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Tripterygium wilfordii Hook F has significant anti-inflammatory and immunosuppressive properties and is widely used for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and kidney disease, especially in traditional Chinese medicine. The mechanisms underlying its effects may be diverse but they remain unclear, and its toxicity and side effects limit its wider clinical application. This review summarizes the clinical application of Tripterygium wilfordii Hook F in recent years, as well as the results of studies into its mechanisms and toxicity, to provide a reference for its future clinical application.
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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and destruction of articular cartilage and bone. With the aging of the population, the incidence of RA is increasing year by year and the burden of public health is becoming more and more serious. Tripterygium wilfordii has the effects of dispelling wind and dredging collaterals, dehumidifying and relieving pain, detoxification and insecticide. It is often used in the treatment of various autoimmune diseases, tumors and skin diseases in clinic, and the prominent effect is observed in the treatment of RA especially. This review systematically summarizes and discusses the latest research progress of T. wilfordii in the treatment of RA in the aspects of experimental pharmacology and clinical research, including its single application, the compatible application with other Chinese materia medica, and the combination of Western medicine, which is expected to promote the innovative drug development and more reasonable and effective clinical application of T. wilfordii in the treatment of RA.
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Objective: To investigate the effect of Tripterygium wilfordii on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mice, analyze its effects on its intestinal flora, and explore its mechanism. Methods: Animal models of UC mice induced by DSS were established and divided into control group (Con), model group (Mod), mesalazine group (Mes), low dose group of T. wilfordii (RT1) and high dose group of T. wilfordii (RT2). The disease activity index (DAI), colon length, colon thickness, colon lesion gross score, colon histopathology score, and TNF-α and IL-6 cytokine expression levels in the serum of the mice were determined. The changes of intestinal flora in mice were detected by high-throughput sequencing, and the mechanism of action of T. wilfordii on UC mice was discussed. Results: After administration of T. wilfordii, it effectively alleviated colonic inflammatory symptoms and reduced the expression of inflammatory factors in mice, and had a good therapeutic effect on UC mice. The sequencing results of the flora showed that the mice in the Mod group were more disordered than the Nor group, and the abundance of the bacteria was reduced. After treatment with T. wilfordii, the recovery rate of intestinal flora was accelerated. Compared with Mod group, the diversity of intestinal flora was significantly improved. The level of portal was mainly decreased by the proportion of Bacteroidetes, and the increase of Firmicutes. The genus was mainly characterized by a decrease in the genus Lachnospiraceae and Bacteroides. Conclusion: T. wilfordii can regulate the composition of UC mouse flora, accelerate the recovery of flora, and have a good therapeutic effect on UC mice.
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Objective: To observe the effect of Tripterygium wilfordii processed by liquorice on the metabolites in the serum of mice, and to explore its possible metabolic pathways to reduce hepatotoxicity. Methods: C57BL/6 mice were randomly divided into control (Con) group, raw T. wilfordii (Raw) group, and T. wilfordii processed by liquorice (Pro) group. Liver histopathological sections and biochemical indexes of liver function and inflammatory factors were detected. LC-MS technology combined with metabolomics methods were used to characterize the differences in metabolism between each group. Results: Compared with Raw group, the liver injury of mice in Pro group was significantly improved, the levels of biochemical indicators and inflammatory factors were significantly decreased, which indicated that TwHF could reduce the hepatotoxicity of mice after processing by liquorice. Twelve potential biomarkers including hexadecanoic acid, phosphatidic acid, glyceride, lecithin and cholic acid were screened, mainly involved nine metabolic pathways including biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, arachidonic acid metabolism, etc. Conclusion: TwHF processed by liquorice could reduce the hepatotoxicity of mice and the mechanism may be related to the regulation of fatty acid metabolism, which provides a reference for clinical rational application.
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As a major active component extracted from traditional Chinese herb Tripterygium wilfordii Hook F, triptolide exhibits multiple pharmacological effects. Autophagy is an evolutionary conserved intracellular catabolic process involved in cytoplasmic materials degradation. Autophagic dysfunction contributes to the pathologies of many human diseases, which makes it a promising therapeutic target. Recent studies have shown that triptolide exerts neuroprotection, anti-tumor activities, organ toxicity, and podocyte protection by modulating autophagy. This article highlights the current information on triptolide-modulated autophagy, analyzes the possible pathways involved, and describes the crosstalk between autophagy and apoptosis modulated by triptolide, in hope of providing implications for the roles of autophagy in pharmacological effects of triptolide and expanding its novel usage as an autophagy modulator.
