The First Affiliated Hospital of Zhengzhou University

Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient’s condition; this phenomenon is known as cerebral ischemia-reperfusion injury. Current studies have elucidated the neuroprotective role of the sirtuin protein family (Sirtuins) in modulating cerebral ischemia-reperfusion injury. However, the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration. In this review, the origin and research progress of Sirtuins are summarized, suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury, including inflammation, oxidative stress, blood–brain barrier damage, apoptosis, pyroptosis, and autophagy. The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways, such as nuclear factor-kappa B signaling, oxidative stress mediated by adenosine monophosphate-activated protein kinase, and the forkhead box O. This review also summarizes the potential of endogenous substances, such as RNA and hormones, drugs, dietary supplements, and emerging therapies that regulate Sirtuins expression. This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors. While Sirtuins show promise as a potential target for the treatment of cerebral ischemia-reperfusion injury, most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans, potentially influencing the efficacy of Sirtuins-targeting drug therapies. Overall, this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.

JOURNAL/nrgr/04.03/01300535-202507000-00028/figure1/v/2024-09-09T124005Z/r/image-tiffAlzheimer’s disease is characterized by deposition of amyloid-β, which forms extracellular neuritic plaques, and accumulation of hyperphosphorylated tau, which aggregates to form intraneuronal neurofibrillary tangles, in the brain. The NLRP3 inflammasome may play a role in the transition from amyloid-β deposition to tau phosphorylation and aggregation. Because NLRP3 is primarily found in brain microglia, and tau is predominantly located in neurons, it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines. Here, we found that neurons also express NLRP3in vitroandin vivo, and that neuronal NLRP3 regulates tau phosphorylation. Using biochemical methods, we mapped the minimalNLRP3promoter and identified FUBP3 as a transcription factor regulatingNLRP3expression in neurons. In primary neurons and the neuroblastoma cell line Neuro2A, FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-β is present. In the brains of aged wild-type mice and a mouse model of Alzheimer’s disease, FUBP3 expression was markedly increased in cortical neurons. Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses. We also found that FUBP3 trimmed the 5′ end of DNA fragments that it bound, implying that FUBP3 functions in stress-induced responses. These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3, and that amyloid-β fundamentally alters the regulatory mechanism ofNLRP3expression in neurons. Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer’s disease mice, FUBP3 could be a safe therapeutic target for preventing Alzheimer’s disease progression.

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.