Tripterygium Glycosides Tablets Research Articles

Altered Iron-Mediated Metabolic Homeostasis Governs the Efficacy and Toxicity of Tripterygium Glycosides Tablets Against Rheumatoid Arthritis

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-resistant 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.

Enhanced efficacy with reduced toxicity of tripterygium glycoside tablet by compatibility with total glucosides of paeony for rheumatoid arthritis therapy

Background and aimsDrug-induced liver injury remains a critical issue to hinder clinical application of Tripterygium Glycosides Tablets (TGTs) for rheumatoid arthritis (RA) therapy. Combination of TGTs with Total Glucosides of Peony (TGP) may be the most common therapeutic strategy for enhancing TGTs’ efficacy and reducing its toxicity. Herein, we aimed to investigate the efficacy-enhancing and toxicity-reducing properties and mechanisms of TGT-TGP combination. MethodsBoth TGT-induced acute and chronic liver injury animal models were established. ELISA, transmission electron microscopy, immunohistochemistry, western blot and quantitative PCR were performed to determine the efficacy, toxicity and regulatory mechanisms of TGT-TGP combination. ResultsThe compatibility of TGP significantly reduced the abnormal serum ALT and AST levels, and improved liver histopathological changes in both acute and chronic DILI animal models induced by TGTs, with the most effective dosage of TGP-M (medium-dose TGP, 450 mg/kg). Additionally, TGP and TGT synergistically alleviated joint swelling and improved the elevation of serum inflammatory factors, in line with the positive changes in joint histopathological features of collagen induced arthritis mice, with the same effective dosage of TGP-M following 5 weeks’ drug combination treatment. Mechanically, TGT significantly increased the number of autophagosomes and the expression of LC3II protein while reducing p62 protein expression in the liver tissues, which were significantly reversed by the compatibility with TGP, similar to the findings based on the inflamed joint tissues. ConclusionsThese findings suggest an enhanced efficacy with reduced toxicity of TGT by the compatibility with TGP for RA therapy, possibly through regulating various autophagy-related proteins.

Anti-rheumatoid arthritis potential of Rhododendron molle G. Don leaf extract in adjuvant induced arthritis rats.

The aim of this study was to test the anti-rheumatic arthritis effects of Rhododendron molle G. Don leaf extract in arthritis rats and inflammatory RAW 264.7cells. Preliminary analysis and comparison of potential medicinal components of three polar extracts by HPLC and UHPLC-Q-TOF-MS. SD rats were subcutaneously injected with complete Freund's adjuvant (CFA) to induce inflammation on the right hind paw. RAW 264.7cells were induced by lipopolysaccharide (LPS) to established cell inflammatory model. The volume of rat hind paw was measured with a volume meter to detect swelling, and the weight of rats was measured with an electronic balance. The severity of arthritis in rats was evaluated by arthritis score. The pathological sections of rat hind paw joints were observed by hematoxylin-eosin staining, and the contents of IL-6 and IL-1β in serum were detected. qRT-PCR was used to detect the expression of IL-1β, IL-6, TNF-α and COX-2 genes in RAW 264.7cells. The release of nitric oxide was measured by Griess reaction. The expression levels of IL-6 and IL-1β were detected by Western-Blot. and discussion: The chloroform extract from R. molle leaves (CERL), Ethyl acetate extract from R. molle leaves (EERL), n-butanol extract from R. molle leaves (BERL) could significantly inhibit hind paws swelling and reduce arthritis index in arthritis rats. And it showed dose dependence. Compared with tripterygium glycosides (TG) tablets, an effective drug of RA treatment, CERL have better anti-RA effect after administration. In addition, the three kinds of the polar extracts of Rhododendron molle leaves (PERL) had lower toxicity, with the LD50 279.87, 239.65, 500.08 (mg/kg) respectively, while TG group's LD50 was 96.00 (mg/kg). In vitro experiments showed that the three PERLs can significantly inhibit the level of pro-inflammatory factors and inflammatory mediator, such as TNF-α, IL-1β, IL-6, COX-2 and NO, which were consistent with their anti-RA ability. Among the three kinds of PERLs, CERL showed the best inhibitory activity. The R. molle leaf is a potential medicinal part for the treatment of RA. This study explored the anti-RA and anti-inflammatory activities of CERL, EERL, BERL, which laid a foundation for further promoting the clinical application of R. molle.

