Anti-Liver Fibrosis Activity and the Potential Mode of Action of Ruangan Granules: Integrated Network Pharmacology and Metabolomics

Shang, Xiaofei; Yuan, Xinghui; Dai, Liyun; Liu, Yang; He, Jian; Chen, Huan; Li, Hongyan; Li, Xiuhui

doi:10.3389/fphar.2021.754807

Cited by 4 publications

(3 citation statements)

References 45 publications

(51 reference statements)

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“…The UHPLC-Q-Orbitrap HRMS analysis of TFPCP revealed the presence of 14 flavonoids, including quercetin, taxifolin, pinocembrin, and luteoloside, among others. Many of these flavonoids exhibit a wide range of pharmacological properties, such as antioxidant, antiinflammatory, and antimicrobial effects (Chirumbolo and Bjorklund, 2018;Shang et al, 2021). In this study, we provided further evidence that TFPCP can ameliorate liver injury and fibrosis.…”

Section: Discussionmentioning

confidence: 52%

Total flavonoids extracted from Penthorum chinense Pursh mitigates CCl4-induced hepatic fibrosis in rats via inactivation of TLR4-MyD88-mediated NF-κB pathways and regulation of liver metabolism

Wang,

Li,

Liu

et al. 2023

Front. Pharmacol.

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Background:Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear.Methods: The chemical composition of TFPCP was determined using UHPLC–Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl4)-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kg∙day)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kg∙day)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%–20% CCl4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics.Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl4-treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1β); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-β1, TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites.Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.

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Section: Discussionmentioning

confidence: 52%

Total flavonoids extracted from Penthorum chinense Pursh mitigates CCl4-induced hepatic fibrosis in rats via inactivation of TLR4-MyD88-mediated NF-κB pathways and regulation of liver metabolism

Wang,

Li,

Liu

et al. 2023

Front. Pharmacol.

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“…Wang and colleagues [ 27 ] have demonstrated that stimulation of HSCs by PDGF leads to cell proliferation and exacerbate fibrogenesis. In another study, Liu and colleagues [ 28 ] examined the protective effects of isorhamnetin in preventing the progression of liver fibrosis induced by carbon tetrachloride (CCl 4 ) in mice. They measured the expression of Smad3 and p38 mitogen-activated protein kinase proteins using Western blotting.…”

Section: Discussionmentioning

confidence: 99%

Isorhamnetin Exerts Antifibrotic Effects by Attenuating Platelet-Derived Growth Factor-BB-induced HSC-T6 Cells Activation via Suppressing PI3K-AKT Signaling Pathway

Rashidi,

Matour,

Beheshtinasab

et al. 2023

IBJ

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Background: Currently, liver fibrosis is growing worldwide; unfortunately, there is no definite cure for this disease. Hence, understanding the molecular pathways involved in the development of liver fibrosis can help to find a proper treatment. In this study, we aimed to evaluate the effects of isorhamnetin as an antifibrotic agent on PDGF-BB-activated HSC-T6 cells in a concentration-dependent manner. We have also attempted to assess signaling pathways that may affect liver fibrosis. Methods: PDGF-BB was used to activate the HSC-T6 rat hepatic stellate cell line. The activated cells were treated with Isorhamnetin for 24 h. Finally, we compared the mRNA expression level of COLA1 and α-SMA and also the level of phosphorylated AKT protein with the control group. Results: The obtained data revealed a significant increase in the expression level of the COLA1 and α-SMA genes (p > 0.05), as well as phosphorylated AKT protein, in the cells treated with PDGF-BB. In addition, 75 and 100 µM concentrations of Isorhamnetin markedly declined the COLA1 and α-SMA expression and also the phosphorylated AKT protein level in the HSC-T6 cells. Conclusion: Our findings suggest that Isorhamnetin decreases HSC-T6 activation, the expression of COLA1 and α-SMA , in vitro, which could act as an antifibrotic element to reduce and treat liver fibrosis disease.

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“…Hepatic fibrosis, as a crucial pathological feature, exists in almost all chronic liver diseases triggered by hepatitis virus, alcoholism, cholestasis and lipodystrophy, etc ( Shang et al, 2022 ). Without appropriate therapy, hepatic fibrosis could further deteriorate into cirrhosis, portal hypertension and hepatocellular carcinoma ( Anuja et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Tandem mass tag-based proteomics analysis reveals the multitarget mechanisms of Phyllanthus emblica against liver fibrosis

et al. 2022

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Phyllanthus emblica (PE), a traditional multiethnic herbal medicine, is commonly applied to treat liver diseases. Our previous study demonstrated that aqueous extract of PE (AEPE) could alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in vivo, but the underlying molecular mechanisms are still unclear. The present study was undertaken to clarify the multitarget mechanisms of PE in treating liver fibrosis by proteomics clues. A CCl4-induced liver fibrosis rat model was established. The anti-liver fibrosis effects of chemical fractions from AEPE were evaluated by serum biochemical indicators and pathological staining. Additionally, tandem mass tag (TMT) - based quantitative proteomics technology was used to detect the hepatic differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene ontology (GO) enrichment and protein-protein interaction (PPI) network were used to perform bioinformatics analysis of DEPs. Western blot analysis was used to verify the key potential targets regulated by the effective fraction of AEPE. The low-molecular-weight fraction of AEPE (LWPE) was determined to be the optimal anti-liver fibrosis active fraction, that could significantly improve ALT, AST, HA, Col IV, PCIII, LN, Hyp levels and reduce the pathological fibrotic lesion of liver tissue in model rats. A total of 195 DEPs were screened after LWPE intervention. GO analysis showed that the DEPs were related mostly to extracellular matrix organization, actin binding, and extracellular exosomes. KEGG pathway analysis showed that DEPs are mainly related to ECM-receptor interactions, focal adhesion and PI3K-Akt signaling pathway. Combined with the GO, KEGG and Western blot results, COL1A2, ITGAV, TLR2, ACE, and PDGFRB may be potential targets for PE treatment of liver fibrosis. In conclusion, LWPE exerts therapeutic effects through multiple pathways and multiple targets regulation in the treatment of liver fibrosis. This study may provide proteomics clues for the continuation of research on liver fibrosis treatment with PE.

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Anti-Liver Fibrosis Activity and the Potential Mode of Action of Ruangan Granules: Integrated Network Pharmacology and Metabolomics

Cited by 4 publications

References 45 publications

Total flavonoids extracted from Penthorum chinense Pursh mitigates CCl4-induced hepatic fibrosis in rats via inactivation of TLR4-MyD88-mediated NF-κB pathways and regulation of liver metabolism

Total flavonoids extracted from Penthorum chinense Pursh mitigates CCl4-induced hepatic fibrosis in rats via inactivation of TLR4-MyD88-mediated NF-κB pathways and regulation of liver metabolism

Isorhamnetin Exerts Antifibrotic Effects by Attenuating Platelet-Derived Growth Factor-BB-induced HSC-T6 Cells Activation via Suppressing PI3K-AKT Signaling Pathway

Tandem mass tag-based proteomics analysis reveals the multitarget mechanisms of Phyllanthus emblica against liver fibrosis

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