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Tripterygium glycosides (TG) is extracted from the roots of Chinese herbal medicine named Tripterygium wilfordii Hook F (TwHF). TG tablets are the representative TwHF-based agents with anti-inflammatory and immunomodulatory activities for treating rheumatoid arthritis. Although the curative effect of TG is remarkable, the clinical application is limited by a variety of organ toxicity. One of the most serious side-effects induced by TG is damage of the male reproductive system and the toxic mechanism is still not fully elucidated. TG-induced testicular injury was observed in male mice by treated with different concentrations of TG. The results showed that TG induced a significant decrease in testicular index. Pathological observation showed that spermatogenic cells were obviously shed, arranged loosely, and the spermatogenic epithelium was thin compared with control mice. In addition, the toxic effect of TG on mouse spermatogonia GC-1 cells was investigated. The results displayed that TG induced significant cytotoxicity in mouse GC-1 cells. To explore the potential toxic components that triggered testicular injury, the effects of 8 main components of TG on the viability of GC-1 cells were detected. The results showed that celastrol was the most toxic component of TG to GC-1 cells. Western blot analysis showed that LC3-II and the ratio of LC3-II/LC3-I were significantly increased and the expression level of p62 were decreased in both TG and celastrol treated cells, which indicated the significant activation of autophagy in spermatogonia cells. Therefore, autophagy plays an important role in the testicular injury induced by TG, and inhibition of autophagy is expected to reduce the testicular toxicity of TG., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Tripterygium wilfordii Hook. f. (TW) is widely used to treat autoimmune and inflammatory diseases; however, its development and application is limited by its significant association with liver injury. The compound formula Qingluotongbi (QLT) employs TW as its main component and is used to treat rheumatoid arthritis with no adverse reactions, suggesting that QLT may reduce the liver toxicity of TW., Aim of the Study: We examined whether TW interferes with lipid metabolism to induce liver injury, and evaluated the protective effect of QLT in in vivo and in vitro experiments., Materials and Methods: After administration of QLT and its ingredients, HepaRG cells and SD rats were tested for biochemical indicators, hepatocytes lipid changes, and rat liver pathological changes, and then we analyzed for the gene expression of liver X receptor α (LXRα), endoplasmic reticulum stress (ERS) key proteins, sterol regulatory element binding protein-1c (SREBP-1c), and lipid-synthesizing enzymes. In HepaRG cells, the protein expression of glucose-regulated protein 78 kDa (GRP78) and LXRα was detected after addition of an LXRα inhibitor, LXRα agonist, and ERS inhibitor., Results: TW caused significant elevation of biochemical indicators and lipid droplet deposition in hepatocytes, as well as upregulated the gene expression of LXRα, ERS key proteins, SREBP-1c, and lipid-synthesizing enzymes in both in vitro and in vivo settings, and caused liver injury in rats. QLT can alleviate the lipotoxic liver injury caused by TW. LXRα agonist further activated ERS induced by TW, whereas LXRα inhibitor significantly reduced ERS and lipotoxic injury induced by TW in HepaRG cells., Conclusions: TW upregulated LXRα to activate ERS and increased the gene expression of SREBP-1c and lipid-synthesizing enzymes, leading to increased lipid synthesis in hepatocytes to result in liver injury. QLT inhibited the LXRα-ERS-SREBP-1c pathway and reduced abnormal lipid synthesis in hepatocytes and the hepatotoxicity of TW., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abstract: To explore the possible molecular mechanism of reproductive toxicity of Tripterygium wilfordii from the perspective of network pharmacology and bioinformatics.The compounds of T wilfordii were obtained by querying the relevant Chinese medicine database, the effective compounds were screened and the corresponding targets were obtained, and then compared with the reproductive toxicities related to disease targets obtained from the disease gene database to infer the potential toxic targets of reproductive toxicity of T wilfordii. Then, the key targets of reproductive toxicity of T wilfordii were screened using Search Tool for the Retrieval of Interacting Genes/Protein and Cytoscape. The gene ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as module analysis, were performed on the key targets using Database for Annotation, Visualization, and Integrated Discovery and Cytoscape, respectively. Finally, the network between effective compounds-toxic targets was conducted to see how the compounds interacted.A total of 48 effective compounds and 482 potential toxic targets related to the reproductive toxicity of T wilfordii were screened. The enrichment analysis results showed that the key targets were mainly enriched in biological processes such as response to drug, ionotropic glutamate receptor signaling pathway, and KEGG pathways such as neuroactive ligand-receptor interaction, cAMP signaling pathway. In the protein-protein interaction network of potential toxic targets, there were 78 key targets such as TP53, INS, IL6, AGT, ADCY3, and so on. Enrichment analysis of the top module with 19 genes from module analysis indicated that T wilfordii might cause reproductive toxicity by gene ontology terms and KEGG pathways such as regulation of vasoconstriction, G-protein coupled receptor signaling pathway, inflammatory response, cAMP signaling pathway, and so on. In the network between effective compounds of T wilfordii and key targets, there were 5 compounds with high degree including Tingenone, Wilfordic Acid, Abruslactone A, Nobilin, and Wilforlide B.The complex molecular mechanism of reproductive toxicity of T wilfordii can be preliminarily elucidated with the help of the network pharmacology method, and the analysis results can provide some reference for the further mechanism research of reproductive toxicity of T wilfordii., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: Cuscuta chinensis Lam. and Lycium barbarum L. (SC-FL) is a commonly used kidney tonic Chinese medicine combination that is widely used in the clinical treatment of oligoasthenospermia.However, its specific mechanism remains unclear and requires in-depth study., Aim of the Study: To explore the potential targets of SC-FL in the treatment of oligoasthenospermia using network pharmacology, and to verify the results with in vivo and in vitro experiments., Materials and Methods: A herb-compound-target-disease network and PPI network were constructed with Cytoscape software. The targets of SC-FL for the treatment of male sterility were introduced into a bioinformatics annotation database, and the GO and KEGG databases were used for pathway enrichment analysis. Subsequently, Tripterygium wilfordii Hook. f. (GTW) polyglycoside was used to induce a spermatogenic dysfunction model in GC-1 spg cells and SD male rats in in vitro and in vivo experiments, respectively. The SC-FL and PI3K pathway inhibitor LY294002 was used to intervene in the spermatogenic dysfunction model to detect the expression of proteins and mRNA related to the PI3K pathway and to detect the indicators related to proliferation and apoptosis., Results: In in vitro experiments, the percentage of spermatogenic cells and the proportion of GC-1 spg cells at G0/G1 and G2/M stages in the model group (GTW group) and the inhibitor group (LY group) were significantly decreased (P < 0.01) compared with the blank control group (NC group). The apoptosis rate of the GTW group was significantly increased (P < 0.01). The ultrastructures of GC-1 spg cells in the GTW group and LY group were obviously destroyed. Compared with the GTW group, the SC-FL group had a significantly reduced apoptosis rate of GC-1 spg cells, reduced percentage of cells in S phase, and a significantly improved mitochondrial membrane potential. SC-FL can repair the ultrastructure of GC-1 spg cells damaged by GTW. The above effects of SC-FL are closely related to up-regulation of GFRa1, RET, PI3K, p-AKT, and Bcl-2 and down-regulation of BAD and BAX proteins and mRNA expression. In vivo, compared with the GTW group, the body mass, testicular mass, and epididymal weight of the GTW + SC-FL group were significantly increased (P < 0.01). Sperm concentrations and the PR + NP of GTW + SC-FL were significantly higher than in the GTW group (P < 0.01 or P < 0.05). FSH, LH, and T levels in the GTW + SC-FL and LY + SC-FL groups were significantly higher than those in the GTW and LY group (P < 0.01 or P < 0.05). HE staining results showed that the morphology of testicular tissue in the GTW + SC-FL and LY + SC-FL groups was superior to that in the GTW and LY group. The above effects of SC-FL are closely related to the up-regulation of proteins and mRNA expression of PI3K, p-AKT, and Bcl-2., Conclusion: Through the PI3K/Akt signaling pathway, SC-FL up-regulates GFRa1, RET, PI3K, p-AKT, and Bcl-2, and down-regulates the expression of BAD and BAX proteins and mRNA, thus reducing the percentage of GC-1 spg cells in S-phase, significantly increasing the mitochondrial membrane potential, significantly reducing cell apoptosis, and improving sperm counts and viability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: We aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity., Methods: Hepatotoxicity was determined based on assessment of liver injury after dosing mice with TW at different circadian time points. Circadian clock control of metabolism, pharmacokinetics and hepatotoxicity was investigated using Clock-deficient (Clock -/- ) mice., Key Findings: Hepatotoxicity of TW displayed a significant circadian rhythm (the highest level of toxicity was observed at ZT2 and the lowest level at ZT14). Pharmacokinetic experiments showed that oral gavage of TW at ZT2 generated higher plasma concentrations (and systemic exposure) of triptolide (a toxic constituent) compared with ZT14 dosing. This was accompanied by reduced formation of triptolide metabolites at ZT2. Loss of Clock gene sensitized mice to TW-induced hepatotoxicity and abolished the time-dependency of toxicity that was well correlated with altered metabolism and pharmacokinetics of triptolide. Loss of Clock gene also decreased Cyp3a11 expression in mouse liver and blunted its diurnal rhythm., Conclusions: Tripterygium wilfordii chronotoxicity was associated with diurnal variations in triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 regulated by circadian clock. Our findings may have implications for improving TW treatment outcome with a chronotherapeutic approach., (© 2020 Royal Pharmaceutical Society.)

