PLANT PHYSIOLOGY
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2024
·Vol. 197
·期 1
·
IF 6.5
Song Ru-Feng,Liao Cai-Yi,Wang Lin-Feng,Lu Kai-Kai,Zhang Chi,Wu Run-Xin,Wu Ji-Xiao,Ma Yu-Qing,Kuang Lei,Guo Ning,Yuan Hong-Mei,Liu Wen-Cheng
The plasma membrane (PM)-localized Na+/H+ antiporter Salt Overly Sensitive1 (SOS1) is essential for plant salt tolerance through facilitating Na+ efflux; however, how SOS1 localization and protein accumulation is regulated in plants remains elusive. Here, we report that Sorting Nexin 1 (SNX1) is required for plant salt-stress tolerance through affecting endosomal trafficking of SOS1 in Arabidopsis (Arabidopsis thaliana). Disruption of SNX1 caused salt hypersensitivity with increased Na+ accumulation and decreased Na+ efflux in Arabidopsis when challenged with high salinity stress. SNX1 co-localized and interacted with SOS1 in endosomes, promoting its PM localization and protein stability in plants under saline conditions. SOS1 overexpression promoted salt tolerance in the wild-type, whereas such effect was greatly compromised in the snx1-2 mutant. Pharmaceutical results showed that SOS1 recycling from the cytosol to the PM was largely blocked while its vacuolar degradation was accelerated in the snx1-2 mutant. Furthermore, salt-induced SOS1 phosphorylation enhanced its interaction and co-localization with SNX1, which is required for SOS1 PM localization in plants. Our study elucidates that SNX1 facilitates SOS1 PM localization and protein accumulation through endosomal trafficking, thereby enhancing salt tolerance in plants.
研究领域:
植物学
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分子生物学
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DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2012
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IF 6.499
Hongfang Zhang,Jinqiang Wang,Weiwei Mao,Jian Huang,Xianguo Wu,Youqing Shen,Meihua Sui
The clinical utility of CPT-11 is restricted by factors such as the low conversion rate to SN38 , high interpatient variability and dose-limiting toxicity. SN38 is significantly more potent than CPT-11, but parental administration of SN38 is impossible due to its poor solubility and low stability. This study aimed to develop a novel SN38 prodrug (OEG-SN38) that may overcome the various drawbacks of CPT-11 and SN38 and be useful for clinics. We attached a very low molecular weight oligo (ethylene glycol) (OEG) chain selected as the hydrophilic part to hydrophobic SN38 via ester bond at the C20 position to form the amphiphilic OEG-SN38. In aqueous solution OEG-SN38 formed micelles with diameter of 28.74 ± 2.51 nm, and showed greatly improved drug loading, solubility and stability, with drug loading as high as 36% (wt.%). Moreover, these micelles were stable in PBS with only 4.71% SN38 released from the prodrug even after 35 h incubation, but released SN38 promptly by esterase hydrolysis. Most importantly, OEG-SN38 exhibited potent antitumor activity against a panel of human tumor cell lines, as well as favorable antitumor activity and high safety in human xenograft models. These encouraging data merit further preclinical and clinical investigation on this novel SN38 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
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-16
·
IF 15.7
Peng Wang,Chen Shu,Ma Jingyu,Wei Wenjie,Lin Naixin,Xing Jinchao,Guo Wenjing,Li Heying,Zhang Liang,Chan Kuiming,Yen Andrew,Zhu Guangyu,Yue Jianbo
The interplay between lipid droplets (LDs) and endosomes remains unknown. Here, we screen and synthesize AP1-coumarin, an LD-specific probe, by conjugating a fluorescent dye coumarin to a triazine compound AP1. AP1-coumarin labels all stages of LDs in live cells and markedly induces the accumulation of enlarged RAB5-RAB7 double-positive intermediate endosomes. The AP1-coumarin-labeled LDs contact these intermediate endosomes, with some LDs even being engulfed in them. When LD biogenesis is inhibited, the ability of AP1-coumarin to label LDs is markedly reduced, and the accumulation of enlarged intermediate endosomes is abolished. Moreover, blocking the biogenesis of LDs decreases the number of late endosomes while increasing the number of early endosomes and inhibits the endosomal trafficking of low-density lipoprotein (LDL) and transferrin. Correspondingly, interference with RAB5 or RAB7, either through knockdown or using dominant-negative mutants, inhibits LD catabolism, whereas the expression of a RAB7 constitutively active mutant accelerates LD catabolism. Additionally, CCZ1 knockdown not only induces the accumulation of intermediate endosomes but also inhibits LD catabolism. These results collectively suggest that LDs and endosomes interact and influence each other’s functions, and endosomal trafficking participates in the catabolic process of LDs to maintain lipid homeostasis.
