High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons

IntroductionNeuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches.MethodsAcute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior.ResultsResults revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability.DiscussionThese findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia

Table_4_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOCX

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

Table_5_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOC

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

Table_1_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOC

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

Table_3_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOC

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

Table_6_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOC

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

Table_2_Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.DOC

ObjectiveIn clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence.MethodsIn this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out.ResultsApproximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60–0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32–0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46–0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age ConclusionNimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication.Systematic review registrationwww.york.ac.uk/inst/crd, identifier: CRD42022334619.</p

mRNA-Laden Lipid-Nanoparticle-Enabled <i>in Situ</i> CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the “superbug” MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials