Résumé
To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P<0.000 01),IL-1β(P<0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P<0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1β(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1β(SMD=-6.29,95%CI[-9.64,-2.93],P<0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P<0.000 01), joint fluid(P<0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1β(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1β(P=0.02), IL-6(P<0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.
Sujets)
Animaux , Humains , Polyarthrite rhumatoïde/traitement médicamenteux , Cytokines , Médicaments issus de plantes chinoises/usage thérapeutique , Hétérosides/usage thérapeutique , Léflunomide/usage thérapeutique , Méthotrexate/usage thérapeutique , Comprimés , Tripterygium/composition chimiqueRésumé
To evaluate the clinical efficacy of single administration of Tripterygium Glycosides Tablets(TGT) or combined administration with methotrexate(MTX) against rheumatoid arthritis(RA) based on American College of Rheumatology(ACR) efficacy standard. Six databases, namely CNKI, WanFang, VIP, PubMed, Embase and Cochrane Library, were retrieved for randomized controlled trials(RCT), and clinical trials were screened out according to the preset inclusion and exclusion criteria. Then, the study quality was evaluated by the risk assessment tools. Data extraction and analysis were performed by using RevMan 5.3 software for Meta-analysis. Sensitivity analysis and publication bias analysis were made to test the stability and reliability of results. Until December 2018, a total of 1 709 articles were obtained, and finally 10 clinical RCT studies with a total of 1 184 patients were included. As a result, the single administration of TGT showed a significantly better ACR efficiency(RR=1.31, 95%CI[1.15, 1.49], P<0.000 1) than methotrexate(MTX). The combined administration of TGT and MTX showed a significantly better ACR efficiency(RR=1.28, 95%CI[1.20, 1.38], P<0.000 01) than the single administration of MTX. In conclusion, the single administration of TGT and the combined administration of TGT and MTX were more effective in achieving ACR20, ACR50, ACR70 compliance than the single administration of MTX. Further validations based on more RCT studies with high-quality are required.
Sujets)
Humains , Antirhumatismaux/usage thérapeutique , Polyarthrite rhumatoïde/traitement médicamenteux , Association de médicaments , Médicaments issus de plantes chinoises/usage thérapeutique , Hétérosides/usage thérapeutique , Méthotrexate/usage thérapeutique , Essais contrôlés randomisés comme sujet , Reproductibilité des résultats , Comprimés , Résultat thérapeutique , Tripterygium/composition chimiqueRésumé
The aim of this study was to systematically evaluate the clinical efficacy of Tripterysium Glycosides Tablets( TGT) alone or in combination with methotrexate( MTX) in the treatment of rheumatoid arthritis( RA) based on the laboratory index criteria and to provide a basis for the clinical application of TGT against RA. Six databases including CNKI,Wan Fang,VIP,PubMed,EMbase and Cochrane were retrieved for randomized controlled trials( RCT) about TGT alone or combination with MTX in the treatment of RA.Then risk assessment tools were used for quality evaluation of the studies,and data extraction and analysis were conducted by using Rev Man 5.3 software for Meta-analysis. A total of 1 709 articles were retrieved,and finally 25 studies were included,with a total sample size of 2 507 cases. Meta-analysis results showed that between TGT alone and TGT alone,MDESR=-2. 66,95%CI[-8.17,2.86],P = 0.35; MDCRP=-2.38,95%CI[-9.01,4.24],P = 0.48; between TGT combined with MTX and MTX alone,MDESR= 8.74,95%CI[6.72,10.76],P<0.000 01; MDCRP= 5.37,95%CI[3.71,7.03],P<0.000 01; SMDRF= 1.05,95%CI[0.51,1.60],P = 0.000 1.The effect of TGT on decreasing CRP and ESR in RA patients was similar to the MTX. In addition,TGT combined with MTX were more effective in decreasing CRP,ESR,RF than MTX alone. However,due to the potential bias in the included studies,more and high-quality randomized controlled trials would be needed to improve the level of evidence.
