Tibial fracture surgery in elderly mice caused postoperative neurocognitive disorder via SOX2OT lncRNA in the hippocampus.

Increasing evidence indicates the major role of mitochondrial function in neurodegenerative disease. However, it is unclear whether mitochondrial dynamics directly affect postoperative neurocognitive disorder (PND). This study aimed to analyze the underlying mechanisms of mitochondrial dynamics in the pathogenesis of PND. Tibial fracture surgery was performed in elderly mice to generate a PND model in vivo. Cognitive behavior was evaluated 3 days post-surgery using novel object recognition and fear conditioning. A gradual increase in the SOX2OT mRNA level and decrease in the SOX2 mRNA level were noted, with impaired cognitive function, in the mice 3 days after tibial surgery compared with mice in the sham group. To evaluate the role of SOX2OT in PND, SOX2OT knockdown was performed in vitro and in vivo using lentivirus transfection in HT22 cells and via brain stereotactic injection of lentivirus, respectively. SOX2OT knockdown reduced apoptosis, inhibited oxidative stress, suppressed mitochondrial hyperdivision, attenuated surgery-induced cognitive dysfunction, and promoted downstream SOX2 expression in elderly mice. Furthermore, Sox2 alleviated mitochondrial functional damage by inhibiting the transcription of mitochondrial division protein Drp1. Our study findings indicate that SOX2OT knockout alleviates surgery-induced mitochondrial fission and cognitive function defects by upregulating the expression of Sox2 in mice, resulting in the inhibition of drp1 transcription. Therefore, regulation of the SOX2/Drp1 pathway may be a potential mechanism for the treatment of patients with PND.

Investigating the molecular mechanisms of delirium-like neuropsychiatric disorder induced by electromagnetic pulse based on bioinformatics analysis.

Electromagnetic pulse (EMP), a unique type of electromagnetic radiation, may induce diverse neuropsychiatric disorders, such as irritability, hyperkinesis, retardation of learning and memory. However, the underlying mechanism of EMP exposure on neuronal injury has not been elucidated. Here, we aimed to delineate the regulatory expression networks based on high-throughput sequencing data to explore the possible molecular mechanisms related to EMP-induced delirium-like neuropsychiatric disorder in rats. It's shown that EMP exposure induced anxiety, cognitive decline and short-term memory impairment. The expression profiles of the long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, were explored in rats after EMP exposure. We identified 41 differentially expressed lncRNAs (DELs) and 266 differentially expressed mRNAs (DEMs) between EMP and sham groups. Sixty-one co-expression relationships between 18 DELs and 56 DEMs were mostly associated with synapse- and metabolic-related pathways. We predicted 51 DEL-miRNA pairs and 290 miRNA-mRNA pairs using the miRanda database to constructed a DEL-miRNA-DEM network. LncRNA AABR07042999.1 and mRNA Tph2, Slc6a4, Dbh and Th were upregulated, and the contents of serotonin, dopamine and norepinephrine were increased in both PFC and HIP after EMP exposure. The current study provided a better understanding of the ceRNA network, which might reveal the pathological mechanism and provide more treatment options for the EMP-induced neurobehavioral disorder.

Optimizing the prediction of sepsis-associated encephalopathy with cerebral circulation time utilizing a nomogram: a pilot study in the intensive care unit.

Background: Sepsis-associated encephalopathy (SAE) is prevalent in intensive care unit (ICU) environments but lacks established treatment protocols, necessitating prompt diagnostic methods for early intervention. Traditional symptom-based diagnostics are non-specific and confounded by sedatives, while emerging biomarkers like neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) have limited specificity. Transcranial Doppler (TCD) indicators, although is particularly relevant for SAE, requires high operator expertise, limiting its clinical utility. Objective: This pilot study aims to utilize cerebral circulation time (CCT) assessed via contrast-enhanced ultrasound (CEUS) as an innovative approach to investigate the accuracy of SAE prediction. Further, these CCT measurements are integrated into a nomogram to optimize the predictive performance. Methods: This study employed a prospective, observational design, enrolling 67 ICU patients diagnosed with sepsis within the initial 24 h. Receiver operating characteristic (ROC) curve analyses were conducted to assess the predictive accuracy of potential markers including NSE, S100B, TCD parameters, and CCT for SAE. A nomogram was constructed via multivariate Logistic Regression to further explore the combined predictive potential of these variables. The model's predictive performance was evaluated through discrimination, calibration, and decision curve analysis (DCA). Results: SAE manifested at a median of 2 days post-admission in 32 of 67 patients (47.8%), with the remaining 35 sepsis patients constituting the non-SAE group. ROC curves revealed substantial predictive utility for CCT, pulsatility index (PI), and S100B, with CCT emerging as the most efficacious predictor, evidenced by an area under the curve (AUC) of 0.846. Multivariate Logistic Regression identified these markers as independent predictors for SAE, leading to the construction of a nomogram with excellent discrimination, substantiated by an AUC of 0.924 through bootstrap resampling. The model exhibited satisfactory concordance between observed and predicted probabilities, and DCA confirmed its clinical utility for the prompt identification of SAE. Conclusion: This study highlighted the enhanced predictive value of CCT in SAE detection within ICU settings. A novel nomogram incorporating CCT, PI, and S100B demonstrated robust discrimination, calibration, and clinical utility, solidifying it as a valuable tool for early SAE intervention.