Single-cell transcriptome analysis uncovers underlying mechanisms of acute liver injury induced by tripterygium glycosides tablet in mice

Tripterygium glycosides tablet (TGT), the classical commercial drug of Tripterygium wilfordii Hook. F. has been effectively used in the treatment of rheumatoid arthritis, nephrotic syndrome, leprosy, Behcet's syndrome, leprosy reaction and autoimmune hepatitis. However, due to its narrow and limited treatment window, TGT-induced organ toxicity (among which liver injury accounts for about 40% of clinical reports) has gained increasing attention. The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing (scRNA-seq) technology. The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Using the mouse model, we identified 15 specific subtypes of cells in the liver tissue, including endothelial cells, hepatocytes, cholangiocytes, and hepatic stellate cells. Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations; led to marked inflammatory response, apoptosis and fatty acid metabolism dysfunction in hepatocytes; activated hepatic stellate cells; brought about the activation, inflammation, and phagocytosis of liver capsular macrophages cells; resulted in immune dysfunction of liver lymphocytes; disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways. Thus, these findings elaborate the mechanism underlying TGT-induced acute liver injury, provide new insights into the safe and rational applications in the clinic, and complement the identification of new biomarkers and therapeutic targets for liver protection.

Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury

Background and aimsDrug-induced liver injury (DILI) remains a critical issue and a hindrance to clinical application of Tripterygium Glycosides Tablet (TGT) despite its favorable therapeutic efficacy in rheumatoid arthritis. Herein, we aimed to elucidate the molecular mechanisms underlying TGT-induced hepatotoxicity. MethodsChemical profiling of TGT was identified by UPLC-Q/TOF-MS/MS and its putative targets were predicted based on chemical structure similarity calculation. Following “DILI-related gene-TGT putative target” interaction network construction, a list of key network targets was screened according to nodes' topological importance and functional relevance. Both in vivo and in vitro experiments were performed to determine drug hepatotoxicity and the underlying mechanisms. ResultA total of 49 chemical components and 914 putative targets of TGTs were identified. Network calculation and functional modularization screened RAS-ERK and mTOR signalings-associated autophagy to be one of the candidate targets of TGT-induced hepatotoxicity. Experimentally, TGT significantly activated RAS-ERK axis, elevated the number of autophagosomes and the expression of LC3II protein, but reduced the expression of p62 protein and suppressed mTOR phosphorylation in the liver tissues of TGT-induced acute liver injury mice and chronic liver injury mice in vivo and AML12 cells in vitro. Moreover, TGT and mL-098 (an activator of RAS) co-treatment reduced AML12 cell viability via regulating autophagy and TGT-induced liver injury-related indicators more dramatically than TGT treatment alone, whereas Salirasib (an inhibitor of RAS) had an opposite effect. ConclusionRAS-ERK-mTOR cross-talk may play a crucial role in TGT-induced hepatocyte autophagy, offering a promising target for developing novel therapeutics to combat TGT-induced hepatotoxicity.

Integrated metabolomics and network analysis reveal changes in lipid metabolisms of tripterygium glycosides tablets in rats with collagen-induced arthritis

Tripterygium glycosides tablets (TGT) are the commonly used preparation for rheumatoid arthritis (RA). However, the changes in TGT on RA are still unclear at the metabolic level. This study aimed to reveal the biological processes of TGT in collagen-induced arthritis (CIA) rats through integrated metabolomics and network analysis. First, the CIA model in rats was established, and the CIA rats were given three doses of TGT. Then, the endogenous metabolites in the serum from normal rats, CIA rats, and CIA rats treated with varying doses of TGT were detected by UHPLC-QTOF-MS/MS. Next, univariate and multivariate statistical analyses were performed to find the differential metabolites. Finally, differential metabolites, metabolic pathways, and hub genes were analyzed integrally to reveal the biological processes of TGT in CIA rats. The paw diameter, arthritis score, immunoglobulin G (IgG) concentration, CT image, and histological assay showed that TGT had evident therapeutic effects on CIA rats. Untargeted metabolomics revealed that TGT could ameliorate the down-regulation of lipid levels in CIA rats. Four key differential metabolites were found including LysoP(18:0), LysoPA(20:4), LysoPA(18:2), and PS(O-20:0/17:1). The glycerophospholipid metabolic pathway was perturbed in treating CIA with TGT. A total of 24 genes, including PLD1, LPCAT4, AGPAT1, and PLA2G4A, were found to be the hub genes of TGT in CIA rats. In conclusion, the integrated analysis provided a novel and holistic perspective on the biological processes of TGT in CIA rats, which could give helpful guidance for further TGT on RA. Future studies based on human samples are necessary.