Sujets)
Humains , Antirhumatismaux , Utilisations thérapeutiques , Polyarthrite rhumatoïde , Traitement médicamenteux , Association de médicaments , Médicaments issus de plantes chinoises , Utilisations thérapeutiques , Hétérosides , Utilisations thérapeutiques , Méthotrexate , Utilisations thérapeutiques , Essais contrôlés randomisés comme sujet , Comprimés , Résultat thérapeutique , Tripterygium , ChimieRésumé
To systematically review the improvement effects of Tripterygium Glycosides Tables( TGT) alone or in combination with methotrexate( MTX) on the clinical signs and symptoms of rheumatoid arthritis( RA),and provide a basis for the rational use of TGT in clinic,in the current study,six literature databases including CNKI,Wan Fang,VIP,PubMed,EMbase,and Cochrane Library,were systematically searched,according to the inclusion and exclusion criteria. Review Manager 5.3 software was used to input the literatures,and we assessed the risk bias on the level of outcome indicators for each included literature. A total of 18 literatures were included,and the classification results showed that: compared with MTX,TGT alone can reduce the number of joint swelling( MD =0. 18,95%CI[-1.06,1.42],P = 0.78) and joint tenderness( MD =-0.06,95% CI[-1.69,1.56],P = 0.94) in RA patients with the same effect as MTX. In terms of drug combination,TGT combined with MTX had an advantage over MTX alone in lessening the morning stiffness time( MD = 18. 24,95% CI[12. 64,23. 84],P < 0. 000 01) of RA,joint tenderness( MD = 2. 65,95% CI[1. 85,3. 44],P<0.000 01) and joint swelling( MD = 3.01,95% CI[2.09,3.39],P< 0.000 01). In conclusion,this Meta-analysis suggest that TGT alone was superior to MTX in improving joint swelling and tenderness in RA patients,TGT combined with MTX may improve the clinical manifestation of RA patients better than MTX alone.
Sujets)
Humains , Antirhumatismaux , Utilisations thérapeutiques , Polyarthrite rhumatoïde , Traitement médicamenteux , Association de médicaments , Médicaments issus de plantes chinoises , Utilisations thérapeutiques , Hétérosides , Utilisations thérapeutiques , Méthotrexate , Utilisations thérapeutiques , Comprimés , Résultat thérapeutique , Tripterygium , ChimieRésumé
Growing clinical evidence shows that a partial rheumatoid arthritis( RA) patient treated with Tripterygium Glycosides Tablets( TGT) may fail to achieve clinical improvement. It is of great clinical significance to predict the therapeutic effect of TGT in RA. Therefore,the aim of the current study was to identify potential biomarkers for TGT treatment in RA. Affymetrix EG1.0 arrays were applied to detect gene expression in peripheral blood mononuclear cells obtained from 6 RA patients( 3 responders and 3 non-responders) treated with TGT. By integrating differential expression data analysis and biomolecular network analysis,360 mRNAs( 185 up-regulated and 175 down-regulated) and 24 miRNAs( 7 up-regulated and 17 down-regulated) which were differentially expressed between TGT responder and non-responder groups were identified. A total of 206 candidate target genes for the differentially expressed miRNAs were obtained based on miRanada and Target Scan databases,and then the miRNA target gene coexpression network and miRNA-mediated gene signal transduction network were constructed. Following the network analyses,three candidate miRNAs biomarkers( hsa-miR-4720-5 p,hsa-miR-374 b-5 p,hsa-miR-185-3 p) were identified as candidate biomarkers predicting individual response to TGT. Partialleast-squares( PLS) was applied to construct a model for predicting response to TGT based on the expression levels of the candidate gene biomarkers in RA patients. The five-fold cross-validation showed that the prediction accuracy( ACC) of this PLS-based model efficacy was 100.00%,100.00%,100.00%,66.67% and 66.67% respectively,and all the area under the receiver operating characteristic curve( AUC) were 1.00,indicating the highly predictive efficiency of this PLS-based model. In conclusion,the integrating transcription data mining and biomolecular network investigation show that hsa-mir-4720-5 p,hsa-mir-374 b-5 p and hsa-mir-185-3 p may be candidate biomarkers predicting individual response to TGT. In addition,the PLS model based on the expression levels of these candidate biomarkers may be helpful for the clinical screen of RA patients,which potentially benefit individualized therapy of RA in a daily clinical setting.
