本周hzangs在最新文献中选取了8篇分享给大家，第1篇文章研究发现放疗诱发的花生四烯酸积累会促进肿瘤细胞释放更多包含亚精胺合酶的细胞外囊泡，造成放疗诱发的肌肉损伤；第2篇文章研究发现心理压力通过细胞外囊泡调控肿瘤神经支配和进展；第6篇文章报道了脐带来源的细胞外囊泡在脊柱手术中的应用；第8篇文章报道了神经元来源细胞外囊泡内容物可以预测唐氏患者的痴呆进展。
- Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation.
花生四烯酸触发原发性肿瘤分泌亚精胺合酶，从而在照射后引起骨骼肌无力。
[Cell Metab] PMID: 40541182
Abstract: Radiotherapy reduces the risk of cancer recurrence and death, but the fact that it's accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify that cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles to trigger skeletal muscle weakness upon radiotherapy. Mechanistically, irradiation-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of the SRM protein, facilitating SRM packaging into extracellular vesicles from the primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon radiotherapy, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of radiotherapy-mediated muscle weakness when combined with losartan treatment.
- Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer via extracellular vesicle transfer of RNA.
心理压力引起的 ALKBH5 缺乏通过 RNA 的细胞外囊泡转移促进肿瘤神经支配和胰腺癌。
[Nat Cell Biol] PMID: 40419796
Abstract: The pathological role and mechanism of psychological stress in cancer progression are little known. Here we show in a mouse model that psychological stress drives pancreatic ductal adenocarcinoma (PDAC) progression by stimulating tumour nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerves to release noradrenaline, downregulating RNA demethylase alkB homologue 5 (Alkbh5) in tumour cells. Alkbh5 deficiency in these cancer cells causes aberrant N6-methyladenosine (m6A) modification of RNAs, which are packed into extracellular vesicles and delivered to nerves in the tumour microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are inversely correlated with tumour innervation and survival time in patients with PDAC. Animal experiments identify a natural flavonoid, fisetin, that prevents neurons from taking in extracellular vesicles containing m6A-modified RNAs, thus suppressing the excessive innervation and progression of PDAC tumours. Our study sheds light on a molecular mechanism by which crosstalk between the neuroendocrine system and cancer cells links psychological stress and cancer progression and raises a potential strategy for PDAC therapy.
- Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation.
中性粒细胞分泌外泌体相关 DNA 来解决无菌急性炎症。
[Nat Cell Biol] PMID: 40404894
Abstract: Acute inflammation, characterized by a rapid influx of neutrophils, is a protective response that can lead to chronic inflammatory diseases when left unresolved. We previously showed that secretion of LTB4-containing exosomes via nuclear envelope-derived multivesicular bodies is required for effective neutrophil infiltration during inflammation. Here we report that the co-secretion of these exosomes with nuclear DNA facilitates the resolution of the neutrophil infiltrate in a mouse skin model of sterile inflammation. Activated neutrophils exhibit rapid and repetitive DNA secretion as they migrate directionally using a mechanism distinct from suicidal neutrophil extracellular trap release and cell death. Packaging of DNA in the lumen of nuclear envelope-multivesicular bodies is mediated by lamin B receptor and chromatin decondensation. These findings advance our understanding of neutrophil functions during inflammation and the physiological relevance of DNA secretion.
- Heat shock proteins function as signaling molecules to mediate neuron-glia communication in C. elegans during aging.
热休克蛋白作为信号分子，在衰老过程中介导秀丽隐杆线虫中的神经元-神经胶质细胞通讯。
[Nat Neurosci] PMID: 40533573
Abstract: The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interactions on the cell membrane. Here we show a new mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of Caenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1-XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.
- Short-Term Severe Energy Restriction Promotes Molecular Health and Reverses Aging Signatures in Adults With Prediabetes in the PREVIEW Study.
PREVIEW 研究表明，短期严重能量限制可促进分子健康并逆转糖尿病前期成年人的衰老特征。
[Aging Cell] PMID: 40524498
Abstract: Prediabetes, characterized by impaired fasting glucose and/or glucose tolerance, is associated with organ damage, increased mortality, and accelerated aging, even before diabetes onset. Severe short-term energy restriction while maintaining essential nutrient intake is among the most effective strategies for weight loss, metabolic health improvement, and delaying type 2 diabetes progression. Extracellular vesicles contribute to these metabolic benefits; however, the impact of energy-restriction-induced weight loss on the extracellular vesicle proteome remains incompletely understood. This study employed targeted and untargeted proteomics to investigate the effect of an 8-week severely energy-restricted diet on the plasma proteome in adults with prediabetes from Sydney, Australia, as part of the PREVIEW study. Circulating extracellular vesicles were enriched in plasma using an immunoaffinity-based protocol. A total of 44 participants who achieved at least a 12% weight loss and provided informed consent were included in the study. Paired changes in over 2000 proteins between baseline and week 8 were analyzed. Following the intervention, multiple proteins associated with inflammation and senescence were significantly reduced, reversing the increase commonly associated with aging. The decline in inflammatory and senescence markers may have been mediated by extracellular vesicles, as indicated by significantly lower circulating levels of several vesicular markers. Additionally, several markers of protein synthesis downstream of mTORC1 and protein degradation were significantly reduced in vesicle-enriched plasma, suggesting decreased intercellular secretion and/or trafficking. Overall, this study identifies a diet-induced proteomic signature suggestive of reduced inflammation, lower senescence, and enhanced vesicle-associated proteostasis, potentially conferring health benefits beyond glycemic control.