Scutellarin alleviates cerebral ischemia/reperfusion by suppressing oxidative stress and inflammatory responses via MAPK/NF-κB pathways in rats.

Neuroinflammation contributes to the progression of cerebral ischemia/reperfusion (I/R) damage. Scutellarin (SL) is a glucuronide flavonoid that has apoptotic, anti-inflammatory, and anti-tumor properties. It is anti-oxidant and anti-inflammatory mechanism as a neuroprotective against ischemic brain injury is unknown. The purpose of the study was to examine the role and mechanism of SL in preventing I/R damage in a rat model. SL (40 and 80 mg/kg) was given to the rats for 14 days before the ischemic stroke. SL administration prevented I/R mediated brain injury, and neuronal apoptosis. Malondialdehyde, superoxide dismutase, glutathione, IL-6, and IL-1ß and nitric oxide were modulated by SL. SL suppressed the p65 and p38 expressions in particular. The findings show that SL protects rats from cerebral damage caused by I/R through the nuclear factor kappa-B p65 and p38 mitogen-activated protein kinase signaling pathway. Thus, SL protected the brain of rats from ischemic injury by inhibiting the inflammatory process.

The increased in vivo firing of pyramidal cells but not interneurons in the anterior cingulate cortex after neuropathic pain.

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which was further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.

Case report: Post-thoracoscopy pendelluft monitoring.

Asynchronous alveolar ventilation is called pendelluft, which may induce lung injury in spontaneously breathing patients. We report a case that electrical impedance tomography (EIT) was used to assess the pendelluft in a post-thoracoscopy patient. The pendelluft amplitude was as high as 77.5% of the tidal variation. The average regional time shift was 0.5 s. The patient was instructed to adjust the breathing method, symptomatic treatment was performed, and the symptoms were improved. This is the first case reporting pendelluft in a post-thoracoscopy patient. Our case demonstrated that (1) pendelluft may occur in post-thoracoscopy patients and it effects lung function, and (2) early identification of affected patients and implementation of corresponding treatments could improve patient outcomes.

Isoflurane preconditioning effects on brain damage induced by electromagnetic pulse radiation through epigenetic modification of BDNF gene transcription.

BACKGROUND: The effects of electromagnetic pulse (EMP) radiation on cognitive impairment have attracted much attention, but the mechanism is still unclear. Regulation of brain-derived neurotrophic factor (BDNF) gene expression has been found to promote memory formation and neuronal survival. Isoflurane preconditioning (IP) was reported to have a neuroprotective effect. In this study, we verified the protective effect of IP against brain injury induced by EMP exposure and examined the relation of this effect with BDNF gene regulation. METHODS: Twenty-four hours before EMP exposure, rats were pretreated with 2% inhaled isoflurane for 30 minutes. At 24 hours after EMP injury, the Morris water maze test was carried out. Meanwhile, the other rats were executed and their brain tissues were used for Nissl staining, qRT-PCR, western blot and chromatin immunoprecipitation. RESULTS: The Morris water maze results showed that 2% IP improved the spatial learning and memory ability of the rats. The Nissl staining results showed 2% of IP alleviated neuronal damage. Also, we detected the mRNA and protein expression of BDNF, and 2% IP significantly increased the expression of BDNF. We also found the expression level of histone deacetylase 2 (HDAC2) was increased and that EMP exposure significantly decreased H3 acetylation, while 2% IP reversed these phenomena, individually, BDNF transcription was activated, and neurogenesis after EMP exposure was alleviated. CONCLUSIONS: Our results suggested that 2% of IP alleviates cognitive impairment induced by EMP exposure in rats. Also, the sustained elevated level of BDNF gene transcription may be an essential mechanism for stimulating neurogenesis because of the increased level of HDAC2-dependent H3 acetylation.

