Medicina-Lithuania
·
2018
·Vol. 54
·期 3
·39
·
IF 1.429
Wei Li,Bi-De Liu,Kai Liao,Yong Liu,Zi-Jin Wan,Yu-Fen Dong,Qian-Qian Cao,Qian Zhu,Xiao Gu
Background and Objective:Although triptolide was effective for prostate cancer (PCa), the mechanism is still unclear. Androgen receptor (AR) plays a large role in the development and progression of PCa, even after castration. The present study aimed at investigating the effects of triptolide on AR protein stability and the possible mechanism.Materials and Methods:By blocking protein synthesis with cycloheximide (CHX), the effect of triptolide on AR protein stability was investigated with western blot assay. The potential role of calpains in triptolide reduced AR protein stability was investigated with calpain inhibitor and Ca2+chelator.Results:Triptolide down-regulated AR protein level when protein synthesis was blocked by CHX, demonstrating the decrease of AR protein stability. The AR protein level was restored when the cells were co-treated with triptolide and calpain inhibitor or Ca2+chelator, indicating the important role of calpains.Conclusions:The results indicate that triptolide can activate calpain via promoting intracellular Ca2+accumulation, and thus decrease the stability of AR protein, subsequently resulting in the breakdown of the AR protein in LNCaP cells. This work provides an experimental basis and evidence to elucidate the anti-PCa mechanisms of triptolide.Keywords:triptolide;androgen receptor;calpain;protein stability
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Jihang Dai,Yu Sun,Duoyun Chen,Yaxin Zhang,Lianqi Yan,Xiaolei Li,Jingcheng Wang
Fibroblasts excessive proliferation was considered as a decisive reason for epidural fibrosis , which was known as a serious complication of lumbar laminectomy. As a traditional Chinese medicine , triptolide (TP) was used to be proved effective in preventing several fibrosis scar formation diseases. However, little is known about the effect of TP on preventing epidural fibrosis and its possible mechanism. Here, we performed in vitro and in vivo experiments to detect the possible mechanism of TP in preventing epidural fibrosis. In vitro, the effect of TP on impacting fibroblasts proliferation activities was detected by CCK-8, cell cycle assay and EdU incorporation assay. Also, the expressions of cell proliferation protein markers and the expressions of p-PI3K, p-AKT, p-mTOR were detect by Western blot . Besides, the effect of TP on inducing fibroblast apoptosis and autophagy was tested by Western blots, flow cytometry, TUNEL staining , Transmission electron microscope (TEM) analysis and LC3 immunofluorescent staining. The results suggested that TP could suppress the activation of PI3K/AKT/mTOR signaling pathway. Meanwhile, TP could inhibit fibroblast proliferation and induce fibroblast apoptosis as well as autophagy, which was known as two cellular self-destructions. Furthermore, we speculated the possible molecular pathway, through which that TP could inhibit fibroblast proliferation, induce fibroblast apoptosis and autophagy. We used PI3-kinase activator (740Y-P) to activate the PI3K/AKT/mTOR signaling. Activation of PI3K/AKT/mTOR signaling pathway increase the proliferation of fibroblasts and suppressed the autophagy and apoptosis induced by TP. In vivo, we built epidural fibrosis models in rats and locally applied TP of various concentrations. Hematoxylin–eosin (HE) and Masson's trichrome were used to detect the effect of TP on reducing epidural fibrosis. And the results showed that TP could significantly reduce the surgery-induced epidural fibrosis. In conclusion, the results above shown that TP could reduce epidural fibrosis formation, and the potential mechanism might through inhibiting fibroblast proliferation and stimulating apoptosis and autophagy via suppressing PI3K/AKT/mTOR signaling pathway. It might provide a novel thought for reducing surgery-induced epidural fibrosis.
研究领域:
药理学
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神经外科
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细胞生物学
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DOI
PubMed
高影响因子
Cancer Medicine
·
2019
·Vol. 8
·期 11
·5313-5326
·
IF 3.357
Han-Qing Zhu,Chao Zhang,Zhu-Ying Guo,Jun-Mei Yang,Jia-Hui Guo,Chen Chen,Qiang-Hua Yao,Feng Liu,Quan-Wu Zhang,Feng-Hou Gao
Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis- and cell cycle arrest-related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53-induced Mdm2 (E3 ubiquitin-protein ligase Mdm2) to generate Mdm2-p60. The generation of Mdm2-p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2-p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.