Subject(s)
Animals , Humans , Apoptosis , Autophagy , Diterpenes , Pharmacology , Epoxy Compounds , Pharmacology , Neoplasms , Drug Therapy , Pathology , Neuroprotective Agents , Pharmacology , Phenanthrenes , Pharmacology , PodocytesABSTRACT
Tripterygium wilfordii Hook F (TwHF) and its extracts have long been used for the treatment of rheumatoid arthritis, autoimmune diseases, and kidney disease due to their anti-inflammatory, immunoregulatory, and other pharmacological effects. However, the clinical immunoregulatory effects of TwHF and its extracts remain unclear, so we reviewed their effects for use in clinical practice. This review provides a comprehensive summary of the recent literature on the immunoregulatory effects of TwHF and its extracts in clinical studies. TwHF and its extracts affect the proliferation and activation of Tand B cells; ratio of Tcell subsets; inflammatory response of monocytes, macrophages, and immunoglobulins; and secretion of many cytokines. Together, these effects dictate immune function in a variety of diseases. TwHF and its extracts can be used alone or in combination with existing therapies against many immune disorders through immunomodulation.
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Objective To study the intestinal absorption kinetics of Tripterygium wilfordii (TW) solid dispersions and the effects of different intestinal segments, drug concentrations, pH value, and P-glycoprotein (P-gp) on intestinal absorption. Methods The absorption behavior was investigated in situ with a single-pass intestinal perfusion (SPIP) model in rats. The content of each index component was determined by HPLC. The gravimetric method was used to correct the data and calculate the absorption rate constant (Ka) and apparent permeability coefficient (Papp) of each index component. Results The index components of TW were absorbed in the whole intestine, and the absorption rate constant (Ka) of all the index components of TW solid dispersion was significantly increased than that of extract (P < 0.05), and had some differences among different segments. With the increase of drug concentration, the absorption of each index component had saturation phenomenon, which indicated that it may be carrier-mediated transport mechanism. Acidic environment (pH 5.4) was beneficial to the absorption of various index components, especially the acidic content celastrol. After adding P-gp inhibitor, the Ka and Papp of celastrol were significantly different from those without P-gp inhibitor (P < 0.05), which suggested that it may be the P-gp substrate. Conclusion All the index components of TW solid dispersion are absorbed in the whole intestine and have saturation phenomenon, which suggested the absorption may be carrier-mediated transport mechanism. Acidic environment is beneficial to the absorption of all components. The absorption process of celastrol is affected by drug concentration and P-gp inhibitor, which indicated that it may be P-gp substrate. The preparation of solid dispersing can significantly enhance the absorption of various components of TW, suggesting that all the index components are BCS II drugs, and the bioavailability of the preparation may be improved.
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Tripterygium wilfordii, a traditional Chinese herbal medicine with multiaspect pharmacological activities, contains abundant chemical constituents. Based on the new concept of quality markers (Q-markers) of traditional Chinese medicine put forward by Academician Chang-xiao Liu, this paper systematically reviewed the chemical constituents and pharmacological activities of T. wilfordii, the Q-markers of T. wilfordii were predicted and analyzed according to the definition of quality markers and the research of its traditional efficacy, traditional medicinal properties, new clinical use, measurable composition, plasma composition, and compatibility, in order to provide reference for further study on the quality of T. wilfordii.
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Objective To improve the dissolution in vitro, thereby to prepare the solid dispersion (SD) from the extract of Tripterygium wilfordii (ETW). Methods Polyethylene glycol 6000 (PEG 6000) and poloxamer 188 (F68) were used as carrier to prepare ETW-SD by solvent-melting method. The triptolide, triptonide, wilforine, tripterine and wilforlide were used as the evaluation indexes to characterize the optimal prescription of ETW-SD by dissolution in vitro, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Results The optimal formulation for ETW-SD composed of ETW-PEG 6000-F68 (1∶2∶1). Compared with the raw materials, the dissolution of triptonide, triptolide and wilforine increased by a factor of 3.32, and wilforine by 2 times, while the dissolution of tripterine and wilforlide reached more than 83% within 60 min.
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Tripterygium wilfordii Hook. F. (TWF) belongs to celastraceae under Tripterygium family. It is a traditional Chinese medicine with a variety of pharmacological effects such as anti- inflammatory, analgesic, anti- tumor, immunomodulation and so on, which is applied for many diseases because of its significant effects. However, its toxic and side effects frequently occur, especially liver injury, affecting its safety in clinical practice. In this paper, the clinical characteristics of liver injury of TWF were preliminarily explored by combining with literature analysis and single center clinical epidemiological investigation. Furthermore, the main toxic constituents and mechanism of TWF are reviewed. Finally, the key issues have been raised and analyzed on clinical diagnosis, clinical characteristics and toxicological mechanism of liver injury of TWF, and brought forward the future research directions.