Ethnopharmacological Relevance: Diminished ovarian reserve (DOR) can lead to poor fertility and shorten the reproductive lifespan of females. The Dingkun Pill (DKP), a traditional Chinese-patented medication, has been an integral part of traditional Chinese medicinal treatment for the management of gynecological diseases for centuries. Relevant clinical studies have shown that DKP is able to protect against DOR, however, its mechanism of action is not yet fully elucidated., Study Goals: This study was conducted with the aim of exploring the impact of tripterygium wilfordii polyglycosidium (TWP) on the PI3K/AKT/mTOR pathway in the context of the pathophysiology of DOR and the mechanism of action of DKP., Materials and Methods: Eighty female balb/c mice with regular estrous cycles were assigned to Blank, Model, DKP and hormone replacement therapy (HRT) groups in a random manner. With the exception of the Blank group, mice in the other groups were exposed to 40 mg/kg/d TWP suspension for 30 days to DOR induction. Following this, either DKP or hormones were orally administrated to determine their effect on disease progression. During the experiment, changes in body weight and the estrous cycles of the mice were observed. Post treatment, serum sample anti-mullerian hormone (AMH), estradiol (E 2 ), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were quantified using enzyme-linked immunosorbent assay (ELISA). The mice were then sacrificed in order to harvest their ovaries for hematoxylin and eosin (HE) staining. This process allowed for the assessment of ovarian morphology and follicular quantification. Apoptotic ovarian cells of the ovary were assessed using TUNEL technique, while Caspase-3 and Cytochrome C (Cyt C) expressions of the ovary were examined through immunohistochemistry (IHC). Western blotting analysis was used to quantify levels of Bax, Bcl-2, Caspase-3, Cyt C, mTOR, P-mTOR, AKT, P-AKT, P-PI3K and PI3K proteins, while mRNA levels of Bax, Bcl-2, PI3K, AKT and mTOR were measured in ovarian tissue using RT-PCR., Results: The findings revealed that DKP was able to improve levels of serum hormones and promote the recovery of the estrous cycle. DKP augmented the total amount of primordial follicles while reducing the number of follicles that were atretic follicles. The apoptosis index of growing follicles and Bax, Cyt C and Caspase-3 expressions decreased, while the Bcl-2: Bax ratio increased. DKP suppressed levels of phosphorylation and the mRNA expressions of mTOR, AKT and PI3K., Conclusions: It was demonstrated that DKP was able to increase ovarian reserves through inhibition of the PI3K/AKT/mTOR signaling pathway, which lead to the suppression of primordial follicle activity and a reduction in levels of apoptosis of early growing follicles. This highlights its potentially beneficial role for the treatment of DOR., (Copyright © 2020. Published by Elsevier B.V.)

