MOLECULES
·
2022
·Vol. 27
·期 12
·3686
·
IF 4.927
Xinlong Wang,Huahui Zeng,Xin Zhu,Duanjie Xu,Qikang Tian,Can Wang,Lingzhou Zhao,Junwei Zhao,Mingsan Miao,Xiangxiang Wu
Triptolide (TP) is a potential drug candidate for the treatment of cancer, but its use was hampered by its systemic toxicity and poor water solubility. Hence, a TP-CSO prodrug was synthesized by conjugating TP to chitosan oligosaccharide (CSO), and characterized by1H NMR, FTIR, DSC and XRD analyses. The TP-CSO containing about 4 wt% of TP exhibited excellent water solubility (15 mg/mL) compared to TP (0.017 mg/mL). Compared with TP, the pharmacokinetics of the conjugate after oral administration showed a three-fold increase in the half-life in the blood circulation and a 3.2-fold increase in AUC(0–∞). The orally administered TP-CSO could more effectively inhibit tumor progression but with much lower systemic toxicity compared with TP, indicating significant potential for further clinical trials. In conclusion, CSO-based conjugate systems may be useful as a platform for the oral delivery of other sparingly soluble drugs.Keywords:triptolide;toxicity;water solubility;pharmacokinetics;pancreatic cancer
研究领域:
药学
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癌症研究
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药物递送系统
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DOI
PubMed
高影响因子
Materials Express
·
2023
·Vol. 13
·期 8
·1339-1345
·
IF 0.7
Liao Wanrong,Fang Wang,Xu Juan
Lung cancer is a common malignancy of the respiratory system with a high morbidity and mortality. We intended to identify the apoptosis-promoting role of tripterine in lung cancer. Lung cancer SPC-A-1 cells were exposed to low, moderate, and high dosage of tripterine (2, 5 and 10 μmol/L)
with the model group not being intervened. After treatment, the role of tripterine in SPC-A-1 cell apoptosis was observed. In addition, lung cancer cells were transfected with TNF-α mimic (pc-TNF-α group) and TNF-α inhibitor (si-TNF-α group).
Tripterine +pc-TNF-α group was set up to determine the interaction between tripterine and TNF-α. The cell survival rate, TNF-α and Caspase-3 expression levels then were detected by MTT and flow cytometry. Tripteryglide treatment dose-dependently decreased
lung cancer cell viability and induced cell apoptosis, resulting in an increase of TNF-α expression. However, when TNF-α expression was inhibited upon transfection, SPC-A-1 cell apoptosis was suppressed. TNF-α mimics activated apoptosis and up-regulated
Caspase-3 expression. Combination of tripteryglide and TNF-α mimics more significantly elevated apoptotic rate of lung cancer cells when elevating the content of Caspase-3. SPC-A-1 cells are highly sensitive to TNF-α and TNF-α significantly increases
the activity and expression of Caspase-3. Tripteryglide can up-regulate TNF-α expression to facilitate lung cancer cell apoptosis and increase Caspase-3 expression.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Ping Zhou,Chonghao Chen,Xuan Yue,Jinming Zhang,Chi Huang,Shiyi Zhao,Anxing Wu,Xuebo Li,Yan Qu,Chen Zhang
Osteoarthritis (OA) is a chronic disease that seriously impairs people’s physical function and quality of life. Triptolide (TP), as a promising anti-inflammatory drug for the treatment of OA, has limited clinical application due to its severe systemic toxicity, poor solubility and rapid elimination in the body. To extend its application prospect for OA treatment. We have developed a liposome-loaded dissolving microneedle (DMN) system, which can effectively deliver poorly water-soluble TP and improve OA symptoms. To incorporate TP into DMNs, triptolide liposome (TP-Lipo) with entrapment efficiency of 90.25% was prepared by ethanol injection. Subsequently, TP-Lipo was concentrated by ultrafiltration tube and mixed with hyaluronic acid solution to prepare DMNs, TP-Lipo-loaded DMNs (TP-Lipo@DMNs) showed sufficient mechanical and insertion properties to penetrate about 200 μm of rat skin. The drug distribution in vivo showed that TP-Lipo@DMNs had a slow-release effect compared with intra-articular injection. In vivo pharmacodynamic research showed that TP-Lipo@DMNs significantly reduced knee joint swelling and the level of inflammatory cytokines (TNF-α, IL-1β, IL-6). Micro-CT and histological evaluation showed that TP-Lipo@DMNs effectively reduced cartilage destruction and alleviated OA symptoms. These results support that TP@Lipo@DMNs may be a promising option for OA treatment.