研究领域:
肿瘤学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2013
·
IF 3.458
Jingyi Shen,Dianrui Zhang,Zhongxi Zhao,Lejiao Jia,Dandan Zheng,Guangpu Liu,Leilei Hao,Qiang Zhang,Xiaona Tian,Caiyun Li,Hejian Guo
Oridonin (ORI), a diterpenoid compound with promising antitumor activity , was proved to possess potent antileukemia efficacies in vitro and in vivo recently. However, the development and application of ORI was limited by its poor solubility and rapid plasma clearance. The purpose of this study was to solve these problems. PEGylated oridonin linked with succinic acid (SA) as spacer moiety (PEG-SA-ORI conjugate) was synthesized. mPEG amines with four specifications of molecular weight (MW) were utilized. All polymeric conjugates showed satisfactory aqueous solubility and in vitro studies implied that the drug solubility and release features of conjugates were relevant to PEGs. The drug solubility increased more when the MW of PEG was lower, while more significant sustained-release effect was shown with higher PEG MW. Moreover, the release behaviors of conjugates showed a pH-sensitive property. In vivo pharmacokinetic studies demonstrated that the elimination half-life was prolonged in comparison with ORI solution. PEGylation could be a promising method to obtain better efficacy in the field of drug delivery system .
研究领域:
药学
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2021
·
IF 3.935
Xin-Nan Wang,Wen-Rui Xia,Jian-Qun Liu,Fang-Yuan Sun,Zhu-Jun Zhong,Li-Fang Liu,Gui-Zhong Xin
Liver toxicity induced by Triptolide (TP) has limited its clinical application on rheumatoid arthritis (RA). Saponins have been proved as an efficacious remedy to mitigate hepatotoxicity. However, the mechanism of reducing hepatotoxicity by saponins intervention remains incompletely characterized. Tryptophan (Trp) metabolites activate transcriptional regulators to mediate host detoxification responses. Our study aimed to investigate whether Clematichinenoside AR (C-AR) could attenuate TP-induced liver damage by regulating Trp metabolism. We used targeted metabolomics to quantify Trp metabolites in the serum and liver samples of collagen-induced arthritis rats treated by TP. Multiple comparison analyses helped the evaluation of promising biomarkers. The pronounced changed levels of Trp, indole acetic acid, and indole-3-carboxaldehyde in the serum and indole acetic acid , indole , and tryptamine in the liver are relevant to TP-induced liver injury. Intervention with C-AR could relieve TP-induced hepatotoxicity evidenced by ameliorative serum parameters and hepatic histology. In addition, C-AR regulated the levels of these indoles biomarker candidates to normal. Therapeutic modulation with natural compounds might be a useful clinical strategy to ameliorate toxicity induced by TP. Deciphering Trp metabolism will facilitate a better understanding of the pathogenesis of diseases and drug responding.
研究领域:
药理学
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代谢组学
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毒理学
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免疫学
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DOI
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 2
·553
·
IF 4.6
Meng Yang,Jianxia Meng,Lu Han,Xiaoyan Yu,Zhimin Fan,Yongfang Yuan
Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the “first pass effect” of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components ofTripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin–blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three−layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery.Keywords:triptolide;transdermal drug delivery;nanoemulsion gel;multiscale mathematical modeling;synchronous microdialysis
研究领域:
药剂学
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药物代谢动力学
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中药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2020
·Vol. 72
·期 12
·1854-1864
·
IF 2.571
Zhao Huan,Tong Yongbin,Lu Danyi,Wu Baojian
ObjectivesWe aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity.MethodsHepatotoxicity 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 findingsHepatotoxicity 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.ConclusionsTripterygium 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.
研究领域:
药理学
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毒理学
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时间生物学
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分子生物学
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2018
·
IF 3.095
Qin-You Tan,Qian Hu,Sheng-Nan Zhu,Lu-Lu Jia,Juan Xiao,Hua-Zhen Su,Shao-Yuan Huang,Jing Zhang,Junfei Jin
Triptolide, the predominant biologically active component of the Chinese herb Tripterygium wilfordii Hook f., possesses numerous pharmacological activities, including anti-inflammatory, anti-fertility, anti-neoplastic, and immunosuppressive effects. However, toxicity and severe adverse effects, particularly hepatotoxicity, limit the clinical application of triptolide. Licorice root extract contains various bioactive compounds and is potent hepatoprotective. Magnesium isoglycyrrhizinate, a magnesium salt of the 18α-glycyrrhizic acid stereoisomer of glycyrrhizic acid, is used clinically in China to treat chronic viral hepatitis and acute drug-induced liver injury. The aim of this study was to investigate the role of the factor erythroid 2-related factor 2 pathway in the protective effects of LE and MIG against triptolide-induced hepatotoxicity. Hepatotoxicity models were established in L-02 cells and rats using triptolide, and the protective effects of LE and MIG were investigated in vitro and in vivo, respectively. LE and MIG significantly protected against triptolide-induced cytotoxicity. Additionally, triptolide decreased the mRNA and protein levels of Nrf2 and down-regulated Nrf2 target genes, including UGT1A, BSEP, and MRP2, while pretreatment with LE and MIG reversed these effects. Finally, Nrf2-involved antioxidant responses were activated in the presence of LE and MIG.
