ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yishi Lu,Ziyue Zu,Nan Zhong,Yang Li,Xuan Sha,Shangyu Lu,Jie Zhang,Hanyao Sun,Xi Luo,Ziqing Xu,Feiyun Wu,Yuxia Tang,Shouju Wang
Autophagy blockade has emerged as a promising strategy to enhance the antitumor efficacy of pancreatic ductal adenocarcinoma (PDAC). However, autophagy inhibition in PDAC may induce compensatory macropinocytosis to maintain cellular homeostasis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, lysosomal-activated nanoreactors loaded with the NRF2 inhibitor ML385 (CPZI-Ms) are developed to spatiotemporally block autophagy and inhibit macropinocytosis. The nanoreactors, which preferentially accumulate in lysosomes, undergo degradation in the acidic lysosomal environment, triggering a Fenton-like reaction between the released Cu 2 ⁺ ions and H₂O₂ to generate hydroxyl radicals. This results in lysosomal membrane permeabilization, which further leads to not only lysosomal autophagy blockade, but also the leakage of Cu 2 ⁺ and ML385 into the cytoplasm. Cu 2 ⁺ induces extensive oxidative stress throughout the whole cell, while ML385 suppresses compensatory macropinocytosis response activated by autophagy blocking. As a result, the Panc02 cells become a “besieged fortress”, with impaired autophagic clearance and restricted nutrient uptake. In vivo, CPZI-Ms effectively suppress tumor growth in Panc02-bearing mice, offering a promising nanoplatform for enhancing cancer cell killing. Taken together, the present work provides an innovative anti-tumor insight by spatiotemporally blocking autophagic flux and inhibiting compensatory macropinocytosis.
研究领域:
肿瘤学
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药理学
·
纳米医学
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产品关联
DOI
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2024
·
IF 1.4
Chen Xue,Kang Yulai,Tang Chunhua,Zhang Lili,Guo Lu
Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential non-receptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/ml lipopolysaccharide (LPS) and 200 μg/ml native LDL (nLDL). We observed a significant increase in TLR4 protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.
研究领域:
心血管生物学
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细胞生物学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
Biomedical Materials
·
2023
·Vol. 18
·期 4
·045019
·
IF 4
Yingyu Ma,Lei Chen,Lian Deng,Xuebing Li,Xiu Zhao,Daobing Jiang,Jiabao Liu,Yang Song,Junda Liu,Nan Cui,Neng Qiu
Podophyllotoxin (PPT) is an active natural pharmaceutical component with potent anticancer activity. However, due to its poor water solubility and serious side effects, its medical applications are limited. In this work, we synthesized a series of PPT dimers, which can be self-assembled into stable nanoparticles of 124–152 nm in aqueous solution and can significantly increase the solubility of PPT in aqueous solution. In addition, PPT dimer nanoparticles exhibited high drug loading capacity (>80%) and could store at 4 °C in aqueous state with good stability for at least 30 d. In vitro release studies showed that nanoparticles with disulfide bonds (SS NPs) can quickly release (about 96.5% drug released within 24 h) the conjugated drug in PBS buffer (pH = 7.4) in the presence of DTT. Cell endocytosis experiments showed that SS NPs enhanced cell uptake (18.56 times higher than PPT for Molm-13, 10.29 times for A2780S and 9.81 times for A2780T) and maintained antitumor effect against human ovarian tumor cells (A2780S and resistant A2780T) and human breast cancer cells (MCF-7). In addition, the endocytosis mechanism of SS NPs was revealed that these nanoparticles were mainly up-taken by macropinocytosis-mediated endocytosis. We believe that these PPT dimer-based nanoparticles will become an alternative formula for PPT, moreover the assembly behavior of PPT dimer can be extended to other therapeutic drugs.