Sujets)
Humains , Polyarthrite rhumatoïde , Traitement médicamenteux , Marqueurs biologiques , Fouille de données , Médicaments issus de plantes chinoises , Utilisations thérapeutiques , Hétérosides , Utilisations thérapeutiques , Agranulocytes , microARN , Génétique , Comprimés , Tripterygium , ChimieRésumé
Objective:To systematically identify the chemical constituents in extract of Baihu Jia Guizhi Tang (BHGZT) by ultra-fast liquid chromatography/triple time-of-flight tandem mass spectrometry (UFLC-Triple-TOF-MS/MS). Method:Phenomenex C18 (3.0 mm×100 mm,2.6 μm) was eluted with acetonitrile (containing 0.1%formic acid) and 0.1%formic acid solution as the mobile phase in a gradient mode. The column temperature was set at 40℃,the flow rate was 0.3 mL·min-1,and the injection volume was 5 μL. High-resolution triple quadrupole flight mass spectrometry was adopted to test in both positive and negative modes. Formula finder function in peakview software was used to calculate the element composition of the compounds,and IDA explore function in the software was invoked to obtain secondary fragmentation ions of this mass number. And the compounds were identified based on literature data and the reference substances. Result:On the basis of the mass fragmentation regularity of accurate molecular weight, 35 compounds were identified in BHGZT,including 16 steroid saponins,6 triterpenoid saponins,7 flavonoids,and 4 organic acids and 2 others. Among them,10 components (timosaponin AⅢ,timosaponin I,timosaponin BⅢ,timosaponin BⅡ,new mangiferin,mangiferin,liquiritin apioside,liquiritin,glycyrrhizic acid and cinnamic acid) were confirmed by comparing with reference substances,and the sources of the compound were identified. Conclusion:UFLC-Triple-TOF-MS/MS can be used to characterize the chemical composition of BHGZT simply and quickly. Relevant researches provide references for the research of pharmacodynamic material basis,the quality control and the explanation of mechanism of action.
Résumé
Wu-tou decoction (WTD) was originally recorded in the synopsis of the golden chamber and it had been widely used for the treatment of neuropathic pain (NP) with exact therapeutic efficacy. However, the underlying molecular mechanisms still remain unclarified. Thus, in this research, we aimed at clarifying the underlying molecular mechanisms of WTD against NP by combining network analysis and experimental validation based on the spinal nerve ligation (SNL) model. Firstly, the network analysis indicated that key targets of WTD were significantly involved in the MAPK signaling pathway (P = 4.04E-12) and four important components of the above pathway, AKT kinase (AKT), MAP kinase kinase 4 (MKK4), c-Jun N-terminal kinase (JNK) and transcription factor AP-1 (JUN) had been reported to play a vital role in neuroinflammation during the disease process of NP. Then, experimental validation results proved that WTD markedly reduce the severity of mechanical allodynia (P<0.01) and cold hypersensitivity (P<0.05) of SNL rats. In addition, Western blot results provided evidence that the phosphorylated protein expression levels of AKT, MKK4, JNK and JUN in the superficial lamina of spinal cord of SNL rats were markedly increased (P<0.001), and WTD could improve the phosphorylated protein expression level of AKT (P<0.001) which was reported to be nerve protective and attenuate the phosphorylated protein expression levels of MKK4, JNK and JUN (P<0.01) which were closely involved into neuroinflammation. In conclusion, this study indicated that WTD might exert anti-hyperalgesia action through the inhibition of neuroinflammation mediated by AKT-MKK4-JNK-JUN which belong to the MAPK signaling pathway. These findings also provided scientific evidences that WTD might be a promising candidate for NP. Animal experiments in this study were approved by the Ethics Committee of Experimental Animals of the China Academy of Chinese Medical Sciences.
