Confirmation of inhibitingTLR4/MyD88/NF-κB Signalling Pathway by Duhuo Jisheng Decoction on Osteoarthritis: A Network Pharmacology Approach-Integrated Experimental Study.
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ABSTRACT:
SUBMITTER: Liu L
PROVIDER: S-EPMC8818874 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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Confirmation of inhibitingTLR4/MyD88/NF-κB Signalling Pathway by Duhuo Jisheng Decoction on Osteoarthritis: A Network Pharmacology Approach-Integrated Experimental Study.
Liu Linglong L Xu Limei L Wang Shengjie S Wang Lili L Wang Xiaoning X Xu Huifeng H Li Xihai X Ye Hongzhi H
Frontiers in pharmacology 20220124
This study was conducted to identify whether the TLR4/MyD88/NF-κB signalling pathway plays a vital role in osteoarthritis (OA) treatment with Duhuo Jisheng Decoction (DHJSD) on the basis of a network pharmacology approach (NPA)-integrated experiment. Two experiments were conducted as follow: NPA for DHJSD using six OA-related gene series and the key pathway was screened out using NPA. NPA identified a vital role for the TLR4/MyD88/NF-κB signalling pathway in OA treatment with DHJSD, the conventi ...[more]
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Project description:In this study, network pharmacology and molecular docking technology were used to explore the molecular mechanisms of the Duhuo Jisheng decoction in the treatment of osteoarthritis (OA). The chemical composition of the prescriptions was obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database and the retrieved literature. Targets for the active ingredients were obtained using TCMSP and the Swiss Target Prediction Database. Disease targets were obtained from GeneCards and DisGeNET databases. The online tool, Venny, was used to obtain common targets for drugs and diseases. Protein-protein interactions (PPI) between common targets were analyzed using the search tool for the retrieval of interacting genes/proteins (STRING) database. Common targets were analyzed for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment using the database for annotation, visualization and integrated discovery (DAVID) database. Molecular docking of the first 10 targets and first 10 components was verified using AutoDock Tools software, and the docking diagram was visualized using PyMOL software. After screening, 210 chemical components of the Duhuo Jisheng decoction (DHJSD) were identified. The 253 common targets of drugs and diseases were combined by eliminating repeat values. Based on PPI network analysis, the top ten targets were SRC, STAT3, MAPK3, MAPK1, RELA, PIK3R1, HSP90AA1, TP53, EP300, and AKT1. KEGG analysis showed that DHJSD could regulate the HIF-1, PI3K-Akt, and JAK-STAT signaling pathways. The biological processes involved include inflammatory reactions, the negative regulation of apoptosis, and the positive regulation of cell proliferation. Molecular docking results showed that all targets, except the RELA protein, showed good binding to the compounds, indicating that the 10 components might exert therapeutic effects by binding to the above targets. DHJSD can treat OA by regulating the HIF-1, PI3K-Akt, and JAK-STAT signaling pathways. The proteins involved were SRC, STAT3, MAPK3, MAPK1, and PIK3R1. In this study, network pharmacology was used to predict the mechanism of DHJSD in OA treatment, which was verified by molecular docking to provide experimental research ideas and scientific basis for OA treatment.
| S-EPMC9592334 | biostudies-literature
Project description:ObjectiveThe purpose of this work is to study the mechanism of action of Duhuo Jisheng Decoction (DHJSD) in the treatment of osteoporosis based on the methods of bioinformatics and network pharmacology.MethodsIn this study, the active compounds of each medicinal ingredient of DHJSD and their corresponding targets were obtained from TCMSP database. Osteoporosis was treated as search query in GeneCards, MalaCards, DisGeNET, Therapeutic Target Database (TTD), Comparative Toxicogenomics Database (CTD), and OMIM databases to obtain disease-related genes. The overlapping targets of DHJSD and osteoporosis were identified, and then GO and KEGG enrichment analysis were performed. Cytoscape was employed to construct DHJSD-compounds-target genes-osteoporosis network and protein-protein interaction (PPI) network. CytoHubba was utilized to select the hub genes. The activities of binding of hub genes and key components were confirmed by molecular docking.Results174 active compounds and their 205 related potential targets were identified in DHJSD for the treatment of osteoporosis, including 10 hub genes (AKT1, ALB, IL6, MAPK3, VEGFA, JUN, CASP3, EGFR, MYC, and EGF). Pathway enrichment analysis of target proteins indicated that osteoclast differentiation, AGE-RAGE signaling pathway in diabetic complications, Wnt signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, calcium signaling pathway, and TNF signaling pathway were the specifically major pathways regulated by DHJSD against osteoporosis. Further verification based on molecular docking results showed that the small molecule compounds (Quercetin, Kaempferol, Beta-sitosterol, Beta-carotene, and Formononetin) contained in DHJSD generally have excellent binding affinity to the macromolecular target proteins encoded by the top 10 genes.ConclusionThis study reveals the characteristics of multi-component, multi-target, and multi-pathway of DHJSD against osteoporosis and provides novel insights for verifying the mechanism of DHJSD in the treatment of osteoporosis.