Effectiveness and safety of tripterygium glycosides tablet for lupus nephritis: a systematic review and Meta-analysis.

To investigate the effectiveness and safety of tripterygium glycosides (TG) tablet for the treatment of Lupus nephritis (LN). Several databases were systematically searched including PubMed, Embase, Cochrane, Wiley, China National Knowledge Infrastructure Database, SinoMed and Wanfang Library till June 20, 2020. Revman5.3 was utilized to analyze the data according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. In total, 8 randomized controlled trials involving 583 participants were identified. Meta-analyses showed that, compared with glucocorticoids (GC) alone, the combination with TG tablet provided a statistically significant improvement in total remission (TR) ( = 1.27, 95% : 1.08-1.50, = 0.004), complete remission (CR) ( = 1.61, 95% : 1.05-2.47, = 0.03) and C3 levels ( = 0.27, 95% : 0.14-0.39, < 0.000 1), C4 levels ( = 0.12, 95% : 0.07-0.17, < 0.000 01). No significant differences were seen in TR, CR, proteinuria, serum creatinine, C3 and C4 (TR: = 1.00, 95% : 0.87-1.16, = 0.95; CR: = 1.10, 95% : 0.78-1.56, = 0.58; proteinuria levels: = -0.06, 95% : -0.13 to 0.01, = 0.10; serum creatinine levels: = -0.01, 95%: -7.36 to 7.35, = 1.00; C3 levels: = 0.01, 95%: -0.06 to 0.07, = 0.84; C4 levels: = -0.01, 95%: -0.03 to 0.01, = 0.49) between azathioprine (AZA) / leflomit (LEF) + GC and TG tablet + GC. Adverse events (hepatic dysfunction, nausea, vomitting) showed no statistical differences between the TG tablet + GC group and the GC group. There were more new onset of irregular menstruation in the TG tablet + GC group than those in the AZA + GC ( = 3.57, 95% : 1.40-9.11, = 0.008) /LEF+ GC ( = 6.69, 95% : 2.42-18.46, = 0.000 2) group, but leucopenia lower than those in AZA + GC group ( = 0.38, 95% : 0.17-0.85, = 0.02) and alopecia ( = 0.14, 95% : 0.03-0.77, = 0.02) and rash ( = 0.09, 95% : 0.01-0.69, = 0.02) lower than those in LEF + GC group. This review indicates that TG tablet maybe effective in LN treatment. Nevertheless, adverse events cannot be ignored. Large sample, multi-center, high-quality clinical studies are needed to verify the exact effects and safety of TG tablet in treatment of LN.

Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS.

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGTS) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF’s prolonged elimination half-life and TGT’s narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the Cmax and AUC0-t of TER were significantly decreased with separate co-administration, as the Cmax and AUC0-t were 30.17 ± 1.55 μg/mL and 24.47 ± 2.50 μg/mL, 374.55 ± 15.54 μg h/mL and 336.94 ± 21.19 μg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb–drug interactions between LEF and TGT have been proven.

Comprehensive Evaluation of the Quality of Tripterygium Glycosides Tablets Based on Multi-Component Quantification Combined with an In Vitro Biological Assay.