Celastrol (CS), an active triterpene derived from traditional Chinese medicine Tripterygium wilfordii Hook. f, has been used to treat chronic inflammation, arthritis and other diseases. However, it has been reported that CS can trigger cardiotoxicity and the molecular mechanism of heart injury induced by CS is not clear. Considering the wide application of Tripterygium wilfordii Hook. f in clinics, it is necessary to develop an accurate and reliable method to assess the safety of CS, and to elucidate as much as possible the mechanism of cardiotoxicity induced by CS. In this study, Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomics revealed clues to the mechanism of CS-induced heart injury. Palmitic acid significantly increased in plasma from CS-treated rats, and this increase resulted in oxidative stress response in vivo. Excessive ROS further activate TNF signaling pathway and caspase family, which were obtained from the KEGG enrichment analysis of network toxicology strategy. Protein expression level of caspase-3, caspase-8, bax were significantly increased by western blot. Q-PCR also showed the similar results as western blot. It means that apoptosis plays a key role in the process of celastrol induced cardiotoxicity. Blocking this signal axis may be a potential way to protect myocardial tissue., (Copyright © 2019. Published by Elsevier Inc.)

The aim of this paper was to systematically evaluate the toxicity-reducing effect of Tripterygium-licorice in animal experiments,and also to provide evidence for basic research on the toxicity reduction of Tripterygium wilfordii. The PubMed,EMbase,Web of Science,CBM,CNKI and Wan Fang Databases from their establishment to August 31 th,2018 were searched. Two independent reviewers screened the papers,extracted the data,assessed the risk of bias using SYRCLE assessment tool and conducted Meta-analysis with Rev Man 5. 3 software. A total of 10 papers involving 31 studies were finally included,15 studies of which were used for Meta-analysis. Four studies were included for chronic hepatotoxicity animal model. In experimental group( 34 animals),Tripterygium was administered at dose of 0. 09-0. 1 mg·kg-1·d-1,and glycyrrhizic acid was administered at dose of 90-100 mg·kg-1,both for 2 weeks; in control group( 34 animals),glycyrrhizic acid was replaced with equal volume of normal saline. Eleven studies were included for acute hepatotoxicity animal model. In experimental group( 66 animals),glycyrrhizic acid was administered at dose of 75-480 mg·kg-1 for 7 days,then glycyrrhizic acid was stopped,and Tripterygium began to be administered at dose of 0. 6-1. 0 mg·kg-1 per 24 h or 48 h for a total of 1-2 times; in control group( 66 animals),glycyrrhizic acid was replaced with equal volume of normal saline or corresponding solvent. The results of Meta-analysis showed that in both chronic hepatotoxicity animal model and acute hepatotoxicity animal model,the transaminase levels in the experimental group were lower than those in the control group( P < 0. 05). Subgroup analysis of acute hepatotoxicity animal model showed that the transaminase levels in the experimental group were lower than those in the control group for every subgroup except " glycyrrhizic acid 75 mg·kg-1" subgroup. However,in terms of the mean difference( MD) and confidence interval( CI),there was no significant difference in transaminase decline between each subgroup. Low dose of glycyrrhizic acid( 90-100 mg·kg-1) has a toxicity-reduction effect on chronic hepatotoxicity induced by tripterygium( 0. 09-0. 10 mg·kg-1). Middle and high doses of glycyrrhizic acid( 120-480 mg·kg-1) have a toxicity-reduction effect on acute hepatotoxicity induced by tripterygium( 0. 6-1. 0 mg·kg-1),but with no significant dose-effect relationship.

Tripterygium wilfordii multiglycoside( GTW),an extract derived from T. wilfordii,has been used for rheumatoid arthritis and other immune diseases in China. However its potential hepatotoxicity has not been investigated completely. Firstly,the content of triptolid( TP) in GTW was 0. 008% confirmed by a LC method. Then after oral administration of GTW( 100,150 mg·kg-1) and TP( 12 μg·kg-1) in female Wistar rats for 24 h,it was found that 150 mg·kg-1 GTW showed more serious acute liver injury than 12 μg·kg-1 TP,with the significantly increased lever of serum ALT,AST,TBA,TBi L,TG and bile duct hyperplasia even hepatocyte apoptosis. The expression of mRNA and proteins of liver bile acid transporters such as BSEP,MRP2,NTCP and OATP were down-regulated significantly by GTW to inhibit bile acid excretion and absorption,resulting in cholestatic liver injury. Moreover,GTW was considered to be involved in hepatic oxidative stress injury,although it down-regulated SOD1 and GPX-1 mRNA expression without significant difference in MDA and GSH levels. In vitro,we found that TP was the main toxic component in GTW,which could inhibit cell viability up to 80% in Hep G2 and LO2 cells at the dose of 0. 1 μmol·L-1. Next a LC-MS/MS method was used to detect the concentration of triptolid in plasma from rats,interestingly,we found that the content of TP in GTW was always higher than in the same amount of TP,suggesting the other components in GTW may affect the TP metabolism. Finally,we screened the substrate of p-glycoprotein( p-gp) in Caco-2 cells treated with components except TP extrated from GTW,finding that wilforgine,wilforine and wilfordine was the substrate of p-gp. Thus,we speculated that wilforgine,wilforine and wilfordine may competitively inhibit the excretion of TP to bile through p-gp,leading to the enhanced hepatotoxity caused by GTW than the same amount of TP.