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In this study, rats were used to evaluate the effect of Radix glycyrrhiza on reducing liver toxicity of Tripterygium wilfordii. Metabonomics techniques were used to analyze the changes of small molecular metabolites and the metabolic pathways involved in the beneficial process. Different groups of rats were given for the extractions from Tripterygium wilfordii and Tripterygium wilfordii together with Radix glycyrrhiza. The general state, pathological changes of liver tissue, biochemical indexes of liver function and the changes of inflammatory factors in rats were observed. The results showed that the liver tissue injury of Tripterygium wilfordii group was significant, and the injury was reduced by Radix glycyrrhiza. Biochemical indexes and inflammatory factors also suggested that Tripterygium wilfordii together with Radix glycyrrhizaeffectively decreased the liver toxicity. HPLC-MS/MS-IT-TOF was used to characterize the difference of serum metabolism in rats. Multivariate statistical analysis was used to screen 15 potential biomarkers, such as fatty acid, glycerol ester, glycerol phosphate, phosphatidylethanolamine and phosphatidylcholine. It mainly involved in 7 metabolic pathways, such as glycerol phospholipid metabolism, linoleic acid metabolism, alpha linoleic acid metabolism, and glycosyl phosphatidylinositol terminal biosynthesis. The results showed that the Tripterygium wilfordii compatibility of Radix glycyrrhizaeffectively decreased the liver toxicity induced by Tripterygium wilfordii. Phospholipid metabolism may be the key metabolic pathway of Tripterygium wilfordii hepatotoxicity and the target of Radix glycyrrhiza. This study provides a reference for the control of liver toxicity of Tripterygium wilfordii.
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Objective:To investigate the proliferation of rat glomerular mesangial cells (GMC) influenced by different ethanol extracts of Tripterygium wilfordii HooK F.(TWHF).Methods:An HPLC method was used to establish the fingerprints of 5 different ethanol extracts of TWHF,and GMC was chosen to study the effects of different ethanol extracts of TWHF on cell proliferation.After statistical analysis,the spectrum-activity relationship was analyzed by using partial least squares regression(PLSR).Results:The HPLC fingerprints of the 5 different ethanol extracts of TWHF were established,and 32 characteristic peaks were characterized by the HPLC fingerprints.60%,70% and 95% ethanol extracts and glycosides tablets showed dose-effect relationship,and with the increase of dose,the more significant inhibition of cell proliferation was exhibited.The absorbance values of the 60% ethanol extracts at medium and high doses were lower than those of the other extracts at the same dose.The proliferation inhibition rate of GMC was used as the potency index and analyzed by PLSR,and 20 peaks were potency peaks at high dose(40 μg·L-1),17 ones were potency peaks at medium dose(20 μg·L-1) and 15 ones were potency peaks at low dose(10 μg·L-1).Conclusion:Part of the potency peaks has regular dose-effect relationship with the changes of dose.
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Objective: To clone the full-length cDNA of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase in Tripterygium wilfordii (TwPTEN) and predicted its biological functions. Methods: The specific primers were designed based on the transcriptome data of Tripterygium wilfordii, TwPTEN gene was cloned by Polymerase Chain Reaction. The full-length cDNA of TwPTEN was then analyzed by a series of bioinformatics analysis. Results: It was showed that the full length of TwPTEN cDNA was 2 247 bp encoding 614 amino acids. The theoretical isoelectric point was 5.84 and the molecular weight was about 66 900. Sequence alignment and phylogenetic analysis demonstrated that TwPTEN had relative close relationship to PTEN from other species. Differential expression analysis revealed that the relative expression level of TwPTEN increased significantly after being induced by methyl jasmonate (MeJA). It indicated that the TwPTEN gene was relative to the biosynthesis of secondary metabolites. Conclusion: PTEN gene is firstly cloned from T. wilfordii, which provides a basis for further studying the functions of TwPTEN.
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Objective To investigate the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) combined with renin-angiotensin system (RAS) blockers in chronic kidney disease (CKD) stages 2~3 of IgA nephropathy. Methods 109 patients were randomized into the observation group and the control group. On the basis of taking RAS blockers, patients in the observation group received TwHF, and patients in the control group received methylprednisolone. The proteinuria, renal function and adverse effect were observed during treatment. Results At 3, 6, 9 and 12 months of treatment, proteinuria in the two groups was lower than the baseline(P 0.05). Besides, there was no significant difference in terms of proteinuria, eGFR and effective rate in the two groups. The occurrence rate of adverse effects was 9.8% vs 27.4% and there was significant difference in the two groups (P < 0.05). Conclusions TwHF combined with RAS blockers can decrease proteinuria, protect renal function and have less adverse effects, and it is a useful therapeutic options for CKD stages 2 ~ 3 of IgAN.
