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
·
毒理学
·
肝病学
·
分子生物学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2019
·
IF 4.511
Caili Huang,Tao Zeng,Jiawen Li,Lishan Tan,Xiulong Deng,Yanchao Pan,Qi Chen,Aiqing Li,Jianqiang Hu
Triptolide (TP) has been widely used in clinical medicine; however, it has created a dilemma due to its toxicity and nonspecificity. Here, we reported a biocompatible and high-efficiency renal-targeting nanoplatform for renal ischemia/reperfusion injury (IRI) therapy, in which the toxic drug of TP was encapsulated into folate (FA)-modified Pluronic F127/P123 nanoparticles (FPNPs). The TP-loaded FPNPs (TP-FPNPs) had good stability and could effectively reduce the cytotoxicity of TP. Compared with the Pluronic nanoparticles (PNPs) group, cellular uptake ability of FPNPs significantly improved because of folate receptor-mediated endocytosis effect. Ex vivo organ imaging and pharmacokinetic results indicated that FPNPs possessed high kidney selectivity and long retention time. The therapeutic effect of TP-FPNPs on renal IRI was more superior to that of free TP, such as lower acute tubular injury index (2.9-fold), renal function indexes of serum creatinine (4.3-fold), urea nitrogen (2.0-fold), and Western blotting (2.4-fold). Systemic toxicity assay suggested that TP-FPNPs had much lower nephrotoxicity, hepatotoxicity, and genital system toxicity than free TP. Thus, renal-targeting FPNPs will be a potential delivery platform of hydrophobic drugs for treatment of renal diseases.
研究领域:
药学
·
纳米医学
·
肾脏病学
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DOI
PubMed
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
·
药理学
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DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 17
·4073
·
IF 4.2
Beihua Xu,Zhenyu Wang,Huimin Zhang,Xiao Xu,Mengjie Tang,Gang Wang,Zhongpeng Ding,Ruihao Yu,Meihong Ding,Ting Zhang,Senlin Shi
Objective: The aim of this study was to optimize the formulation of a C60-modified self-microemulsifying drug delivery system loaded with triptolide (C60-SMEDDS/TP) and evaluate the cytoprotective effect of the C60-SMEDDS/TP on normal human cells. Results: The C60-SMEDDS/TP exhibited rapid emulsification, an optimal particle size distribution of 50 ± 0.19 nm (PDI 0.211 ± 0.049), and a near-neutral zeta potential of −1.60 mV. The release kinetics of TP from the C60-SMEDDS/TP exhibited a sustained release profile and followed pseudo-first-order release kinetics. Cellular proliferation and apoptosis analysis indicated that the C60-SMEDDS/TP (with a mass ratio of TP: DSPE-PEG-C60 = 1:10) exhibited lower toxicity towards L02 and GES-1 cells. This was demonstrated by a higher IC50 (40.88 nM on L02 cells and 17.22 nM on GES-1 cells) compared to free TP (21.3 nM and 11.1 nM), and a lower apoptosis rate (20.8% on L02 cells and 26.3% on GES-1 cells, respectively) compared to free TP (50.5% and 47.0%) at a concentration of 50 nM. In comparison to the free TP group, L02 cells and GES-1 cells exposed to the C60-SMEDDS/TP exhibited a significant decrease in intracellular ROS and an increase in mitochondrial membrane potential (ΔψM). On the other hand, the C60-SMEDDS/TP demonstrated a similar inhibitory effect on BEL-7402 cells (IC50 = 28.9 nM) and HepG2 cells (IC50 = 107.6 nM), comparable to that of the free TP (27.2 nM and 90.4 nM). The C60-SMEDDS/TP group also exhibited a similar intracellular level of ROS and mitochondrial membrane potential compared to the SMEDDS/TP and free TP groups. Method: Fullerenol-Grafted Distearoyl Phosphatidylethanolamine-Polyethylene Glycol (DSPE-PEG-C60) was synthesized and applied in the self-microemulsifying drug delivery system. The C60-SMEDDS/TP was formulated using Cremophor EL, medium-chain triglycerides (MCT), PEG-400, and DSPE-PEG-C60, and loaded with triptolide (TP). The toxicity and bioactivity of the C60-SMEDDS/TP were assessed using normal human liver cell lines (L02 cells), normal human gastric mucosal epithelial cell lines (GES-1 cells), and liver cancer cell lines (BEL-7402 cells and HepG2 cells). The production of reactive oxygen species (ROS) after the C60-SMEDDS/TP treatment was assessed using 2′,7′-dichlorofluorescein diacetate (DCFDA) staining. The alterations in mitochondrial membrane potential (ΔψM) were assessed by measuring JC-1 fluorescence. Conclusions: The cytoprotection provided by the C60-SMEDDS/TP favored normal cells (L02 and GES-1) over tumor cells (BEL-7402 and HepG2 cells) in vitro. This suggests a promising approach for the safe and effective treatment of TP.