Tripterygium glycosides tablets (TGTs) are widely used in clinical practice to treat rheumatoid arthritis and other autoimmune diseases, with significant beneficial effects but also high toxicity, necessitating rigorous quality evaluation and control. In current study, a rapid resolution liquid chromatography tandem electrospray ionization triple quadrupole mass spectrometry (RRLC–ESI–MS/MS) method was developed and validated for the quantitative analysis of 14 components of ten batches of TGTs produced by different manufacturers, including four diterpenoids, three triterpenoids, and seven sesquiterpene alkaloids. Meanwhile, the NO inhibition effects of these TGTs were evaluated in LPS-induced RAW264.7 cells for their downstream anti-inflammatory activities, as well as their cytotoxicity. The results indicate that the TGTs from different manufacturers showed poor quality consistency, as evidenced by large variations in chemical profiles and biological effects, which may increase the risks associated with clinical use. To improve the quality status of TGTs, it is crucial to identify indicator components whose characterization can accurately reflect the efficacy and toxicity of TGTs from which they were derived. Our study reveals that triptolide, triptoquinone B, celastrol, and demethylzelaysteral considerably contributed to the anti-inflammatory activity and/or cytotoxicity of TGTs, implying that they should be further investigated as candidate indicator components for TGT quality control.

Synchronous Investigation of the Mechanism and Substance Basis of Tripterygium Glycosides Tablets on Anti-rheumatoid Arthritis and Hepatotoxicity.

Tripterygium Glycosides Tablets (TGT) has shown obvious anti-rheumatoid arthritis (RA) effects accompanied by hepatotoxicity. Despite that many studies looked at TGT's anti-RA or hepatotoxic mechanism and substance basis, the results were still insufficient. Furthermore, the anti-RA and hepatotoxicity investigations of TGT were undertaken separately, neglecting the relationship between efficacy and toxicity. Herein, an integrated approach combining metabolomics, network pharmacology, serum pharmacochemistry, and molecular docking was adopted to elucidate the mechanism and substance basis of Tripterygium Glycosides Tablets (TGT) on anti-rheumatoid arthritis and hepatotoxicity simultaneously. The results showed that 33 components in TGT were absorbed into rat serum. Two toxic targets (PRKCA, FASN), three effective targets (PLA2G10, PTGES, PLA2G1B), and four effective and toxic targets (PTGS1, PTGS2, PLA2G2A, ALOX5) were obtained by metabolomics combined with network analysis and network pharmacology. A component-target-RA-hepatotoxicity network was constructed and five hepatotoxic components (1-desacetylwilforgine, wilfordconine, wilforgine, wilformine, wilfornine D), eight effective-toxic components (14-oxo-19-(4 → 3) abeo-abieta-3,8,12-tetraen-19,18-olide, 7-oxo-18(4 → 3) abeo-abieta-3,8,11,13-tetraen-18-oic acid, hypoglaulide, triptotriterpenic acid A, wilforol F, wilforlide B, triptoquinone B, wilforlide A); and 23 non-effective and non-toxic components were acquired and validated by molecular docking. In addition, our research revealed that glycerophospholipid metabolism and ether lipid metabolism were correlated to both hepatotoxicity and anti-RA of TGT. While in sphingolipid metabolism, ceramidases regulated ceramide-sphingosine and phytoceramide-phytosphingosine reaction were found to be correlated to hepatotoxicity, sphinganine-1-phosphate lyase (SPL) regulated sphingosine 1-phosphate (S1P)-phosphoethanolamine and sphinganine 1-phosphate-phosphoethanolamine were found to be attributed to anti-RA effects.

Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin-Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity.

Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the in vivo exposure of the six key TGT components was performed to screen the anti–NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated in vitro. The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and in vitro verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti–NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti–NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.

Metabonomic and transcriptomic analyses of Tripterygium glycosides tablet-induced hepatotoxicity in rats

We aimed to explore novel biomarkers involved in alterations of metabolism and gene expression related to the hepatotoxic effects of Tripterygium glycosides tablet (TGT) in rats. Rats were randomly divided into groups based on oral administration of TGTs for 6 weeks: control, low-dose (9.5 mg/kg), and high-dose (18.9 mg/kg). Serum samples and total liver RNA were subjected to metabonomic and transcriptomic analyses. Thirteen metabolites were significantly up-regulated by liver injury induced by Tripterygium glycosides. Five potential biomarkers were more sensitive than Alanine aminotransferase (ALT) for accurate and timely prediction of hepatic damage. The four metabolic pathways most obviously regulated by hepatotoxicity were D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, ether lipid metabolism, and tryptophan metabolism. Transcriptomics revealed significant differences in 1792 mRNAs and 400 long non-coding (lnc) RNAs. Dysregulated lncRNAs in the TGT-induced hepatotoxicity group were associated with genes involved in amino acid metabolism using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Up-regulated expression of Ehhadh, Gpt, and Got1, and down-regulated expression of dopa decarboxylase (Ddc), Cyp1a2, Ido2, Aldh1b1, and asparagine synthetase (Asns) was validated by quantitative real-time PCR. This multiomics study has elucidated the relationship between amino metabolism and liver injury, revealing potential biomarkers.

