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While these approaches show promise in preclinical models, clinical translation faces substantial hurdles: most nanoparticles achieve only modest brain accumulation with heterogeneous parenchymal distribution, and their long-term safety, biodistribution, and immunogenicity remain poorly characterized (192)

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RES also targets NF-B pathways, ameliorating anxiety and depression-like behaviors in stress models and showing greater efficacy than fluoxetine in regulating NF-B/NLRP3 signaling pathways [160,161]

Through its action on ATF4, HRI upregulates SESTRIN2 and REDD1 (stress-induced protein, generally upregulated by DNA damage and ROS)