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Exploring the Mechanism of Dangguiliuhuang Decoction Against Hepatic Fibrosis by Network Pharmacology and Experimental Validation.

ABSTRACT: Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.

SUBMITTER: Cao H

PROVIDER: S-EPMC5844928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatic fibrosis (HF) represents the excessive wound healing where an excess amount of connective tissues is formed within the liver, finally resulting in cirrhosis or even hepatocellular carcinoma (HCC). Therefore, it is significant to discover the efficient agents and components to treat HF, thus restraining the further progression of hepatopathy. Astragalus membranaceus (Fisch.) Bunge [also called Astragali Radix (AR)] is a famous herb in traditional Chinese medicine (TCM), which possesses a variety of biological activities and exerts good therapeutic effects in the treatment of HF. Flavonoids account for the major active ingredients related to the AR pharmacological effects. Total AR flavonoids have been proved to exert inhibitory effects on hepatic fibrosis. This study aimed to further undertake network pharmacology analysis coupled with experimental validation and molecular docking to investigate the effects and mechanism of multiple flavonoid components from AR against liver fibrosis. The results of the network pharmacology analysis showed that the flavonoids from AR exerted their pharmacological effects against liver fibrosis by modulating multiple targets and pathways. The experimental validation data showed that the flavonoids from AR were able to suppress transforming growth factor beta 1 (TGF-β1)-mediated activation of hepatic stellate cells (HSCs) and reduce extracellular matrix deposition in HSC-T6 cells via regulating the nuclear factor kappa B (NF-κB) signal transduction pathway. The results of the molecular docking study further showed that the flavonoids had a strong binding affinity for IκB kinase (IKKβ) after docking into the crystal structure. The above results indicated that, flavonoids possibly exerted the anti-inflammatory effect on treating HF by mediating inflammatory signaling pathways. The potential mechanism of these flavonoids against liver fibrosis may be related to suppression of the NF-κB pathway through effective inhibition of IKKβ. This study not only provides a scientific basis for clarifying the effects and mechanism of AR flavonoids against liver fibrosis but also suggests a novel promising therapeutic strategy for the treatment of liver fibrosis.

Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear. Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests. Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD. Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2. Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.

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Project description:BackgroundTingli Dazao Xiefei decoction (TDXD) has been shown to have a therapeutic effect on heart failure (HF). Nevertheless, its molecular mechanism for treating HF is still unclear.Materials and methodsTDXD and HF targets were collected from the databases, and protein-protein interaction (PPI) analysis and enrichment analysis were performed on the overlapping targets. Then, AutoDock was employed for molecular docking. Finally, we used the left anterior descending coronary artery (LAD) ligation to induce HF model rats for in vivo experiments and verified the effect and mechanism of TDXD on HF.ResultsNetwork pharmacological analysis showed that the main active components of TDXD in treating HF were quercetin, kaempferol, beta-carotene, isorhamnetin, and beta-sitosterol, and the core targets were IL-6, VEGFA, TNF, AKT1, and MAPK1. Multiple gene functions and signaling pathways were obtained by enrichment analysis, among which inflammation-related, PI3K/Akt, and MAPK signaling pathways were closely related to HF. Furthermore, the molecular docking results showed that the core targets had good binding ability with the main active components. Animal experiments showed that TDXD could effectively improve left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS), decrease left ventricular internal diastolic diameter (LVIDd) and left ventricular internal systolic diameter (LVIDs), reduce the area of myocardial fibrosis, and decrease serum BNP, LDH, CK-MB, IL-6, IL-1β, and TNF-α levels in HF rats. Meanwhile, TDXD could upregulate the expression of Bcl-2, downregulate the expression of Bax, and reduce cardiomyocyte apoptosis. At the same time, it was verified that TDXD could significantly decrease the expression of PI3K, P-Akt, and P-MAPK. Captopril showed similar effects.ConclusionsCombining network pharmacological analysis and experimental validation, this study verified that TDXD could improve cardiac function and protect against cardiac injury by inhibiting the activation of PI3K/Akt and MAPK signaling pathways.

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Exploring the Mechanism of Dangguiliuhuang Decoction Against Hepatic Fibrosis by Network Pharmacology and Experimental Validation.

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