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.

This paper summarizes the research progress of reproductive toxicity of Tripterygium wilfordii from 1979,and the toxicity characterization,damage mechanism,and attenuated measures are summarized. It was found that,the reproductive toxicity caused by T. wilfordii is mainly distributed on components of Tripterygium glycosides,triptolide,tripchlorolide,and clinically preparations,such as Leigongteng Tablets and Tripterygium Glycosides Tablets. Adverse reactions to male reproductive system caused by Tripterygium preparations mainly include decreased sperm motility,oligospermia or spermatozoa,decreased fertility or infertility,etc. Long-term drug use may also lead to testicular atrophy and decreased sexual desire. Adverse reactions to women are mainly manifested as menstrual disorders,decreased menstrual volume or even amenorrhea,decreased sexual desire,infertility,etc. The reproductive toxicity of T. wilfordii is related to apoptosis of reproductive cells,disturbance of spermatogenesis or oogenesis,damage of testis and ovary in reproductive target tissues,and changes of internal environment in gonad tissues( hormones,hormone synthesis rate-limiting enzymes and energy metabolism). Drug compatibility,hormone replacement,medication duration and dosage form changes can help reduce the damage of T. wilfordii to the reproductive system. In addition,in view of the existing problems in the current study,the author proposes new directions in clinical studies,pharmacological metabolism mechanism,preparation quality standards and new therapeutic effects,etc.,to provide a basis for the safe and reasonable clinical application of T. wilfordii.

Tripterygium Glycosides Tablets has good anti-inflammatory and immunomodulatory activities,but its reproductive damage is significant. Previous studies of the research group have found that Cuscutae Semen flavonoids can improve spermatogenic cell damage caused by Tripterygium Glycosides Tablets by regulating spermatogenic cell cycle,apoptosis and related protein expression,but the mechanism of action at the gene level is still unclear. In this study,Illumina high-throughput sequencing platform was applied in transcriptional sequencing of spermatogenic cells of rats after the intervention of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets. Differentially expressed genes were screened out and the GO enrichment and KEGG pathway analysis of differentially expressed genes were conducted to explore the mechanism of Cuscutae Semen flavonoids in improving reproductive injury caused by Tripterygium Glycosides Tablets. The results showed that 794 up-regulated genes and 491 down-regulated genes were screened in Tripterygium Glycosides Tablets group compared with the blank group. Compared with Tripterygium Glycosides Tablets,440 up-regulated genes and 784 down-regulated genes were screened in the Cuscutae Semen flavonoids+Tripterygium Glycosides Tablets group. Among them,the gene closely related to reproductive function is DNMT3 L. Analysis of GO function and KEGG signaling pathway enrichment showed that the above differentially expressed genes were mainly enriched in cell,cell process,catalytic activity,binding,ovarian steroid synthesis,thyroid hormone and other functions and pathways. The thyroid hormone signaling pathway was the common enrichment pathway of the two control groups. In a word,Cuscutae Semen flavonoids has a good treatment effect on male reproductive damage caused by Tripterygium Glycosides Tablets. The mechanism may be closely related to up-regulation of DNMT3 L genes and intervention of thyroid hormone signaling pathway. At the same time,the discovery of many different genes provides valuable information for study on the mechanism of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets compatibility decreasing toxicity and increasing efficiency.

The aim of this paper was to compare the performance of acute liver injury in mice induced by Tripterygium Glycosides Tablets from 6 different manufacturers,and to explore the toxicity mechanism from the perspective of oxidative stress and apoptosis preliminarily. Male or female mice were randomly divided into normal group,Zhejiang group,Hunan group,Hubei group,Shanghai group,Jiangsu group and Fujian group. Mice in Tripgerygium Glycosides Tablets groups were given 16 times the clinical equivalent dose( 300 mg·kg-1) Tripgerygium Glycosides Tablets by oral administration for one time,mice were executed in 24 h after lavaged.Then the visceral brain coefficient of the organ was calculated. Histopathological changes of liver were observed by hematoxylin-eosin staining. Td T-mediated d UTP nick-end labeling was used to detect the apoptosis of the liver cells and the protein content of oxidative stress related factors in liver homogenate. Nuclear transcription factor E2-related factor( Nrf2) and heme oxygenase-1( HO-1) as well as mitochondrial mediated apoptosis-related protein expression levels of Bax and Bcl-2 in hepatic tissue were measured by Western blot.Within 24 hours of administration,6 male mice in Jiangsu group and 2 female mice in Zhejiang group were dying; compared with normal ones,liver coefficients of mice in Zhejiang,Shanghai,Jiangsu and Hunan groups were significantly increased,thymus coefficients in the first two groups were significantly reduced,as well as the lung coefficients of Fujian group mice,the rest was normal. In addition to Hubei group,serum AST,ALT or ALP levels of mice were increased,while TBi L were not being affected. Histopathological changes and apoptosis of liver cells were observed in all mice,and the degree of severity was ranked as Jiangsu,Zhejiang,Shanghai,Hunan,Hubei and Fujian group. All Tripterygium Glycosides Tablets increased the MDA and reduced the content of T-SOD,CAT or GSH in liver tissue while inhibited Nrf2,HO-1 and Bcl-2,increased the protein expression level of Bax( except Hunan group). Tripgerygium Glycosides Tablets from 6 manufacturers all resulted in liver function damage and liver histopathological changes,especially in Jiangsu,Hubei and Fujian,and the mechanism may related to inhibit Nrf2/HO-1 oxidative stress pathway and activate Bax/Bcl-2 apoptosis pathway to mediate lipid peroxidation and induce liver cell apoptosis. Triptolide A may be one of the main toxic components of Tripgerygium Glycosides Tablets that causing drug-induced liver injury. This study was conducted on normal mice with super dose medication,so the relevant results are for reference only.

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.

To evaluate the quality of randomized controlled trials(RCT) on nephrotoxicity of Tripterygium wilfordii preparations according to the CONSORT HARMs statement. The report quality of each included study was evaluated according to the CONSORT HARMs statement， and the number of entries that comply with CONSORT HARMs statement was calculated in each study to evaluate the report quality on nephrotoxicity-related adverse reactions of T. wilfordii preparations and summarize the problems in domestic studies on nephrotoxicity-related adverse reactions. A total of 16 RCTs were included， with an average of 7 entries complying with CONSORT HARMs statement per study. The report of the nephrotoxic-associated RCT of T. wilfordii preparations was of poor quality and the most non-repeating entries included the following ones： using validated tools to report adverse effects， standards for coding of the adverse reactions， describing how and when to collect data on adverse reactions in Method， describing how adverse reactions are attributed to T. wilfordii， clearly stating who has reported the adverse reactions， describing the analysis method of adverse reactions， describing the method of collecting recurrent adverse reaction data， describing any subgroup analysis and exploratory analysis associated with the hazard. We suggest that the studies on adverse reactions of traditional Chinese medicine should strictly report the entries according to the CONSORT HARMs statement， and take the characteristics of traditional Chinese medicine into account to report the details of the Chinese medicine like compositions， dose， taking time， combined medication and the dialectical typology of research objects., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

To provide the basis for the future research on the nephrotoxicity of Chinese herbal medicine through systematic and comprehensive summary of all the Chinese herbal medicines which may lead to nephrotoxicity. Foreign resources included PubMed and Cochrane library， and domestic research resources was China Food and Drug Administration(CDFA) Adverse Drug Reaction Monitoring Center database. The databases were searched from establishment to January 1， 2017. There was no limitation on research type. 28 English studies were found， including 97 Chinese herbs or prescriptions with the risk of nephrotoxicity. The following six Chinese herbal medicines with the risk of nephrotoxicity had a large number of studies： aristolochic acid(5 studies)， Tripterygium wilfordii(4 studies)， Erycibe obtusifolia(2 studies)， Rheum palmatum(2 studies)， Ephedra sinica(2 studies)， and Atractylodes lances(2 studies). The remaining 91 Chinese medicines were reported with risk of nephrotoxicity in only 1 study respectively. CDFA reported 16 Chinese herbal medicines with the risk of nephrotoxicity， including Ganmaoqing Pian(capsule)， Zhenju Jiangya Pian， T. wilfordii preparation， Vc-Yinqiao Pian， Chuanhuning injection， Shuanghuanglian injection， Qingkailing injection， Lianbizhi injection， herbal decoction containing Aristolochiae Radix， Guanxin Suhe Wan， Shugan Liqi Wan， Ershiwuwei Songshi Wan， herbal decoction containing Aristolochia Fangchi， herbal granules containing root of Kaempfer Dutchmanspipe， Ganmaotong(tablets)， and Longdan Xiegan Wan. Currently， in addition to aristolochic acids， the most reported Chinese herbal medicine with the risk of nephrotoxicity is T. wilfordii preparation., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

To investigate the feasibility of applying the evidence-based rapid review in studying the nephrotoxicity of Tripterygium wilfordii preparation. We used four methods in relevant studies on the nephrotoxicity of T. wilfordii preparation. The first method had no limitation on any search terms， which was a traditional approach to retrieve systematic reviews. The second method limited the relevant search terms of T. wilfordii preparation to "all of CHMs containing T. wilfordii preparation approved by CFDA". The third method was to limit the relevant retrieval terms of nephrotoxicity as the "most frequently reported terms related to nephrotoxicity found in the study literature screening process in the early stage of systematic review". The fourth method was to limit the search terms relating to both T. wilfordii preparation and nephrotoxicity. Finally， the results of the last three search methods were compared with those of the first search method， and the feasibility of the rapid review method in the study for the nephrotoxicity of CHM was discussed. For the total number of literatures searched， the fourth method had the smallest number of literatures. For the number of articles in line with the inclusion criteria， the second method had the largest number of eligible literatures. For the type of literatures included， the forth method had a higher coincidence degree. The forth method was the best one， because it was not only consistent with the results， but also could minimize the workload. Rapid review is feasible in the study of nephrotoxicity of T. wilfordii., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

