Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Enhancing Hierarchical Transformers for Whole Brain Segmentation with Intracranial Measurements Integration.

Whole brain segmentation with magnetic resonance imaging (MRI) enables the non-invasive measurement of brain regions, including total intracranial volume (TICV) and posterior fossa volume (PFV). Enhancing the existing whole brain segmentation methodology to incorporate intracranial measurements offers a heightened level of comprehensiveness in the analysis of brain structures. Despite its potential, the task of generalizing deep learning techniques for intracranial measurements faces data availability constraints due to limited manually annotated atlases encompassing whole brain and TICV/PFV labels. In this paper, we enhancing the hierarchical transformer UNesT for whole brain segmentation to achieve segmenting whole brain with 133 classes and TICV/PFV simultaneously. To address the problem of data scarcity, the model is first pretrained on 4859 T1-weighted (T1w) 3D volumes sourced from 8 different sites. These volumes are processed through a multi-atlas segmentation pipeline for label generation, while TICV/PFV labels are unavailable. Subsequently, the model is finetuned with 45 T1w 3D volumes from Open Access Series Imaging Studies (OASIS) where both 133 whole brain classes and TICV/PFV labels are available. We evaluate our method with Dice similarity coefficients(DSC). We show that our model is able to conduct precise TICV/PFV estimation while maintaining the 132 brain regions performance at a comparable level. Code and trained model are available at: https://github.com/MASILab/UNesT/wholebrainSeg.

Commentary: Early-in-life Isoflurane Exposure Alters Resting-State Functional Connectivity in Juvenile Non-human Primates - a Role for Neuroinflammation?

The concern about anesthesia-induced developmental neurotoxicity (AIDN) in infants and young children arises from animal studies indicating potential long-term neurobehavioral impairments following early-in-life anesthesia exposure. While initial clinical studies provided ambiguous results, recent prospective assessments in children indicate associations between early-in-life anesthesia exposure and later behavioral alterations. Ethical constraints and confounding factors in clinical studies pose challenges in establishing a direct causal link and in investigating its mechanisms. This commentary on a recent study in non-human primates (NHPs) focuses on exploring the role of neuroinflammation and alterations in brain functional connectivity in the behavioral impairments following early-in-life anesthesia exposure. In juvenile NHPs, chronic astrogliosis in the amygdala correlates with alterations in functional connectivity between this area with other regions of the brain and with the behavioral impairments, suggesting a potential mechanism for AIDN. Despite acknowledging the study's limitations, these findings emphasize the need for further research with larger cohorts to confirm these associations and to establish a causal link between the neuroinflammation and the behavioral alterations associated with early-in-life anesthesia exposure.

A Sensitive Method for Determination 1,25-Dihydroxyvitamin D3 in Human Brain using Ultra-Pressure Liquid Chromatography Tandem Mass Spectrometry.

The hormonally active form of vitamin D, 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], has been associated with neuroprotective effects in the brain, but has been difficult to measure in human brain tissue because of its low concentration. The aim of this study was to develop and validate a sensitive method to quantify 1,25(OH)2D3 in the human brain. Prior to analysis by the LC-MS/MS, the samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione. The method showed good linearity of 1,25(OH)2D3 over the physiological range (R 2 = 0.9998). The limit of detection was 2.5 pg/g, >10 times lower than the previously reported limit of detection. The average 1,25(OH)2D3 concentrations in 3 regions of human brain tissue samples were: anterior watershed 30.7 pg/g; mid-temporal cortex 19.2 pg/g; and cerebellum 18.5 pg/g. This validated method to quantify 1,25(OH)2D3 in human brain tissue can be applied to obtain information about its presence in various regions of the human brain associated with neurodegenerative diseases.

Impaired energy metabolism and altered brain histoarchitecture characterized by inhibition of glycolysis and mitochondrial electron transport-linked enzymes in rats exposed to diisononyl phthalate.