研究领域:
药学
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纳米技术
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癌症研究
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Ziming Zheng,Xianglin Pan,Haoyu Wang,Zhijing Wu,Mitchell A. Sullivan,Yuxuan Liu,Junxi Liu,Kaiping Wang,Yu Zhang
Lentinan (LNT), a typical triple helix β-glucan extracted from Lentinus edodes, has been widely used as a functional food and an orally administered drug. However, its oral pharmacokinetics has been rarely reported. The aim of this work is to systematically study the pharmacokinetics and intestinal absorption mechanism of LNT after oral administration. Radioactive 99m-technetium (99mTc) was introduced to label LNT to determine the plasma concentration, tissue distribution, and excretion of the β-glucan in rats after oral administration. The results confirmed the absorption of LNT, with the maximal plasma concentration reached at 1 h. 5-([4,6-Dichlorotriazin-2-yl]amino)fluorescein (DTAF) was used to label LNT to explore the absorption mechanism of LNT, utilizing both a Ussing chamber and a monolayer of Caco-2 cells. These transport assays showed that LNT could penetrate through the intestine and epithelial monolayer, which was mediated by macropinocytosis and clathrin-mediated endocytosis. These findings provide a pharmacokinetic reference for LNT and help provide a greater understanding of the absorption of β-glucans in general.
研究领域:
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2018
·
IF 13.709
Chunlei Zhang,Amin Zhang,Wenxiu Hou,Tianliang Li,Kan Wang,Qian Zhang,Jesús M de la Fuente,Weilin Jin,Daxiang Cui
Biological systems provide the richest spectrum of sophisticated design for materials engineering. We herein provide a paradigm of Au22(SG)18-engineered (SG, glutathione thiolate) and hydrogen bonds engaged assemblies for mimicking capsid protein self-assembly. The water-evaporation-induced self-assembly method allows discrete ultrasmall gold nanoclusters (GNCs) to be self-assembled into super-GNCs assemblies (SGNCs) ranging from nano-, meso- to microscale in water-dimethyl sulfoxide binary solvents in a template-free manner. After removing free and hydration layer water molecules, the formation of SGNCs is engaged by the collective cohesion of hydrogen bonds between glutathione ligands of gradually approaching GNCs. Then, a series of tightly orchestrated cellular events induced by the complexes of Au22(SG)18-engineered assemblies and folic acid are demonstrated to mimic the invasion of eukaryotic cells by pathogens. First, the activation of macropinocytosis mimics the macropinocytic entry used by the pathogens to invade host cells. Then the cytoplasmic vacuolization is a mimicry of vacuolating effects induced by the oligomeric vacuolating toxins secreted by some bacteria. Lastly, the escaping from macropinosomes into cytosol is in a vacuolating toxin’s strategy. The findings demonstrate the capabilities of artificial pathogens to emulate the structures and functions of natural pathogens.
研究领域:
纳米技术
·
材料科学
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细胞生物学
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仿生学
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2018
·
IF 5.738
Jie Zhou,Aisha Roshan Mohamed Wali,Shengnan Ma,Yiyan He,Dong Yue,James Zhenggui Tang,Zhongwei Gu
In the progress of designing a gene carrier system, what is urgently needed is a balance of excellent safety and satisfactory efficiency. Herein, a straightforward and versatile synthesis of a cationic guanidine-decorated dendronized pullulan (OGG3P) for efficient genetic photodynamic therapy was proposed. OGG3P was able to block the mobility of DNA from a weight ratio of 2. However, G3P lacking guanidine residues could not block DNA migration until at a weight ratio of 15, revealing guanidination could facilitate DNA condensation via specific guanidinium-phosphate interactions. A zeta potential plateau (∼+23 mV) of OGG3P complexes indicated the nonionic hydrophilic hydroxyl groups in pullulan might neutralize the excessive detrimental cationic charges. There was no obvious cytotoxicity and hemolysis, but also enhancement of transfection efficiency with regard to OGG3P in comparison with that of native G3P in Hela and HEK293T cells. More importantly, we found that the uptake efficiency in Hela cells between OGG3P and G3P complexes was not markedly different. However, guanidination caused changes in uptake pathway and led to macropinocytosis pathway, which may be a crucial reason for improved transfection efficiency. After introducing a therapeutic pKillerRed-mem plasmid, OGG3P complexes achieved significantly enhanced KillerRed protein expression and ROS production under irradiation. ROS-induced cancer cells proliferation suppression was also confirmed. This study highlights the guanidine-decorated dendronized pullulan could emerge as a reliable nonviral gene carrier to specifically deliver therapeutic genes.