With the deepening of the study of toxicology of traditional Chinese medicine, the mechanism of hepatotoxicity caused by Tripterygium wilfordii has been gradually revealed. As one of the characteristics of traditional Chinese medicine, Chinese medicine compatibility show its more reasonable and scientific effect in terms of reducing toxicity. In this paper, the author summarizes the research on the basis and mechanism of toxic substances in T. wilfordii, and sum up the compatibility of traditional Chinese medicine (preparation) to reduce its role of hepatotoxicity, so as to provide reference for the rationality and safety in clinical application of T. wilfordii, thereby reducing liver adverse reactions., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Background: Kidney tonifying - spleen strengthening method being one of the modalities for treatment of astheno-oligozoospermia is currently commonly used in the clinical setting. To investigate the mechanism of YiShenJianPi (YSJP) Recipe, used in Traditional Chinese Medicine to benefit "the kidney" and strengthen "the spleen"., Materials and Methods: Oligoasthenozoospermia, male BALB/c mice were randomly divided into normal control, disease model, positive control, low-dosage and high-dosage groups. Oligoasthenozoospermia was induced by tripterygium glucosides intragastric administration before treatment started. Through using computer-aided sperm analysis to test the changes in sperm quality, utilizing flow cytometry to test the percentage of sperm with normal mitochondrial transmembrane potential (JC-1 + %), utilizing X-ray microscopy to observe epididymal sperm ultra-microstructure placing special emphasis and photographing the differences in mitochondria of the flagellum region., Results: Compared with DM, sperm quality of the treated mice was significantly better (P<0.05, respectively). Compared with PC, the LD group had significantly better quality sperms, while the parameters in the HD group were numerically better. Compared with NC, all other groups had significantly lower percentage of sperms with normal mitochondrial membrane potential. In PC, LD and HD groups, the percentage of sperms with normal mitochondrial membrane potential was significantly higher than that of D. The 9+9+2 mitochondrial sheath structure was complete in NC but damaged in DM. In the treatment groups, this structure was fairly clear., Conclusion: YSJP improved semen quality with oligoasthenozoospermia by improving sperm mitochondrial membrane potential and restoring sperm mitochondrial ultrastructure.

To explore the effect of the licorice-processed Tripterygium wilfordii on reducing the liver toxicity. In animal experiments, the liver toxicity of T. wilfordii was evaluated both before and after processing, and the differences in liver tissue biopsy, serum biochemical indexes and inflammatory cell factor among blank group, T. wilfordii group and licorice-processed T. wilfordii group were observed. Liver tissue biopsy results showed that liver tissue injury was obvious in T. wilfordii group, and no obvious injury was found in licorice-processed T. wilfordii group. As compared with the blank group, the levels of AST, ALT and CRE were significantly increased (P<0.01), UREA was increased (P<0.05), and ALB level was significantly decreased (P<0.01) in the T. wilfordii group. As compared with T. wilfordii group, the levels of AST, ALT, CRE, and UREA were decreased (P<0.01), while ALB was increased (P<0.01) in the licorice-processed T. wilfordii group. The results of inflammatory factors in rats showed that the levels of IL-1β, IL-6, and TNF-α in T. wilfordii group were significantly higher than those in blank group (P<0.01); the levels of IL-1β, IL-6, and TNF-α in licorice-processed T. wilfordii group were significantly lower than those in T. wilfordii group (P<0.01). Overall, licorice processing of T. wilfordii can effectively reduce the liver toxicity and reduce the liver injury caused by T. wilfordii. The experiment can provide reference for the clinical rational use of the T. wilfordii, and provide data support for the studies on reducing the liver toxicity of T. wilfordii by licorice processing., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

In this paper, the spectrum-effect correlation analysis method was used to explore the main effective components of Tripterygium wilfordii for liver toxicity, and provide reference for promoting the quality control of T. wilfordii. Chinese medicine T.wilfordii was taken as the study object, and LC-Q-TOF-MS was used to characterize the chemical components in T. wilfordii samples from different areas, and their main components were initially identified after referring to the literature. With the normal human hepatocytes (LO2 cell line)as the carrier, acetaminophen as positive medicine, and cell inhibition rate as testing index, the simple correlation analysis and multivariate linear correlation analysis methods were used to screen the main components of T. wilfordii for liver toxicity. As a result, 10 kinds of main components were identified, and the spectrum-effect correlation analysis showed that triptolide may be the toxic component, which was consistent with previous results of traditional literature. Meanwhile it was found that tripterine and demethylzeylasteral may greatly contribute to liver toxicity in multivariate linear correlation analysis. T. wilfordii samples of different varieties or different origins showed large difference in quality, and the T. wilfordii from southwest China showed lower liver toxicity, while those from Hunan and Anhui province showed higher liver toxicity. This study will provide data support for further rational use of T. wilfordii and research on its liver toxicity ingredients., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Lipid metabolic pathways play pivotal roles in liver function, and disturbances of these pathways are associated with various diseases. Thus, comprehensive characterization and measurement of lipid metabolites are essential to deciphering the contributions of lipid network metabolism to diseases or its responses to drug intervention. Here, we report an integrated lipidomic analysis for the comprehensive detection of lipid metabolites. To facilitate the characterization of untargeted lipids through fragmentation analysis, nine formulas were proposed to identify the fatty acid composition of lipids from complex MS (n) spectrum information. By these formulas, the co-eluted isomeric compounds could be distinguished. In total, 250 lipids were detected and characterized, including diacylglycerols, triacylglycerols, glycerophosphoethanolamines, glycerophosphocholines, glycerophosphoserines, glycerophosphoglycerols, glycerophosphoinositols, cardiolipins, ceramides, and sphingomyelins. Integrated with the targeted lipidomics, a total of 27 inflammatory oxylipins were also measured. To evaluate the aberrant lipid metabolism involved in liver injury induced by Tripterygium wilfordii, lipid network metabolism was further investigated. Results indicated that energy lipid modification, membrane remodeling, potential signaling lipid alterations, and abnormal inflammation response were associated with injury. Because of the important roles of lipids in liver metabolism, this new method is expected to be useful in analyzing other lipid metabolism diseases.

