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    Autophagy in Triptolide-Mediated Cytotoxicity in Hepatic Cells. Wei Yan Ming,Luan Zhi Hua,Liu Bi Wang,Wang Yong Hui,Chang Yin Xia,Xue Hui Qing,Ren Jin Hong International journal of toxicology Triptolide is a major active ingredient isolated from the traditional Chinese herb Hook F. However, its use in clinical practice is limited due to its severe hepatotoxicity. Autophagy, a highly conserved intracellular process, is essential for maintaining cytoplasmic homeostasis. Considering that abnormalities in autophagy are closely associated with drug-mediated hepatotoxicity, we applied human normal liver HL7702 cells to elucidate the roles of autophagy in triptolide-induced hepatotoxicity. Our study revealed that triptolide was cytotoxic to HL7702 cells. It markedly increased autophagosome formation and expression of autophagy-related proteins, namely Beclin1 and microtubule-associated protein 1 light chain 3II, and induced oxidative stress. These proautophagic effects were counteracted by pretreatment with N-acetylcysteine, a reactive oxygen species scavenger. Moreover, the pharmacological suppression of autophagy further exacerbated triptolide-elicited decrease in cell viability, increase in lactate dehydrogenase leakage, and activation of apoptosis proteases (caspase 3 and caspase 9). Our findings suggest that triptolide-induced oxidative stress consequently enhances autophagic activity, and autophagy is a cytoprotective mechanism against triptolide-induced cytotoxicity in HL7702 cells. 10.1177/1091581819864518
    Triptolide induces toxicity in inner ear stem cells via promoting DNA damage. Tang Xuxia,Wang Congpin,Hsieh Yuelin,Wang Chengjin,Wang Jinyu,Han Zhao,Cong Ning,Ma Rui,Chi Fanglu Toxicology in vitro : an international journal published in association with BIBRA Emerging evidence and clinical case reports have observed a risk of cytotoxic effects of triptolide in patients. We aimed to investigate the triptolide-induced toxicity in mouse inner ear stem cells. The utricular sensory epithelium from adult BALB/C6 mice was used for the isolation of inner ear stem cells. Sphere formation assay was applied to examine the stemness of the cells. Cell count kit-8 and Bromodeoxyuridine assays were employed to detect the cell proliferation ability. Cell apoptosis was measured with Annexin V-FITC & propidium iodide Apoptosis kit. The relative expression levels of gamma H2A histone family member X (γH2AX), tumor suppressor p53-binding protein 1 (53BP1) and optic atrophy 1 (OPA-1) were measured by Western Blot. Mitochondrial function was analyzed by the MitoGreen green-fluorescent mitochondrial dye kit. Triptolide significantly inhibited the cell viability and proliferation and suppressed the capability of sphere formation. Furthermore, triptolide induced apoptosis as indicated by increased expression of DNA damage repair markers γH2AX and 53BP1. Moreover, triptolide influenced the function of mitochondria by inducing the cleavage of OPA-1. Our work clarifies the toxicity of triptolide in mouse inner ear stem cells, which provides clues of the toxicology mechanism for future studies and basis for clinical use. 10.1016/j.tiv.2019.104597
    [Study advances in regulation effect of Tripterygium wilfordii and its extracts on innate immune system in rheumatoid arthritis cases]. Li Jian-Ming,Jiang Quan,Tang Xiao-Po,Yang Hui,Zhou Zhi-Qiang Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Rheumatoid arthritis( RA) is an autoimmune disease characterized by chronic and aggressive polyarthritis. The innate immunity mechanism plays a key role in the pathogenesis of RA. Tripterygium wilfordii and its extracts have regulatory effects on innate immune cells including macrophages,dendritic cells,neutrophils,mast cells,NK cells,NKT cells,etc.,as well as a variety of innate immune molecules including cytokines,adhesion molecules,patterns recognition receptor( PRR) and the complement molecules,showing a regulatory effect in the pathogenesis of RA innate immunity. In this paper,the recent domestic and foreign researches on the pathogenesis of RA with innate immunity involved were reviewed and the research status of T. wilfordii and its extracts on the regulation of innate immunity involved in RA was summarized. 10.19540/j.cnki.cjcmm.20190103.001
