奈米銀（AgNPs）已在家庭、醫療和工業領域中廣泛作為抗菌劑。在果蠅中，奈米銀透過飲食暴露後會誘導ROS介導的細胞反應，例如：抗氧化訊號路徑的活化及亞致死劑量的奈米銀造成的壽命縮短並降低其對於氧化壓力的耐受性。然而，目前對於奈米銀在腸道中，是否誘導ROS介導的壓力反應從而導致腸道功能障礙，並造成壽命縮短的機轉尚不清楚，另外，當利用具有抗氧化功能的植物萃取物紫檀芪是否可以恢復奈米銀所誘導的毒性作用，目前也尚不清楚。在這裡，我們發現在果蠅幼蟲時期暴露奈米銀後，隨著老化的發生，銀離子會在果蠅體內長期積累。接著我們證實果蠅幼蟲口服奈米銀後，會隨著老化的過程中增加腸道屏障的破壞並減少中腸長度。重要的是，奈米銀在腸道幹細胞所在的中腸當中誘導ROS介導的壓力反應，並導致腸道細胞過度增生。然而，紫檀芪可以減緩奈米銀誘導的壽命縮短，並且恢復奈米銀誘導腸道屏障的破壞。除此之外，在果蠅的中腸，紫檀芪減少奈米銀誘導的ROS和過度增殖的現象。最後我們專一性在腸道幹細胞中活化Nrf2路徑，在百草枯 (paraquat) 大量誘發氧化壓力的情況下時，活化抗氧化路徑能夠挽救奈米銀造成的致死性。綜上所述，我們的發現表明，奈米銀誘導腸道中的ROS介導的傷害，進而導致壽命的減短，而紫檀芪可減緩奈米銀的毒性作用。而我們的研究可能提供有關奈米銀誘導毒性的機制和保護策略的相關見解，並有助於奈米銀安全管理上，建立科學性的基礎。

Silver nanoparticles (AgNPs) have emerged as widely used antimicrobial agents in the household, medical and industrial fields. Dietary AgNPs induce ROS-mediated stress responses, such as antioxidant signaling, and sublethal doses of AgNPs shorten the adult lifespan and reduce their tolerance to oxidative stress in Drosophila. However, whether and how AgNPs induce ROS-mediated stress responses in the gut to cause intestinal dysfunction and shortened lifespan, and whether pterostilbene (PT), a natural plant antioxidant, can reverse AgNPs induced toxic effects, remain unclear. Here, using Drosophila as a model system, we first find that silver is highly accumulated in adults during aging upon oral exposure of AgNPs only in larvae. Moreover, AgNPs increase disruption of adult intestinal barriers and decrease midgut length during aging. AgNPs induce ROS-mediated stress responses and cause overproliferation in the adult midgut, where intestinal stem cells reside. Importantly, PT rescues AgNPs-induced shortened lifespan, and restores adult intestinal length and barriers from AgNPs-induced damage. Furthermore, PT reduces AgNPs-induced ROS and overproliferation in the midgut. Finally, tissue-specific activation of Nrf2 signaling in intestinal stem cells rescues AgNPs-induced lethality upon paraquat-mediated oxidative stress. Taken together, our findings suggest that AgNPs shorten lifespan by inducing ROS-mediated damage in the gut, and PT reverses the adverse effects of AgNPs. Our research may provide insights into mechanisms and protective strategies of AgNPs-induced toxicity, and help establish the scientific foundation for the safety management of AgNPs usage.

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