[Electromagnetic pulse irradiation up-regulates methyl-CpG-binding protein 2 (MeCP2) and down-regulates neurogenin 2 in rat hippocampus].

Objective To investigate the alterations in hippocampus neuron morphology, the expression of neurogenin 2 (Ngn2) and methyl-CpG-binding protein 2 (MeCP2) in hippocampus after electromagnetic pulse (EMP) irradiation. Methods Adult healthy male SD rats were randomly divided into control group, EMP 7-day group, and EMP 14-day group (n=12). Hippocampus neuron morphology was tested by HE staining; the expression of Ngn2 and MeCP2 were measured by Western blotting and fluorescent immunohistochemistry; the protein levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) were measured by Western blotting. Results Compared with the control group, the number of pyramidal cells in the EMP 7-day group and EMP 14-day group was reduced, the neuron boundary was blurred, and the nuclear outline was blurred. Compared with the EMP 7-day group, the hippocampus neuron structure in the EMP 14-day group was more severely damaged. Compared with the control group, the expression of Ngn2, BDNF, and PSD95 significantly decreased, while the expression of MeCP2 increased in the EMP 14-day group and EMP 7-day group. Conclusion EMP exposure leads to the pathological damage of hippocampus neurons in rats, increases MeCP2 expression and decreases Ngn2, PSD95, BDNF expression.

MicroRNA-665-3p attenuates oxygen-glucose deprivation-evoked microglial cell apoptosis and inflammatory response by inhibiting NF-κB signaling via targeting TRIM8.

Microglial inflammation induced by ischemic stroke aggravates brain damage. MicroRNAs (miRNAs) have emerged as pivotal regulators in ischemic stroke-induced inflammation in microglial cells. miR-665-3p has been reported as a critical inflammation-associated miRNA. However, whether miR-665-3p participates in regulating microglial inflammation during ischemic stroke is underdetermined. This study investigated the potential role of miR-665-3p in stroke-induced inflammation in microglial cells using a cellular model of oxygen-glucose deprivation (OGD)-stimulated microglial cells in vitro. We found that miR-665-3p expression was decreased in microglial cells exposed to OGD treatment. Functional experiments demonstrated that the overexpression of miR-665-3p attenuated OGD-induced apoptosis and inflammation in microglial cells. Notably, tripartite motif 8 (TRIM8) was identified as a target gene of miR-665-3p. TRIM8 expression was induced by OGD treatment in microglial cells and the knockdown of TRIM8 protected microglial cells from OGD -induced cytotoxicity and inflammation. Moreover, TRIM8 knockdown or miR-665-3p overexpression blocked OGD-induced activation of nuclear factor (NF)-κB signaling in microglial cells. In addition, TRIM8 overexpression partially reversed the miR-665-3p overexpression-mediated inhibitory effect on OGD-induced inflammation in microglial cells. Taken together, these results indicate that miR-665-3p up-regulation protects microglial cells from OGD-induced apoptosis and inflammatory response by targeting TRIM8 to inhibit NF-κB signaling.

Downregulation of TRIM8 protects neurons from oxygen-glucose deprivation/re-oxygenation-induced injury through reinforcement of the AMPK/Nrf2/ARE antioxidant signaling pathway.

Tripartite motif 8 (TRIM8) has emerged as a crucial regulator of cell survival, apoptosis, and oxidative stress in various pathological processes. However, TRIM8's involvement in regulating neuronal injury in cerebral ischemia/reperfusion injury remains largely uncharacterized. In the present study, we aimed to investigate the potential function and molecular mechanism of TRIM8 in regulating neuronal apoptosis and oxidative stress induced by oxygen-glucose deprivation/re-oxygenation (OGD/R) in an in vitro model to study cerebral ischemia/reperfusion injury. Herein, we found that TRIM8 expression was upregulated in neurons exposed to OGD/R. Knockdown of TRIM8 improved the viability and decreased the apoptosis and reactive oxygen species (ROS) generation in OGD/R-exposed neurons, whereas TRIM8 overexpression showed the opposite effect. Notably, TRIM8 inhibition increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Moreover, TRIM8 inhibition promoted the transcriptional activity of the Nrf2/antioxidant response element (ARE). However, AMPK inhibition partially reversed TRIM8 downregulation-mediated Nrf2/ARE activation and the neuroprotective effect in OGD/R-exposed neurons. Additionally, silencing of Nrf2 also markedly abrogated TRIM8 downregulation-mediated neuroprotection. Overall, these results demonstrate that downregulation of TRIM8 protects from OGD/R-induced neuronal injury by reinforcing the activation of Nrf2/ARE antioxidant signaling via AMPK, suggesting a potential role for TRIM8 in cerebral ischemia/reperfusion injury.