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Objective To observe the effect ofTripterygium Wilfordii Hook. F. andTripterygium Hypoglaucum (Lévl.) Hutch on macrophage inflammatory factor, and to provide the oretical basis and experimental basis for the clinical application of these drugs.Methods Two batches ofTripterygium Wilfordii Hook. F. andTripterygium Hypoglaucum (Lévl.) Hutch were collected, and then the samples turned into alcohol extract by extraction and isolation. The IC50values of alcohol extracts were measured by MTT in BMDM cell. BMDM cell induced by the 4 batches of samples with IC50, then IL-6, IL-10, iNOS were detected by Elisa. Results The content of IL-6 (5.08 ± 0.96 pg/ml, 6.24 ± 0.20 pg/mlvs. 7.92 ± 0.84 pg/ml) and iNOS (0.14 ± 0.04 ng/ml, 0.36 ± 0.11 ng/mlvs. 0.86 ± 0.13 ng/ml) in Anhui and Guizhou groups were significantly lower than sulfasalazine (P<0.05), and the content of IL-10 (21.20 ± 4.24 pg/ml, 26.49 ± 4.44 pg/mlvs. 9.06 ± 0.40 pg/ml) in Anhui and Guizhou groups were significantly higher than sulfasalazine (P<0.05). The content of IL-6 (4.22 ± 0.38 pg/ml, 4.55 ± 0.44 pg/mlvs. 7.92 ± 0.84 pg/ml) and iNOS (0.07 ± 0.04 ng/ml, 0.28 ± 0.10 ng/mlvs. 0.86 ± 0.13 ng/ml) in Hunan and Zhejiang groups were significantly lower than sulfasalazine (P<0.05) .Conclusion The anti-inflammatory effect ofTripterygium WilfordiiHook. F. treat rheumatoid arthritis is better than sulfasalazine andTripterygium Hypoglaucum (Lévl.) Hutch.
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Objective Sirolimus ( SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after re-nal transplantation.Nevertheless, the occurrence of proteinuria has recently been recognized among patients treated with SRL-based therapy.The aim of this study was to investigate the therapeutic effect of tripterygium wilfordii hook F ( T II) on proteinuria caused by SRL in renal transplant recipients who were treated by trilogy immunosuppressive therapy of sirolimus combined with mycophenolate and hormone. Methods 52 recipients were divided into 2 groups randomly:TⅡgroup (n=27) and valsartan group (n=25).The TⅡgroup was administered 1 mg/kg/d, and the valsartan group 80-160 mg/d for consecutive 12 months.Based on primary trilogy immu-nosuppressive therapy of sirolimus combined with mycophenolate and hormone, the dosage of sirolimus was adjusted according to the target concentration 6-10 ng/ml( ELASA approach) and mycophenolate was administered 750 mg twice per day, adjusting dosage ac-cording to the mycophenolate AUC 0-12 level(35-45 mg· h/L).The evaluation of therapeutic effect includes: complete remission, proteinuria decreased by>50%; partial remission, proteinuria decreased by 20% to 50%; ineffective, proteinuria decreased by<20%. Results During the 12 month follow-up, the total effective rates in the TⅡgroup and the valsartan group were 95.2%and 86.7%respectively, in which the TⅡ group decreased more significantly (P<0.01).The total cholesterol level and triglyceride level in TⅡgroup were obviously lower than those in valsartan group(P<0.01). The total cholesterol level and triglyceride level in valsartan group increased ([6.60±0.2]mmol/L vs [7.11±1.13]mmol/L, [2.47± 1.48]mmol/L vs [2.49±0.32] mmol/L).The serum protein level in TⅡ group was obviously higher than that in valsartan group ([41.1±1.2]g/L vs [37.9±4.2]g/L, P<0.05).At 3 month, 6 month and 12 month follow-up, the average serum creatinine levels in TⅡgroup were obviously lower than those in valsartan group ([1.5±0.4]mg/dl vs [1.6±0.3]mg/dl, P<0.05), ([1.3±0.3]mg/dl vs [1.8±0.5]mg/dl, P<0.05), ([1.1±0.4]mg/dl vs [2.1±0.5]mg/dl, P<0.05).The incidence rate of adverse reaction in valsartan group was obviously greater compared with TⅡgroup( P<0.05) . Conclusion Both tripterygium wilfordii multiglycosides and valsar-tan can reduce proteinuria caused by SRL in renal transplant patients,while the application of TⅡhas more remarkable effect.