| S-EPMC8046540 | biostudies-literature
Project description:BackgroundThe purpose of this study was to examine the mechanism of Duhuo Jisheng Decoction (DHJSD) in the treatment of intervertebral disc degeneration (IVDD).MethodsThe active compounds of DHJSD and their corresponding targets were obtained from the TCMSP database. "Intervertebral disc degeneration" was used as a search term in the DisGeNET, GeneCards, Comparative Toxicogenomics Database, and MalaCards database to obtain disease-related targets. Following the discovery of overlapping DHJSD and IVDD targets, enrichment analyses for Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, and WikiPathways were performed. Cytoscape 3.9.1 was used to build the "DHJSD-Active Ingredients-Target Genes-IVDD" network and protein-protein interaction network, and CytoHubba was used to screen the pivotal genes. Molecular docking confirmed the binding activity of hub genes and key components.ResultsThe bioinformatic analysis of DHJSD in the treatment of IVDD revealed 209 potential therapeutic gene targets, including 36 important gene targets and 10 of these crucial gene targets. Enrichment analysis of 36 key therapeutic targets showed that the biological processes involved in the Gene Ontology analysis of DHJSD in treating IVDD were mainly cytokine-mediated signaling pathway, inflammatory response, negative regulation of apoptotic process, and vascular endothelial growth factor production. The Kyoto Encyclopedia of Genes and Genomes signaling pathway is mainly involved in TNF signaling pathway, Th17 cell differentiation, IL-17 signaling pathway, and HIF-1 signaling pathway. The Recactome signaling pathway is mainly involved in cytokine signaling in immune system, cellular responses to stress, immune system, cytokines, and inflammatory response. HIF1A and PPARG regulation of glycolysis are mostly involved in the WikiPathways signaling system. The findings demonstrated that to cure IVDD, DHJSD affects the pathogenic processes of inflammation, extracellular matrix, cellular senescence, autophagy, apoptosis, focal death, and proliferation through the aforementioned targets and signaling pathways. The results of molecular docking demonstrated that the protein can be effectively bound by the DHJSD active component. Further evidence was provided for the molecular mechanism through which DHJSD works to treat IVDD.ConclusionThis study uncovers the multi-component, multi-target, and multi-pathway characteristics of DHJSD for the treatment of IVDD, offering fresh perspectives to further investigate the mechanism of DHJSD for the treatment of IVDD.
| S-EPMC10238016 | biostudies-literature
Project description:BackgroundNeuropathic pain (NP) is the most prevalent form of chronic pain resulting from nerve damage or injury. Despite the widespread use of Duhuo Jisheng decoction (DHJSD) in traditional Chinese medicine (TCM) to treat chronic pain, the mechanism underlying its analgesic action remains unclear.MethodsUsing network pharmacology, we obtained DHJSD and NP-related target information from public databases to construct protein-protein interactions (PPI) and compound-target networks based on common target genes. These networks were further analyzed using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG). The interaction between molecules was verified through molecular docking using AutoDock Tools software. Additionally, we treated a chronic constriction injury (CCI) rat model with DHJSD and determined the mechanical withdrawal threshold (MWT). We used an enzyme-linked immunosorbent assay kit to determine the levels of inflammatory cytokines. Furthermore, qRT-PCR was employed to analyze ACHE, NOS2, MAPK3, PTGS2, AKT1, and PPARG mRNA expression, and immunofluorescence was used to evaluate changes in microglia.ResultsOur screening of compounds and targets identified 252 potential targets of DHJSD associated with NP. PPI analysis, along with GO and KEGG analyses, revealed that the potential mechanism of DHJSD in NP treatment may be related to inflammatory reactions, the IL-17 signaling pathway, MAP kinase activity, and endocrine activity. Based on molecular docking, the core target showed significant affinity for DHJSD's active components. Moreover, DHJSD treatment repaired the CCI-induced inflammatory reaction in the spinal cord while regulating the expression of ACHE, NOS2, MAPK3, PTGS2, AKT1, and PPARG mRNA. Immunofluorescence results indicated that the active components of DHJSD may regulate microglial M1 polarization to improve neuroinflammation, PPARG may have been involved in the process.ConclusionThe multi-component, multi-target, and multi-pathway actions of DHJSD provide new insights into its therapeutic mechanism in NP.