研究领域:
药理学
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生物医学工程
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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
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Hang Chen,Xinyu Wang,Mengmeng Liu,Jiefen Yang,Yanting Kuang,Ruting Wei,Zongguang Tai,Quangang Zhu,Zhongjian Chen,Jianming Chen,Xin Wu
The prognosis of pancreatic cancer (PCa) is extremely poor because of its resistance to conventional therapies. Many previous studies have demonstrated that triptolide (TPL) has a potent tumoricidal activity on PCa. However, the clinical application of TPL in tumor therapy has been greatly limited by its poor aqueous solubility, short half-time, high toxicity and inefficient delivery. Here, through the engineering of prodrug technology combined with the nanodrug-delivery system (NDDS) strategy, we modified the main active site of TPL C14-OH by esterification reaction to obtain a highly lipophilic prodrug, and then encapsulated the drug in a phospholipid bilayer in liposomal vehicles through the thin-film hydration method for efficient delivery. A delivery system based on TPL lignocerate liposomes (TPL-LA-lip) for drug loading for targeted therapy against PCa was established. Our results showed that TPL-LA demonstrates exceptional compatibility with the phospholipid layer of liposomes, thereby enhancing drug retention in liposomal vehicle and improving tumor targeting and cellular uptake. Moreover, The system of TPL-LA-lip exhibited a sustained drug release profile in vitro , and intravenous administration significantly impedes tumor progression while reducing the toxicity of TPL in the PCa mouse model. These results demonstrated that the prodrug-loaded liposomes could significantly reduce the toxicity of TPL and enhance the biosafety. Overall, this prodrug approach is a simple and effective method to transform the highly toxic TPL into a safe and efficacious nanomedicine with excellent in vivo tolerability for PCa treatment.
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DOI
PubMed
高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2026
·
IF 3.1
Shan-Shan Wang,Hong-Cheng Wei,Lin Jiang,Yi-Sen Shao
Tongue squamous cell carcinoma, the most aggressive subtype of oral squamous cell carcinoma, which is associated with high mortality, frequent recurrence, and early lymph-node metastasis. Triptolide, a bioactive diterpenoid from Tripterygium wilfordii , exhibits broad anticancer activity. Although its inhibitory action on OSCC has been established, its specific molecular regulatory mechanisms in TSCC, a distinct and aggressive subtype, remain largely underexplored. The present study investigates the regulatory role of triptolide in the PI3K–AKT signaling pathway, which is a critical axis intimately linked to tumor survival and metastasis. A network-pharmacology workflow was used to intersect triptolide putative targets with TSCC-related genes. Core hubs were identified with Cytoscape; KEGG and GO analyses highlighted the PI3K–AKT axis as the top enriched pathway. Binding kinetics were quantified by molecular docking and surface plasmon resonance (SPR). Cellular assays (CCK-8, Transwell, wound-healing, Western blot and immunofluorescence) validated the predictions. We retrieved 389 common targets and shortlisted eight key nodes (JUN, MAPK1, MAPK3, AKT1, TP53, BCL2, STAT3, MYC). SPR revealed high-affinity binding of triptolide to AKT1 and PI3K. Functionally, triptolide dose-dependently suppressed TSCC cell proliferation, invasion, and migration, downregulated PI3K–AKT signaling proteins, and reduced the colocalization and phosphorylation levels of p-PI3K and p-AKT. This study is the first to demonstrate the pivotal role of the PI3K–AKT signaling pathway in mediating the antitumor effects of triptolide in tongue squamous cell carcinoma. Our findings thereby provide a novel theoretical foundation for the development of traditional Chinese medicine-based therapeutic strategies targeting this malignancy.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Xiuying Li,Fengyuan Zhang,Xin Wang,Xizhu Chen,Qinqing Li,Yandong Li,Fan Zeng,Caixia Liu
Macrophage polarization imbalance is closely implicated in the pathogenesis of rheumatoid arthritis (RA). Triptolide (TP) can effectively regulate macrophage polarization but is severely limited by its high toxicity and narrow therapeutic window. Calycosin (CAL) not only alleviates TP-induced toxicity but also exhibits anti-inflammatory and chondroprotective effects, making their combination a promising strategy for safer and more effective RA therapy. However, this free combined therapy suffers from high dosage requirements and nonspecific systemic distribution in vivo . Herein, we developed a high drug-loading, lesion-targeted, and stimuli-responsive delivery system for co-delivery of TP and CAL. Using polyamidoamine (PAMAM) as the carrier, we fabricated a locked (LD)-type folate-targeted