Background: Subarachnoid hemorrhage (SAH), an acute cerebrovascular accident, features with its high death and disability rate. Sirtuin3 (SIRT3) is a NAD+ dependent deacetylase which mainly located in mitochondria. Reduced SIRT3 function was indicated to involve in many disorders of central nervous system. Herein, we aimed to explore the neuroprotective effects of SIRT3 on SAH and to furtherly explore the underlying mechanisms.Methods: Adult C57BL/6 J male mice (8–10 weeks) were used to establish SAH models. The pharmacological agonist of SIRT3, Honokiol (HKL), was injected in an intraperitoneal manner (10 mg/kg) immediately after the operation. Brain edema and neurobehavioral score were assessed. Nissl staining and FJC staining were used to evaluate the extent of neuronal damage. The changes of mitochondria morphology were observed with transmission electron microscopy. Western blot was used for analyzing the protein level of SIRT3 and the downstream signaling molecules.Result: SIRT3 was downregulated after SAH, and additional treatment of SIRT3 agonist HKL alleviated brain edema and neurobehavioral deficits after SAH. Additionally, electron microscopy showed that HKL significantly alleviated the morphological damage of mitochondria induced by SAH. Further studies showed that HKL could increase the level of mitochondrial fusion protein Mfn1 and Mfn2, thus maintaining (mitochondrial morphology), protecting mitochondrial function and promoting neural survival. While, additional Compound C (CC) treatment, a selective AMPK inhibitor, abolished these protective effects.Conclusions: Activation of SIRT3 protects against SAH injury through improving mitochondrial fusion in an AMPK dependent manner.

Although astrocytes undergo functional changes in response to brain injury and may be the driving force of subsequent neuronal death, the underlying mechanisms remain incompletely elucidated. Here, we showed that extracellular vesicle (EV)-shuttled miRNA-382-5p may serve as a biomarker for the severity of traumatic brain injury (TBI), as the circulating EV-miRNA-382-5p level was significantly increased in both human patients and TBI model mice. Mechanistically, astrocyte-derived EVs delivered the shuttled miRNA-382-5p to mediate astrocyte–neuron communication, which promoted neuronal mitochondrial dysfunction by inhibiting the expression of optic atrophy-1 (OPA1). Consistent with these findings, genetic ablation of neuronal OPA1 exacerbated mitochondrial damage and neuronal apoptosis in response to TBI. Moreover, engineered RVG-miRNA-382-5p inhibitor-EVs, which can selectively deliver a miRNA-382-5p inhibitor to neurons, significantly attenuated mitochondrial damage and improved neurological function after TBI. Taken together, our data suggest that EV-shuttled miRNA-382-5p may be a critical mediator of astrocyte-induced neurotoxicity under pathological conditions and that targeting miRNA-382-5p-OPA1 signaling has potential for clinical translation in the treatment of traumatic brain injury.

Death-associated protein kinase 1 (DAPK1), a Ca²⁺/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer’s disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL⁺ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What’s more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.

Various forms of neuronal death contribute to neurological injury after traumatic brain injury (TBI), leading to irreversible neurological deficits. Among these, ferroptosis is a form of regulated cell death characterized by the accumulation of iron-dependent lipid hydroperoxides and induced by the incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes. Adiponectin (APN), a cytokine secreted by adipocytes, have showed neuroprotective effects by binding to adiponectin receptors (AdipoRs), which are widely expressed in the central nervous system. However, the role of APN-AdipoRs signaling in ferroptosis after TBI remains unexplored. Our clinical analysis revealed a significant correlation between serum levels of APN and 6-month outcomes of TBI patients. Subsequent studies confirmed that TBI-induced ferroptosis was more pronounced in APN knockout mice compared to wild-type mice, while additional APN receptor agonist (AdipoRon) treatment significantly mitigated TBI induced ferroptosis. Furthermore, AdipoR1 knockdown significantly diminished the protective effects of AdipoRon against erastin-induced ferroptosis in primary neurons. Correspondingly, in the neuron-specific AdipoR1 conditional knockout (AdipoR1^CKO) mice, neurons were more susceptible to ferroptosis after TBI, leading to increased brain edema and lesion volume, and exacerbated neurological deficits. Mechanically, activation of APN-AdipoR1 signaling promoted adenosine monophosphate activated protein kinase (AMPK) -mediated phosphorylation of acetyl-CoA carboxylase-1 (ACC1), thus suppressed the PUFAs biosynthesis, which determines theferroptosissensitivity of neurons. Taken together, these findings provided compelling evidence for the protective role of APN-AdipoR1 signaling against TBI-induced ferroptosis by inhibiting AMPK-ACC1.

Glioma therapy faces substantial challenges primarily due to the restrictive nature of the blood-brain barrier (BBB), limiting effective drug penetration and reducing therapeutic efficacy. Recent advancements in novel drug delivery systems (DDS), including exosome-mediated carriers, drug conjugates, and ultrasound-assisted delivery, have demonstrated promising results in overcoming these limitations. Exosomes offer superior biocompatibility, efficient BBB crossing, and natural cellular targeting capabilities; drug conjugates enable highly selective drug delivery through tumor-specific ligands; and ultrasound-assisted systems transiently disrupt the BBB to permit greater drug entry. Despite encouraging preclinical and early clinical outcomes, significant translational barriers remain. Challenges such as exosome manufacturing scalability, conjugate stability, and immunogenicity, as well as the optimization of ultrasound protocols, must be thoroughly addressed to achieve clinical translation. Overcoming these hurdles requires ongoing multidisciplinary collaboration and rigorous clinical evaluation. Continued progress in refining these innovative DDS approaches holds the potential to markedly improve therapeutic outcomes and patient prognosis in glioma treatment.

Background: Despite advances in decompressive craniectomy (DC) for the treatment of traumatic brain injury (TBI), these patients are at risk of having a poor long-term prognosis. The aim of this study was to predict 1-year mortality in TBI patients undergoing DC using logistic regression and random tree models. Methods: This was a retrospective analysis of TBI patients undergoing DC from January 1, 2015, to April 25, 2019. Patient demographic characteristics, biochemical tests, and intraoperative factors were collected. One-year mortality prognostic models were developed using multivariate logistic regression and random tree algorithms. The overall accuracy, sensitivity, specificity, and area under the receiver operating characteristic curves (AUCs) were used to evaluate model performance. Results: Of the 230 patients, 70 (30.4%) died within 1 year. Older age (OR, 1.066; 95% CI, 1.045–1.087; P < 0.001), higher Glasgow Coma Score (GCS) (OR, 0.737; 95% CI, 0.660–0.824; P < 0.001), higher d-dimer (OR, 1.005; 95% CI, 1.001–1.009; P = 0.015), coagulopathy (OR, 2.965; 95% CI, 1.808–4.864; P < 0.001), hypotension (OR, 3.862; 95% CI, 2.176–6.855; P < 0.001), and completely effaced basal cisterns (OR, 3.766; 95% CI, 2.255–6.290; P < 0.001) were independent predictors of 1-year mortality. Random forest demonstrated better performance for 1-year mortality prediction, which achieved an overall accuracy of 0.810, sensitivity of 0.833, specificity of 0.800, and AUC of 0.830 on the testing data compared to the logistic regression model. Conclusions: The random forest model showed relatively good predictive performance for 1-year mortality in TBI patients undergoing DC. Further external tests are required to verify our prognostic model.