- First-In-Human Application of Human Umbilical Cord-Derived Extracellular Vesicles in Tethered Spinal Cord Release Surgery.
人类脐带来源的细胞外囊泡在脊髓栓系释放手术中的首次人体应用。
[J Extracell Vesicles] PMID: 40536443
Abstract: Spina bifida is a congenital neural tube defect that has a high risk of secondary neurological deterioration due to tethering of the spinal cord. We present the first application of human umbilical cord-derived mesenchymal stromal cell-derived extracellular vesicle (UC-MSC-EV) therapy in humans during spina bifida surgery. We discuss the application, post-operative outcome and highlight the potential of extracellular vesicle therapy in the management of spina bifida. Administration of extracellular vesicles containing therapeutically active agents has emerged as a potential new treatment modality for neurological disorders. By direct intrathecal application during surgery, UC-MSC-EVs can deliver therapeutic payloads to target cells and the extracellular environment, offering a novel approach to neuroprotection and tissue repair. A 2-year-old girl diagnosed with spina bifida presented with progressive syringomyelia as sign of secondary tethered cord syndrome with intramedullary dermoid inclusion tumour after postnatal spina bifida repair. After pre-operative assessment and multidisciplinary consultation, it was decided to proceed with spinal cord release surgery with the use of EV. During the surgical procedure, the tethered cord was released, dermoid and lipoma tissue were resected. Concurrently, UC-MSC-EVs were administered directly onto the released placode and spinal cord. Post-operative MRI demonstrated a good de-tethering effect and no medullary oedema. No adverse events were reported. The neurological deficit remained unchanged at 6 months follow-up examination. Intraoperative application of UC-MSC-EVs might be an option to ameliorate intrathecal scarring following spina bifida surgery. Whether EVs will result in significant effects for the long-term neurological outcome needs to be studied in randomised clinical trials.
- Engineering of CD63 Enables Selective Extracellular Vesicle Cargo Loading and Enhanced Payload Delivery.
CD63 工程化改造实现了选择性细胞外囊泡货物装载和增强有效载荷运送。
[J Extracell Vesicles] PMID: 40527733
Abstract: Extracellular vesicles (EVs) are mediators of intercellular communication through the transfer of nucleic acids, lipids and proteins between cells. This property makes bioengineered EVs promising therapeutic vectors. However, it remains challenging to isolate EVs with a therapeutic payload due to the heterogeneous nature of cargo loading into EVs. In this study, enrichment of EVs with a desired cargo was possible through engineering of the hallmark CD63 transmembrane protein. E-NoMi refers to engineered CD63 with mCherry on the inside of the EV membrane and a tag (3xFLAG) exposed on the outside of the EV membrane. To facilitate EV loading during biogenesis, cargo proteins, such as EGFP, Cre recombinase and the CRISPR-Cas nuclease (SaCas9), were fused to a nanobody (Nb) protein with a high affinity for mCherry. FLAG-tag-based immunocapture from cell conditioned media allowed selection of cargo-loaded E-NoMi-EVs, and tobacco etch virus (TEV) protease cleavage sites were used to remove the 3xFLAG-tag from the surface of E-NoMi-EVs after capture. For functional payload delivery to recipient cells, the vesicular stomatitis virus G (VSV-G) fusogenic protein was incorporated into E-NoMi-EVs to form fusogenic EV-based vectors (EVVs) and proved to be 10-fold more effective at cargo delivery than EVs generated by size-exclusion chromatography. Functional delivery of cargo with E-NoMi-EVVs was validated in two mouse brain models in vivo.
- Cargo of small extracellular vesicles from neuronal origin shows progression of dementia in individuals with Down syndrome.
来自神经元的小细胞外囊泡的货物显示唐氏综合症患者的痴呆症进展。
[Alzheimers Dement] PMID: 40524460
Abstract: Introduction: Individuals with Down syndrome (DS) are at an ultra-high risk of developing Alzheimer's disease (AD). Diagnosis of AD onset in people with DS can be challenging due to the variable degrees of intellectual disability and cognitive impairment among individuals. Methods: Plasma samples from individuals with DS diagnosed with AD dementia (n = 33), prodromal AD (n = 31), or cognitively stable (n = 43) were enriched for neuron-derived extracellular vesicles (NDEV) using immunocapture with the L1CAM antibody. We used single-molecule array technology to quantify amyloid-β (Aβ) peptides, Tau, phosphorylated Tau, neurofilament light chain (NfL), and synaptosomal-associated protein 25 (SNAP25) across diagnostic groups. Results: NDEV levels of Aβ40, Aβ42, Tau, pTauT181, pTauT231, NfL, and SNAP25 were significantly higher in people with DS diagnosed with prodromal AD compared to those with no cognitive decline. Middle-aged or older women had higher levels of NDEV biomarkers compared to males. Discussion: NDEV biomarker levels can inform on the onset of AD in individuals with DS.
今天的整理就到这里。希望大家可以有所收获。大家下周见！
