The Exosome-Mediated Cascade Reactions for the Transfer and Inflammatory Responses of Fine Atmospheric Particulate Matter in Macrophages

Exposure to atmospheric particulate matter (PM) is a frequent occurrence to humans, and their adverse outcomes have become a global concern. Although PM-induced inflammation is a common phenomenon, a clear picture of the mechanisms underlying exosome-mediated inflammation of PM has not yet emerged. Here, we show that exosomes can mediate the cascade reactions for the transfer of PM and inflammatory responses of macrophages. Specifically, two fine PM2.5, namely F1 (<0.49 μm) and F2 (0.95–1.5 μm), stimulated a substantial release of exosomes from macrophages (THP-1 cells) with the order of F1 > F2, via regulation of the P2X7 receptor (P2X7R). Inhibiting P2X7R with a specific inhibitor largely prevented the secretion of exosomes. In particular, we found that exosomes served as a mediator for the transfer of PM2.5 to the recipient macrophages and activated NF-κB signaling through toll-like receptor 4 (TLR-4), thereby stimulating inflammatory cytokine release and altering the inflammatory phenotype of recipients. Importantly, the exosomes derived from PM2.5-treated macrophages induced the inflammatory responses of lung in mice. Our results highlight that exosomes undergo a secretion–particle transfer–adverse outcome chain in macrophages treated with PM2.5. Given the ubiquitous atmospheric particulate matter, these new findings underscore an urgent need for assessing the secretion of exosomes and their impact on human health via exosome-centric physiological pathways

Plastin 3 down-regulation augments the sensitivity of MDA-MB-231 cells to paclitaxel via the p38 MAPK signalling pathway

Plastin 3 (PLS3) overexpression may serve as a marker for predicting chemotherapeutic outcomes in drug-resistant cancer cells, but the mechanism is unclear. Herein, we show that the down-regulation of PLS3 by PLS3 gene silencing augments the sensitivity of MDA-MB-231 triple-negative breast cancer cells to paclitaxel. Interestingly, a low concentration of paclitaxel was able to induce strong apoptosis in the PLS3-silenced cells. Further study revealed that p38 MAPK signalling was responsible for the increased sensitivity to paclitaxel in these cells, as the p38 MAPK inhibitor SB203580 impaired the changes mediated by PLS3 down-regulation in response to paclitaxel. Therefore, our study identifies PLS3 as a potential target for enhancing the p38 MAPK-mediated apoptosis induced by paclitaxel. Unlike paclitaxel, Abraxane was unable to induce strong apoptosis in the PLS3-silenced cells. As PLS3 was found to be involved in the process of endocytosis in breast cancer cells, the reliance of cellular Abraxane uptake on this process may render it not as efficient as paclitaxel in PLS3-depleted tumour cells. The finding that PLS3 could be a critical regulator of paclitaxel sensitivity may have important implications for breast cancer chemotherapy.</p

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

Secretome Analyses of Aβ_1–42 Stimulated Hippocampal Astrocytes Reveal that CXCL10 is Involved in Astrocyte Migration

Amyloid-beta (Aβ) aggregation plays an important role in the development of Alzheimer’s disease (AD). In the AD brain, amyloid plaques are surrounded by reactive astrocytes, and many essential functions of astrocytes have been reported to be mediated by protein secretion. However, the roles of activated astrocytes in AD progression are under intense debate. To provide an in-depth view of the secretomes of activated astrocytes, we present in this study a quantitative profile of rat hippocampal astrocyte secretomes at multiple time points after both brief and sustained Aβ_1–42 stimulation. Using SILAC labeling and LC–MS/MS analyses, we identified 19 up-regulated secreted proteins after Aβ_1–42 treatment. These differentially expressed proteins have been suggested to be involved in key aspects of biological processes, such as cell recruitment, Aβ clearance, and regulation of neurogenesis. Particularly, we validated the role played by CXCL10 in promoting astrocyte aggregation around amyloid plagues through <i>in vitro</i> cell migration analysis. This research provides global, quantitative profiling of astrocyte secretomes produced on Aβ stimulation and hence provides a detailed molecular basis for the relationship between amyloid plaques and astrocyte aggregation; the findings thus have important implications for further investigations into AD development and therapy

E. coli Membrane Vesicles as a Catalase Carrier for Long-Term Tumor Hypoxia Relief to Enhance Radiotherapy

Hypoxia is one of the most important factors that limit the effect of radiotherapy, and the abundant H2O2 in tumor tissues will also aggravate hypoxia-induced radiotherapy resistance. Delivering catalase to decompose H2O2 into oxygen is an effective strategy to relieve tumor hypoxia and radiotherapy resistance. However, low stability limits catalase’s in vivo application, which is one of the most common limitations for almost all proteins’ internal utilization. Here, we develop catalase containing E. coli membrane vesicles (EMs) with excellent protease resistance to relieve tumor hypoxia for a long time. Even treated with 100-fold of protease, EMs showed higher catalase activity than free catalase. After being injected into tumors post 12 h, EMs maintained their hypoxia relief ability while free catalase lost its activity. Our results indicate that EMs might be an excellent catalase delivery for tumor hypoxia relief. Combined with their immune stimulation features, EMs could enhance radiotherapy and induce antitumor immune memory effectively