| S-EPMC10463324 | biostudies-literature
Project description:AimThe aim of this study is to provide evidence of the effect of Duhuo Jisheng decoction (DHJSD) on knee osteoarthritis (KOA) of the cold-dampness obstruction syndrome type.MethodsWe searched PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure, the Wanfang database, and the China Biology Medicine for randomized controlled trials (RCTs) evaluating DHJSD or DHJSD combined with other conventional therapies (DHJSD group) compared to conventional therapy (control group) for cold-dampness obstruction syndrome-type KOA. We calculated the pooled odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) using fixed- or random-effects models.ResultsEleven RCTs, with a total of 895 patients, were included. The results showed that DHJSD could significantly improve the effective rate (OR = 3.13, 95%CI = 2.07 to 4.72, P < 0.001), reduce both the WOMAC (MD = -12.06, 95%CI = -16.34 to -7.79, P < 0.001) and VAS (MD = -1.02, 95%CI = -1.54 to -0.50, P = 0.0001) scores, and reduce the serum IL-6 (MD = -0.80, 95%CI = -0.90 to -0.69, P < 0.001) and TNF-α (MD = -2.49, 95%CI = -2.77 to -2.21, P < 0.001) levels during the treatment of cold-dampness obstruction syndrome-type KOA. The subgroup analysis showed that compared with glucosamine sulfate (GS) alone, DHJSD combined with GS significantly improved the effective rate (OR = 2.59, 95%CI = 1.19 to 5.65, P = 0.02) and reduced the WOMAC (MD = -13.83, 95%CI = -16.14 to -11.51, P < 0.001) and VAS (MD = -0.91, 95%CI = -1.27 to -0.55, P < 0.001) scores. DHJSD + warm-needle acupuncture (WA) lowered the VAS score more than WA alone. There was no significant difference in the decrease in serum IL-1β between the DHJSD and control groups.ConclusionThis study shows that DHJSD can improve the clinical efficacy and reduce the VAS and WOMAC scores in the treatment of cold-dampness obstruction syndrome-type KOA. Compared with GS or WA alone, the combined application of DHJSD with GS or WA could better reduce both the VAS and WOMAC scores.
| S-EPMC9239816 | biostudies-literature
Project description:BackgroundKnee osteoarthritis (KOA) is a common degenerative joint condition that causes disability and pain in the elderly population. The prevalence of KOA among persons aged 63 or above is approximately 30%. Previous studies have reported the positive effects of Tui-na treatment and the Chinese herbal formula Du-Huo-Ji-Sheng Decoction (DHJSD) for KOA treatment. The current study aims to evaluate the add-on therapeutic effect of oral administration of DHJSD on KOA in addition to Tui-na.MethodsWe conducted a prospective, randomized, controlled clinical trial. Seventy study subjects with KOA were randomly assigned to the treatment and control groups in a 1:1 ratio. Both two groups received eight sessions of Tui-na manipulation for 4 weeks. The DHJSD was only administered to the study subjects in the treatment group. The primary outcome measure was rated using the WOMAC at the end of treatment (4 weeks). Secondary outcomes were assessed using EQ-5D-5L, a health-related quality of life with 5-level EQ-5D version at end of treatment (week 4) and follow-up (week 8).ResultsNo statistically significant difference was found between two groups on WOMAC scores at the end of treatment. The mean WOMAC Pain subscale score was significantly lower in the treatment group than control group at week 8 follow up (mean difference, MD - 1.8, 95% CI - 3.5 to - 0.02, P = 0.048). The mean WOMAC Stiffness subscale score was significantly lower in the treatment group than in the control group at week 2 (MD 0.74, 95% CI 0.05 to 1.42, P = 0.035) and week 8 follow up (MD 0.95, 95% CI 0.26 to 1.65, P = 0.008). The mean EQ-5D index value was significantly improved in the treatment group than in the control group at week 2 (MD 0.17, 95% CI 0.02 to 0.31, P = 0.022). The analysis of WOMAC scores and EQ-5D-5L in both groups showed statistically significant improvement with time. No significant adverse effect was found during the trial.ConclusionDHJSD may have an add-on effect in addition to Tui-na manipulation relieving pain and improving stiffness as well as quality of life (QOL) in patients with KOA. The combined treatment was generally safe and well tolerated. Trial registration The study was registered at the ClinicalTrials.gov (website: https://clinicaltrials.gov/ct2/show/NCT04492670 , registry number: NCT04492670), registered on 30 July 2020.