研究领域:
药剂学
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生物医学工程
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风湿病学
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DOI
PubMed
高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2024
·Vol. 26
·期 4
·1-18
·
IF 2.1
Lu Zhimeng,Yan Kun,Liu Chunlei,Wang Jiapeng,Yu Guiping,Zhang Hao
Tripterygium wilfordii Hook F, a traditional medicine in China has bioactive but toxic triptolide (TP, a diterpenoid triepoxide) as its main active constituents. The applications of TP are hampered by its prominent toxicity and low solubility in water. In this study, a safe pH-sensitive material [methoxy polyethylene glycol (mPEG)- adipic dihydrazide (ADH)] was synthesized and loaded with TP to form pH-sensitive polymeric micelles, thereby improving the safety and solubility of TP, as well as providing a theoretical basis for the wide application of TP. The mPEG-ADH/TP micelles were characterized by a series of indicators [namely entrapment efficiency (EE), critical micellar concentration (CMC), electrokinetic potential, stability, polydispersed index (PDI), and particle size]. Also, we ascertained the in vitro release of TP from mPEG-ADH/TP micelles along with pharmacokinetic investigations in vivo. Besides, we evaluated the cytotoxicity of mPEG-ADH/TP micelles against A549 cells, HCT116 cells, and HaCat cells and further conducted in vivo toxicity studies in rats. The TP-loaded mPEG-ADH micelles had smaller sized particles (48.3 nm), excellent PDI (0.142), stable property and higher EE (89.87%). Importantly, the TP in the mPEG-ADH/TP micelles was almost completely released at acidic pH (pH 5.0), while the drug was released slowly and sparingly at physiological pH (pH 7.4). The results suggest the release of TP from mPEG-ADH/TP micelles was sensitive to pH, which could facilitate targeting of the drug into intra-cellularly low pH endosomes and lysosomes as well as enhance cytotoxicity in cancer tissues. Moreover, mPEG-ADH/TP micelles exhibited excellent proliferation inhibition on tumor cells. In addition, the liver injury of rats in the 1 mg/kg dose of mPEG-ADH/TP micelles group was significantly reduced by Hematoxylin–eosin (HE) staining. Taken together, mPEG-ADH/TP micelles could act as a promising alternative to enhance the efficacy of oncologic treatments.
研究领域:
药理学
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肿瘤学
·
药物递送系统
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF NEUROSCIENCE
·
2019
·
IF 1.852
Yi Wang,Song Zhang,Zijian Li,Huanhuan Zeng,Hua Xian,Yingru Huang
Purpose: To investigate the effects of triptolide (T10) on the cellular activity of cryopreserved rat sciatic nerves and nerve regeneration after allotransplantation.Materials and methods: After the optimal T10 concentration was determine, sciatic nerve fragments from Sprague-Dawley (SD) rats were randomly divided into 5 groups: the fresh nerve group (group A), the Dulbecco’s modified Eagle’s medium (DMEM)-preservation group (group B), the T10-preservation group (group C), the T10-pretreatment, DMEM-preservation group (group D), and the T10-pretreatment, T10-preservation group (group E). The nerves in the preservation groups were preserved at 4 °C for 4 w. Then, either cryopreserved or fresh nerves were used to repair 10-mm sciatic nerve defects in Wistar rats (group A′, group B′, group C′, group D′, and group E′, which correspond to the nerve groups described above); in addition, one fresh homologous transplantation group (group F′) was established.Results: Nerve growth factor (NGF) was expressed at significantly higher levels in the groups treated with the T10 solution at 37 °C. After rat sciatic nerves were cryopreserved for 4 w, group E had increased numbers of live nerve cells and increased levels of biological activity (P < 0.001) and reduced levels of immunogenicity (P < 0.001) when compared with those for the other groups. Sixteen weeks after transplantation, recipient nerve regeneration in group E′ was increased compared with that in groups A′, B′, C′, and D′ (P < 0.05).Conclusions: The application of T10 in vitro induced the expression of neurotrophic factors in rat sciatic nerves, increased the biological activity of cryopreserved nerves, reduced immunogenicity, and promoted recipient nerve regeneration after allotransplantation.
研究领域:
神经科学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 3
·1252
·
IF 6.208
Jing Yang,Xujiao Tang,Xue Ke,Yutong Dai,Jinsong Shi
Triptolide (TP), the main active ingredient ofTripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.Keywords:acute pancreatitis;triptolide;inflammatory responses;oxidative stress
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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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2020
·Vol. 12
·期 3
·202
·
IF 4.421
Lan Zhang,Min Yan,Kun Chen,Qikang Tian,Junying Song,Zijuan Zhang,Zhishen Xie,Yong Yuan,Yaquan Jia,Xin Zhu,Zhenqiang Zhang,Xiangxiang Wu,Huahui Zeng
A new platform for triptolide (TP) delivery was prepared by conjugating TP to a carboxylmethyl chitosan (CMCS). Compared with the natural TP, the TP-conjugate (TP-CMCS) containing TP of ~5 wt% exhibited excellent aqueous solubility (>5 mg/mL). Results of in vitro experiments showed that TP-CMCS could relieve TP-induced inhibition on RAW264.7 cells and apoptosis, respectively. Compared with the TP group, TP-CMCS could effectively alleviate the toxicity injury of TP and decreased the mortality rate of the mice (p< 0.05). TP-CMCS did not cause much damage to the liver (AST and ALT) and kidney (BUN and CRE) (p< 0.05). After administration, the levels of IL-6, IL-1β, and TNF-α decreased, and the arthritis detumescence percentages increased significantly, and the bony erosion degree was distinctly decreased in the TP-CMCS groups and TP group. Our results suggested that TP-CMCS was a useful carrier for the treatment of RA, which enhanced aqueous solubility of free TP and reduced drug toxicity in vitro and in vivo.Keywords:triptolide;toxicity;water solubility;carboxylmethyl chitosan;drug carrier system
研究领域:
药理学
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生物医学工程
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风湿病学
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DOI
PubMed
高影响因子
Communications Biology
·
2019
·Vol. 2
·期 1
·1-11
·
IF 0
Lin Yanke,Wang Shuai,Zhou Ziyue,Guo Lianxia,Yu Fangjun,Wu Baojian
Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.