    [Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pharmacology]. Dong Yi-Zhu,Zhang Bing,Lin Zhi-Jian,Zhang Xiao-Meng Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity. 10.19540/j.cnki.cjcmm.20181119.001
    Efficacy and safety of Tripterygium wilfordii Hook. f. for oral lichen planus: Evidence from 18 randomized controlled trials. Luo Yue,Kuai Le,Chen Jia,Sun Xiaoying,Liu Liu,Luo Ying,Ru Yi,Xing Meng,Ding Xiaojie,Zhou Mi,Li Bin,Li Xin Phytotherapy research : PTR Glycosides from the roots of Tripterygium wilfordii Hook. f. are used for the treatment of oral lichen planus (OLP), a chronic inflammatory disease affecting the oral mucosa. To investigate the effectiveness and safety of Tripterygium glycosides (TGs) for OLP treatment, we conducted a systematic review of 18 randomized controlled trials, comprising 1,339 participants, from international and Chinese databases. We evaluated outcomes of TGs alone or in combination with conventional treatments. In combination with topical glucocorticoids (TGCs), including triamcinolone acetonide and prednisone, the total effectiveness rate (risk ratio [RR], 1.17; 95% confidence interval [CI], 1.09-1.25; p < .00001), symptom score reducing index (mean difference [MD], -2.44; 95% CI, -3.12 to -1.77; p < .0001), and visual analog scale score (MD, -1.61; 95% CI, -2.22 to -1.00; p < .0001) were significantly improved. Patients treated with TGs combined with TGCs experienced lower recurrence rates (RR, 0.37; 95% CI, 0.18-0.76; p = 0.007). The occurrence of adverse events was not significantly different between the TGs groups and controls. The combination of TG and TGCs improved clinical efficacy and reduced recurrence without increasing the risk of adverse events. A high-quality multicenter clinical study is needed to corroborate these findings. 10.1002/ptr.6672
    [Overview of hepatotoxicity studies on Tripterygium wilfordii in recent 20 years]. Tian Ya-Ge,Su Xiao-Hui,Liu Li-Ling,Kong Xiang-Ying,Lin Na Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Tripterygium wilfordii is widely used in the treatment of rheumatism with curative effect. However,its toxicity and adverse reactions,especially the hepatotoxicity,rank the first in the herbs induced liver injury,is the key factors hindering its clinical application. This paper reviewed the literatures related to the hepatotoxicity of T. wilfordii in recent 20 years,and summarized the characteristic of hepatotoxicity induced by T. wilfordii,the factors causing liver injury,the mechanism of toxicity,and the measures to reduce toxicity. In animal experiments,the T. wilfordii induced-hepatotoxicity in physiological state was more serious than pathological state. The T. wilfordii induced-hepatotoxicity is related to various toxic components contained in it,but alkaloids are the most toxic one.Overdose and cumulative overdose are the lead causing of hepatotoxicity induced by T. wilfordii. The theory of oxidative stress is still an important mechanism of T. wilfordii induced-hepatotoxicity,and Nrf2,as a key regulatory enzyme of oxidative stress,has become an important target for drugs to against T. wilfordii induced-hepatotoxicity. Mitochondrial autophagy and liver hypersensitivity are new mechanisms of liver injury induced by T. wilfordii. The measures such as dosage control,drug compatibility and dosage form variations can help to reduce the hepatotoxicity induced by T. wilfordii. This paper clarified the current situation and shortcomings of safety research on T. wilfordii,so as to propose new research strategies and provide ideas for rational evaluation of safety and clinical safe drug use of T. wilfordii. 10.19540/j.cnki.cjcmm.20190527.408
