Advanced Science
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2024
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IF 14.3
Jiankun Zang,Yousheng Wu,Xuanlin Su,Kaiwei Cai,Man Ke,Niu He,Huili Zhu,Zefeng Tan,Jielin Zhu,Wensheng He,Min Peng,Shiqing Zhang,Hongcheng Mai,Anding Xu,Dan Lu
Small extracellular vesicles (sEVs) contain abundant circular RNAs (circRNAs) and are involved in cellular processes, particularly hypoxia. However, the process that packaging of circRNAs into neuronal sEVs under hypoxia is unclear. This study revealed the spatial mechanism of the Fused in Sarcoma protein (FUS) that facilitates the loading of functional circRNAs into sEVs in hypoxia neurons. It is found that FUS translocated from the nucleus to the cytoplasm and is more enriched in hypoxic neuronal sEVs than in normal sEVs. Cytoplasmic FUS formed aggregates with the sEVs marker protein CD63 in cytoplasmic stress granules (SGs) under hypoxic stress. Meanwhile, cytoplasmic FUS recruited of functional cytoplasmic circRNAs to SGs. Upon relief of hypoxic stress and degradation of SGs, cytoplasmic FUS is transported with those circRNAs from SGs to sEVs. Validation of FUS knockout dramatically reduced the recruitment of circRNAs from SGs and led to low circRNA loading in sEVs, which is also confirmed by the accumulation of circRNAs in the cytoplasm. Furthermore, it is showed that the FUS Zf_RanBP domain regulates the transport of circRNAs to sEVs by interacting with hypoxic circRNAs in SGs. Overall, these findings have revealed a FUS-mediated transport mechanism of hypoxia-related cytoplasmic circRNAs loaded into sEVs under hypoxic conditions.
研究领域:
神经科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Chemical & Biomedical Imaging
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2023
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IF 0
Yan Zhang,Ning Xu,Chunyu Yan,Xuelian Zhou,Qinglong Qiao,Lu Miao,Zhaochao Xu
The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid–liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.
研究领域:
神经退行性疾病
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细胞生物学
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生物化学
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分子生物学
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DOI
EXPERIMENTAL NEUROLOGY
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2022
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IF 5.62
Shusheng Wu,Yuye Yin,Longfei Du
As is the case with neurodegenerative diseases , abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke . However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis . FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke.
研究领域:
神经科学
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病理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
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2024
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IF 3.9
Jin Tian,Shihuan Zhou,Yanli Chen,Yuyan Zhao,Song Li,Piao Yang,Xianlin Xu,Yongzheng Chen,Xiaoling Cheng,Jiawei Yang
Graphical An unconventional biocatalytic oxidation-reduction cascade system with cofactor regeneration was established for the synthesis of enantiopure sulfoxides using prochiral sulfildes as substrates. Heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were prepared in >90 % conversion with >90 % ee through the cascade catalysis of MsrA, Fus-SMO and three other auxiliary enzymes (Trx, Trx-R, and GDH). Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating “non-selective oxidation and selective reduction” cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this “one-pot, one step” cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess ( ee ) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.
研究领域:
生物化学
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有机合成
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酶工程
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2022
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IF 7.033
Zhengyue Kang,Min Yang,Xiaoling Feng,Hongjian Liao,Zhifei Zhang,Yonghong Du
Purpose Triple negative breast cancer (TNBC) is challenging for effective remission due to its very aggressive, extremely metastatic and resistant to conventional chemotherapy. Herein, a multifunctional theranostic nanoparticle was fabricated to enhance tumor targeted imaging and promote focused ultrasound (FUS) ablation and chemotherapy and sonodynamic therapy (SDT). A multi-modal synergistic therapy can improve the therapeutic efficacy and prognosis of TNBC.Methods AS1411 aptamer modified PEG@PLGA nanoparticles encapsulated with perfluorohexane (PFH) and anti-cancer drug doxorubicin (DOX) were constructed (AS1411-DOX/PFH-PEG@PLGA) to enhance tumor targeted imaging to guide ablation and synergistic effect of FUS/chemotherapy. FUS was utilized to trigger the co-release of doxorubicin and simultaneously PFH phase transition and activate DOX for SDT effect. The physicochemical, phase-changeable imaging capability, biosafety of nanoparticles and multi-mode synergistic effects on growth of TNBC were thoroughly evaluated in vivo and in vitro.Results The synthesized AS1411-DOX/PFH-PEG@PLGA (A-DPPs) nanoparticles are uniformly round with an average diameter of 306.03 ± 5.35 nm and the zeta potential of −4.05 ± 0.13 mV, displaying high biosafety and FUS-responsive drug release in vitro and in vivo. AS1411 modified NPs specifically bind to 4T1 cells and elevate the ultrasound contrast agent (UCA) image contrast intensity via PFH phase-transition after FUS exposure. Moreover, the combined treatment of A-DPPs nanoparticles with FUS exhibited significantly higher apoptosis rate, stronger inhibitory effect on 4T1 cell invasion in vitro, induced more reactive oxygen species (ROS), and enhanced anti-tumor effect compared to a single therapy (p < 0.05). Additionally, the joint strategy resulted in more intense cavitation effect and larger ablated areas and reduced energy efficiency factor (EEF) both in vitro and in vivo.Conclusion The multifunctional AS1411-DOX/PFH-PEG@PLGA nanoparticles can perform as a marvelous synergistic agent for enhanced FUS/chemotherapy, promote real-time contrast enhanced US imaging and improve the therapeutic efficacy and prognosis of TNBC.
