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Gegen Qinlian Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats via Oxidative Stress, Inflammation, and the NLRP3 Signal Axis.

ABSTRACT: Gegen Qinlian Decoction (GQD), a classic Chinese herbal formula, has been widely used in Chinese clinic for centuries and is well defined in treating nonalcoholic fatty liver disease (NAFLD). However, the mechanism action of GQD on NAFLD is still rarely evaluated. The present study aims to investigate the effect of GQD on treatment of NAFLD in rats and to further explore the underlying mechanism. The rat NAFLD model established by high-fat-diet feeding was used in the research. Our results exhibited the liver lesions and steatosis was significantly alleviated in NAFLD rats treated with GQD via Oil Red O and H&E staining. Body weight and liver index in GQD groups were reduced significantly (P < 0.05). Moreover, the biochemical analyzer test results showed that GQD significantly decreased blood lipid levels total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and liver injury indicators alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), while it increased the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05). The levels of interferon-? (IFN-?), tumor necrosis factor-? (TNF-?), and malondialdehyde (MDA) after the GQD treatment were significantly lower, and then interleukin-2 (IL-2), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were lifted significantly (P < 0.05). Further, GQD blocked the expression of NLRP3, ASC, caspase-1 mRNA, and proteins in the liver tissues significantly (P < 0.05). These findings indicated that GQD can ameliorate the hepatic steatosis and injury of NAFLD. Its possible mechanism involves the modulation of inflammatory cytokines and antioxidative stress and the inhibition of NLRP3 signal axis activation. The results support that GQD may be a promising candidate in the treatment of NAFLD.

SUBMITTER: Ying Y

PROVIDER: S-EPMC7902151 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Gegen Qinlian Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats <i>via</i> Oxidative Stress, Inflammation, and the NLRP3 Signal Axis.

Ying Yuqi Y Zhang Haitao H Yu Dian D Zhang Wei W Zhou Dongling D Liu Shuangchun S

Evidence-based complementary and alternative medicine : eCAM 20210216

Gegen Qinlian Decoction (GQD), a classic Chinese herbal formula, has been widely used in Chinese clinic for centuries and is well defined in treating nonalcoholic fatty liver disease (NAFLD). However, the mechanism action of GQD on NAFLD is still rarely evaluated. The present study aims to investigate the effect of GQD on treatment of NAFLD in rats and to further explore the underlying mechanism. The rat NAFLD model established by high-fat-diet feeding was used in the research. Our results exhib ...[more]

PMID: 33643422

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Project description:Background: Gegen Qinlian decoction (GGQLD) is a typical traditional Chinese medicine (TCM) prescription documented in Shang Han Lun. Clinically, GGQLD has been utilized to manage the inflammatory symptoms of metabolic diseases and to protect against renal damage in China. In the present study, a hypothesis was proposed that the multi-target solution of GGQLD produced anti-inflammatory effects on ameliorating hyperuricemia (HUA). Methods: A total of 30 primary HUA patients receiving GGQLD treatment (two doses daily) for 4 weeks were selected. Then, differences in uric acid (UA) levels and expression of peripheral blood mononuclear cells (PBMCs) and urinary exosomes before and after treatment were analyzed. The therapeutic indexes for the active ingredients in GGQLD against HUA were confirmed through pharmacological subnetwork analysis. Besides, the HUA rat model was established through oral gavage of potassium oxonate and treated with oral GGQLD. In addition, proximal tubular epithelial cells (PTECs) were stimulated by UA and intervened with GGQLD for 48 h. Subsequently, RNA-seq, flow cytometry, and confocal immunofluorescence microscopy were further conducted to characterize the differences in UA-mediated inflammation and apoptosis of human renal tubular epithelial cells pre- and post-administration of GGQLD. In the meanwhile, quantitative real-time PCR (qPCR) was carried out to determine gene expression, whereas a western blotting (WB) assay was conducted to measure protein expression. Results: Our network analysis revealed that GGQLD treated HUA via the anti-inflammatory and antiapoptotic pathways. Additionally, NLPR3 expression significantly decreased in PBMCs and urinary exosomes of HUA patients after GGQLD treatment. In vivo, GGQLD treatment alleviated HUA-induced renal inflammation, which was associated with decreased expression of NLRP3 inflammasomes and apoptosis-related mRNAs. Moreover, GGQLD promoted renal UA excretion by inhibiting the activation of GSDMD-dependent pyroptosis induced by NLRP3 inflammasomes and by reducing apoptosis via the mitochondrial apoptosis signaling pathway in vitro. Conclusion: This study indicates that GGQLD efficiently reduces inflammatory responses while promoting UA excretion in HUA. Our findings also provide compelling evidence supporting the idea that GGQLD protects against the UA-mediated renal tubular epithelial cell inflammation through the mitochondrial apoptosis signaling pathways. Taken together, these findings have demonstrated a novel therapeutic method for the treatment of HUA.