The brain is an energy demanding organ, constituting about 20 % of the body's resting metabolic rate. An efficient energy metabolism is critical to neuronal functions. Glucose serves as the primary essential energy source for the adult brain and plays a critical role in supporting neural growth and development. Endocrine disrupting chemicals (EDCs) such as phthalates has been shown to have a negative impact on neurological functions. The impact of diisononyl phthalate (DiNP) on neural energy transduction using cellular energy metabolizing enzymes as indicators was examined. Over the course of 14 days, eighteen (18) albino rats divided into three groups (1,2 and 3) of six albino rats were given Tween-80/saline, 20 and 200 mg/kg body weight respectively. In the brain, we assessed histological changes as well as activities of selected enzymes of energy metabolism such as the glycolytic pathway, citric acid cycle and mitochondrial electron transport-linked complexes. Activities of the glycolytic and TCA cycle enzymes assayed were significantly decreased except citrate synthase activity with no statistically significant change following the administration of DiNP. Also, respiratory chain complexes (Complex I-IV) activities were significantly reduced when compared to control. DiNP exposure altered the histological integrity of various brain sections. These include degenerated Purkinje neurons, distortion of the granular layer and Purkinje cell layer. Data from this study indicated impaired brain energy metabolism via down-regulation of enzymes of cellular respiration of the glycolytic and oxidative phosphorylation pathways and altered brain histoarchitecture orchestrated by DiNP exposure.

Application of the bicharacteristic attention residual pyramid for the treatment of brain tumors.

Currently, surgery remains the primary treatment for craniocerebral tumors. Before doctors perform surgeries, they need to determine the surgical plan according to the shape, location, and size of the tumor; however, various conditions of different patients make the tumor segmentation task challenging. To improve the accuracy of determining tumor shape and realizing edge segmentation, a U-shaped network combining a residual pyramid module and a dual feature attention module is proposed. The residual pyramid module can enlarge the receptive field, extract multiscale features, and fuse original information, which solves the problem caused by the feature pyramid pooling where the local information is not related to the remote information. In addition, the dual feature attention module is proposed to replace the skip connection in the original U-Net network, enrich the features, and improve the attention of the model to space and channel features with large amounts of information to be used for more accurate brain tumor segmentation. To evaluate the performance of the proposed model, experiments were conducted on the public datasets Kaggle_3M and BraTS2021. Because the model proposed in this study is applicable to two-dimensional image segmentation, it is necessary to obtain the crosscutting images of fair class in the BraTS2021 dataset in advance. Results show that the model accuracy, Jaccard similarity coefficient, Dice similarity coefficient, and false negative rate (FNR) on the Kaggle_3M dataset are 0.9395, 0.8812, 0.8958, and 0.007, respectively. The model accuracy, Jaccard similarity coefficient, Dice similarity coefficient, and FNR on the BraTS2021 dataset were 0.9375, 0.9072, 0.8981, and 0.0087, respectively. Compared with existing algorithms, all the indicators of the proposed algorithm have been improved, but the proposed model still has certain limitations and has not been applied to actual clinical trials. For specific datasets, the generalization ability of the model needs to be further improved. In the future work, the model will be further improved to address the aforementioned limitations.

Convolutional neural network framework for EEG-based ADHD diagnosis in children.

Purpose: Attention-deficit hyperactivity disorder (ADHD) stands as a significant psychiatric and neuro-developmental disorder with global prevalence. The prevalence of ADHD among school children in India is estimated to range from 5% to 8%. However, certain studies have reported higher prevalence rates, reaching as high as 11%. Utilizing electroencephalography (EEG) signals for the early detection and classification of ADHD in children is crucial. Methods: In this study, we introduce a CNN architecture characterized by its simplicity, comprising solely two convolutional layers. Our approach involves pre-processing EEG signals through a band-pass filter and segmenting them into 5-s frames. Following this, the frames undergo normalization and canonical correlation analysis. Subsequently, the proposed CNN architecture is employed for training and testing purposes. Results: Our methodology yields remarkable results, with 100% accuracy, sensitivity, and specificity when utilizing the complete 19-channel EEG signals for diagnosing ADHD in children. However, employing the entire set of EEG channels presents challenges related to the computational complexity. Therefore, we investigate the feasibility of using only frontal brain EEG channels for ADHD detection, which yields an accuracy of 99.08%. Conclusions: The proposed method yields high accuracy and is easy to implement, hence, it has the potential for widespread practical deployment to diagnose ADHD.

The efficacy and safety of continuous theta burst stimulation for auditory hallucinations: a systematic review and meta-analysis of randomized controlled trials.

