Background: Microglia-induced excessive neuroinflammation plays a crucial role in the pathophysiology of multiple neurological diseases, such as ischaemic stroke. Controlling inflammatory responses is considered a promising therapeutic approach. Sirtuin 5 (SIRT5) mediates lysine desuccinylation, which is involved in various critical biological processes, but its role in ischaemic stroke remains poorly understood. This research systematically explored the function and potential mechanism of SIRT5 in microglia-induced neuroinflammation in ischaemic stroke. Methods: Mice subjected to middle cerebral artery occlusion were established as the animal model, and primary cultured microglia treated with oxygen–glucose deprivation and reperfusion were established as the cell model of ischaemic stroke. SIRT5 short hairpin RNA, adenovirus and adeno-associated virus techniques were employed to modulate SIRT5 expression in microglia both in vitro and in vivo. Coimmunoprecipitation, western blot and quantitative real-time PCR assays were performed to reveal the molecular mechanism. Results: In the current study, we showed that SIRT5 expression in microglia was increased in the early phase of ischaemic stroke. SIRT5 interacts with and desuccinylates Annexin A1 (ANXA1) at K166, which in turn decreases its SUMOylation level. Notably, the desuccinylation of ANXA1 blocks its membrane recruitment and extracellular secretion, resulting in the hyperactivation of microglia and excessive expression of proinflammatory cytokines and chemokines, ultimately leading to neuronal cell damage after ischaemic stroke. Further investigation showed that microglia-specific forced overexpression of SIRT5 worsened ischaemic brain injury, whereas downregulation of SIRT5 exhibited neuroprotective and cognitive-preserving effects against ischaemic brain injury, as proven by the decreased infarct area, reduced neurological deficit scores, and improved cognitive function. Conclusions: Collectively, these data identify SIRT5 as a novel regulator of microglia-induced neuroinflammation and neuronal damage after cerebral ischaemia. Interventions targeting SIRT5 expression may represent a potential therapeutic target for ischaemic stroke.

Background: Excessive and unresolved neuroinflammation plays an important role in the pathophysiology of many neurological disorders, such as ischemic stroke, yet there are no effective treatments. Tripartite motif-containing 67 (TRIM67) plays a crucial role in the control of inflammatory disease and pathogen infection-induced inflammation; however, the role of TRIM67 in cerebral ischemia‒reperfusion injury remains poorly understood. Results: In the present study, we demonstrated that the expression level of TRIM67 was significantly reduced in middle cerebral artery occlusion and reperfusion (MCAO/R) mice and primary cultured microglia subjected to oxygen–glucose deprivation and reperfusion. Furthermore, a significant reduction in infarct size and neurological deficits was observed in mice after TRIM67 upregulation. Interestingly, TRIM67 upregulation alleviated neuroinflammation and cell death after cerebral ischemia‒reperfusion injury in MCAO/R mice. A mechanistic study showed that TRIM67 bound to IκBα, reduced K48-linked ubiquitination and increased K63-linked ubiquitination, thereby inhibiting its degradation and promoting the stability of IκBα, ultimately inhibiting NF-κB activity after cerebral ischemia. Conclusion: Taken together, this study demonstrated a previously unidentified mechanism whereby TRIM67 regulates neuroinflammation and neuronal apoptosis and strongly indicates that upregulation of TRIM67 may provide therapeutic benefits for ischemic stroke. Graphical

Cranioplasty is a common neurosurgical procedure; however, the optimal material choice remains controversial. At the time of this writing, autologous bone, the preferred choice for primary cranioplasty, has a high incidence of complications such as infection and resorption, thus requiring frequent use of synthetic materials. Therefore, this study aimed to compare the clinical benefits of titanium mesh (Ti), polyetheretherketone (PEEK), and composite bone cement (CBC) in cranioplasty to provide a clear selection basis for clinicians and patients. This study retrospectively collected data from 207 patients who underwent cranioplasty with Ti (n=129), PEEK (n=54), and CBC (n=24) between January 2018 and December 2020 at Henan Provincial People’s Hospital. Postoperative follow-up information after 6 months was used to compare the long-term effects of the 3 materials on the patients. There were no significant differences in the overall complication rate after cranioplasty among the 3 materials. However, subcutaneous effusion was more frequent with PEEK (24.07%) and CBC (20.83%) than with Ti (2.33%). Second, there were no significant differences in the increase in Glasgow Outcome Scale and Karnofsky Performance Status scores after cranioplasty among the 3 materials. Finally, we found that PEEK had the highest patient satisfaction and hospitalization cost, whereas the opposite was true for Ti. Although the surgical outcomes of the 3 implant materials were similar, an examination of clinical outcomes such as patient satisfaction showed significant differences, deepening people’s perceptions of the 3 materials.