Tripterygium wilfordii Hook. f. induced-hepatotoxicity was the main limitation for its usage in clinic. Qingluo Tongbi formulation showed obvious attenuation for hepatotoxicity in clinic and fundamental research in vivo. To explore the potential mechanism of the attenuation, we conducted a study on the plasma metabolomic profiles of T. wilfordii and Qingluo Tongbi formulation in rats by a sensitive gas chromatography-mass spectrometry (GC-MS/MS) method. In plasma samples, a total of 72 compounds were analyzed by EI source MS, and were successfully identified by matching NIST database. The semi-quantification results were then calculated by OPLS-DA model with SIMCA-P 13.0 software. The three groups were clearly distinguished in OPLS-DA score plot. In addition, the observation values of Qingluo Tongbi formulation showed the obvious trend towards the control levels, suggesting the detoxicity effect of the formulation. Variation metabolites were further analyzed by VIP and One Way ANOVAs, and the results showed a significant increase in compounds of glycogenic amino acids, such as alanine, proline, serine and glutamine after the administration of T. wilfordii, indicated that the tissue proteins were decomposed and amino acids were leakage into blood. Qingluo Tongbi formulation could reverse the amino acids into normal level. On the contrary, the levels of glucose, lactic acid and hydroxy butyrate decrease, and the formulation can relieve the disorder in the levels of lactic acid, suggesting the regulation of the energy metabolism. Additionally, the level of branched chain amino acid was decreased, suggested the toxicity was induced, but the formulation cannot increase it into the normal levels. Nevertheless, all the above results suggested that the classical Qingluo Tongbi formulation displayed the liver protection effect by adjusting the amino acid levels and regulating the energy metabolism. Qingluo Tongbi formulation was developed based on traditional Chinese medicine theory "detoxicity compatibility", and contained Panax notoginseng (Burk.) F. H. Chen to nourish blood and absorb clots. Modern pharmacology suggested that its liver protection effect was correlated with the promotion of protein synthesis. Another important herb is Rehmannia glutinosa Libosch., which can regulate the energy metabolism. Both were consistent with the metabolomic results in this study, which explained the potential mechanism of "detoxicity compatibility" theory. Therefore, the currently developed metabolomic approach and the obtained results would be highly useful for the comprehensive toxicity studies for other herbal medicines and various complex deoxicity formulations., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

The arrenotokous toxicity of triptolide was evaluated, and the rate of sperm abnormality, the changes of the lipid peroxide, the enzyme activity and the hormone in male rats were observed. With the negative and positive control group, the healthy rats were respectively given by gavage triptolide suspension at the dose of 0.025, 0.05, 0.1 mg x kg(-1) for 30 days. Then the rats were killed for the measurement of the indicators in testis and serum, as well as the study on the sperm abnormality. The results showed that the positive control group had significant difference, compared with the negative control group. The content of SOD, LDH, G-6-PD, Na+ -K+ -ATPase, Ca+ -Mg+ -ATPase decreased significantly in 0.05 mg x kg(-1) group, and reduced more obviously with exposure to the dose of 0.1 mg x kg(-1). The levels of GSH-Px and beta-G showed a significant decrease in the testis of rats only at the dose of 0.1 mg x kg(-1). Nevertheless, the MDA levels, the FSH levels and the LH levels showed no significant difference. The deformity rate of sperm increased significantly in 0.05 mg x kg(-1) group and 0.1 mg x kg(-1) group. The results indicated the triptolide had the effect of the lipid peroxidation to damage Spermatogenic cells, Sertolis cells and Leydig cells. At the same time, the triptolide interfered not only with the energy supply process of aerobic and anaerobic glycolysis,but also with the energy utilization in testis by affecting the activities of testis marker enzymes, and produced a damage chain of the male reproductive system

Objective: To study the anti-immune inflammation efficacy and toxicity of Tripterygium wilfordii decoction, in order to provide experimental basis for studies on its "efficacy-toxicity" correlation., Method: The delayed hypersensitivity model was established by dinitrofluorobenzene in mice. Different doses of T. wilfordii decoction was administered for 5 consecutive days. The ear swelling inhibition ratio and the toxic action were observed. After the final administration, the biochemical indexes of PGE2, TNF-α, IL-2, ALT, AST, PA, TBA, TBIL in serum were detected, and the visceral indexes of heart, liver, spleen and kidney were measured., Result: The DNFB-induced ear swelling could be notably inhibited by multiple oral administration of T. wilfordii decoction, with the ED50 and its 95% confidence limit of 0.34 (0.21-0.42) g x kg(-1). The contents of PGE2, TNF-α, IL-2 in serum decreased in a dose-dependent manner. The activities of serum AST, ALT, TBA, TBIL and the PA content reduced., Conclusion: T. wilfordii decoction shows a significant anti-immune inflammation efficacy within the dosage range between 0.59 and 2.34 g x kg(-1) in a dose-dependent manner. With a certain hepatotoxicity, high dose (2.34-4.68 g x kg(-1)) of T. wilfordii decoction can cause substantial liver injury, with a dose dependence in liver function index. Therefore, the efficacy and toxicity of T. wilfordii is dose dependent, which provides reference for preventing adverse drug reactions in clinic and developing early-warning schemes and ensure the clinical medication safety of T. wilfordii.

Premature ovarian insufficiency (POI) is one of clinical manifestations of ovarian damage. This study is to evaluate biochemical changes of oxidative stress in POI induced by tripterygium glycosides (TG) via subcutaneous injection. 24 female KM mice were assigned to two groups: control group and TG group. The mice in TG group were subjected to 50 mg.kg(-1).d(-1) TG for 35 days, while these in control group were fed with parallel volume of sterile water. Blood samples were separately obtained in day 15, 22, 29, 36 and 43. Ovarian histopathological changes were determined when finished the administration and observed under optical microscope. Serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and anti-mullerian hormone (AMH) and ovarian homogenates levels of MDA, SOD, GSH-Px and AMH were assessed by ELISA. AMH expression in the ovaries was analyzed by immunohistochemistry. Compared with control group, the results in TG group showed a significant reduction of serum levels of SOD and GSH-Px in day 15, 22, 29, 43 and increase of MDA in day 22, 36. They also presented decreased SOD and GSH-Px levels and increased MDA level in ovarian homogenates. Our data suggested that oxidative stress was involved in POI and might be the potential pathogenesis of POI induced by TG.