研究领域:
药学
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生物医学工程
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Plant Science
·
2023
·
IF 5.6
Haihong Chen,Yiyi Hu,Guanpin Yang,Pingping Li,Jingru Yin,Xiaoqing Feng,Qiong Wu,Jingyu Zhang,Baoheng Xiao,Zhenghong Sui
Macropinocytosis is an endocytic process that plays an important role in animal development and disease occurrence but until now has been rarely reported in organisms with cell walls. We investigated the properties of endocytosis in a red alga, Gracilariopsis lemaneiformis . The cells non-selectively internalized extracellular fluid into large-scale endocytic vesicles (1.94 ± 0.51 μm), and this process could be inhibited by 5-(N-ethyl-N-isopropyl) amiloride, an macropinocytosis inhibitor. Moreover, endocytosis was driven by F-actin, which promotes formation of ruffles and cups from the cell surface and facilitates formation of endocytotic vesicles. After vesicle formation, endocytic vesicles could be acidified and acquire digestive function. These results indicated macropinocytosis in G. lemaneiformis . Abundant phosphatidylinositol kinase and small GTPase encoding genes were found in the genome of this alga, while PI3K, Ras, and Rab5, the important participators of traditional macropinocytosis, seem to be lacked. Such findings provide a new insight into endocytosis in organisms with cell walls and facilitate further research into the core regulatory mechanisms and evolution of macropinocytosis.
研究领域:
植物学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
·
2024
·Vol. 221
·期 7
·e20240111
·
IF 12.6
Xue Yun,Chen Yuting,Sun Sijia,Tong Xinyuan,Chen Yujia,Tang Shijie,Wang Xue,Bi Simin,Qiu Yuqin,Zhao Qiqi,Qin Zhen,Xu Qin,Ai Yingjie,Chen Leilei,Zhang Beizhen,Liu Zhijie,Ji Minbiao,Lang Meidong,Chen Luonan,Xu Guoliang,Hu Liang,Ye Dan,Ji Hongbin
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)–mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3–CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to–cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
研究领域:
肿瘤学
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免疫学
·
分子生物学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2012
·
IF 3.35
Liqian Mo,Lianbing Hou,Dan Guo,Xiaoyan Xiao,Ping Mao,Xixiao Yang
Many studies have demonstrated the uptake mechanisms of various nanoparticle delivery systems with different physicochemical properties in different cells. In this study, we report for the first time the preparation and characterization of teniposide (VM-26) poly( d , l -lactide-co-glycolide) (PLGA) nanoparticles (NPs) and their cellular uptake pathways in human glioblastoma U87MG cells. The nanoparticles prepared with oil-in-water (O/W) single-emulsion solvent evaporation method had a small particle size and spherical shape and provided effective protection against degradation of teniposide in PBS solution. Differential scanning calorimeter (DSC) thermograms concluded that VM-26 was dispersed as amorphous or disordered crystalline phase in the PLGA matrix. A cytotoxicity study revealed that, in a 24 h period, blank PLGA NPs had no cytotoxicity, whereas teniposide-loaded PLGA NPs (VM-26-NPs) had U87MG cytotoxicity levels similar to free teniposide. Confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) images showed the distribution and degradation processes of nanoparticles in cells. An endocytosis inhibition test indicated that clathrin-mediated endocytosis and macropinocytosis were the primary modes of engulfment involved in the internalization of VM-26-NPs. Our findings suggest that PLGA nanoparticles containing a sustained release formula of teniposide may multiplex the therapeutic effect and ultimately degrade in lysosomal within human glioblastoma U87MG cells.
