Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC–MS based metabolomics study

Ma, Bo; Qi, Huanhuan; Li, Jing; Xu, Hong; Chi, Bo; Zhu, Jianwei; Yu, Lisha; An, Guohua; Zhang, Qi

doi:10.1016/j.tox.2015.07.008

Cited by 68 publications

(34 citation statements)

References 43 publications

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“…f. possesses multiple pharmacological activities, including anti-inflammatory ( Wang et al, 2014c ), anti-fertility ( Li et al, 2015 ), anti-cystogenesis, and anticancer activities ( Li et al, 2015 ). However, triptolide has a narrow therapeutic window, and its clinical applications are limited due to its severe toxicities, including hepatotoxicity ( Li X. et al, 2014 ), nephrotoxicity ( Sun et al, 2013 ), immunotoxicity ( Wang et al, 2014a ), and developmental and reproductive toxicities ( Ni et al, 2008 ; Ma et al, 2015 ). Among the adverse effects of triptolide, hepatotoxicity is non-negligible and has a high incidence.…”

Section: Introductionmentioning

confidence: 99%

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Jiang

Huang

et al. 2016

Front. Pharmacol.

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Triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., exerts a unique bioactive spectrum of anti-inflammatory and anticancer activities. However, triptolide’s clinical applications are limited due to its severe toxicities. Fatty liver toxicity occurs in response to triptolide, and this toxic response significantly differs between males and females. This report investigated the pathogenesis underlying the sex-related differences in the dyslipidosis induced by triptolide in rats. Wistar rats were administered 0, 150, 300, or 450 μg triptolide/kg/day by gavage for 28 days. Ultrastructural examination revealed that more lipid droplets were present in female triptolide-treated rats than in male triptolide-treated rats. Furthermore, liver triglyceride, total bile acid and free fatty acid levels were significantly increased in female rats in the 300 and 450 μg/kg dose groups. The expression of liver X receptor α (LXRα) and its target genes, cholesterol 7α-hydroxylase (CYP7A1) and Sterol regulatory element-binding transcription factor 1(SREBP-1), increased following triptolide treatment in both male and female rats; however, the female rats were more sensitive to triptolide than the male rats. In addition, the expression of acetyl-CoA carboxylase 1(ACC1), a target gene of SREBP-1, increased in the female rats treated with 450 μg triptolide/kg/day, and ACC1 expression contributed to the sex-related differences in the triptolide-induced dysfunction of lipid metabolism. Our results demonstrate that the sex-related differences in LXR/SREBP-1-mediated regulation of gene expression in rats are responsible for the sex-related differences in lipid metabolism induced by triptolide, which likely underlie the sex-related differences in triptolide hepatotoxicity. This study will be important for predicting sex-related effects on the pharmacokinetics and toxicity of triptolide and for improving its safety.

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Section: Introductionmentioning

confidence: 99%

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Jiang

Huang

et al. 2016

Front. Pharmacol.

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“…For example, Bo Ma showed the reproductive toxicity and testis injuries observed due to the down-regulation of PPAR-α in testicular tissue, which subsequently led to an insufficient energy metabolism [ 21 ]. Secondly, PPREs have been proved to regulate some antioxidant genes, such as catalase (CAT) and Cu 2+ /Zn 2+ -superoxide dismutase (SOD) [ 22 ]. It was more persuasive that Nakajima T. showed that PPAR alpha-null mice exhibited marked hepatomegaly, hepatic inflammation, cell toxicity, fibrosis, apoptosis, and mitochondrial swelling after being treated with ethanol, compared with wild-type mice [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity Mechanisms

Liu

Lin

et al. 2017

Molecules

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A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.

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“…Tripterygium glycosides (TGs) have been used to model spermatogenesis disorders in animals since 1980s in China [18]. Studies have shown that the antifertility effects of TGs are related to dysfunction of sperm cells, Sertoli cells, Leydig cells and spermatogenesis related genes [19,20]. Ma et al have explored the optimum dosage and time for establishing spermatogenic dysfunction rat model, with sperm concentration and motility, and pathological changes of testicular tissue used as evaluation criteria [21].…”

Section: Introductionmentioning

confidence: 99%

Effects of Qilin pills on spermatogenesis, reproductive hormones, oxidative stress, and the TSSK2 gene in a rat model of oligoasthenospermia

Zhang

et al. 2020

BMC Complement Med Ther

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AbstractsBackground: Qilin pills (QLPs), a classic Traditional Chinese Medicine (TCM) formula for treating male infertility, effectively improve semen quality in clinical trials. This study was designed to evaluate the effects of QLPs on spermatogenesis, reproductive hormones, oxidative stress, and the testis-specific serinekinase-2 (TSSK2) gene in a rat model of oligoasthenospermia. Methods: Forty adult male Sprague-Dawley (SD) rats were randomly divided into four groups. The rat model with oligoasthenospermia was generated by intragastric administration of tripterygium glycosides (TGs) once daily for 4 weeks. Then, two treatment groups were given different doses (1.62 g/kg and 3.24 g/kg) of QLPs once daily for 60 days. Sperm parameters, testicular histology and reproductive hormone measurements, oxidative stress tests, and TSSK2 expression tests were carried out.Results: QLPs effectively improved semen parameters and testicular histology; restored the levels of FSH, LH, PRL, fT, and SHBG; reduced the levels of oxidative stress products (ROS and MDA); increased testicular SOD activity; and restored the expression of spermatogenesis-related gene TSSK2. Conclusion:QLPs have a therapeutic effect on a rat model of oligoasthenospermia, and this effect is manifested as improvement of semen quality and testis histology, gonadal axis stability, decreased oxidative stress, and the regulation of testis-specific spermatogenesis-related gene TSSK2.

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Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC–MS based metabolomics study

Cited by 68 publications

References 43 publications

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity Mechanisms

Effects of Qilin pills on spermatogenesis, reproductive hormones, oxidative stress, and the TSSK2 gene in a rat model of oligoasthenospermia

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