Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii H...Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii Hook.f.(TwHF)-based therapy,exhibit satisfactory clinical efficacy for RA treatment.However,drug-induced liver injury(DILI)remains a critical issue that hinders the clinical application of TGTs,and the molecular mechanisms underlying the efficacy and toxicity of TGTs in RA have not been fully elucidated.To address this problem,we integrated clinical multi-omics data associated with the anti-RA efficacy and DILI of TGTs with the chemical and target profiling of TGTs to perform a systematic network analysis.Subsequently,we identified effective and toxic targets following experimental validation in a collagen-induced arthritis(CIA)mouse model.Significantly different transcriptome–protein–metabolite profiles distinguishing patients with favorable TGTs responses from those with poor outcomes were identified.Intriguingly,the clinical efficacy and DILI of TGTs against RA were associated with metabolic homeostasis between iron and bone and between iron and lipids,respectively.Particularly,the signal transducer and activator of transcription 3(STAT3)–hepcidin(HAMP)/lipocalin 2(LCN2)–tartrate-resis tant acid phosphatase type 5(ACP5)and STAT3–HAMP–acyl-CoA synthetase long-chain family member 4(ACSL4)–lysophosphatidylcholine acyltransferase 3(LPCAT3)axes were identified as key drivers of the efficacy and toxicity of TGTs.TGTs play dual roles in ameliorating CIA-induced pathology and in inducing hepatic dysfunction,disruption of lipid metabolism,and hepatic lipid peroxidation.Notably,TGTs effectively reversed“iron–bone”disruptions in the inflamed joint tissues of CIA mice by inhibiting the STAT3–HAMP/LCN2–ACP5 axis,subsequently leading to“iron–lipid”disturbances in the liver tissues via modulation of the STAT3–HAMP–ACSL4–LPCAT3 axis.Additional bidirectional validation experiments were conducted using MH7A and AML12 cells to confirm the bidirectional regulatory effects of TGTs on key targets.Collectively,our data highlight the association between iron-mediated metabolic homeostasis and the clinical efficacy and toxicity of TGT in RA therapy,offering guidance for the rational clinical use of TwHF-based therapy with dual therapeutic and toxic potential.展开更多
Objectives:To explore and summarize the beneficial effects of a traditional Chinese medicine preparation,Tripterygium glycosides tablets(TGT),in rheumatoid arthritis(RA)animal models of neovascularization,and to provi...Objectives:To explore and summarize the beneficial effects of a traditional Chinese medicine preparation,Tripterygium glycosides tablets(TGT),in rheumatoid arthritis(RA)animal models of neovascularization,and to provide a reference for future clinical applications and research on its pharmacologic mechanism.Methods:We searched the databases PubMed,Embase,Web of Science,Chinese National Knowledge Infrastructure,VIP,Wan Fang and SinoMed(China Biomedical Document Service System)to identify studies of TGT with outcome indicators of angiogenesis-related factors that were published before April2020.Subgroup analysis and meta-regression were performed for dosage and duration of TGT.Statistical tests and subgroup analysis were conducted using RevMan 5.3,and meta-regression and sensitivity analysis were conducted using STATA/SE 15.0.Results:Fourteen studies of TGT in RA rats were included in this analysis.Treatment with TGT significantly reduces synovial microvessel density and the expression of vascular endothelial growth factor(VEGF),VEGF receptor 2,hypoxia inducible factor a,c-Fos,c-Jun,angiopoietin-1 and angiopoietin-2 compared with control groups(P<.05).Subgroup analysis did not show a significant association of the mRNA levels of VEGF in synovium,assessed using quantitative real-time PCR,with duration or dosage of TGT.Meta-regression analysis also indicated that the effects of dosage and duration were not significantly associated with differences in VEGF mRNA levels.Sensitivity analysis on VEGF m RNA levels did not fundamentally change the results.Conclusions:TGT can reduce synovial neovascularization by decreasing synovial microvessel density and expression of VEGF,VEGF receptor 2,hypoxia-inducible factor a,c-Fos,c-Jun,Ang-1 and Ang-2,thereby suppressing pannus formation and bone destruction in rat models of RA.Additional well-designed studies are required to confirm these findings.展开更多
Objective: To summarize the evidence from systematic reviews(SRs) on the benefits and safety of Tripterygium glycosides(TG) and total glucosides of paeony(TGP), commonly used to treat rheumatoid arthritis(RA) in China...Objective: To summarize the evidence from systematic reviews(SRs) on the benefits and safety of Tripterygium glycosides(TG) and total glucosides of paeony(TGP), commonly used to treat rheumatoid arthritis(RA) in China, for patients with RA. Methods: SRs of randomized controlled trials(RCTs) on TG or TGP in treating RA were included, by searching 8 databases from their inception until December 2017. Two authors extracted data independently. We assessed the quality of SRs using AMSTAR and graded the quality of evidence according to the GRADE approach. Results: Eleven SRs containing an average of 7.6 RCTs, involving a total of 7,012 participants were included in this overview. On the basis of included SRs, TG and TGP could improve the following indexes for RA patients: American College of Rheumatology(ACR) 20 response rate, ACR50 response rate and ACR70 response rate, swollen joint count, tender joint count, erythrocyte sedimentation rate and C-reactive protein. Moreover, TGP could reduce incidence of hepatotoxicity. The most common adverse effects of TG were gastrointestinal discomfort and gonad toxicity, while for TGP was mild to moderate diarrhea. The overall quality of evidence for these findings ranged from "low" to "moderate". Conclusions: TG and TGP might be 2 potentially effective complementary and alternative drugs for patients with RA. Nevertheless, due to gonad toxicity, TG should only be considered in elderly patients or patients without reproductive needs. More evidence from high quality RCTs and SRs is warranted to support the use of TG and TGP for RA patients.展开更多
基金supported by the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences(CI2021A03807 and CI2021A01501)the National Natural Science Foundation of China(82330124)+2 种基金the Beijing Municipal Natural Science Foundation(7212186)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002)the Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences.