Isoflurane Preconditioning Attenuates Brain Injury Induced by Electromagnetic Pulse via the TLR4/NFκB Signaling Pathway.

Electromagnetic pulse (EMP) is a unique type of electromagnetic radiation, and EMP exposure causes a series of biological effects. The nervous system is sensitive to EMP. We studied the neuroprotective effects of isoflurane preconditioning against EMP exposure and used hematoxylin-eosin staining (HE) to observe the effects of electromagnetic pulse and isoflurane preconditioning on neurons. Inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the expression of caspase-3, CD11b, TLR4, and NFκBp65. We found that after EMP exposure, the number of abnormal neurons had increased, and the expression of caspase-3, CD11b, TLR4, and NFκBp65 had also increased. Isoflurane preconditioning can reverse the above phenomenon. Moreover, we found that isoflurane preconditioning can reduce neuronal apoptosis and improve cognitive impairment induced by EMP. These findings indicate that isoflurane preconditioning can protect neurons in the cerebral cortex from EMP exposure, alleviate the inflammatory reaction and cell apoptosis, and improve cognitive impairment induced by EMP. These effects may occur through the downregulation of the TLR4/NFκB signaling pathway and the inhibition of microglial activation.

Isoflurane preconditioning ameliorates electromagnetic pulse-induced neural damage by shifting microglia polarization toward anti-inflammatory phenotype via upregulation of SOCS1.

With the speedy technological advances during the past few decades, human exposure to the electromagnetic field (EMF) has become increasingly common. Exposure to EMF may induce neural injuries and dysfunction of various organs, likely involving neuroinflammation and activation of microglial cells. Isoflurane preconditioning (IP) is shown to provide neuroprotection in various neurological diseases by inhibiting excessive neuroinflammatory responses. Brain samples harvested from rats exposed to electromagnetic pulse (EMP) with or without IP were subjected to qPCR, Western blot assay, and immunohistochemistry to determine the expression of pro-inflammatory/anti-inflammatory microglia markers and a variety of pro- and anti-inflammatory mediators. Suppressor of cytokine signaling 1 (SOCS1) siRNA was used in cultured N9 microglia cells to examine the roles of SOCS1 in the effect of IP. In both in vivo and in vitro experiments, EMP-exposed microglia were predominantly pro-inflammatory microglia, accompanied by increased expression of pro-inflammatory cytokines and chemokines, and activation of TLR4 pathway, leading to neuronal death. IP reversed the changes induced by EMP and switched the activated microglia to an anti-inflammatory phenotype. SOCS1 siRNA abolished the beneficial effects of IP. IP ameliorates EMP-induced neural injuries by shifting microglia polarization from pro-inflammatory to anti-inflammatory phenotype via upregulation of SOCS1.

Anandamide protects HT22 cells exposed to hydrogen peroxide by inhibiting CB1 receptor-mediated type 2 NADPH oxidase.

BACKGROUND: Endogenous cannabinoid anandamide (AEA) protects neurons from oxidative injury in rodent models; however the mechanism of AEA-induced neuroprotection remains to be determined. Activation of neuronal NADPH oxidase 2 (Nox2) contributes to oxidative damage of the brain, and inhibition of Nox2 can attenuate cerebral oxidative stress. We aimed to determine whether the neuronal Nox2 was involved in protection mediated by AEA. METHODS: The mouse hippocampal neuron cell line HT22 was exposed to hydrogen peroxide (H2O2) to mimic oxidative injury of neurons. The protective effect of AEA was assessed by measuring cell metabolic activity, apoptosis, lactate dehydrogenase (LDH) release, cellular morphology, intracellular reactive oxygen species (ROS), and antioxidant and oxidant levels and Nox2 expression. RESULTS: HT22 cells exposed to H2O2 demonstrated morphological changes, decreased LDH release, reduced metabolic activity, increased levels of intracellular ROS and oxidized glutathione (GSSG), reduced levels of superoxide dismutase (SOD), and reduced glutathione (GSH) and increased expression of Nox2. AEA prevented these effects, a property abolished by simultaneous administration of CB1 antagonist AM251 or CB1-siRNA. CONCLUSION: Nox2 inhibition is involved in AEA-induced cytoprotection against oxidative stress through CB1 activation in HT22 cells.