研究领域:
药理学
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毒理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2021
·
IF 6.419
Xin-Yi Liu,Wen-Jun Pei,Ye-Zhen Wu,Fang-Li Ren,Si-Yu Yang,Xiu Wang
The aim of this study was to develop and evaluate a triptolide phospholipid complex (TPCX) for the treatment of rheumatoid arthritis (RA) by transdermal delivery. TPCX was prepared and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR) analysis, transmission electron microscope (TEM), and scanning electron microscope (SEM). The solubility of TPCX was determined. Then, a TPCX cream was prepared to evaluate its percutaneous permeability and the antiarthritis effect. The transdermal permeability was determined using the Franz method, and a microdialysis system was used for skin pharmacokinetic study. A rat model of RA was prepared to evaluate the pharmacological effects. TPCX increased the solubility of triptolide in water, and the percutaneous permeability of TPCX cream was greatly enhanced compared with triptolide cream. The skin pharmacokinetic study indicated that TPCX cream has a longer biological half-life (t1/2) and mean residence time (MRT), but it has a shorter Tmax than that of triptolide cream in vivo. The area under the curve (AUC0–t)/AUC0–∞) and the peak concentration (Cmax) of TPCX cream were obviously higher than those of triptolide cream. The TPCX-loaded cream alleviated paw swelling and slowed down the progression of arthritis by inhibiting the inflammatory response by down regulating the TNF-α, IL-1β, and IL-6 levels, thus exhibiting excellent antiarthritic effects. In summary, the prepared TPCX effectively increases the hydrophilicity of triptolide, which is good for its percutaneous absorption and enhances its effect on RA rats. TPCX can be a good candidate for the transdermal delivery to treat RA.
研究领域:
药理学
·
药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 2
·257-263
·
IF 1.5
Qingzhi Wan,Lisha Tang,Kaili Jin,Xuanyi Chen,Yinghuan Li,Xiaofeng Xu
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
研究领域:
药理学
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细胞生物学
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中医药
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生殖生物学
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2021
·Vol. 70
·期 3
·323-341
·
IF 4.575
Wang Yu
Objective Tripterine (Trip) is frequently applied to alleviate inflammation in various diseases such as rheumatoid arthritis. Macrophages have both anti-inflammatory and pro-inflammatory functions. However, whether Trip can inhibit cell inflammation in gouty arthritis (GA) remains undiscovered and whether the mechanism involved in macrophage polarization is also undetermined. This paper aims to study the effects of Trip on inflammation and macrophage polarization in GA. Methods Monosodium urate (MSU) crystals were used to establish GA mouse models, and bone marrow-derived macrophages (BMDMs) were induced to construct GA cell models. Pretreatments of Trip and injection of Antagomir-449a/Agomir-449a were performed on mice for 6 days. The effects of Trip and miR-449 on toe swelling, joint damage of GA mouse were examined. The alternations on cell morphology, cell proliferation marker Ki67, inflammatory cytokines, NLRP3 inflammasome, and NF-κB signaling-related proteins were also determined both in vivo and in vitro. Dual-luciferase reporter gene assay and RIP assay were adopted to estimate the targeting relationship between miR-449a and NLRP3. Results GA mouse model had increased M1 macrophage, intensified inflammation response, along with suppressed miR-449a expression. Following administration of Trip attenuated cell inflammation, promoted macrophage polarize to M2 phenotype, elevated miR-449a expression, repressed the phosphorylation levels of NF-κB signaling-related proteins, and diminished IκBα expression in vivo and in vitro. However, inhibition of miR-449a hindered the favorable effect of Trip on GA and increased NLRP3 inflammasome expression. MiR-449a directly targeted NLRP3. Overexpression of NLRP3 partially eliminated the biological effects of miR-449a agonist. Conclusion Trip regulates macrophage polarization through miR-449a/NLRP3 axis and the STAT3/NF-κB pathway to mitigate GA. The elucidation on the molecular mechanism of Trip in GA may provide theoretical guidance for clinical therapy of GA.
研究领域:
药理学
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免疫学
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分子生物学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INSECT PHYSIOLOGY
·
2022
·
IF 2.608
Junjun Zhang,Zhengwei Wang,Katrina Klett,Yufeng Qu,Ken Tan
The thunder god vine , Tripterygium hypoglaucum, is a toxic nectar plant distributed across China. A terpenoid, called triptolide (TRP), found in nectar can impair honeybees’ foraging responses, dance communication, and olfactory learning. In the present study, we tested the tolerances of the native honeybee Apis cerana and the introduced honeybee A. mellifera to short-term and long-term exposure to TRP. The results showed that introduced A. mellifera is more vulnerable in fatality to high concentrations of TRP sucrose solution (5 and 10 µg TRP mL −1 ) than A. cerana . We also compared the short-term and long-term exposure effects of TRP on olfactory learning and memory between the two honeybee species, and the olfactory learning and memory of both honey bee species showed impaired performance after both 2 h or 7 days of being fed with TRP sucrose solution. However, A. cerana showed a higher tolerance and resistance to TRP toxin than A. mellifera. Our results support a coevolution hypothesis in that the native species A. cerana has higher toxin tolerance than the introduced species A. mellifera .
研究领域:
昆虫学
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毒理学
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生态学
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产品关联
DOI
PubMed
高影响因子
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