Objective: Auditory hallucinations are the most frequently occurring psychotic symptom in schizophrenia. Continuous theta burst stimulation (cTBS) has been used as an adjuvant treatment for auditory hallucinations. This meta-analysis focused on randomized controlled clinical trials (RCTs) to assess the efficacy of adjuvant cTBS on auditory hallucinations in schizophrenia. Methods: We performed a comprehensive search of four international databases from their inception to January 14, 2024, to identify relevant RCTs that assessed the effects of adjuvant cTBS on auditory hallucinations. The key words included "auditory hallucinations", "continuous theta burst stimulation" and "transcranial magnetic stimulation". Inclusion criteria included patients with auditory hallucinations in schizophrenia or schizoaffective disorder. The Revised Cochrane risk-of-bias tool for randomized trials (RoB1) were used to evaluate the risk of bias and the Review Manager Software Version 5.4 was employed to pool the data. Results: A total of 4 RCTs involving 151 patients with auditory hallucinations were included in the analysis. The Cochrane risk of bias of these studies presented "low risk" in all items. Preliminary analysis showed no significant advantage of adjuvant cTBS over sham stimulation in reducing hallucinations [4 RCTs, n = 151; SMD: -0.45 (95%CI: -1.01, 0.12), P = 0.13; I2 = 61%]. Subgroup analysis revealed that patients treated with adjuvant cTBS for more than 10 stimulation sessions and total number of pulses more than 6000 [3 RCTs, n = 87; SMD: -4.43 (95%CI: -8.22, -0.63), P = 0.02; I2 = 47%] had a statistically significant improvement in hallucination symptoms. Moreover, the rates of adverse events and discontinuation did not show any significant difference between the cTBS and sham group. Conclusions: Although preliminary analysis did not revealed a significant advantage of adjuvant cTBS over sham stimulation, subgroup analysis showed that specific parameters of cTBS appear to be effective in the treatment of auditory hallucinations in schizophrenia. Further large-scale studies are needed to determine the standard protocol of cTBS for treating auditory hallucinations. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024534045.

Cerebrospinal fluid characteristics of patients presenting for evaluation of pediatric acute-neuropsychiatric syndrome.

Objectives: This study characterizes cerebral spinal fluid (CSF) indices including total protein, the albumin quotient, IgG index and oligoclonal bands in patients followed at a single center for pediatric acute-neuropsychiatric syndrome (PANS) and other psychiatric/behavioral deteriorations. Methods: In a retrospective chart review of 471 consecutive subjects evaluated for PANS at a single center, navigational keyword search of the electronic medical record was used to identify patients who underwent lumbar puncture (LP) as part of the evaluation of a severe or atypical psychiatric deterioration. Psychiatric symptom data was ascertained from parent questionnaires and clinical psychiatric evaluations. Inclusion criteria required that subjects presented with psychiatric deterioration at the time of first clinical visit and had a lumbar puncture completed as part of their evaluation. Subjects were categorized into three subgroups based on diagnosis: PANS (acute-onset of severe obsessive compulsive disorder (OCD) and/or eating restriction plus two other neuropsychiatric symptoms), autoimmune encephalitis (AE), and "other neuropsychiatric deterioration" (subacute onset of severe OCD, eating restriction, behavioral regression, psychosis, etc; not meeting criteria for PANS or AE). Results: 71/471 (15.0 %) of patients underwent LP. At least one CSF abnormality was seen in 29% of patients with PANS, 45% of patients with "other neuropsychiatric deterioration", and 40% of patients who met criteria for autoimmune encephalitis. The most common findings included elevated CSF protein and/or albumin quotient. Elevated IgG index and IgG oligoclonal bands were rare in all three groups. Conclusion: Elevation of CSF protein and albumin quotient were found in pediatric patients undergoing LP for evaluation of severe psychiatric deteriorations (PANS, AE, and other neuropsychiatric deteriorations). Further studies are warranted to investigate blood brain barrier integrity at the onset of the neuropsychiatric deterioration and explore inflammatory mechanisms.

Investigation of the relationship between neuroplasticity and grapheme-color synesthesia.