文摘Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii Hook.f.(TwHF)-based therapy,exhibit satisfactory clinical efficacy for RA treatment.However,drug-induced liver injury(DILI)remains a critical issue that hinders the clinical application of TGTs,and the molecular mechanisms underlying the efficacy and toxicity of TGTs in RA have not been fully elucidated.To address this problem,we integrated clinical multi-omics data associated with the anti-RA efficacy and DILI of TGTs with the chemical and target profiling of TGTs to perform a systematic network analysis.Subsequently,we identified effective and toxic targets following experimental validation in a collagen-induced arthritis(CIA)mouse model.Significantly different transcriptome–protein–metabolite profiles distinguishing patients with favorable TGTs responses from those with poor outcomes were identified.Intriguingly,the clinical efficacy and DILI of TGTs against RA were associated with metabolic homeostasis between iron and bone and between iron and lipids,respectively.Particularly,the signal transducer and activator of transcription 3(STAT3)–hepcidin(HAMP)/lipocalin 2(LCN2)–tartrate-resis tant acid phosphatase type 5(ACP5)and STAT3–HAMP–acyl-CoA synthetase long-chain family member 4(ACSL4)–lysophosphatidylcholine acyltransferase 3(LPCAT3)axes were identified as key drivers of the efficacy and toxicity of TGTs.TGTs play dual roles in ameliorating CIA-induced pathology and in inducing hepatic dysfunction,disruption of lipid metabolism,and hepatic lipid peroxidation.Notably,TGTs effectively reversed“iron–bone”disruptions in the inflamed joint tissues of CIA mice by inhibiting the STAT3–HAMP/LCN2–ACP5 axis,subsequently leading to“iron–lipid”disturbances in the liver tissues via modulation of the STAT3–HAMP–ACSL4–LPCAT3 axis.Additional bidirectional validation experiments were conducted using MH7A and AML12 cells to confirm the bidirectional regulatory effects of TGTs on key targets.Collectively,our data highlight the association between iron-mediated metabolic homeostasis and the clinical efficacy and toxicity of TGT in RA therapy,offering guidance for the rational clinical use of TwHF-based therapy with dual therapeutic and toxic potential.
基金the National Natural Science Foundation of China(No.81660836)。
文摘Objectives:To explore and summarize the beneficial effects of a traditional Chinese medicine preparation,Tripterygium glycosides tablets(TGT),in rheumatoid arthritis(RA)animal models of neovascularization,and to provide a reference for future clinical applications and research on its pharmacologic mechanism.Methods:We searched the databases PubMed,Embase,Web of Science,Chinese National Knowledge Infrastructure,VIP,Wan Fang and SinoMed(China Biomedical Document Service System)to identify studies of TGT with outcome indicators of angiogenesis-related factors that were published before April2020.Subgroup analysis and meta-regression were performed for dosage and duration of TGT.Statistical tests and subgroup analysis were conducted using RevMan 5.3,and meta-regression and sensitivity analysis were conducted using STATA/SE 15.0.Results:Fourteen studies of TGT in RA rats were included in this analysis.Treatment with TGT significantly reduces synovial microvessel density and the expression of vascular endothelial growth factor(VEGF),VEGF receptor 2,hypoxia inducible factor a,c-Fos,c-Jun,angiopoietin-1 and angiopoietin-2 compared with control groups(P<.05).Subgroup analysis did not show a significant association of the mRNA levels of VEGF in synovium,assessed using quantitative real-time PCR,with duration or dosage of TGT.Meta-regression analysis also indicated that the effects of dosage and duration were not significantly associated with differences in VEGF mRNA levels.Sensitivity analysis on VEGF m RNA levels did not fundamentally change the results.Conclusions:TGT can reduce synovial neovascularization by decreasing synovial microvessel density and expression of VEGF,VEGF receptor 2,hypoxia-inducible factor a,c-Fos,c-Jun,Ang-1 and Ang-2,thereby suppressing pannus formation and bone destruction in rat models of RA.Additional well-designed studies are required to confirm these findings.
基金Supported by the National Natural Science Foundation of China(No.81673941,81603588 and 81804042)
文摘Objective: To summarize the evidence from systematic reviews(SRs) on the benefits and safety of Tripterygium glycosides(TG) and total glucosides of paeony(TGP), commonly used to treat rheumatoid arthritis(RA) in China, for patients with RA. Methods: SRs of randomized controlled trials(RCTs) on TG or TGP in treating RA were included, by searching 8 databases from their inception until December 2017. Two authors extracted data independently. We assessed the quality of SRs using AMSTAR and graded the quality of evidence according to the GRADE approach. Results: Eleven SRs containing an average of 7.6 RCTs, involving a total of 7,012 participants were included in this overview. On the basis of included SRs, TG and TGP could improve the following indexes for RA patients: American College of Rheumatology(ACR) 20 response rate, ACR50 response rate and ACR70 response rate, swollen joint count, tender joint count, erythrocyte sedimentation rate and C-reactive protein. Moreover, TGP could reduce incidence of hepatotoxicity. The most common adverse effects of TG were gastrointestinal discomfort and gonad toxicity, while for TGP was mild to moderate diarrhea. The overall quality of evidence for these findings ranged from "low" to "moderate". Conclusions: TG and TGP might be 2 potentially effective complementary and alternative drugs for patients with RA. Nevertheless, due to gonad toxicity, TG should only be considered in elderly patients or patients without reproductive needs. More evidence from high quality RCTs and SRs is warranted to support the use of TG and TGP for RA patients.