Objective: The purpose of this research is to study the effect of Roucongrong (Herba Cistanches Deserticolae) on reproductive toxicity in mice induced by a glycoside extracted from Leigongteng (Radix et Rhizoma Tripterygii) (GRT)., Methods: Forty-eight BALB/c mice were randomly divided into two groups in the ratio of 1:3, 12 in one group and 36 in the other. The 12-mouse group was the control group that was intragastrically administered physiological saline for 3 weeks. The 36 mice in the other group were given 30 mg x kg(-1) x d(-1) GRT for 3 weeks, then randomly divided into 3 subgroups: the model group, GRT group and Roucongrong (Herba Cistanches Deserticolae) group, with 12 mice in each group. In the model group, 0.25 mL physiological saline was intragastrically administered; in the GRT group, GRT, 0.25 mL at 30 mg x kg(-1) x d(-1) was intragastrically administered once a day; in the Roucongrong (Herba Cistanches Deserticolae) group, mice were administered Roucongrong (Herba Cistanches Deserticolae) decoction equivalent to 0.25 mL at a final dose of 10 g x kg(-1) x d(-1) crude drug (calculated as per 20 times of 0.5 g x kg(-1) x d(-1) for adults), and GRT 0.25 mL at 30 mg x kg(-1) x d(-1) daily. After another 3 weeks of exposure, expression levels of the reproduction-related genes DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked, B-cell CLL/lymphoma 6 and Signal transducer and activator of transcription 3 were evaluated., Results: After 6 weeks of GRT treatment, the spermatogenic cell population in the convoluted tubule of testis was in disorder and the tubule cavity expanded. Sertoli cell and Leydig cells exhibited atrophy or disappeared. The number of sperm decreased. The spermatogenic cell level of testis for male mice was ranked in order and sperm was produced in the cavity of the spermatogenic cell. The expression levels of DDX3Y, BCL6 and STAT3 were, Conclusion: GRT affected reproduction-related genes. Roucongrong (Herba Cistanches Deserticolae) reversed reproductive toxicity in mice induced by GRT.

Objective: To investigate the therapeutic effect and the impact on liver function of different-dose Tripterygium wilfordii compound recipe gel (TWCG) for external use on adjuvant-induced arthritis (AA) rats., Methods: Freund's adjuvant-induced arthritis rats were dressed with different doses of TWCG, voltaren as positive control and blank gel as blank control. The ankle swelling degrees were evaluated; the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) were detected by ELISA; the levels of matrix metalloproteinase-3 (MMP-3) in ankle cartilage were determined by immunohistochemical method; the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were tested with the automatic biochemical analyzer., Results: Compared with the model group (dressed with blank gel), the ankle swelling degrees in TWCG groups and voltaren group were significantly reduced (P<0.05); the levels of TNF-α markedly decreased and IL-4 increased in sera (P<0.05); the content of MMP-3 in ankle joint tissues was significantly reduced (P<0.05). The effects in high-dose TWCG group and median-dose TWCG group were better than that in voltaren group and low-dose TWCG group (P<0.05). However, the levels of ALT and AST were not statistically different among the groups (P>0.05)., Conclusion: TWCG has obvious anti-inflammatory and detumescence effects on AA rat. It can protect cartilage tissue effectively without significant hepatotoxicity.

The present study is trying to produce a transdermal microemulsion drug delivery system (TMDDS) for Tripterygium Wilfordii Hook f. (TWHF) and attempting to solve male reproductive toxicity problem of TWHF. The formulation was optimized by the central composite design with response surface methodology and was decided as 12% oleic acid, 19.7% Labrasol S, 19.7% ethanol and 19.7% Pharmasolve, and 29% water. TMDDS for TWHF had stronger transdermal ability than free TWHF, and TWHF microemulsion significantly inhibited the adjuvant-induced arthritis and at the same time, had preferable anti-inflammatory effect with the long-time administration. Various pharmacodynamics parameters proved that TWHF microemulsion can reduce the male reproductive toxicity and hepatotoxicity of rats. All these suggested that TMDDS could be a suitable delivery system for TWHF., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The protective effects of tripterygium glycoside-loaded solid lipid nanoparticles (TG-SLNs) on male reproductive toxicity were investigated in rats. Thirty-six male Sprague-Dawley rats were randomly divided into three groups of 12: control group, tripterygium glycoside (TG) group, and TG-SLN group. After the animals had been orally administered with the substances for 28 consecutive days, their sperm count and sperm motility, organ coefficients, serum testosterone levels, testicular ultrastructure, and reproductive ability were observed. The results showed that the sperm motility rate in the TG group was only 3%, whereas the rates in the TG-SLN and control groups were 33% and 71%, respectively. Compared with those in the control group, the motion counts of path velocity, track speed, progressive velocity, straightness, linearity, beat cross frequency, amplitude of lateral head displacement, and sperm concentrations in the TG-SLN group were not significantly different while those in the TG group significantly decreased (p < 0.01). TG-SLNs did not cause testicular atrophy and instead maintained normal serum testosterone levels. The effect of TG-SLNs on the testicular ultrastructure was very evident; the morphologies of Sertoli, spermatogonial, mitochondrial, and sperm cells were normal. In terms of reproductive ability, one rat (17%) from the TG-SLN group and five rats (83%) from the control group became pregnant, whereas none of the rats from the TG group became pregnant. These data indicate that TG-SLNs have potentially protective effects on male reproductive toxicity in rats.