Nanomedicine
·
2026
·
IF 4.6
Jing Zhang,Dongdong Gao
Background Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with poor therapeutic outcomes due to drug resistance, systemic toxicity, and limited tumor-targeted drug delivery. This study aimed to develop dual-drug-loaded exosome nanocarrier encapsulating rapamycin (RAP) and Astragaloside IV (AST-IV) (RAP@AST-IV/EXO NC) to inhibit PI3K/Akt/mTOR signaling and enhance mitochondrial apoptosis in HCC.Methods Bone marrow mesenchymal stem cell-derived exosomes (BM-MSC-Exos) were isolated and used for co-delivery of RAP and AST-IV via sonication-assisted loading. Physicochemical properties, drug loading, and release behavior were evaluated. In vitro efficacy was assessed through cell viability, apoptosis, ROS generation, mitochondrial membrane potential, migration, and Western blot assays. In vivo therapeutic efficacy and safety were evaluated in male BALB/c mice bearing HepG2 xenografts.Results RAP@AST-IV/EXO NC showed favorable physicochemical characteristics, sustained drug release, enhanced apoptosis, increased ROS generation, mitochondrial membrane disruption, and inhibition of cancer cell migration. The RAP@AST-IV/EXO NC significantly reduced cell viability and suppressed phosphorylated PI3K, Akt, and mTOR expression while activating mitochondrial apoptotic markers. In vivo, RAP@AST-IV/EXO NC markedly inhibited tumor growth without evident systemic toxicity.Conclusion RAP@AST-IV/EXO NC represent a promising biocompatible strategy for targeted HCC therapy through combined PI3K/Akt/mTOR inhibition and mitochondrial apoptosis induction.
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DOI
高影响因子
Applied Materials Today
·
2022
·
IF 8.663
Hua Zhang,Haijie Zhao,Yan Huang,Guodong Sun,Yi Zhang
The combination of chemotherapy and immunotherapy (also known as chemo/immunotherapy) promoted by nanomedicine has the potential to enhance the therapeutic effect in more patient populations. However, it is still affected by the inactivation of immune cells induced by traditional chemotherapy, which greatly impairs the synergistic effect of chemotherapy/immunotherapy substantially. Moreover, once tumor cells lose their MHC expression, the current popular CD8 + T cell-based immunotherapy may fail consequently. Herein, rapamycin, as mTOR signaling inhibitor associated with serious side effect once systemically administered, was incorporated into shell-core theranostic nanoplatform to augment synergy of chemotherapy and γδ T cell-mediated MHC-unrestricted immunotherapy against tumor without toxicity on γδ T cells. This nano-platform assembled from a cleavable shell and a carbonized polymer dot core can achieve accurate delivery of rapamycin with traceable imaging and cascade response. Such cascaded responsiveness has endowed it with improved blood compatibility, effective tumor accumulation, microenvironment-selective endocytosis, and hierarchical drug release facilitated by microenvironment-triggered programmable properties (size shrinkage, charge conversion and degradability) transition responding to blood-tissue-cells multi-level biological barriers. In vitro and in vivo experiments have shown that the nanoplatform not only promotes tumor chemotherapy by down-regulating mTOR signals, but also enhances γδ T cell-mediated immunotherapy by promoting the NKG2D pathway in a microenvironment-selective manner. In addition, the TCR-δ knockout mouse model was used to verify the synergy of chemical/immunotherapy promoted by the nanoplatform. In addition to multifunctional integrated therapeutic and diagnostic strategies, we also provide a paradigm to enhance the synergistic effect of chemotherapy/immunotherapy, and broaden the horizons of immunotherapy through γδ T cell-mediated replacement therapy assisted by nano-drugs.
研究领域:
纳米医学
·
癌症治疗
·
免疫学
·
药学
·
生物医学工程
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DOI
高影响因子
CURRENT NEUROVASCULAR RESEARCH
·
2017
·Vol. 14
·期 2
·132-140
·
IF 2.298
Zhu Yingchun,Tang Qiqiang,Wang Guopin,Han Ruodong
Background: Tanshinone IIA is a key active ingredient of danshen, which is derived from the dried root or rhizome of Salviae miltiorrhizae Bge. The tanshinone IIA has protective effects against the focal cerebral ischemic injury. However, the underlying mechanisms remain unclear.
Methods: An in vitro model of cerebral ischemia was established by subjecting cultures of hippocampal neuronal cells to oxygen-glucose deprivation followed by reperfusion (OGD/R). The probes of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CMH2DCFDA)
and 5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine,iodide (JC-1) were used to determine the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production. Western-blot was used to detect the expression of proteins in HT-22 cells.