PAMAM nanomicelle (LD-PAMAM-TP&CAL) by coating a matrix metalloproteinases (MMPs)-responsive detachable PEG shell, based on MMPs overexpression in RA microenvironment. This engineered nanomicelle showed uniform morphology, high encapsulation efficiency, and MMPs-triggered conversion from a locked (LD) state to an open state for intelligent drug release. In vitro , it achieved folate receptor (FR)-mediated targeted macrophage uptake, regulated M1/M2 polarization, protected chondrocytes, and effectively resolved the toxicity-efficacy paradox of TP. In vivo , it significantly enhanced drug accumulation in arthritic joints, alleviated joint swelling and bone destruction in CIA rats, modulated inflammatory and bone-related factor expression, balanced synovial macrophage function, and ensured systemic safety. Collectively, this “Lock-and-Release” nanomicelle integrates functional carrier innovation, drug synergy, and inflammatory microenvironment-responsive intelligent lock-to-release behavior. It successfully overcomes the clinical bottlenecks of TP and enables high-efficiency, low-toxicity RA therapy via regulating macrophage polarization, providing a promising functional nanoplatform for clinical RA treatment.
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DOI
PubMed
高影响因子
Biotechnology & Genetic Engineering Reviews
·
2023
·
IF 3.2
Lei Zhao,Houbin Zhang,Peiyou Ren,Xiangjun Sun
Triptolide (TP) is involved in the progression of liver cancer. However, the detailed molecular network regulated through TP is still unclear. Long non-coding RNA (LncRNA) SLC9A3 exerts roles in various pathological progresses. Nevertheless, whether SLC9A3 affects the sensitivity of liver cancer cells to TP have not been uncovered. The content of SLC9A3-AS1 and miR-449b-5p was estimated by utilizing quantitative real-time polymerase-chain reaction (qRT-PCR). Cell counting kit 8 (CCK-8) assay was introduced to assess cell viability. Additionally, cell viability as well as invasion was tested via transwell assay. The direct binding between miR-449b-5p and SLC9A3-AS1 or LDHA was confirmed through luciferase reporter gene assay. Moreover, glycolysis rate was tested by calculating the uptake of glucose in addition to the production of lactate in Huh7 cells. LncRNA SLC9A3-AS1 was up-regulated in liver cancer tissue samples and cells. Knockdown of SLC9A3-AS1 notably further inhibited viability, migration as well as invasion in Huh7 cells. MiR-449b-5p was the direct downstream miRNA of SLC9A3-AS1 and was down-regulated by SLC9A3-AS1 in Huh7 cells. In addition, miR-449b-5p was reduced in liver cancer tissues and cells. Overexpressed miR-449b-5p increased the sensitivity of Huh7 cells to TP remarkably. Moreover, miR-449b-5p negatively regulated LDHA expression in Huh7 cells. This work proved that SLC9A3-AS1 increased the sensitivity of liver cancer cells to TP by regulating glycolysis rate mediated via miR-449b-5p/LDHA axis. These findings implied that TP is likely to be a potent agent for treating patients diagnosed with liver cancer.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Tianyang Wang,Cheng Huang,Ziyuan Fang,Abudureheman Bahatibieke,Danping Fan,Xing Wang,Hongyan Zhao,Yajie Xie,Kun Qiao,Cheng Xiao,Yudong Zheng
High oxidative stress and inflammatory cell infiltration are major causes of the persistent bone erosion and difficult tissue regeneration in rheumatoid arthritis (RA). Triptolide (TPL) has become a highly anticipated anti-rheumatic drug due to its excellent immunomodulatory and anti-inflammatory effects. However, the sudden drug accumulation caused by the binding of “stimulus-response” and “drug release” in a general smart delivery system is difficult to meet the shortcoming of extreme toxicity and the demand for long-term administration of TPL. Herein, we developed a dual dynamically cross-linked hydrogel (SPT@TPL), which demonstrated sensitive RA microenvironment regulation and microenvironment modulation-independent TPL release for 30 days. The abundant borate ester/tea polyphenol units in SPT@TPL possessed the capability to respond and regulate high reactive oxygen species (ROS) levels on-demand. Meanwhile, based on its dense dual crosslinked structure as well as the spontaneous healing behavior of numerous intermolecular hydrogen bonds formed after the breakage of borate ester, TPL could remain stable and slowly release under high ROS environments of RA, which dramatically reduced the risk of TPL exerting toxicity while maximized its long-term efficacy. Through the dual effects of ROS regulation and TPL sustained-release, SPT@TPL alleviated oxidative stress and reprogrammed macrophages into M2 phenotype, showing marked inhibition of inflammation and optimal regeneration of articular cartilage in RA rat model. In conclusion, this hydrogel platform with both microenvironment initiative regulation and TPL long-term sustained release provides a potential scheme for rheumatoid arthritis.
