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Bupleurum marginatum Wall.ex DC in Liver Fibrosis: Pharmacological Evaluation, Differential Proteomics, and Network Pharmacology.

ABSTRACT: Liver fibrosis is a common pathological feature of many chronic liver diseases. Bupleurum marginatum Wall.ex DC (ZYCH) is a promising therapeutic for liver fibrosis. In this study, 25 compounds were isolated from ZYCH, and the effects of ZYCH on DMN-induced liver fibrosis in rats were evaluated. The optimal effect group (H-ZYCH group) was selected for further proteomic analysis, and 282 proteins were altered in comparison to the DMN model group (FC > 1.2 or < 0.83, p < 0.05). Based on GO annotation analysis, clusters of drug metabolism, oxidative stress, biomolecular synthesis and metabolism, positive regulation of cell growth, extracellular matrix deposition, and focal adhesion were significantly regulated. Then networks of the altered proteins and compounds was generated by Cytoscape. Importantly, triterpenoid saponins and lignans had possessed high libdock scores, numerous targets, important network positions, and strong inhibitory activity. These findings may suggest that triterpenoid saponins and lignans are important active compounds of ZYCH in liver fibrosis and targeted by proteins involved in liver fibrosis. The combination of network pharmacology with proteomic analysis may provide a forceful tool for exploring the effect mechanism of TCM and identifying bioactive ingredients and their targets.

SUBMITTER: Liu X

PROVIDER: S-EPMC5968385 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Bupleurum marginatum Wall.ex DC in Liver Fibrosis: Pharmacological Evaluation, Differential Proteomics, and Network Pharmacology.

Liu Xiujie X Shi Yu Y Hu Yinghui Y Luo Ke K Guo Ying Y Meng Weiwei W Deng Yulin Y Dai Rongji R

Frontiers in pharmacology 20180517

Liver fibrosis is a common pathological feature of many chronic liver diseases. Bupleurum marginatum Wall.ex DC (ZYCH) is a promising therapeutic for liver fibrosis. In this study, 25 compounds were isolated from ZYCH, and the effects of ZYCH on DMN-induced liver fibrosis in rats were evaluated. The optimal effect group (H-ZYCH group) was selected for further proteomic analysis, and 282 proteins were altered in comparison to the DMN model group (FC > 1.2 or < 0.83, p < 0.05). Based ...[more]

PMID: 29867514

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Project description:Background and Aims: The rapid development of society has resulted in great competitive pressures, leading to the increase in suicide rates as well as incidence and recurrence of depression in recent years. Proprietary Chinese medicines containing Bupleurum chinense DC. (Chaihu) are widely used in clinical practice. This study aimed at evaluating the efficacy and safety of oral proprietary Chinese medicines containing Chaihu for treating depression by network meta-analysis (NMA) and exploring the potential pharmacological mechanisms of the optimal drugs obtained based on NMA. Methods: This study searched for clinical randomized controlled trial studies (RCTs) about Chaihu-containing products alone or in combination with selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and cyclic antidepressants (CAS) for depression in eight databases. The search deadline is from data inception to April 2021. For efficacy assessment, the clinical response rate, the Hamilton Depression Scale-17 (HAMD-17), and adverse reactions were calculated. The methodological quality of the included studies was assessed for risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions, and the data were subjected to NMA via the Stata version 16.0 software. Subsequently, the optimal drug obtained from the NMA results, Danzhi Xiaoyao pill (DZXY), was used to conduct network pharmacology analysis. We searched databases to acquire bioactive and potential targets of DZXY and depression-related targets. The protein-protein interaction (PPI) network, component-target network, the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the STRING database, Cytoscape 3.9.0 software, and R version 4.1.2, respectively. Results: Thirty-seven RCTs, with a total of 3,263 patients, involving seven oral proprietary Chinese medicines containing Chaihu, were finally included. The results of the NMA demonstrated that the top four interventions with the best efficiency were Jiawei Xiaoyao + SSRI, DZXY + SNRI, Xiaoyao pill + SSRI, and Jieyu pill + SNRI; the top four interventions reducing HAMD score were DZXY + SNRI, Jiawei Xiaoyao, Jieyu pill, and Puyu pill + SNRI; the top four interventions with the least adverse effects were Jieyu pill, Anle pill + SSRI, DZXY + SNRI, and Puyu pill + SNRI. In the aspects above, DZXY + SNRI performed better than other treatments. After network meta-analysis, we conducted a network pharmacology-based strategy on the optimal drugs, DZXY, to provide the pharmacological basis for a conclusion. A total of 147 active compounds and 248 targets in DZXY were identified, of which 175 overlapping targets related to depression. Bioinformatics analysis revealed that MAPK3, JUN, MAPK14, MYC, MAPK1, etc. could become potential therapeutic targets. The MAPK signaling pathway might play an essential role in DZXY against depression. Conclusion: This is the very first systematic review and network meta-analysis evaluating different oral proprietary Chinese medicines containing Chaihu in depressive disorder. This study suggested that the combination of proprietary Chinese medicines containing Chaihu with antidepressants was generally better than antidepressant treatment. The incidence of adverse reactions with antidepressants alone was higher than that with proprietary Chinese medicines containing Chaihu alone or in combination with antidepressants. DZXY + SNRI showed significantly better results in efficacy, HAMD scores, and safety. The antidepressant effect of DZXY may be related to its regulation of neuroinflammation and apoptosis.