研究领域:
细胞生物学
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脂质代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Yan Zhang,Qin LiMiao,Feng MengFan,Xianghui Yu,Yuqing Wu
Small interfering RNA (siRNA), comprising 21-23 nucleotides, functions by complementary binding to specific mRNA sequences, thereby suppressing target protein expression. Despite their vast potential in disease therapy, siRNAs face challenges due to their susceptibility to degradation and high electronegativity, rendering them unstable in the bloodstream and impeding their passage across endothelial barriers. Moreover, successful intracellular delivery necessitates overcoming endosomal entrapment, posing a significant hurdle for carrier material development. In this study, leveraging the strong affinity of histidine oligomers (His6) for metal ions, we engineered nanoparticles (HmA) by gentle assembly with divalent zinc ions under pH=8 conditions. We designed the RNA-binding functional peptide L2-NTD to enhance siRNA stability and delivery efficiency when complexed with HmA. The resulting siRNA+L2-NTD@HmA nanoparticles were formed via in situ encapsulation, ensuring efficient siRNA delivery into cells with minimal cytotoxicity and degradation. This approach presents a novel strategy for the design and artificial fabrication of carriers for effective RNA delivery.
研究领域:
分子生物学
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药物递送
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jingming Niu,Yuanquan Ran,Qiong Hu,Nian Yang,Lanlan Yang,Huan Zhao,Bing Yang,Dongxin Tang,Minyi Tian
Ethnopharmacological relevance Eomecon chionantha , a traditional Chinese medicine, is a perennial herb widely cultivated for its medical properties and has been used to treat cancer. However, there are few studies on its anticancer properties. Aim of the study This work aimed to identify the chemical composition of E . chionantha root and firstly assess its anti-lung cancer effects in vitro and in vivo . Materials and methods E. chionantha root was extracted by reflux using different solvents in sequence to prepare petroleum ether extract (PEE), ethyl acetate extract (EAE), n-butanol extract (NBE), and water extract (WE). Phytoconstituent analysis of E. chionantha root WE was performed by UHPLC-Q-Orbitrap-MS. In in vitro assays, cytotoxicity of four samples from E. chionantha root on non-cancerous MRC-5 cell line and A549 lung cancer cell line was done by MTT. The impact of E. chionantha root WE on A549 cell proliferation was tested by colony formation assay, and flow cytometry with PI staining was utilized for evaluating its influence on the cell cycle. We performed morphological observations, AO/EB staining, Hoechst 33258 staining, and Annexin V-FITC/PI staining assays to investigate the capacity of E. chionantha root WE to induce A549 cell apoptosis. Wound healing and transwell invasion tests assessed its potential to inhibit A549 cell migratory and invasive abilities. Western blot was used to determine its effect on protein levels associated with proliferation, apoptosis, and metastasis in A549 cells. To further validate its in vivo anticancer efficiency, we established an A549 cell xenograft tumor nude mouse model, recorded tumor volume and weight, and conducted histopathological changes using H&E staining and TUNEL assay. Results Sixty-one constituents were identified from E . chionantha root WE. For in vitro anticancer properties, E . chionantha root WE displayed selective cytotoxicity against A549 cells (IC 50 = 5.39 ± 0.18 μg/mL) and lower toxicity to MRC-5 cells (IC 50 = 11.75 ± 1.10 μg/mL). E. chionantha root WE triggered G1 phase arrest via up-regulating p21 levels and down-regulating CDK4, CDK6, and cyclin D3 levels, which markedly suppressed A549 cell proliferation. It induced A549 cell apoptosis via a mitochondria-mediated pathway, leading to Bax up-regulation, ΔΨm down-regulation, Cyt C release, activation of caspase 9 and caspase 3, and PARP cleavage. In addition, it repressed the migratory and invasive abilities of A549 cells through lowering MMP-2 and N-cadherin levels. Regarding in vivo antitumor activity, E . chionantha root WE effectively inhibited A549 xenograft tumor growth and induced cell apoptosis in nude mice. Hence, E . chionantha root WE repressed A549 cell proliferation, induced apoptosis, and inhibited the migratory and invasive abilities in vitro and suppressed tumor growth by inducing apoptosis in vivo . Conclusions E. chionantha root WE exhibited pronounced anti-lung cancer efficiency in vivo and in vitro and can be considered a novel source of anticancer agents with great value for development in the pharmaceutical industry.