Identification and comparison of compounds in commercial Tripterygium wilfordii genus preparations with HPLC-QTOF/MS based on molecular networking and multivariate statistical analysis

Tripterygium wilfordii genus preparations (TWGP) are widely used in traditional Chinese medicines for the treatment of autoimmune diseases and immune diseases with definite therapeutic effects but high toxicity. The aim of this study is to identify and compare chemical compounds in three types of commercial TWGP using UHPLC-QTOF-MS/MS and molecular networking (MN) technology. First, the mass fragmentation pathways of 10 compounds were investigated, which included two sesquiterpene alkaloids, four diterpenoids, and four triterpenoids. The chemical compounds were then identified using UHPLC-QTOF-MS/MS and a conventional database. Following that, molecular network technology was used to further identify the GNPS platform. Finally, metabonomic data analysis was used to compare 92 commercial TWGP samples from 13 manufacturers. A total of 103 compounds were identified, with the molecular network detecting 40 of them. Moreover, the quality of commercial Tripterygium glycoside tablets varies greatly and 26 compounds, including triptolide, wilforine, wilforgine, and demethylzeylasteral, were discovered to be the main differential compounds in tripterygium glycosides tablets. This was the first time MN technology was used for compound analysis in TWGP, laying the foundation for classifying effective and toxic substances and TWGP quality control.

Chinese herbal medicine for incomplete immune reconstruction in patients with AIDS undergoing antiretroviral treatment: A systematic review of randomized trials

To evaluate the effectiveness and safety of Chinese herbal medicines (CHMs) for incomplete immune reconstruction in patients with HIV/AIDS. Eight electronic databases were searched for randomized controlled trials (RCTs) on the use of CHM for patients with HIV/AIDS with incomplete immune reconstruction. Outcomes included CD4 + cell count, quality of life, and adverse events/effects. The Cochrane Risk of Bias was employed to evaluate the methodological quality of the included RCTs. We identified 13 eligible RCTs, with an overall high risk of bias, on 10 different CHMs. There was a significant increase in CD4 + cell count after the use of Jianpi Yiqi medicinal paste for 3 months; tripterygium glycosides tablets (TGTs) for 3 months (mean difference [MD] 52.63 cells/μL, 95% confidence interval [CI, 46.98, 58.28]), 6, 9, and 12 months; Wenshen Jianpi granules for 6 months; Shenling Fuzheng capsules for 6 months (MD 49.53 cells/μL, 95% CI [8.45, 90.61]) and 12 months; Aikeqing granules for 9 months (MD 61.51 cells/μL, 95% CI [16.25, 106.77]) and 12 months; Guipi decoction for 12 months; Mianyi No.2 granules (JT) for 12 and 18 months; and Chinese medicine granules for 18 months. The increase in the mean difference of CD4 + cell count from 6 to 18 months was larger in Chinese medicine granules and Mianyi No.2 granules (JT). Guipi decoction and Jianpi Qushi decoction improved the Karnofsky score. Four RCTs reported the outcome of adverse events/effects, while four cases of minor adverse effects were reported in the TGTs group. Jianpi Yiqi medicinal paste, Wenshen Jianpi granules, Shenling Fuzheng capsules, Aikeqing granules, Guipi decoction, and TGTs may be effective in increasing CD4 + within 12 months, and Mianyi No.2 granules (JT) and Chinese medicine granules may show long-term effects. High-quality large RCTs on the effectiveness and safety of CHMs are still warranted.

