科研之友
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摘要
The biological function of radicals is a broad continuum from signaling to killing. Yet, biomedical exploitation of radicals is largely restricted to the theme of healing-by-killing. To explore their potential in healing-by-signaling, robust radical generation methods are warranted. Acyl radicals are endogenous, exhibit facile chemistry and elicit matrix-dependent biological outcomes. Their implications in health and disease remain untapped, primarily due to the lack of a robust generation method with spatiotemporal specificity. Fusing the Norrish chemistry into the xanthene scaffold, we developed a novel general and modular molecular design strategy for photo-triggered generation of acyl radicals, i.e., acyl-caged rhodamine (ACR). A notable feature of ACR is the simultaneous release of a fluorescent probe for cell redox homeostasis allowing real-time monitoring of the biological outcome of acyl radicals. With a donor of the endogenous acetyl radical (ACR575a), we showcased its capability in precise and continuous modulation of the cell redox homeostasis from signaling to stress, and induction of a local oxidative burst to promote differentiation of neural stem cells (NSCs). Upon intracerebral-injection of ACR575a and subsequent fiber-optical activation, early AD mice exhibited enhanced differentiation of NSCs toward neurons, reduced formation of A beta plaques, and significantly improved cognitive abilities, including learning and memory. @@@ A general design strategy for photo-triggered release of acyl radicals was developed. With an acetyl radical donor, we showed the potential of acyl radicals to precisely modulate cell redox homeostasis, to promote NSC differentiation, and to improve the cognitive abilities of early AD mice.
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单位上海交通大学; y; 华东理工大学