研究领域:
药理学
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肿瘤学
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植物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-15
·
IF 15.7
Liu Zhen,Wu Jiacai,Wang Ning,Lin Yongqi,Song Ruiteng,Zhang Min,Li Bin
Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.
研究领域:
分子生物学
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纳米医学
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药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2017
·Vol. 10
·期 3
·1063-1071
·
IF 7.367
Huahua Yue,Xiaoming Zhou,Meng Cheng,Da Xing
Direct cellular delivery of CRISPR/Cas9 complexes is of great significance for genome editing and other recently developed applications, such as gene expression regulation and RNA/DNA imaging. Here, we first constructed a graphene oxide (GO)-polyethylene glycol (PEG)-polyethylenimine (PEI) nanocarrier for the delivery of high-molecular-weight Cas9/single-guide RNA (sgRNA) complexes for endocytosis, endosomal escape, nuclear entry, and gene editing. The results demonstrate that the nanocarrier can be used successfully for efficient gene editing in human AGS cells with an efficiency of ∼39%. The results also show that this nanocarrier can protect sgRNA from enzymatic degradation, thus exhibiting extremely high stability, which is critical for future in vivo applications. Thus, this GO-mediated Cas9/sgRNA delivery system has potential as a new approach for biomedical research and targeted gene engineering applications.
研究领域:
生物技术
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遗传学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2023
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IF 5.2
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The emergence of liposomes has provided a breakthrough for the clinical use of highly toxic chemotherapeutic drugs . However, the clinical effects of conventional drug-loaded liposomes are unsatisfactory due to the lack of specific targeting of cancer cells and the inability to achieve endosome escape and controllable release in vivo. In this paper, a cRGD-PEOz-Hz-DOB (cPzD) molecule with specific targeting, endosomal escape, and endogenous acid-sensitive controlled release ability was creatively designed and synthesized to prepare drug-loaded liposomes cPzDGX encapsulating the anticancer drug Doxorubicin (DOX) in order to enhance the anticancer performance of DOX. The study found that the hydrazone bond in cPzD reached a breakage rate of 42% within 48 h at pH 5.0, so the cumulative release rate of cPzDGX at pH 5.0 for 48 h was as high as 82.9%, which was 22.5% higher than that at pH 7.4. Moreover, the uptake of cPzDGX in A549/ADR cells was increased by 62% at 2 h, and the expression of the green fluorescent protein gene EGFP was also increased by 36% relative to the targeting control group, indicating that cRGD modification could effectively improve the targeting ability of liposomes to cancer cells. In addition, it was demonstrated that PEOz modification could help drug carriers achieve endosome escape because the green fluorescent protein expression in the PEOz-modified liposome group was 60.5% higher than that in the PEG-modified group. Finally, the cell viability of the cPzDGX group decreased by 17.2% relative to the free DOX group when the DOX concentration was 1 μg/mL in the cytotoxicity assay, and the diameter reduction of 3D tumor MCs increased by 34.4%. And cPzDGX could effectively enhance the permeability of free DOX to solid tumors. The above results indicate that the DOX-loaded liposomes cPzDGX we designed have great prospects for the accurate and efficient treatment of cancer.