Résumé
Paeoniflorin (PAE), the major active compounds of Chinese herbs Radix Paeoniae Alba andChinese patent drug "Total Glucosides of Paeony Capsules", which is effective in the treatment of rheumatoid arthritis (RA), exerted multi-pharmacological activities, such as anti-inflammatory, immune-regulatory, etc. However, its potential action mechanisms remain unclear. Herein, we predicted the putative targets of Radix Paeoniae Alba and constructed an interaction network of putative targets of Radix Paeoniae Alba and known RA-related genes. A list of key putative targets was identified by calculating their topological features (degree, node betweenness and closeness) in the above pharmacological network. Importantly, pathway enrichment analysis revealed that these key putative targets were significantly enriched in several RA-related pathways, including cartilage damage-related IL1B-TNF-TLR2-JUN-MMP1-MMP3 signaling pathway. Further molecular docking simulation showed that PAE, the major active compounds of Radix Paeoniae Alba, has strong binding affinity with MMP1 and MMP3 proteins. Next, in vivo experiments based on the adjuvant-induced arthritis (AIA) animal models showed that PAE significantly alleviated the disease severity and the syndromes of severe redness or swelling in hind limbs of AIA rats, including decreasing the arthritis score, the diameter of the limbs, and elevating body weight and pain thresholds (all P<0.05). ELISA assay indicated that PAE obviously suppressed the abnormal up-regulation of serum inflammatory factors including IL-1β, TNF-α, IL-6, IL-17 and IFN-γ in AIA rats (all P<0.001). Western blot analysis found that PAE simultaneously modulated the abnormal up-regulation of MMP1 and MMP3 proteins in the ankle tissues of AIA rats (all P<0.001) (all procedures in the current study were performed in accordance with the ethical standards of the Center for Laboratory Animal Care, China Academy of Chinese Medical Sciences). In conclusion, PAE alleviated the cartilage damage and disease severity in the progressive process of RA via regulating the IL1B-TNF-TLR2-JUN-MMP1-MMP3 pathway. This study provided the theoretical basis of the PAE for its immune-regulatory effects, and as well provided references for the action mechanism study of extract compounds of Chinese herbs.
Résumé
Wu-tou decoction (WTD) and Baihu-Guizhi decoction (BHGZD) as described in the Synopsis of the Golden Chamber have been used extensively for the treatment of rheumatoid arthritis (RA) with apparent therapeutic efficacy. However, characteristics of pharmacological effects and their underlying molecular mechanisms have not been fully elucidated due to a lack of appropriate scientific methodology. In the current study, we performed an integrative approach applying gene expression profiling and network analysis to examine the therapeutic effects and molecular mechanisms of WTD and BHGZD based on adjuvant-induced arthritis (AIA) animal model. Results demonstrated that both WTD and BHGZD could relieve the severity of arthritis in AIA rats, while the significant differences were observed in the changes of the withdrawal response scores and latency time of AIA rats treated with WTD and BHGZD. Mechanistically, our network pharmacology-based investigation demonstrated that the major candidate targets of WTD and BHGZD were significantly associated with several inflammation-immune regulatory pathways, such as Toll-like receptor signaling pathway, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, B cell receptor signaling pathway, antigen processing and presentation, Fc epsilon RI signaling pathway, natural killer cell mediated cytotoxicity, as well as leukocyte transendothelial migration. In particular, the major candidate targets of WTD were also involved in the regulation of hormone and energy metabolism, which might be imbalanced during RA progression. In conclusion, the current study revealed differences and similarities regarding the effects and network regulatory mechanisms of WTD and BHGZD. These findings may present a scientific basis for elucidation of mechanisms by which WTD and BHGZD alleviates RA.