研究领域:
药理学
·
分子生物学
·
时间生物学
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产品关联
DOI
PubMed
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Qihang Guo,Yue Mao,Jiyu Zhang,Yangyang Zhou,Yue Zhao,Ying Li,Jinglong Lv,Huiyu Yang,Bingrong Liu
Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting NOXA transcriptional activity and activating the NOXA-BCL2 axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the NOXA-BCL2 axis signaling pathway. This treatment is both safe and effective, presenting a promising prospect for combined therapeutic application in ESCC management.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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中医药学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Ke Wang,Huina Hu,Wenbo Cui,Xuelian Zhang,Qi Tang,Nuan Liu,Xianyong Lan,Chuanying Pan
As a widely existing traditional Chinese medicine component, TP (triptolide) has serious reproductive toxicity which causes severe damage to the reproductive system and limits its application prospect. TP and MET (metformin) have shown great potential in combined with each other in anticancer and anti-inflammatory. Whether metformin can resist the reproductive toxicity caused by triptolide, the effects of MET on TP-induced reproductive capacity has not been reported. In this study, metformin was used to investigate the therapeutic effect on reproductive toxicity induced by TP in rat. The results showed that metformin had significant therapeutic effects on oxidative stress damage, destruction of the blood-testosterone barrier and apoptosis. And it proved that its therapeutic effect is mainly to restore the structural and functional stability of testis through antioxidant stress. It will provide guidance for the treatment of reproductive toxicity caused by TP and the adjuvant detoxification of TP application.
研究领域:
药理学
·
生殖生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Chen Xu,Ri-jin Song,Pei Lu,Jian-chun Chen,Yong-qiang Zhou,Gang Shen,Min-jun Jiang,Wei Zhang
Aim To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study.Materials and methods The nanocarrier was constructed by conjugating 3,3′-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment.Results Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group.Conclusion These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.
研究领域:
药剂学
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肿瘤学
·
生物材料
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DOI
PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 3
·821
·
IF 5.4
Yuehong Ren,Chunli Qi,Shuxian Ruan,Guangshang Cao,Zhiguo Ma,Xingwang Zhang
The oral delivery of insoluble and enterotoxic drugs has been largely plagued by gastrointestinal irritation, side effects, and limited bioavailability. Tripterine (Tri) ranks as the hotspot of anti-inflammatory research other than inferior water-solubility and biocompatibility. This study was intended to develop selenized polymer-lipid hybrid nanoparticles loading Tri ([email protected]) for enteritis intervention by improving its cellular uptake and bioavailability.[email protected]were fabricated by a solvent diffusion-in situ reduction technique and characterized by particle size, ζ potential, morphology, and entrapment efficiency (EE). The cytotoxicity, cellular uptake, oral pharmacokinetics, and in vivo anti-inflammatory effect were evaluated. The resultant[email protected]were 123 nm around in particle size, with a PDI of 0.183, ζ potential of −29.70 mV, andEEof 98.95%.[email protected]exhibited retardant drug release and better stability in the digestive fluids compared with the unmodified counterpart (Tri-PLNs). Moreover,[email protected]manifested higher cellular uptake in Caco-2 cells as evidenced by flow cytometry and confocal microscopy. The oral bioavailability of Tri-PLNs and[email protected]was up to 280% and 397% relative to Tri suspensions, respectively. Furthermore,[email protected]demonstrated more potent in vivo anti-enteritis activity, which resulted in a marked resolution of ulcerative colitis. Polymer-lipid hybrid nanoparticles (PLNs) enabled drug supersaturation in the gut and the sustained release of Tri to facilitate absorption, while selenium surface engineering reinforced the formulation performance and in vivo anti-inflammatory efficacy. The present work provides a proof-of-concept for the combined therapy of inflammatory bowel disease (IBD) using phytomedicine and Se in an integrated nanosystem. Selenized PLNs loading anti-inflammatory phytomedicine may be valuable for the treatment of intractable inflammatory diseases.Keywords:tripterine;selenium;polymer-lipid hybrid nanoparticles;bioavailability;enteritis;anti-inflammation
研究领域:
药学
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纳米技术
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炎症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）