研究领域:
材料科学
·
药学
·
生物医学工程
·
风湿病学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2016
·Vol. 37
·期 11
·1467-1480
·
IF 3.166
Fu Yu,Lin Qing,Gong Tao,Sun Xun,Zhang Zhi-rong
Aim: We previously reported a novel triptolide (TP)-glucosamine conjugate (TPG) that specifically accumulated in kidneys and protected renal function from acute ischemia/reperfusion (I/R) injury in rats. In this study we further examined the molecular mechanisms underlying the renoprotective action of TPG. Methods: The renal-targeting of TPG was investigated in a human proximal renal tubular epithelial cell line (HK-2) by measuring cell uptake of TP or TPG. The effects of TP or TPG on cell cycle distribution and apoptosis rate of HK-2 cells were assessed, and the activities of caspase-3 and caspase-9 were also measured. SD rats were subjected to bilateral renal ischemia by temporarily clamping both renal pedicles. The rats were administered TP (4.17 μmol·kg −1 ·d −1 , iv) or TPG (4.17 μmol·kg −1 ·d −1 , iv) for 3 d before the renal surgery. The kidneys were harvested after 24 h of recovery from the surgery. The levels of oxidative stress, proinflammatory cytokines, chemotactic cytokines and intracellular adhesion molecules in kidneys were examined. Results: The uptake of TPG in HK-2 cells was 2–3 times higher than that of TP at the concentrations tested. Furthermore, TPG targeting the proximal tubules was mediated through interactions with megalin receptors. TP (40–160 nmol/L) concentration-dependently increased G 2 /M arrest, apoptosis and caspase-3/caspase-9 activity in HK-2 cells, whereas the same concentrations of TPG did not show those features when compared with the control group. In I/R-treated rats, TPG administration caused more robust down-regulation of proinflammatory cytokines (TNF-α, IL-6, IL-1, TGF-β) and chemotactic cytokines (MCP-1) in the kidneys compared with TP administration, suggesting the inhibition of the proliferation and accumulation of lymphocytes. And TPG administration also caused more prominent inhibition on the levels of oxidative stress and intracellular adhesion molecules in the kidneys, compared with TP administration. Conclusion: The renal-targeting TPG is more effective and less toxic than TP, in amelioration of I/R-induced rat renal injury, which may provide a new avenue for the treatment of acute kidney injury.
研究领域:
药理学
·
肾病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
IF 6.633
Wen Li,Yuzhu Fan,Chaoqun Yan,Yan Du,Tingting Liang,Chunqiang Wang,Liwei Wang,Lingling Han,Qingshan Li,Taigang Liang
The potential drug-drug interaction is essential to monitor for the combination therapy of Tripterygium wilfordii Hook F and methotrexate in rheumatoid arthritis, a Chinese clinical approach. The purpose was to investigate the binding mechanisms of triptolide, the active ingredient extracted from Tripterygium wilfordii Hook F, and methotrexate with BSA, individually and in combination, using multi-spectroscopic experiments, molecular docking, and molecular dynamic simulation. Fluorescence studies indicated that triptolide/methotrexate interacted with BSA at Site I through the static quenching mechanism and synchronous fluorescence, 3D fluorescence, and UV–vis absorption spectra obtained results for changes in micro-environmental polarity around amino acid residues. For the ternary system, methotrexate was replaced from the binding site as triptolide had a higher affinity for BSA, which possibly can result in an increased plasma drug concentration of methotrexate. Besides, CD studies implied that α-helix content of BSA decreased more when reacted with triptolide than methotrexate. Further, molecular docking and molecular dynamic simulation demonstrated that BSA-triptolide had lower binding energy compared with BSA-methotrexate due to the van der Waals forces, hydrogen bonds, and hydrophobic interactions. This study provided information about the safety of triptolide and methotrexate for synergistic clinical treatment of rheumatoid arthritis.
研究领域:
药理学
·
生物化学
·
分子生物学
·
临床医学
·
风湿病学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）