研究领域:
肿瘤学
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药剂学
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生物化学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Yun Zhu,Tingting Meng,Yanan Tan,Xiqin Yang,Yupeng Liu,Xuan Liu,Fangying Yu,Lijuan Wen,Suhuan Dai,Hong Yuan,Fuqiang Hu
The critical process and step in achieving effective antitumor therapies is facilitating endosomal escape, which can enhance the intracellular target delivery of therapeutics. However, the normally adopted approaches tend to result in colloidal instability as a result of the inevitable interactions between the resulting positively charged surfaces of micelles and proteins in vivo. Herein, negatively charged surface shielded polymeric micelles, consisting of polymethylacrylamide derivatives and hydrophilic chitosan (Mw = 18.8 kDa) linked by 3,3′-dithiodipropionic, are constructed. Until the pH decreases to less than 4.5, the DOX-loaded polymeric micelles (CSO-SS-PDPA/DOX) retain a negative surface charge as a result of the abundant amide groups, which could resist formation of the protein “corona” as visualized by transmission electron microscopy. Robust endosomal escape within tens of minutes due to protonated amine groups and specific redox-responsive drug release is visualized by confocal microscopy. The superior therapeutic efficacy in both 3D tumor spheroids and MCF-7 bearing mice further suggested that the prepared CSO-SS-PDPA/DOX is a promising approach for maintaining colloidal stability while achieving intracellular endosomal/lysosomal escape, which opens new opportunities for drug delivery.
研究领域:
药剂学
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生物医学工程
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2025
·
IF 4.1
Zengmei Lan,Yangli Tian,Chengang Li,Yudong Wang,Ping Yi,Rongying Zhang
P4-ATPases are phospholipid flippases responsible for the transbilayer lipid asymmetry. ATP8A1, a P4-ATPase family member, has been reported to be involved in phosphatidylserine (PS) translocation at the trans -Golgi network, early endosomes and recycling endosomes. However, the possible roles of the PS on late endosomes/lysosomes pathway and how they are regulated remain to be elucidated. This study showed enrichment of ATP8A1 in Rab7-positive late endosomal compartments, and that ATP8A1 primarily flips the endosomal PS from the luminal leaflet to the cytosolic leaflet but not the PS in the inner leaflet of the plasma membrane. ATP8A1 depletion accelerates the lysosome-destined cargo proteins transfer into the intraluminal vesicles (ILVs) of multivesicular bodies (MVBs) and alters the signaling of epidermal growth factor receptor. Mechanistically, ATP8A1 depletion leads to PS loading in the luminal leaflet of MVB’s limiting membrane, which fine-tunes ILVs initiation and endosomal sorting complex required for transport (ESCRT) component recruitment.
研究领域:
细胞生物学
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分子生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STAR Protocols
·
2025
·
IF 1.3
Peng Xu,Jianbo Yue
Summary Here, we present a protocol to study epidermal growth factor (EGF) receptor (EGFR) or transferrin trafficking in mammalian cells. We describe steps for using fluorescent ligands or antibodies, confocal imaging, and quantitative analysis to track their movement. We detail procedures for cell culture preparation, labeling membrane proteins, optimizing imaging, and isolating cell lysates for the biochemical analysis of EGFR degradation after EGF treatment. This protocol is adaptable to various cell types and for assessing genetic or pharmacological impacts on endosomal trafficking. For complete details on the use and execution of this protocol, please refer to Ye et al., 1 Ye et al., 2 and Wang et al. 3
研究领域:
细胞生物学
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分子生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2016
·Vol. 40
·期 11
·9806-9812
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IF 3.277
Zhibing Sun,Dezhong Zhou
Three oligomeric linear poly(beta-amino esters) (PAEs) were synthesized and used to improve the gene transfection efficiency and reduce the cytotoxicity of poly(L-lysine) (PLL). The synthesized PAEs can co-assemble with PLL and plasmid DNA to form PLL/PAE/DNA ternary complexes of nanoscale sizes and moderate surface charges. The existence of multiple tertiary amines on PAE backbones imparts the ternary complexes with strong proton buffering capacity and therefore enhances the endosomal escape ability of the ternary complexes. In HeLa cells, the PLL/PAE/DNA ternary complexes show up to 476-fold enhancement in gene transfection efficiency when compared with the PLL/DNA binary complexes. Meanwhile, the incorporation of PAE oligomers significantly reduced the cytotoxicity of PLL. The strategy proposed here may provide insights into the development of PLL based gene delivery systems.
研究领域:
生物化学
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分子生物学
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基因治疗
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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）