Project description:Renal fibrosis, characterized by the destruction of renal tubules and interstitial capillaries and the accumulation of extracellular matrix proteins, is a common outcome of chronic renal diseases and has a wide spectrum of etiologies. Fibrosis can affect any organ and has similar pathological mechanisms. Fuzheng Huayu formula (FZHY), as the approved anti-liver fibrosis medicine in China, also can inhibit the kidney fibrosis induced by HgCl2 or unilateral ureteral obstruction. However, little is known about the mechanisms underlying the beneficial effects of FZHY on renal fibrosis. This study aimed to identify the mechanisms of FZHY acts on renal fibrosis through network pharmacological analysis and in vivo experiments. Data from online databases were mined and screened to predict the target related genes of FZHY acts on renal fibrosis. The STRING and Cytoscape were used to construct the protein-protein interaction (PPI) networks for FZHY and CKD target proteins. Mouse models with CKD induced by Aristolochic Acid I (AAI) were used to validate the effects of FZHY on renal fibrosis and their underlying mechanisms by detecting kidney function, renal fibrosis, and related intersection genes. A total of 129 FZHY-CKD crossover proteins were filtered and constructed into a protein-protein interaction network complex and designated as the potential targets of FZHY. One of the highest-scoring genes, FOS, and its related signaling pathways were more activated in CKD. The results demonstrated that FZHY can exert an anti-renal fibrosis effect by improving the levels of serum creatinine and blood urea nitrogen and alleviating excessive collagen deposition in kidney tissue, FZHY also could reduce the levels of TNF-α, IL-1β, and IL-6 and inhibit the expression of MAPK/FOS signal molecules. Our study findings provide insights into predicting the effects of FZHY on CKD through network pharmacology. FZHY can protect the kidney from inflammatory injury caused by AAI and can antagonize inflammatory factor-stimulated MAPK/FOS activation in fibrotic kidneys. These effects constitute the mechanisms of FZHY for renal fibrosis.

Project description:Purpose:We explored the mechanism of Shugan Jianpi Formula (SGJPF) and its effective components for the treatment of liver fibrosis (LF). Materials and Methods:We collected the active ingredients in SGJPF through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and screened the effective components by absorption, distribution, metabolism, and excretion. Herb-associated target proteins were predicted and screened based on the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and Search Tool for Interactions of Chemicals databases. LF-associated target proteins were predicted and screened based on the Online Mendelian Inheritance in Man® Database and Comparative Toxicogenomics Database. Common genes with LF and herbs were selected, and Cytoscape 3.5.1 software was used to construct an herb pathway and component-LF common target network. The Search Tool for the Retrieval of Interacting Genes/Proteins was used to build a protein-protein interaction, and quantitative PCR was used to verify the related target genes. Finally, clusterProfiler was applied for the analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. Results:The pharmacological network contained 252 active compounds (e.g., Astragaloside A, saikosaponin, linoleic acid, and Poria acid A), 84 common target genes, and 94 significant signaling pathways. Among them, interleukin 6 (IL-6), tumor protein 53 p53 (TP53), prostaglandin-endoperoxide synthase 2 (PTGS2), AKT1, IL-1?, and the nucleotide-binding and oligomerization domain-like receptor and Janus kinase-signal transducer and activator of transcription signaling pathways were selected as the critical target gene and critical signal pathway, respectively. Conclusion:The mechanisms of SGJPF in protecting against LF include the regulation of multiple targets such as IL-6, TP53, PTGS2, and AKT1. These target proteins affect LF through various signal transduction pathways.

