Xiu-Ju Luo

Ischemic stroke poses a significant threat to public health, and its therapeutic efficacy is limited by blood-brain barrier permeability and multifactorial pathophysiology (such as oxidative stress and inflammation). In this study, a self-assembled metal-organic framework (Zn-DB) was decorated with CeO₂ nanoparticles to construct the CZB nanocomposite with antioxidative and antiapoptotic properties. The CZB-D-A multifunctional nanocomposite was developed by co-loading deferoxamine and an anti-C5a aptamer, and CZB-D-A was camouflaged with neutrophil-like membranes modified with RVG₂₉ to synthesize a biomimetic nanoplatform (RH@CZB-D-A) for precise targeting and penetration of the blood-brain barrier as well as immune evasion. Consequently, this nanoplatform precisely delivered therapeutic agents and released them better in the acidic lesion owing to its pH-acid response. It was designed to depolarize microglia from the destructive M1 phenotype to the protective M2 phenotype and alleviate ischemia-reperfusion injury by suppressing neuroinflammation, scavenging reactive oxygen species, and mitigating oxidative stress. Meanwhile, it synergistically promoted neuroprotection by multiple mechanisms of antioxidation, antiapoptosis, antiferroptosis, and anti-inflammation, both in vitro and in vivo. Additionally, administration of RH@CZB-D-A to MCAO mice not only enhanced neuronal regeneration but also improved neurological deficits and promoted spatial memory and learning ability. Therefore, this study could bring an alternative approach for developing promising therapeutic strategies against ischemic stroke for clinical applications.

Caspase-3-dependent apoptosis is believed to contribute to the brain injury of ischemic stroke, and a caspase-3 inhibitor has been repeatedly reported to reduce the brain injury of ischemic stroke. However, currently recognized caspase-3 inhibitors are still only used as a research tool, and none of them is available in the clinic to treat brain injury of ischemic stroke. Based on the concept of drug repositioning and bioinformatics techniques, we have identified Cerdulatinib, a multitargeted tyrosine kinase inhibitor to treat tumors and immune-related diseases in the clinic, as a potential caspase-3 inhibitor. This study aims to explore the effect of Cerdulatinib on brain injury from ischemic stroke and the underlying mechanisms. In mice with ischemic stroke, Cerdulatinib significantly decreased infarct volume and improved sensorimotor function, memory ability, and cognitive function. In nerve cells exposed to hypoxia, Cerdulatinib increased cell viability and decreased LDH release. Mechanistically, Cerdulatinib inhibited the protein level of cleaved caspase-3 and the activity of caspase-3, resulting in a decrease in brain cell apoptosis. Based on these results, we conclude that Cerdulatinib can protect the brain against ischemic injury by reducing apoptosis, which is related to the suppression of caspase-3 cleavage and caspase-3 activity. This study may extend the clinical indications of Cerdulatinib in the treatment of patients with an ischemic stroke.

Introduction: Heme-oxidized iron regulatory protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) is believed to contribute to the ubiquitination of IRP2, which facilitates the transcription of transferrin receptor 1 (TfR1) while preventing the transcription of ferroportin-1 (FPN-1). Bioinformatics analysis predicts that nadolol (a β-blocker) interacts with the HOIL-1. Method: The present study is intended to explore whether nadolol suppresses ferroptosis in the brains of rats suffering from ischemic stroke via targeting the HOIL-1/IRP2 pathway. A rat model of ischemic stroke was established by blocking the middle cerebral artery for 2 h plus 24 h reperfusion, and nadolol (2.5 or 5 mg/kg) was given at 1h after reperfusion. HT22 cells were subjected to 12 h of hypoxia, followed by 24 h of reoxygenation for simulating ischemic stroke, and nadolol (0.1 or 0.25 μM) was administered to the culture medium before reoxygenation. Results: The stroke rats showed evident brain injury (increases in neurological deficit score and infarct volume) and ferroptosis, along with up-regulation of IRP2 and TfR1 while downregulation of HOIL-1 and FPN-1; these phenomena were reversed in the presence of nadolol. In the cultured HT22 cells, hypoxia/reoxygenation-induced LDH release, ferroptosis, and changes in the levels of relevant proteins (IRP2, TfR1, HOIL-1, and FPN-1) were also reversed by nadolol. Conclusion: In terms of these findings, it is concluded that nadolol can protect the ischemic rats’ brains against ferroptosis by targeting the HOIL-1/IRP2 pathway, thereby preventing intracellular iron overload. Thus, nadolol may be a novel indication for treating patients with ischemic stroke.