    Efficacy and safety of Tripterygium wilfordii hook F for chronic urticaria: a systematic review and meta-analysis. Liu Liu,Zhao Huaibo,Sun Xiaoying,Zheng Qi,Luo Ying,Ru Yi,Zhang Ying,Chen Xi,Zhu Bo,Yin Chengqian,Li Bin,Li Xin BMC complementary and alternative medicine BACKGROUND:The first-line agents comprising antihistamines for chronic urticaria, are not completely satisfactory. Tripterygium wilfordii Hook F (TwHF), a Chinese herb, has been developed into several Tripterygium agents and have definite effects on autoimmune and inflammatory diseases. In chronic urticaria, however, their values of practical application remain unclear. The aim of this study was to investigate the efficacy and safety of TwHF in patients with chronic urticaria. METHODS:Several databases were systematically searched including PubMed, Embase, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure, Chinese Scientific Journals Database, Wan Fang Database, and Chinese Biomedicine. Randomized controlled trials comparing antihistamines with TwHF or Tripterygium agents in combination with antihistamines were included. Revman5.3 was utilized to calculate risk ratios (RR) with 95% confidence intervals (CI). This study was registered with PROSPERO, number CRD42018091595. RESULTS:Twenty-one trials with 2565 participants were included in this analysis. Meta-analysis showed that, when antihistamines were combined with TwHF and Tripterygium agents, the curative effect in cases of chronic urticaria was superior to that of antihistamines alone (RR: 1.40; 95% CI: 1.33-1.46). The incidence rates of gastrointestinal disorder (RR: 2.91; 95% CI: 1.70-4.99) and menstrual disorder (RR: 6.00; 95% CI: 1.79-20.13) in drug combination groups were higher than those in controls, while other adverse events were similar between the two groups. After treatment, Dermatology Life Quality Index (RR: 1.23; 95% CI: 1.09-1.40), quality of sleep (RR: 1.50; 95% CI: 1.07-2.12), and daily activity (RR: 1.49; 95% CI: 1.25-1.78) were all improved. Furthermore, drug combination groups demonstrated less relapse (RR: 0.34; 95% CI: 0.25-0.45). CONCLUSIONS:TwHF and Tripterygium agents, in combination with antihistamines, appear to be more effective than antihistamines alone. Nevertheless, adverse events cannot be ignored. Large sample, multi-center, high-quality clinical studies are needed to verify the exact effects and safety of TwHF and Tripterygium agents in treatment of chronic urticaria. 10.1186/s12906-018-2305-7
    Overexpression and RNAi-mediated downregulation of TwIDI regulates triptolide and celastrol accumulation in Tripterygium wilfordii. Wang Jiadian,Zhao Yujun,Zhang Yifeng,Su Ping,Hu Tianyuan,Lu Yun,Zhang Rui,Zhou Jiawei,Ma Baowei,Gao Wei,Huang Luqi Gene The aim of this study was to verify the effects of TwIDI (GenBank: KT279355.1) on triptolide and celastrol accumulation in the biosynthesis of terpenoids in Tripterygium wilfordii and the regulation of the expression of related genes in the triptolide and celastrol biosynthesis pathway. After bioinformatics analysis of TwIDI, we cloned the full-length CDS and a specific 398 bp fragment to construct overexpression and RNAi vectors, respectively. The specific amplification of hygromycin and kanamycin resistance gene fragments confirmed that the expression vectors had been successfully delivered into Tripterygium wilfordii suspension cells. qRT-PCR was used to detect the expression of TwIDI and related genes in the triptolide and celastrol biosynthesis pathway. The expression of TwIDI was increased to 157% of the control group (empty vector) in the overexpression group, and was reduced to 71% of the control group in the RNAi group. Notably, the expression of other genes in the triptolide and celastrol biosynthesis pathway also showed differences. For example, TwMCS was reduced to 62% of the control when TwIDI was overexpressed and increased to 188% in the RNAi group. The expression of TwDXS did not change significantly both during TwIDI overexpression and RNAi group. The accumulation of triptolide and celastrol in the suspension cells of Tripterygium wilfordii was detected by UPLC, revealing that the contents of triptolide and celastrol were increased 1.36- and 1.20-fold over the control group in the overexpression group, and decreased to 0.16 and 0.36 of the control group in the RNAi group. Based on these findings, the effect on the accumulation of active terpenoids in Tripterygium wilfordii and the feedback regulation of genes in the triptolide and celastrol biosynthesis pathway was verified through TwIDI overexpression and RNAi experiments. 10.1016/j.gene.2018.08.072