研究领域:
肿瘤学
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纳米技术
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医学影像
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癌症治疗
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生物医学工程
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2022
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IF 10.383
Pengying Wu,Zhen Ya,Yan Li,Mingting Zhu,Lei Zhang,Yujin Zong,Shifang Guo,Mingxi Wan
The combination of checkpoint blockade with focused ultrasound (FUS) physical therapy can enhance antitumor immune response by improving the precision and efficiency of immunotherapy. However, one of the major disadvantages of conventional FUS treatment is the small lesion size, which prolongs treatment duration. We constructed a focused acoustic vortex (FAV) system with a hollow cylindrical focal region, which exhibited a larger focal region compared to conventional FUS of the same frequency. We developed an all-in-one synergistic therapy against metastatic breast cancer based on integrated FAV double combination sequence-regulated phase-transformation nanodroplets (CPDA@PFH) with checkpoint blockade immunotherapy. A single treatment with FAV + CPDA@PFH resulted in 2.25-fold higher inhibition of tumor growth compared to that with FUS + CPDA@PFH. In addition, FAV-regulated CPDA@PFH combined with ICB induced a systemic immune response that not only inhibited the growth of primary (98.41% inhibition rate) and distal (80.71%) 4T1 tumors but also reduced the progression of lung metastasis. In addition, the synergistic therapy achieved long-term immune memory that effectively prevented tumor growth and improved the survival time of mice. The long-term survival rate of 4T1 tumor-bearing mice treated with FAV + CPDA@PFH + Anti-PD-L1 was 57.14% on day 60 after treatment. Our study is a proof-of-concept of cascade-amplified synergistic tumor therapeutics based on ultrasonic-hyperthermia, cavitation, sonodynamic therapy (SDT), and checkpoint blockade immunotherapy through FAV-regulated CPDA@PFH phase-transformation nanodroplets.
研究领域:
肿瘤学
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生物医学工程
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免疫疗法
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诊疗一体化
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
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2023
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IF 6.1
Wen-Pu Shi,Wen-Juan Lin,Wan-Yi Ge,Liang-Liang Chen,Tuo-Di Zhang,Wei-Hong Guo,Jian-Li Liu,Da-Chuan Yin
The abnormal accumulation of fused in sarcoma (FUS) is a pathological hallmark in a proportion of patients with frontotemporal dementia and amyotrophic lateral sclerosis. Therefore, the clearance of FUS aggregates is a possible therapeutic strategy for FUS-associated neurodegenerative diseases. This study reports that curcumin can strongly suppress FUS droplet formation and stress granule aggregation of FUS. Fluorescence spectra and isothermal titration calorimetry showed that curcumin can bind FUS through hydrophobic interactions, thereby reducing the β-sheet content of FUS. Aggregated FUS sequesters pyruvate kinase, leading to reduced ATP levels. However, results from a metabolomics study revealed that curcumin changed the metabolism pattern and differentially expressed metabolites were enriched in glycolysis. Curcumin attenuated FUS aggregation-mediated sequestration of pyruvate kinase and restored cellular metabolism, consequently increasing ATP levels. These results indicate that curcumin is a potent inhibitor of FUS liquid–liquid phase separation and provide novel insights into the effect of curcumin in ameliorating abnormal metabolism.
研究领域:
神经科学
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分子生物学
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药理学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
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2024
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IF 5.3
Wan-Yi Ge,Wen-Pu Shi,Xue-Ting Wang,Huan Liang,Xu-Dong Deng,Liang-Liang Chen,Xiao-Qian Jin,Wei-Hong Guo,Da-Chuan Yin
Protein liquid–liquid phase separation (LLPS) is a significant process in biology and material sciences. Finding suitable conditions for protein LLPS is essential for its in-depth and systematic study. Here, we provide a mixed solution screening kit based on biomacromolecule crowding agents to find protein LLPS conditions. The screening kit consists of 96 chemical formulations, in which the biomacromolecule crowding agents are used as the key components. The aqueous solution of the target protein is mixed with each chemical agent in the kit and then placed in an incubator for some time. The LLPS conditions for the target protein can be found by examining the LLPS phenomena in the droplets. We used nine proteins as model target proteins—lysozyme, bovine serum albumin, bovine hemoglobin, ovalbumin, catalase, FUS, Aβ, Tau, and α-Synuclein—to evaluate the performance of the screening kit. We found that utilization of the screening kit is efficient and useful to find different conditions for LLPS of proteins. The screening results reveal two types of conditions: those that promote and those that inhibit LLPS. Both conditions are extremely valuable because those that promote LLPS can be used to do extensive studies on the LLPS processes of the proteins of interest, whereas those that inhibit LLPS can be utilized as leads for developing novel medications to treat LLPS-related disorders. Furthermore, novel applications for the kit were investigated by utilizing the screening products.
研究领域:
生物学
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材料科学
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生物物理学
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药学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）