Grapheme-color synesthesia is a normal and healthy variation of human perception. It is characterized by the association of letters or numbers with color perceptions. The etiology of synesthesia is not yet fully understood. Theories include hyperconnectivity in the brain, cross-activation of adjacent or functionally proximate sensory areas of the brain, or various models of lack of inhibitory function in the brain. The growth factor brain-derived neurotrophic (BDNF) plays an important role in the development of neurons, neuronal pathways, and synapses, as well as in the protection of existing neurons in both the central and peripheral nervous systems. ELISA methods were used to compare BDNF serum concentrations between healthy test subjects with and without grapheme-color synesthesia to establish a connection between concentration and the occurrence of synesthesia. The results showed that grapheme-color synesthetes had an increased BDNF serum level compared to the matched control group. Increased levels of BDNF can enhance the brain's ability to adapt to changing environmental conditions, injuries, or experiences, resulting in positive effects. It is discussed whether the integration of sensory information is associated with or results from increased neuroplasticity. The parallels between neurodegeneration and brain regeneration lead to the conclusion that synesthesia, in the sense of an advanced state of consciousness, is in some cases a more differentiated development of the brain rather than a relic of early childhood.

Mechanisms and treatments of methamphetamine and HIV-1 co-induced neurotoxicity: a systematic review.

Combination antiretroviral therapy (cART) has dramatically reduced mortality in people with human immunodeficiency virus (HIV), but it does not completely eradicate the virus from the brain. Patients with long-term HIV-1 infection often show neurocognitive impairment, which severely affects the quality of life of those infected. Methamphetamine (METH) users are at a significantly higher risk of contracting HIV-1 through behaviors such as engaging in high-risk sex or sharing needles, which can lead to transmission of the virus. In addition, HIV-1-infected individuals who abuse METH exhibit higher viral loads and more severe cognitive dysfunction, suggesting that METH exacerbates the neurotoxicity associated with HIV-1. Therefore, this review focuses on various mechanisms underlying METH and HIV-1 infection co-induced neurotoxicity and existing interventions targeting the sigma 1 receptor, dopamine transporter protein, and other relevant targets are explored. The findings of this review are envisaged to systematically establish a theoretical framework for METH abuse and HIV-1 infection co-induced neurotoxicity, and to suggest novel clinical treatment targets.

Psychosocial Impact of Brain Tumors: A Cross-Sectional Study on Existential Anxiety in Saudi Arabian Patients.

Background Existential anxiety is a significant concern for patients with life-threatening illnesses like brain tumors. This study explores the prevalence and impact of existential anxiety among brain tumor patients in Saudi Arabia, examining relationships between demographic, clinical, and psychological variables and death anxiety. Methods A cross-sectional study was conducted with 120 brain tumor patients from inpatient and outpatient settings at King Abdulaziz University Hospital, King Fahad Hospital, and King Abdullah Medical Complex in Saudi Arabia. Data were collected using the Death Anxiety Scale (DAS), Spiritual Well-Being Scale (SWBS), Meaning in Life Questionnaire (MLQ), and the 12-item Short Form Survey (SF-12). Descriptive and inferential statistics analyzed the relationships between variables. Results Females exhibited significantly higher DAS scores (77.9 ± 14.2) compared to males (48.5 ± 19.4) (p < 0.001). Educational attainment was inversely related to DAS, with illiterate patients scoring highest (83 ± 13.5) and those with higher education scoring lowest (47.3 ± 18.2) (p < 0.001). Widowed patients had higher anxiety (68.5 ± 22.1) compared to married (51.4 ± 21.5) and single patients (50 ± 12) (p < 0.001). Monthly income showed an inverse relationship with DAS. Patients with chronic medical conditions reported lower DAS scores compared to those without (p = 0.004). The tumor stage significantly influenced DAS, with third-stage patients showing lower anxiety than those in the first and second stages (p < 0.001). Longer duration since diagnosis was associated with lower DAS scores (p = 0.03). Conclusion This study highlights the significant psychosocial impact of brain tumors on Saudi Arabian patients, emphasizing the need to address demographic factors in managing death anxiety. Findings indicate that chronic medical conditions and advanced tumor stages might be associated with lower anxiety, revealing potential resilience factors. The positive influence of spiritual well-being and meaning in life on quality of life underscores the importance of holistic care approaches. Integrating psychological and spiritual support tailored to individual patient demographics could enhance management strategies and improve patient outcomes. Future research should explore longitudinal changes in existential anxiety, the role of cultural factors, and the effectiveness of holistic interventions in reducing anxiety and improving quality of life.

Case report: outcome of anlotinib treatment in breast cancer patient with brain metastases.