Results: The results of cell proliferative assays showed that the tanshinone IIA attenuated OGD/Rmediated neuronal cell death, with the evidence of increased cell viability. In addition, OGD/R exposure led to increase the levels of intracellular reactive oxygen species (ROS), which were
significantly suppressed by tanshinone IIA treatment. Furthermore, tanshinone IIA treatment inhibited elevations in MMP and autophagy following exposure to OGD/R. Additionally, OGD/R promoted cell death with concomitant inhibiting phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/
mammalian target of Rapamycin (mTOR) pathway, which was reversed by tanshinone IIA. Conclusion: These results suggest that the tanshinone IIA protects against OGD/R-mediated cell death in HT-22 cells, in part, due to activating PI3K/Akt/mTOR pathway.
研究领域:
神经科学
·
药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE WORLD AQUACULTURE SOCIETY
·
2020
·Vol. 53
·期 1
·133-150
·
IF 1.451
Dahai Gu,Jingying Zhao,Samwel Mchele Limbu,Yunan Liang,Junming Deng,Baoliang Bi,Lingfu Kong,Hui Yan,Xiaowen Wang,Qing Hu,Yu Gao,Dan Jia,Hua Rong
Arginine (Arg) is an important essential amino acid required for optimum fish growth. However, its role in plant-rich diets on growth and the required level in juvenile Hemibagrus wyckioides are currently unknown. This study evaluated the effects of Arg supplementation in plant-rich diets on growth, feed utilization, whole body composition, blood biochemical indicators and gene expressions of the target of rapamycin (TOR) signaling pathway in juvenile H. wyckioides . A total of 450 fish (6.40 ± 0.06 g) were randomized into six equal groups and fed on diets with graded Arg levels: 0 (control), 3, 6, 9, 12 and 15 g/kg of dry feed for eight weeks. The results revealed that specific growth rate (SGR) and feed conversion ratio of juvenile H. wyckioides were significantly improved and reduced, respectively in fish fed on 9 g/kg of Arg supplementation ( p < .05). The optimum amount of dietary Arg content in plant-rich diets for H. wyckioides was 63.77 g/kg diet based on SGR. Feeding fish with dietary Arg supplementation ranging from 9 to 12 g/kg improved significantly ( p < .05) whole body protein contents and decreased lipid deposition. The mRNA levels of TOR, eukaryotic translation initiation factor 4E (4EBP) and ribosomal protein S6 kinase 1 (S6K1) in muscle and liver were significantly affected by increasing dietary Arg levels. Meanwhile, the mRNA relative expression levels of TOR and S6K1 in the liver and muscle increased significantly as Arg supplementation increased. On the other hand, the mRNA relative expression levels of 4EBP was significantly higher in fish fed on the 9 g/kg Arg diet compared to those fed on the control and 15 g/kg Arg diets. In conclusion, our current results indicate that dietary Arg supplementation in plant-rich diets, might activate the TOR signaling pathway, which promotes protein synthesis and reduces lipid accumulation of H. wyckioides , resulting in improved growth.
研究领域:
水产养殖
·
营养学
·
分子生物学
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DOI
高影响因子
REPRODUCTION FERTILITY AND DEVELOPMENT
·
2021
·Vol. 33
·期 12
·700-712
·
IF 2.311
Xin Zhan,Yiran Xie,Liping Sun,Qi Si,Hongkai Shang,Xin Zhan,Yiran Xie,Liping Sun,Qi Si,Hongkai Shang
This study explored the molecular mechanism underlying the effects of dexamethasone (DEX, 1 µM) on glucose transporters (GLUT) in JEG-3 human placental choriocarcinoma cells. JEG-3 cells were treated with DEX, an expression plasmid encoding human glucocorticoid receptor α (GRα), pcDNA3.1-GRα, GRα short interference (si) RNA, LY294002, xanthine oxidase (XO)/hypoxanthine (HX), rapamycin, insulin-like growth factor (IGF) 1, N-acetylcysteine (NAC) or phosphatidic acid (PA), and cell proliferation, apoptosis, mitochondrial membrane potential (MMP), human chorionic gonadotrophin (hCG) content, human placental lactogen (hPL) content, glucose uptake, reactive oxygen species levels and signalling pathway modulation were evaluated. Treatment of JEG-3 cells with DEX (1 µM), GRα siRNA, LY294002 (50 µM), XO/HX (7.2 µM/36 nM) or rapamycin (80 nM) inhibited cell proliferation, induced apoptosis, significantly decreased MMP and hCG and hPL content and increased ROS levels. In addition, glucose uptake was decreased through downregulation of the mRNA and protein expression of GRα, GLUT1 and GLUT3. Treatment of JEG-3 cells with GRα siRNA, LY294002, XO/HX or rapamycin inhibited phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, glycogen synthase kinase 3 and mammalian target of rapamycin (mTOR) and induced the phosphorylation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex 2. The effects of GRα overexpression and IGF1 (100 nM), NAC (5 nM) or PA (100 µM) treatment on JEG-3 cells contrasted with those of DEX treatment. DEX blocked glucose uptake by downregulating GRα expression, which reduced GLUT1 and GLUT3 mRNA and protein expression, which, in turn, may have inhibited the PI3K/AKT/mTOR pathway and activated the ROS/AMPK pathway.
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产品关联
DOI
PubMed
高影响因子
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