Project description:BackgroundThe Gegen Qinlian Decoction (GGQLD) is a renowned traditional Chinese medicinal formula that has been used for centuries to effectively treat asymptomatic Hyperuricemia (HUA). This study aims to investigate the underlying mechanism of GGQLD's therapeutic effects on HUA.MethodsThe study enrolled a total of 25 healthy participants and 32 middle-aged and elderly individuals with asymptomatic HUA. All asymptomatic HUA participants were treated with GGQLD. Venous blood samples were collected from all participants to isolate peripheral blood mononuclear cells (PBMCs), which were then analyzed for biological profiles using flow cytometry. Network pharmacology analysis was utilized to identify the potential pathways involved in the therapeutic effects of GGQLD. Transcriptomic patterns of cultured proximal tubule epithelial cells (PTECs) were evaluated via bulk RNA-seq, and critical differentially expressed genes (DEGs) were identified and verified through ELISA. Molecular docking and molecular dynamics (MD) simulation were employed to investigate the potential compounds in GGQLD that may be involved in treating HUA.ResultsNetwork pharmacology analysis revealed that immune-related pathways might be involved in the therapeutic mechanism of GGQLD. RNA-seq analysis confirmed the involvement of innate lymphoid cell (ILC) development-related genes and clock genes. Polychromatic flow cytometric analysis demonstrated that GGQLD treatment reduced the proportion of ILC3s in total ILCs in asymptomatic HUA patients. ELISA results showed that GGQLD treatment reduced the levels of activating factors, such as ILC3-IL-18 and IL-1β, in the plasma of HUA patients. GGQLD was also found to regulate circadian clock gene expression in PBMCs to treat asymptomatic HUA. Furthermore, the interaction between 40 compounds in GGQLD and HDAC3 (Histone Deacetylase 3), NLRP3 (NOD-like receptor protein 3), RORA (RAR-related orphan receptor A), and REV-ERBα (nuclear receptor subfamily 1) revealed that GGQLD may regulate ILCs and clock genes to treat asymptomatic HUA.ConclusionsThe regulation of circadian clock gene expression and the proportion of ILC cells may be involved in the therapeutic effects of GGQLD on asymptomatic HUA patients.

Project description:PurposeGegen Qinlian decoction (GQD) has been used to treat gastrointestinal diseases, such as diarrhea and ulcerative colitis (UC). A recent study demonstrated that GQD enhanced the effect of PD-1 blockade in colorectal cancer (CRC). This study used network pharmacology analysis to investigate the mechanisms of GQD as a potential therapeutic approach against CRC.Materials and methodsBioactive chemical ingredients (BCIs) of GQD were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. CRC-specific genes were obtained using the gene expression profile GSE110224 from the Gene Expression Omnibus (GEO) database. Target genes related to BCIs of GQD were then screened out. The GQD-CRC ingredient-target pharmacology network was constructed and visualized using Cytoscape software. A protein-protein interaction (PPI) network was subsequently constructed and analyzed with BisoGenet and CytoNCA plug-in in Cytoscape. Gene Ontology (GO) functional and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis for target genes were then performed using the R package of clusterProfiler.ResultsOne hundred and eighteen BCIs were determined to be effective on CRC, including quercetin, wogonin, and baicalein. Twenty corresponding target genes were screened out including PTGS2, CCNB1, and SPP1. Among these genes, CCNB1 and SPP1 were identified as crucial to the PPI network. A total of 212 GO terms and 6 KEGG pathways were enriched for target genes. Functional analysis indicated that these targets were closely related to pathophysiological processes and pathways such as biosynthetic and metabolic processes of prostaglandins and prostanoids, cytokine and chemokine activities, and the IL-17, TNF, Toll-like receptor, and nuclear factor-kappa B (NF-κB) signaling pathways.ConclusionThe study elucidated the "multiingredient, multitarget, and multipathway" mechanisms of GQD against CRC from a systemic perspective, indicating GQD to be a candidate therapy for CRC treatment.

Project description:BackgroundThe frequently occurred chemotherapy-induced diarrhea (CID) caused by irinotecan (CPT-11) administration has been the most representative side-effects of CPT-11, resulting in the chemotherapy suspension or failure. Our previous studies indicated that Gegen Qinlian formula exhibited a significant alleviation effect on CPT-11-induced diarrhea. However, referencing to Japanese Kampo medicine, the TCM standard decoction would supply the gap between ancient preparation application and modern industrial production.MethodsThe LC-MS technology combined with network pharmacology was employed to identify the active ingredients and mechanisms of GQD standard decoction for CPT-11-induced diarrhea. The anti-inflammatory activities associated with intestinal barrier function of GQD standard decoction were studied by SN-38 activated NCM460 cells in vitro and CPT-11-induced diarrhea in vivo. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed.ResultsThere were 37 active compounds were identified in GQD standard decoction. Network pharmacology analyses indicated that PI3K-AKT signaling pathway were probably the main pathway of GQD standard decoction in CPT-11-induced diarrhea treatment, and PIK3R1, AKT1, NF-κB1 were the core proteins. Moreover, we found that the key proteins and pathway predicted above was verified in vivo and in vitro experiments, and the GQD standard decoction could protect the cellular proliferation in vitro and ameliorate CPT-11-induced diarrhea in mice model.ConclusionsThis study demonstrated the molecular mechanism of 37 active ingredients in GQD standard decoction against CPT-11-induced diarrhea. And the core proteins and pathway were validated by experiment. This data establishes the groundwork for particular molecular mechanism of GQD standard decoction active components, and this research can provide a scientific reference for the TCM therapy of CID.

Dataset Information

Gegen Qinlian Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats via Oxidative Stress, Inflammation, and the NLRP3 Signal Axis.

Publications

Gegen Qinlian Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats <i>via</i> Oxidative Stress, Inflammation, and the NLRP3 Signal Axis.

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