Brain metastases (BM) represent a common and severe complication of breast cancer (BC), emerging in approximately 10%-16% of all BC patients. The prevalent approach for treating BC patients with BM encompasses a multimodal strategy, combining surgery, whole brain radiation therapy, and stereotactic radiosurgery. Yet, a concrete guideline for localized treatment strategies remains elusive, while systemic treatments like small-molecule-targeted therapy and immunotherapy are still in the clinical trial phase. This case study presents a significant clinical response to anlotinib treatment in a patient with estrogen receptor-negative, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, complicated by BM. After the standard first-line treatment including albumin-bound paclitaxel, trastuzumab and pertuzumab, and a second-line treatment involving pyrotinib, capecitabine, and radiotherapy did not produce the desired results, the patient was then administered anlotinib in combination with pyrotinib and letrozole as a third-line treatment, which led to a partial response (PR). The findings suggest that anti-angiogenic therapy, specifically anlotinib, could be regarded as a promising therapeutic option for BC patients with BM.

The Blood-Brain Barrier in Both Humans and Rats: A Perspective From 3D Imaging.

Background: The blood-brain barrier (BBB) is part of the neurovascular unit (NVU) which plays a key role in maintaining homeostasis. However, its 3D structure is hardly known. The present study is aimed at imaging the BBB using tissue clearing and 3D imaging techniques in both human brain tissue and rat brain tissue. Methods: Both human and rat brain tissue were cleared using the CUBIC technique and imaged with either a confocal or two-photon microscope. Image stacks were reconstructed using Imaris. Results: Double staining with various antibodies targeting endothelial cells, basal membrane, pericytes of blood vessels, microglial cells, and the spatial relationship between astrocytes and blood vessels showed that endothelial cells do not evenly express CD31 and Glut1 transporter in the human brain. Astrocytes covered only a small portion of the vessels as shown by the overlap between GFAP-positive astrocytes and Collagen IV/CD31-positive endothelial cells as well as between GFAP-positive astrocytes and CD146-positive pericytes, leaving a big gap between their end feet. A similar structure was observed in the rat brain. Conclusions: The present study demonstrated the 3D structure of both the human and rat BBB, which is discrepant from the 2D one. Tissue clearing and 3D imaging are promising techniques to answer more questions about the real structure of biological specimens.

Brain-inspired biomimetic robot control: a review.

Complex robotic systems, such as humanoid robot hands, soft robots, and walking robots, pose a challenging control problem due to their high dimensionality and heavy non-linearities. Conventional model-based feedback controllers demonstrate robustness and stability but struggle to cope with the escalating system design and tuning complexity accompanying larger dimensions. In contrast, data-driven methods such as artificial neural networks excel at representing high-dimensional data but lack robustness, generalization, and real-time adaptiveness. In response to these challenges, researchers are directing their focus to biological paradigms, drawing inspiration from the remarkable control capabilities inherent in the human body. This has motivated the exploration of new control methods aimed at closely emulating the motor functions of the brain given the current insights in neuroscience. Recent investigation into these Brain-Inspired control techniques have yielded promising results, notably in tasks involving trajectory tracking and robot locomotion. This paper presents a comprehensive review of the foremost trends in biomimetic brain-inspired control methods to tackle the intricacies associated with controlling complex robotic systems.

Time-Dependent Potentiation of the PERK Branch of UPR by GPR68 Offers Protection in Brain Ischemia.