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Objective: To establish a method suitable to the quality evaluation of the roots in Tripterygium wilfordii based on hepatotoxic potency. Methods: The inhibitory rates of T. wilfordii and its regional substitute-T. hypoglaucum, with normal human hepatocytes (L02 cell line) as carrier, were established by optimizing a series of factors, such as test samples prepared with conditions. Results: Taking p-acetaminophenol as positive control (toxic potency was 400 U/g), The 50% ethanol extract of T. wilfordii was dried under ultrasonic vacuum to obtaine the dry paste. The test solution with crude drug of 3 mg/mL was prepared by medium. The dilution ratio was 1:0.65. The hepatotoxic potencies of 18 batches of T. wilfordii and 5 batches of T. hypoglaucum were 17.78-4131.4 and 209.42-7422.2 U/g, respectively, detected by the reaction parallel line method, and the differences were over 200 and 30 times. There was the significant hepatotoxic potency of T. wilfordii and T. hypoglaucum from the various origins. In addition, the fresh collected samples had the larger hepatotoxic potency than that in the dried samples collected in the market. Conclusion: The preliminarily established hepatotoxic potency bioassay is useful to evaluate the quality of T. wilfordii which directs the correlation with the drug's hepatotoxic adverse effect in clinic. The method can provide the reference for the clinical safety use of T. wilfordii based on the quality control and be as the quantitative method used to screen the toxic components from T. wilfordii.
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Objective: To investigate the immunosuppressive components in Leigongteng Duogan Tablet (LDT). Methods: High performance liquid chromatography (HPLC) was applied to establish the fingerprint for LDT from seven manufactures. The immunosuppressive effect of LDT was observed on Con A-induced mice spleen cells, and the cell proliferation and contents of IFN-γ were recorded. Then the partial least squares regression (PLSR) analysis was used to investigate its spectrum-effect relationship. Results: The HPLC fingerprint for LDT from seven manufactures was established, and 18 characteristic peaks were confirmed. The in vitro cell experimental results showed that the proliferation of mice spleen cells and secretion of IFN-γ were inhibited by all LDT significantly compared with the control group. According to the results of PLSR, No. 1, 2, 6, 7, 17, and 18 peaks were strongly related to the proliferation inhibition of mice spleen cells and No. 1, 2, 6, 7, 8, 9, 12, and 13 peaks were related to the secretion of IFN-γ. Conclusion: The No. 1, 2, 6, 7, 8, 9, 12, 13, 17, and 18 peaks are the principal immunosuppressive substances in LDT.
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Objective: To prepare the ethosomes-based gel of demethylzeylasteral (DMZ) and to investigate its properties and transdermal absorption behavior. Methods: The infusion method was used to prepare DMZ ethosomes. The particle size, entrapment efficiency (EE), analysis methodology, and in vitro release behavior were examined, respectively. The in vitro transdermal absorption of ethosomes-based gel of DMZ was evaluated by Franz diffusion cells. Results: The DMZ ethosomes was yellowish emulsion. The average particle size of the ethosomes was (365.2 ± 14.4) nm and the EE was (72.30 ± 2.31)%. The cumulative permeation curve of DMZ in ethosomes-based gel was consistent with Higuchi equation (Q=80.198 t1/2-71.641, r=0.986 8). Compared with common gel, the ethosomes-based gel had 3.94 times higher cumulative permeation amount in 24 h. Conclusion: The prepared ethosomes- based gel of DMZ could enhance the transdermal permeation, which provides evidence for the development of transdermal drug delivery system of DMZ.
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To summarize advances in the toxicity and attenuation method of Tripterygium preparatum. METHODS: The progresses of studies in the toxicity mechanisms and attenuation method of Tripterygium preparatum based on referring to the related literature in recent years were summarized. RESULTS: Tripterygium preparatum has toxic effects in many tissues and systems. Such as hepatotoxicity, nephrotoxicity, cardiotoxic, genital system toxic, and the researches and expolrations of the attenuation method have achieved certain resulsts in dosage, direction, compatibility, processing, etc. CONCLUSION: But how to apply the resulsts of these studies to reduce the toxicity in Tripterygium preparatum requires more explorations. In the aspect of attenuation and preparatum, the therapeutic index and purification processes need to further improve.