| S-EPMC10331987 | biostudies-literature
Project description:The aims of this study were to explore the protective effect of Xiaochaihu decoction in mice with sepsis induced by intraperitoneal injection; to explore its anti-inflammatory effect on the TLR4-MyD88-NF-κB signalling pathway; and to explore the main material basis of the anti-inflammatory effect of Xiaochaihu decoction, with the aim of supplementing and expanding the associated research and providing a scientific foundation for the clinical use of the decoction. The effects of Xiaochaihu decoction on septic mice were analysed by measurements of white blood cells (WBC) and Platelets (PLT); Nitric Oxide (NO) level in serum; IL-6, IL-1β and TNF-α levels in serum; RT-PCR; Haematoxylin-Eosin (HE) immunohistochemistry; western blotting (WB). The results showed the excellent in vivo anti-inflammatory effects of Xiaochaihu decoction in LPS-induced septic mice, through down regulation of the gene and protein expression of TLR4, MYD88, TRAF6, IKK, IKBα and p65 and the subsequent reduction in the release of inflammatory mediators IL-6, IL-1β, TNF-α and NO. Moreover, significant anti-septic effect was observed from high and medium doses of Xiaochaihu decoction, but not from the low dose.
| S-EPMC10907734 | biostudies-literature
Project description:BackgroundDuhuo Jisheng Decoction (DHJSD) is an ancient compound widely used in the treatment of ankylosing spondylitis (AS). However, its efficacy is controversial, and its mechanism of action is not clear enough. Using meta-analysis and network pharmacology, our study evaluated the clinical efficacy of DHJSD in the treatment of AS and explored its mechanisms of action.MethodsWe searched medical databases, including Embase, PubMed, the China National Knowledge Infrastructure databases, Wanfang, and the Chinese Scientific Journal Database, to identify studies that met the inclusion criteria. RevMan 5.3 software was used for the meta-analysis. The compounds and the potential protein targets of DHJSD were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform. AS was treated as a search query in the NCBI, PharmGKB, TTD, DrugBank, and OMIM databases to obtain disease-related genes. The overlapping targets of DHJSD and AS were identified, and then Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Cytoscape was employed to construct a drug-compound-target network and a protein-protein interaction (PPI) network. CytoHubba was utilized to select the hub genes.ResultsA total of 10 studies involving 860 participants were included in the meta-analysis. Compared with the control, DHJSD treatment significantly improved clinical symptoms; reduced the erythrocyte sedimentation rate (ESR), the C-reactive protein (CPR), and interleukin 6 (IL-6) levels; increased the degree of motion of the chest; reduced the visual analog scale (VAS) pain score; reduced Schober's test values; reduced the finger-to-floor distance; reduced the duration of morning stiffness. However, the differences were not statistically significant in the Bath Ankylosing Spondylitis Functional Index scores, the Bath Ankylosing Spondylitis Disease Activity Index scores, the bone Gla-containing protein (BGP) levels, or the bone alkaline phosphatase (BALP) levels. In terms of adverse events, DHJSD treatment of AS reduced the incidence of gastrointestinal events, the incidence of skin events, and the incidence of abnormal liver function; however, there was no statistically significant reduction in the incidence of adverse renal function events. Subgroup analysis showed that in the treatment of AS, the clinical effect of DHJSD for AS was better than that of the controls for both treatment durations, ≤2 months and >2 months. A total of 178 active compounds and 47 related potential targets were identified for DHJSD in the treatment of AS, including four hub genes (CXCL8, PTGS2, VEGFA, and STAT3). The core active ingredients of DHJSD in the treatment of AS were mainly quercetin, kaempferol, licochalcone A, and isorhamnetin. DHJSD treatment of AS-related pathways mainly involved the IL-17 signaling pathway, the TNF signaling pathway, and the rheumatoid arthritis signaling pathway.ConclusionThe above results suggest that DHJSD acts on AS through multiple targets, components, and pathways with significant clinical efficacy. Future studies may further explore the active components of DHJSD.