Project description:Astragali Radix (AR) has been widely used in traditional Chinese medicine prescriptions for acute and chronic liver injury. However, little is known about the effects of AR on acetaminophen (APAP)-induced liver injury (ALI). In the current study, a network pharmacology–based approach was applied to characterize the action mechanism of AR on ALI. All compounds of AR were obtained from the corresponding databases, and active compounds were selected according to its oral bioavailability and drug-likeness index. The potential genes of AR were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) and PubChem, whereas the potential genes related to ALI were obtained from Online databases (GeneCards and Online Mendelian Inheritance in Man) and Gene Expression Omnibus profiles. The enriched processes, pathways, and target genes of the diseases were analyzed by referring to the Search Tool for the Retrieval of Interacting Genes/Proteins database. A network constructed through Cytoscape software was used to identify the target proteins that connected the compounds in AR with the differential genes of ALI. Subsequently, the potential underlying action mechanisms of AR on ALI predicted by the network pharmacology analyses were experimentally validated in APAP-induced liver injury in mice and HL7702 cells incubated with APAP. The compound-target network included 181 targets, whereas the potential genes related to ALI were 4,621. A total of 49 AR–ALI crossover proteins, corresponding to 49 genes, were filtered into a protein–protein interaction network complex and designated as the potential targets of AR on ALI. Among the genes, the three highest-scoring genes, MYC, MAPK8, and CXCL8 were highly associated with apoptosis in ALI. Then in vitro and in vivo experiments confirmed that AR exhibited its prominent therapeutic effects on ALI mainly via regulating hepatocyte apoptosis related to inhibiting the expressions of MYC (c-Myc), MAPK8 (JNK1), and CXCL8 (IL-8). In conclusion, our study suggested that the combination of network pharmacology prediction with experimental validation might offer a useful tool to characterize the molecular mechanism of AR on ALI.

Project description:BackgroundKeyin pill (KP), a patented medicine in China, is used to treat psoriasis. However, KP has been reported to have liver toxicity, but its toxic substance basis and underlying mechanisms remain unclear. Therefore, this study aimed to explore the pharmacological mechanisms and components of KP-induced liver injury through animal experiments, UPLC-QTOF/MS combined with network pharmacology.MethodsFirstly, based on the immune stress mouse model, liver function parameters and hematoxylin-eosin (H&E) staining were detected to investigate KP-induced liver injury. The UPLC-QTOF/MS method was used to identify the components of KP. CTD database and literature mining were further applied to screen nonliver protective components. Subsequently, the nonliver protective components and their corresponding targets and targets of hepatotoxicity were analyzed by the method of network pharmacology. Finally, key targets from networked pharmacology were examined by the enzyme-linked immunosorbent assay (ELISA) and molecular docking.ResultsOur results indicated that KP had hepatotoxicity in male Kunming mice, which could favor hepatocyte necrosis and infiltration of inflammatory cells. A total of 70 nonliver protective compounds were identified and screened. The results of network pharmacology illustrated that methoxsalen, obacunone, limonin, and dictamnine might be the main compounds that caused liver damage. The potential hepatotoxicity mechanisms of KP might be through the IL17 and apoptosis pathways to regulate IL6, TNFα, CASP3, and CASP8 targets, thereby causing inflammation, excessive release of factors, and hepatocyte necrosis. The results of the ELISA experiments indicated that KP could increase the release of IL6 and TNFα inflammatory factors in liver tissues. Molecular docking suggested that methoxsalen, obacunone, limonin, and dictamnine had moderate binding ability with CASP3 and CASP8.ConclusionIn this study, the material basis and potential pharmacological mechanisms of KP-induced liver injury were preliminarily explored. Our research provides the initial theoretical basis for reducing the toxicity of KP.

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Bupleurum marginatum Wall.ex DC in Liver Fibrosis: Pharmacological Evaluation, Differential Proteomics, and Network Pharmacology.

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<i>Bupleurum marginatum</i> Wall.ex DC in Liver Fibrosis: Pharmacological Evaluation, Differential Proteomics, and Network Pharmacology.

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