Subarachnoid hemorrhage (SAH) is a severe type of stroke featuring exceptionally high rate of morbidity and mortality due to the lack of effective management. Ferroptosis can be defined as a novel iron-dependent programmed cell death in contrast to classical apoptosis and necrosis. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with established therapeutic effect on CNS diseases. However, the exact role of ferroptosis in Astragaloside IV-mediated neuroprotection after SAH is yet to be demonstrated. In the present study, the SAH model of SD male rats with endovascular perforation was used to gauge the neuroprotective effect of AS-IV on SAH-induced early brain injury (EBI) and to clarify the potential molecular mechanism. We found that the induction of SAH reduced the levels of SLC7A11 and glutathione peroxidase 4 (GPX4) in the brain, exacerbated iron accumulation, enhanced lipid reactive oxygen species (ROS) level, and stimulated neuronal ferroptosis. However, the administration of AS-IV and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) enhanced the antioxidant capacity after SAH and suppressed the accumulation of lipid peroxides. Meanwhile, AS-IV triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of SAH. The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. These results consistently suggest that ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway.
Sirtuin-3 (SIRT3) is responsible for maintaining mitochondrial homeostasis by deacetylating substrates in an NAD+-dependent manner. SIRT3, the primary deacetylase located in the mitochondria, controls cellular energy metabolism and the synthesis of essential biomolecules for cell survival. In recent years, increasing evidence has shown that SIRT3 is involved in several types of acute brain injury. In ischaemic stroke, subarachnoid haemorrhage, traumatic brain injury, and intracerebral haemorrhage, SIRT3 is closely related to mitochondrial homeostasis and with the mechanisms of pathophysiological processes such as neuroinflammation, oxidative stress, autophagy, and programmed cell death. As SIRT3 is the driver and regulator of a variety of pathophysiological processes, its molecular regulation is significant. In this paper, we review the role of SIRT3 in various types of brain injury and summarise SIRT3 molecular regulation. Numerous studies have demonstrated that SIRT3 plays a protective role in various types of brain injury. Here, we present the current research available on SIRT3 as a target for treating ischaemic stroke, subarachnoid haemorrhage, traumatic brain injury, thus highlighting the therapeutic potential of SIRT3 as a potent mediator of catastrophic brain injury. In addition, we have summarised the therapeutic drugs, compounds, natural extracts, peptides, physical stimuli, and other small molecules that may regulate SIRT3 to uncover additional brain-protective mechanisms of SIRT3, conduct further research, and provide more evidence for clinical transformation and drug development.
ObjectiveAneurysmal subarachnoid hemorrhage (aSAH) is a common and potentially fatal cerebrovascular disease. Poor-grade aSAH (Hunt-Hess grades IV and V) accounts for 20–30% of patients with aSAH, with most patients having a poor prognosis. This study aimed to develop a stable nomogram model for predicting adverse outcomes at 6 months in patients with aSAH, and thus, aid in improving the prognosis.MethodThe clinical data and imaging findings of 150 patients with poor-grade aSAH treated with microsurgical clipping of intracranial aneurysms on admission from December 2015 to October 2021 were retrospectively analyzed. Least absolute shrinkage and selection operator (LASSO), logistic regression analyses, and a nomogram were used to develop the prognostic models. Receiver operating characteristic (ROC) curves and Hosmer–Lemeshow tests were used to assess discrimination and calibration. The bootstrap method (1,000 repetitions) was used for internal validation. Decision curve analysis (DCA) was performed to evaluate the clinical validity of the nomogram model.ResultLASSO regression analysis showed that age, Hunt-Hess grade, Glasgow Coma Scale (GCS), aneurysm size, and refractory hyperpyrexia were potential predictors for poor-grade aSAH. Logistic regression analyses revealed that age (OR: 1.107, 95% CI: 1.056–1.116, P < 0.001), Hunt-Hess grade (OR: 8.832, 95% CI: 2.312–33.736, P = 0.001), aneurysm size (OR: 6.871, 95% CI: 1.907–24.754, P = 0.003) and refractory fever (OR: 3.610, 95% CI: 1.301–10.018, P < 0.001) were independent predictors of poor outcome. The area under the ROC curve (AUC) was 0.909. The calibration curve and Hosmer–Lemeshow tests showed that the nomogram had good calibration ability. Furthermore, the DCA curve showed better clinical utilization of the nomogram.ConclusionThis study provides a reliable and valuable nomogram that can accurately predict the risk of poor prognosis in patients with poor-grade aSAH after microsurgical clipping. This tool is easy to use and can help physicians make appropriate clinical decisions to significantly improve patient prognosis.
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