| S-EPMC9001112 | biostudies-literature
Project description:Intervertebral disc degeneration (IDD) poses a grim public health impact. Duhuo Jisheng Decoction (DJD), a traditional Chinese medicine formula, has recently received significant attention for its efficacy and safety in treating IDD. However, the pathological processes of IDD in which DJD interferes and molecular mechanism involved are poorly understood, which brings difficulties to the clinical practice of DJD for the treatment of IDD. This study systematically investigated the underlying mechanism of DJD treatment of IDD. Network pharmacology approaches were employed, integrating molecular docking and random walk with restart (RWR) algorithm, to identify key compounds and targets for DJD in the treatment of IDD. Bioinformatics approaches were used to further explore the biological insights in DJD treatment of IDD. The analysis identifies AKT1, PIK3R1, CHUK, ALB, TP53, MYC, NR3C1, IL1B, ERBB2, CAV1, CTNNB1, AR, IGF2, and ESR1 as key targets. Responses to mechanical stress, oxidative stress, cellular inflammatory responses, autophagy, and apoptosis are identified as the critical biological processes involved in DJD treatment of IDD. The regulation of DJD targets in extracellular matrix components, ion channel regulation, transcriptional regulation, synthesis and metabolic regulation of reactive oxygen products in the respiratory chain and mitochondria, fatty acid oxidation, the metabolism of Arachidonic acid, and regulation of Rho and Ras protein activation are found to be potential mechanisms in disc tissue response to mechanical stress and oxidative stress. MAPK, PI3K/AKT, and NF-κB signaling pathways are identified as vital signaling pathways for DJD to treat IDD. Quercetin and Kaempferol are assigned a central position in the treatment of IDD. This study contributes to a more comprehensive understanding of the mechanism of DJD in treating IDD. It provides a reference for applying natural products to delay the pathological process of IDD.
| S-EPMC10243954 | biostudies-literature
Project description:BackgroundModified Duhuo Jisheng Decoction (MDHJSD) is a traditional Chinese medicine prescription for the treatment of osteoporosis (OP), but its mechanism of action has not yet been clarified. This study aims to explore the mechanism of MDHJSD in OP through a combination of network pharmacology analysis and experimental verification.MethodsThe active ingredients and corresponding targets of MDHJSD were acquired from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. OP-related targets were acquired from databases, including Genecards, OMIM, Drugbank, CTD, and PGKB. The key compounds, core targets, major biological processes, and signaling pathways of MDHJSD that improve OP were identified by constructing and analysing the relevant networks. The binding affinities between key compounds and core targets were verified using AutoDock Vina software. A rat model of ovariectomized OP was used for the experimental verification.ResultsA total of 100 chemical constituents, 277 targets, and 4734 OP-related targets of MDHJSD were obtained. Subsequently, five core components and eight core targets were identified in the analysis. Pathway enrichment analysis revealed that overlapping targets were significantly enriched in the tumour necrosis factor-alpha (TNF-α) signaling pathway, an inflammation signaling pathway, which contained six of the eight core targets, including TNF-α, interleukin 6 (IL-6), transcription factor AP-1, mitogen-activated protein kinase 3, RAC-alpha serine/threonine-protein kinase, and caspase-3 (CASP3). Molecular docking analysis revealed close binding of the six core targets of the TNF signaling pathway to the core components. The results of experimental study show that MDHJSD can protect bone loss, inhibit the inflammatory response, and downregulate the expression levels of TNF-α, IL-6, and CASP3 in ovariectomized rats.ConclusionThe mechanism of MDHJSD in the treatment of OP may be related to the regulation of the inflammatory response in the bone tissue.
| S-EPMC9008312 | biostudies-literature