研究领域:
药学
·
纳米技术
·
癌症研究
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-12
·
IF 4.259
Sun Xin-Yuan,Gan Qiong-Zhi,Ouyang Jian-Ming
Urinary crystals with various sizes are present in healthy individuals and patients with kidney stone; however, the cellular uptake mechanism of calcium oxalate of various sizes has not been elucidated. This study aims to compare the internalization of nano-/micron-sized (50 nm, 100 nm, and 1 μm) calcium oxalate monohydrate (COM) and dihydrate (COD) crystals in African green monkey renal epithelial (Vero) cells. The internalization and adhesion of COM and COD crystals to Vero cells were enhanced with decreasing crystal size. Cell death rate was positively related to the amount of adhered and internalized crystals and exhibited higher correlation with internalization than that with adhesion. Vero cells mainly internalized nano-sized COM and COD crystals through clathrin-mediated pathways as well as micron-sized crystals through macropinocytosis. The internalized COM and COD crystals were distributed in the lysosomes and destroyed lysosomal integrity to some extent. The results of this study indicated that the size of crystal affected cellular uptake mechanism, and may provide an enlightenment for finding potential inhibitors of crystal uptake, thereby decreasing cell injury and the occurrence of kidney stones.
研究领域:
细胞生物学
·
肾病学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2021
·Vol. 23
·期 5
·1-14
·
IF 2.253
Yang Shuoye,Niu Yakun,Li Luheng,Liu Jiaxin,Ma Mengjin,Duan Xiaoyu,Zhang Lu,Wang Le,Qu Lingbo
Coenzyme Q10 (CoQ10) has a wide range of physiological functions and therapeutic value. However, its biomedical application as a health product or drug is limited by its insolubility and low bioavailability. Single-walled carbon nanotubes (SWCNTs) have attracted great interest for drug or therapeutic agent delivery due to their unique properties. In this study, the pristine SWCNTs are purified with different oxidizing acid, and the resulting shortened CNTs (CNTs-COOH) are conjugated with poly-(ethylene glycol) (PEG) groups. Afterwards, CoQ10 is loaded by CNTs carriers. CNTs carriers are systematically characterized and evaluated in terms of drug loading, in vitro release, cytotoxicity, and cellular uptake. The results reveal that the sizes (length) of CNTs-COOH and CNTs-PEG are 253.2 and 328.7 nm, respectively, and they have high loading capacity for CoQ10 and low cytotoxicity toward Caco-2 cells. In comparison with CNTs-COOH, CNTs-PEG exhibited better sustained-release property for CoQ10. Also, CNTs-PEG carriers loaded with CoQ10 can be effectively delivered into cells and have enhanced cellular uptake efficiency over time. Further study results of the uptake mechanism illustrate that CNTs-PEG can be internalized into cells through the broader and more efficient entry routes, including direct penetration, clathrin-mediated endocytosis and macropinocytosis pathway. In summary, the PEG-conjugated CNTs may be used as novel nanocarriers, and the findings will contribute to the rational design of multifunctional delivery vehicles for CoQ10. Graphical abstract
研究领域:
纳米技术
·
药学
·
生物医学工程
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
RSC Advances
·
2017
·Vol. 7
·期 66
·41779-41786
·
IF 3.108
Zhou Yang,Fan Wu,Hongjie Yang,Ping Zhou
A novel protein tyrosine phosphatase 1B (PTP1B) inhibitor, FYGL, extracted from Ganoderma lucidum, was first reported to have an efficient hypoglycemic effect and high safety in vivo in our previous study. However, the underlying mechanism of the anti-diabetes activity was still unclear. The dominant effective component of FYGL was demonstrated to be a neutral hyperbranched proteoglycan macromolecule. Therefore, it is necessary to first elucidate how the biomacromolecule works at the cellular level, in order to understand its possible functional mechanism in vivo. Herein, we focused on demonstrating the cell internalization and endocytosis mechanism of FYGL in HepG2 cells. A series of cellular uptake pathways was explored, including clathrin-mediated endocytosis, caveolae/lipid-mediated endocytosis, and macropinocytosis. Confocal laser scanning microscopy and flow cytometry were used to demonstrate the absorption of FYGL by HepG2 cells. Furthermore, pharmacologically selective inhibitors and Western blot methods were used to demonstrate that macropinocytosis mediated by c-Src/PI3K cascades was the preferred route for the uptake of FYGL in cells. Our study provided the basis of uptake of FYGL for an efficient hypoglycemic effect. The functional mechanism of the signaling pathway in vivo will be reported in the future.
研究领域:
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）