    [Research progress on chemical constituents and quality control of Tripterygium wilfordii preparations]. Wang Ya-Dan,Wang Qi,Zhang Jian-Bao,Dai Zhong,Lin Na,Wu Xian-Fu,Ma Shuang-Cheng Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Tripterygium wilfordii preparations,with various biological activities such as immunosuppressive,anti-inflammatory and anti-cancer effects,are widely used in the treatment of autoimmune diseases such as rheumatoid arthritis,lupus erythematosus,and nephrotic syndrome. They have definite therapeutic effect,but often cause serious adverse reactions and result in damages to liver,kidney,blood,reproduction,and other systems due to their complex compositions,great toxicity,and narrow margin between the toxic and therapeutic dosages. At present,T. wilfordii preparations produced by different manufacturers exhibit large variations in clinical efficacy and side effects in account of their different chemical compositions and quality fluctuation due to differences in raw materials and production process. However,the existing quality standards are controversial in terms of index components and content limit,which cannot be effectively used for the overall quality control of the preparations. In this paper,the research progress on chemical constituents,quality standard and quality control methods of four T. wilfordii preparations including Tripterygium Tablets,Tripterygium Zongtie Tablets,Tripterygium Shuangceng Tablets and Tripterygium Glycosides Tablets was reviewed,in order to provide ideas and reference for the quality improvement of this type of preparations. 10.19540/j.cnki.cjcmm.20190606.501
    [Comparative study on dose-toxicity-effect of Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets on CIA model rats]. Liu Li-Ling,Tian Ya-Ge,Su Xiao-Hui,Fan Yuan-Fang,Li Chun,Zhu Xuan-Xuan,Cao Wei,Liu Ting,Wang Hai-Lin,Xu Ying,Kong Xiang-Ying,Lin Na Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica The aim of this paper was to compare the properties of Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets from dose-effect-toxicity on type Ⅱ collagen-induced arthritis( CIA) in rats. SD rats were randomly divided into eight groups,including normal group,model group,Tripterygium Glycosides Tablets groups( 1 times equivalent dose 0.009 g·kg-1,4 times equivalent dose 0.036 g·kg-1,16 times equivalent dose 0.144 g·kg-1),Tripterygium wilfordii Tablets groups( 1 times equivalent dose 0.007 5 mg·kg-1,4 times equivalent dose 0.030 mg·kg-1,16 times equivalent dose 0.120 mg·kg-1). Beginning on the first immunization,Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets administered intraperitoneally once a day. After the second immunization,the symptoms such as redness and swelling of joints were observed,and the clinical score and incidence of arthritis were evaluated. HE and Masson staining were used to examine the histopathological changes of joints. The expression level of anti-type Ⅱ collagen antibody Ig G in serum was detected by ELISA,routine testing of blood components,the concentration of ALP( alkaline phosphatase),ALT( alanine aminotransferase),AST( aspartate aminotransferase),GGT( gamma-glutamyltransferase),TBi L( total bilirubin),CRE( creatinine) and UREA( urea) in serum were detected by enzymatic assay. The rate of sperm deformity in the epididymis was evaluated under light microscope. The extent of damage to the testis and ovarian tissue was assessed by HE staining. Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets attenuated the inflammation,redness,swelling and deformity of joints and reduced the clinical score and incidence of arthritis in CIA rats. Meanwhile,it also exhibited obvious reduction in all pathological features such as joint synovitis,pannus,cartilage erosion and bone destruction. Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets reduced Ig G in a dose-dependent manner,and Tripterygium Glycosides Tablets is better than Tripterygium wilfordii Tablets( P<0.05 or P<0.01). The high doses of Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets could significantly increase the organ coefficient of liver and spleen and reduced RBC and HGB in CIA rats( P<0.01),and severity leading to death. Gastric mucosal injury and morphological changes of liver and kidney were not observed in CIA rats of Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets treatment group. The 4 and 16 times doses of Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets could significantly increase serum ALT,GGT and decrease CRE( P<0.05 or P<0.01). Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets could increase the sperm deformity rate and damage the testicular seminiferous tubules of CIA male rats. Severity increased with dose and time increasing. The effect of Tripterygium Glycosides Tablets( 16 times) is more significant than Tripterygium wilfordii Tablets( 16 times). Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets significantly delayed onset of arthritis and inhibited the paw edema and arthritic score. Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets also caused male reproductive damage,high dose affected hematopoiesis,and maximum dose leading to death. Tripterygium Glycosides Tablets and Tripterygium wilfordii Tablets all depended on dose-effect-toxicity manner. Anti-arthritis effect of Tripterygium Glycosides Tablets is better than Tripterygium wilfordii Tablets,but the toxicity of Tripterygium Glycosides Tablets maximum dose is more obvious. The relevant conclusions of our study will provide experimental references for clinical rational use of drugs,and further clinical studies are needed to confirm our conclusions. 10.19540/j.cnki.cjcmm.20190703.401
    Tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy: A protocol for a systematic review and meta-analysis. Jin Yuxia,Zhang Jiayuan,Wang Yunxia,Xiao Xiao,Zhang Qi Medicine AIM:The aim of this review is to assess the efficacy and safety of tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy. BACKGROUND:Tripterygium wilfordii multiglycosides, a Chinese patent medicine, is widely in-depth research in China, and is proved to have anti-inflammatory and immunosuppressive effect. It has been extensively used in China for the treatment of autoimmune diseases, such as idiopathic membranous nephropathy (IMN). However, there has no relevant systematic review studied on its effects and safety been reported. We plan to perform a systematically reviewing to assess the efficacy and safety of tripterygium wilfordii multiglycosides combined with hormones in the treatment of IMN. METHODS:Seven electronic databases will be searched to identify eligible trials. Randomized controlled trials (RCTs) that compared tripterygium wilfordii multiglycosides combined with prednisone versus standard therapy are included. Methodological quality is assessed using the Cochrane Collaboration Risk of Bias tool. A random- or fixed-effect model is used to analyze outcomes that are expressed as risk ratios (RRs) or mean differences (MD), and the I statistic is used to assess heterogeneity. RESULTS:A high-quality synthesis of current evidence of tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy will be provided in this study. CONCLUSION:This systematic review will provide evidence of whether tripterygium wilfordii multiglycosides is an effective intervention for idiopathic membranous nephropathy.PROSPERO registration number: No.CRD42018118179. 10.1097/MD.0000000000018970
    [Editorial explanation for Clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in treatment of rheumatoid arthritis]. Na Lin,Quan Jiang,Wei Liu,Jian Liu,Qing-Chun Huang,Kuan-Yu W U,Sheng-Hao T U,Zu-Shan Zhou,Wei-Heng Chen,Xiao-Xia L I,Yan-Qiong Zhang,Tai-Xian L I Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Clinical practice guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the treatment of rheumatoid arthritis(T/CACM 1337-2020) was approved on June, 2020 by the Standardization Office of Chinese Association of Chinese Medicine. Our group developed this guideline for the clinical application of Tripterygium Glycosides/Tripterygium wilfordii Tablets according to the manual for the clinical experts consensus of Chinese patent medicine from January, 2018, when this project was approved by Chinese Association of Chinese Medicine. In this article, the detailed information on our compilation process was provided, in order to facilitate the understanding and the application of the guideline, as well as provide reference for the development of clinical practice guideline for other Chinese patent medicine. 10.19540/j.cnki.cjcmm.20200709.405