHT may exert its pharmacological effect on AFLD through 312 potential targets which are involved in many signaling pathways including the PPAR signaling pathway. AFLD mice experiments results showed that YCHT markedly decreased mice serum ALT activity and serum TG levels. YCHT also significantly improved alcohol-induced hepatic injury and steatosis in mice livers. Furthermore, both KEGG analysis of RNA-Seq and AFLD hepatocyte model experiments showed that the PPAR signaling pathway should be the most relevant pathway of YCHT in the prevention and treatment of AFLD. YCHT could remarkably reduce the expression of PPARγ which is related to the lipogenesis pathway. YCHT also could increase the expression of PPARα which is related to the lipolysis pathway. Conclusions: Our study discovered that PPARγ and PPARα are the key targets and the PPAR signaling pathway is the main signaling pathway for YCHT to prevent and treat AFLD.

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A Network Pharmacology-Based Approach for Exploring Key Active Compounds and Pharmacological Mechanisms of Tangshen Formula for Treatment of Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2021/8833688 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Weie Zhou ◽

Xuefeng Zhou ◽

Yuan Zhang ◽

Yuyang Wang ◽

Wenjie Wu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Synergistic Effects ◽

Mapk Signaling ◽

Network Pharmacology ◽

Active Compounds ◽

Promising Source ◽

Tangshen Formula ◽

Compound Target

Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM). The occurrence and development of DN are related to multiple factors in the human body, which makes DN a complex disease, and the pathogeneses of DN have not yet been fully illustrated. Furthermore, DN lacks effective drugs for treatment nowadays. Chinese herbal medicine (CHM) often shows the feature of multicomponents, multitargets, multipathways, and synergistic effects and shows a promising source of new therapeutic drugs for DN. As a CHM, Tangshen Formula (TSF) was used to treat DN patients in China. However, its bioactive compounds and holistic pharmacological mechanisms on DN are both unclear. A network pharmacology approach was firstly applied to explore multiple active compounds and multiple key pharmacological mechanisms for TSF treating DN by drug-targeted interaction databases, herb-compound-target network, protein-protein interaction network, compound-target-pathway network, and analysis methods. And the results showed that TSF have the characteristic of multicomponents, multitargets, multipathways, and synergistic effects for treating DN. The quercetin, naringenin, kaempferol, and isorhamnetin as key active compounds and the PI3K-Akt signaling pathway, TNF signaling pathway, nonalcoholic fatty liver disease (NAFLD), focal adhesion, rap1 signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, and insulin resistance as the key molecular mechanisms play important roles in TSF treating DN. Moreover, quercetin, naringenin, kaempferol, and isorhamnetin were successfully detected in TSF by the UHPLC-MS/MS analysis method. And their concentrations were 0.224, 8.295, 0.0564, and 0.0879 mg·kg-1, respectively. The present findings not only provide new insights for a deeper understanding of the constituent basis and pharmacology of TSF but also provide guidance for further pharmacological studies on TSF.

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