FXR activation prevents liver injury induced by Tripterygium wilfordii preparations

Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) are the preparations of Tripterygium wilfordii used to treat rheumatoid arthritis (RA) in the clinic, but the hepatotoxicity was reported frequently. This study aimed to determine the potential toxicity mechanism of liver injury induced by the preparations of Tripterygium wilfordii in mice. Here, we performed metabolomic analysis, pathological analysis and biochemical analysis of samples from mice with liver injury induced by TGT and TWT, which revealed that liver injury was associated with bile acid metabolism disorder. Quantitative real-time PCR (QPCR) and western blot indicated that the above changes were accompanied by inhibition of farnesoid X receptor (FXR) signalling. Liver injury from TWT could be alleviated by treatment of the FXR agonist obeticholic acid (OCA) via activation of the FXR to inhibit the c-Jun N-terminal kinase (JNK) pathway and improve bile acid metabolism disorder by activating bile salt export pump (BSEP) and organic solute-transporter-β (OSTB). The data demonstrate that FXR signalling pathway plays a key role in T. wilfordii-induced liver injury, which could be alleviated by activated FXR. These results indicate that FXR activation by OCA may offer a promising therapeutic opportunity against hepatotoxicity from the preparations of T. wilfordii.

Alprostadil combined with tripterygium glycosides tablet in treatment of diabetic kidney disease: a systematic review and meta-analysis

Alprostadil combined with tripterygium glycosides tablet in treatment of diabetic kidney disease: a systematic review and meta-analysis

Anti-angiogenic effect of tripterygium glycosides tablets in animal models of rheumatoid arthritis: A systematic review and meta-analysis

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. 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 April 2020. 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. 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 α, 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 mRNA levels did not fundamentally change the results. TGT can reduce synovial neovascularization by decreasing synovial microvessel density and expression of VEGF, VEGF receptor 2, hypoxia-inducible factor α, 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.

Meta-analysis on safety of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.

Benefit and risk of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis based on multi-criteria decision-making analysis

Rheumatoid arthritis(RA) has a high disability rate and is highly harmful. It has a long course of treatment and is prone to adverse reactions or events(ADR/ADE). Selection of drugs in particular shall give consideration to both benefits and risk. Tripterygium Glycosides Tablets(TGT) is one of the important drugs for the treatment of RA. It has a remarkable efficacy, but a strong toxicity, which is controversial in clinical use. The study was oriented to patients, and quantitatively evaluated the efficacy and risk of TGT in treatment of RA, providing an intuitive basis for clinical safety and effective application of TGT. A multi-criteria decision-making analysis(MCDA) model of TGT was built in the treatment of RA, and then benefit and risk indicators were weighted by SWING method. Totally 53 random clinical trials(RCT) in accordance with the evaluation criteria were included by Meta-analysis method. The RCT results were merged by Meta-analysis, indicating that compared with the conventional therapy of chemical immunosuppressant(CISD), TGT could improve the curative effect whether it was used alone or in combination with CISD, but it would increase the incidence of reproductive system damage. The combined administration with CISD would also increase the incidence of liver and kidney damages. Treatment outcomes varied according to the different conditions of the combined administration with CISD. Based on MCDA model and clinical results, the benefit value, risk value and benefit-risk value of different doses, courses and combined administration of TGT in the treatment with RA were compared. The results showed that when the benefit and risk of the drug were equally important to the patient, the benefit-risk value of the single administration of TGT was 59, while that of the combined administration of TGT and CISD was 39. Therefore, the benefit-risk value of the single administration of TGT was 100% better than the combined administration. When the combined administration of TGT and CISD is unavoidable, the benefit-risk value of low-dose TGT(0.10-0.99 mg·kg~(-1)·d~(-1)) was 48, while that of high-dose TGT was 36. Therefore, low-dose TGT combined with CISD was more easily accepted by patients. The 2 to 3-month treatment course had a benefit-risk value of 40, while the long treatment course had a benefit-risk value of 38. Based on existing evidences, the single administration of TGT may be better than the combined administration with CISD. If the patients need to combine with CISD to treat RA, low dosage and 2 to 3-month course may be relatively optimal.

Meta-analysis of RCT studies on clinical efficacy of single administration of Tripterygium Glycosides Tablets or combined administration with methotrexate against rheumatoid arthritis

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&lt;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&lt;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.