BACKGROUND: In ischemia, acidosis occurs in/around injured tissue and parallels disease progression. Therefore, targeting an acid-sensitive receptor offers unique advantages in achieving the spatial and temporal specificity required for therapeutic interventions. We previously demonstrated that increased expression of GPR68 (G protein-coupled receptor 68), a proton-sensitive G protein-coupled receptor, mitigates ischemic brain injury. Here, we investigated the mechanism underlying GPR68-dependent protection. METHODS: We performed biochemical and molecular analyses to examine poststroke signaling. We used in vitro brain slice cultures and in vivo mouse transient middle cerebral artery occlusion (tMCAO) models to investigate ischemia-induced injuries. RESULTS: GPR68 deletion reduced PERK (protein kinase R-like ER kinase) expression in mouse brain. Compared with the wild-type mice, the GPR68-/- (knockout) mice exhibited a faster decline in eIF2α (eukaryotic initiation factor-2α) phosphorylation after tMCAO. Ogerin, a positive modulator of GPR68, stimulated eIF2α phosphorylation at 3 to 6 hours after tMCAO, primarily in the ipsilateral brain tissue. Consistent with the changes in eIF2α phosphorylation, Ogerin enhanced tMCAO-induced reduction in protein synthesis in ipsilateral brain tissue. In organotypic cortical slices, Ogerin reduced pH 6 and oxygen-glucose deprivation-induced neurotoxicity. Following tMCAO, intravenous delivery of Ogerin reduced brain infarction in wild-type but not knockout mice. Coapplication of a PERK inhibitor abolished Ogerin-induced protection. Delayed Ogerin delivery at 5 hours after tMCAO remained protective, and Ogerin has a similar protective effect in females. Correlated with these findings, tMCAO induced GPR68 expression at 6 hours, and Ogerin alters post-tMCAO proinflammatory/anti-inflammatory cytokine/chemokine expression profile. CONCLUSIONS: These data demonstrate that GPR68 potentiation leads to neuroprotection, at least in part, through enhancing PERK-eIF2α activation in ischemic tissue but has little impact on healthy tissue.

CD8+T cell infiltration-associated barrier function of brain endothelial cells is enhanced by Astragalus polysaccharides via inhibiting PI3K/AKT signaling pathway.

Pathogenic CD8+T cells play an essential role in neuroinflammation and neural injury, which leads to the progression of inflammatory neurological disorders. Thus, blocking the infiltration of CD8+T cells is necessary for the treatment of neuroinflammatory diseases. Our previous study demonstrated that Astragalus polysaccharides (APS) could significantly reduce the infiltration of CD8+T cells in experimental autoimmune encephalomyelitis (EAE) mice. However, the mechanism by which APS suppress CD8+T cell infiltration remains elusive. In this study, we further found that APS could reduce the CD8+T cell infiltration in EAE and lipopolysaccharide (LPS)-induced neuroinflammatory model. Furthermore, we established the mouse brain endothelial cell (bEnd.3) inflammatory injury model by interleukin-1ß (IL-1ß) or LPS in vitro. The results showed that APS treatment downregulated the expression of vascular cell adhesion molecule1 (VCAM1) to decrease the adhesion of CD8+T cells to bEnd.3 cells. APS also upregulated the expression of zonula occluden-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) to reduce the trans-endothelial migration of CD8+T cells. The PI3K/AKT signaling pathway might mediate this protective effect of APS on bEnd.3 cells against inflammatory injury. In addition, we demonstrated the protective effect of APS on the integrity of brain endothelial cells in an LPS-induced neuroinflammatory model. In summary, our results indicate that APS can reduce peripheral CD8+T cell infiltration via enhancing the barrier function of brain endothelial cells, it may be a potential for the prevention of neuroinflammatory diseases.

Interoceptive signals shape the earliest markers and neural pathway to awareness at the visual threshold.

Variations in interoceptive signals from the baroreceptors (BRs) across the cardiac and respiratory cycle can modulate cortical excitability and so affect awareness. It remains debated at what stages of processing they affect awareness-related event-related potentials (ERPs) in different sensory modalities. We investigated the influence of the cardiac (systole/diastole) and the respiratory (inhalation/exhalation) phase on awareness-related ERPs. Subjects discriminated visual threshold stimuli while their electroencephalogram, electrocardiogram, and respiration were simultaneously recorded. We compared ERPs and their intracranial generators for stimuli classified correctly with and without awareness as a function of the cardiac and respiratory phase. Cyclic variations of interoceptive signals from the BRs modulated both the earliest electrophysiological markers and the trajectory of brain activity when subjects became aware of the stimuli: an early sensory component (P1) was the earliest marker of awareness for low (diastole/inhalation) and a perceptual component (visual awareness negativity) for high (systole/exhalation) BR activity, indicating that BR signals interfere with the sensory processing of the visual input. Likewise, activity spread from the primary visceral cortex (posterior insula) to posterior parietal cortices during high and from associative interoceptive centers (anterior insula) to the prefrontal cortex during low BR activity. Consciousness is thereby resolved in cognitive/associative regions when BR is low and in perceptual centers when it is high. Our results suggest that cyclic fluctuations of BR signaling affect both the earliest markers of awareness and the brain processes underlying conscious awareness.