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Traumatic brain injury (TBI) is a major cause of chronic disability and death in young adults worldwide. Multiple cellular, molecular and biochemical changes impact the development and outcome of TBI. Neuronal cell apoptosis, which is an important pathological change in secondary brain damage, is crucial to determine the functional recovery after TBI. miR-21, a widely-reported oncogene, which can reduce cell apoptosis in cancer, has been confirmed to be a pronounced up-regulated miRNA after TBI in animal model. Our study is designed to investigate whether miR-21 has the function of antiapoptosis in experimental TBI model in vitro and to explore the possible regulatory mechanism of miR-21 on neuronal apoptosis. The scratch cell injury was performed to mimic TBI-induced apoptosis in neurons, and miR-21 agomir/antagomir was transfected to up-/down-regulate the miR-21 level. Our data suggests that miR-21 can reduce the number of TUNEL-positive neurons. Meanwhile, miR-21 decreased the expression level of PTEN, and increased the phosphorylation of Akt significantly. In neurons transfected with miR-21 agomir, the expression of Bcl-2 was promoted while the caspase-3, caspase-9 and Bax level were down-regulated, which are crucially the downstream apoptosis-related proteins of PTEN-Akt signaling pathway. In conclusion, miR-21 can exert the function of reducing neuronal apoptosis through activating the PTEN-Akt signaling pathway. Our research provides new insights into the molecular mechanisms of neuronal apoptosis following TBI, which reminds that miR-21may be a potential therapeutic target for TBI treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Emulsifier Polysorbate 80 exposure significantly exacerbated age-related cognitive decline, along with increased brain pathological proteins deposition and neuroinflammation, as well as disruption of the blood–brain barrier. • Emulsifier Polysorbate 80 exposure contributed to gut microbiota dysbiosis and the increased of deoxycholic acid in plasma and brain. • Emulsifier Polysorbate 80 induced cognitive decline and neuroinflammation via gut microbiota. • Mechanically, deoxycholic acid activates microglial cells may involve the upregulation of ABCA1-mediated cholesterol transport on lysosomes, thereby promotes the senescence-associated secretory phenotype. Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood–brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae , Lachnospiraceae , and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a primary focus of human healthcare due to the lack of achieved lasting and complete remission strategies to treat AD with the characteristics of heterogeneity and complexity. Exosomes, which is the new emerging approach to intercellular communication, provide novel perspective on identified therapeutic strategies of AD. Mesenchymal stem cell-derived exosomes (MSC-exos) are emerging to be an appealing therapeutic tool for AD, with the donor-derived properties and the characteristics of minimal immunogenicity, effortless storage, nature delivery vehicles, and low risks of tumor formation based on the previous researches. In this review, we elaborate the mechanism of MSC-exos in the treatment of AD and discuss limitations in the clinical application. [ABSTRACT FROM AUTHOR]

Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. Methods: Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2′3′-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. Results: Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2′3′-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. Conclusion: Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Mitochondrial dysfunction and immune responses are important factors in the pathogenesis of AD, but their crosstalk in AD has not been studied. In this study, the independent role and interaction of mitochondria-related genes and immune cell infiltration in AD were investigated using bioinformatics methods. Methods: The datasets of AD were obtained from NCBI Gene Expression Omnibus (GEO), and the data of mitochondrial genes was from MitoCarta3.0 database. Subsequently, differential expression genes (DEGs) screening and GSEA functional enrichment analysis were performed. The intersection of DEGs and mitochondrial related genes was used to obtain MitoDEGs. The MitoDEGs most relevant to AD were determined by Least absolute shrinkage and selection operator and multiple support vector machine recursive feature elimination, as well as protein–protein interactions (PPI) network and random forest. The infiltration of 28 kinds of immune cells in AD was analyzed by ssGSEA, and the relationship between hub MitoDEGs and the proportion of immune infiltration was studied. The expression levels of hub MitoDEGs were verified in cell models and AD mice, and the role of OPA1 in mitochondrial damage and neuronal apoptosis was investigated. Results: The functions and pathways of DEGs were significantly enriched in AD, including immune response activation, IL1R pathway, mitochondrial metabolism, oxidative damage response and electron transport chain-oxphos system in mitochondria. Hub MitoDEGs closely related to AD were obtained based on PPI network, random forest and two machine learning algorithms. Five hub MitoDEGs associated with neurological disorders were identified by biological function examination. The hub MitoDEGs were found to be correlated with memory B cell, effector memory CD8 T cell, activated dendritic cell, natural killer T cell, type 17 T helper cell, Neutrophil, MDSC, plasmacytoid dendritic cell. These genes can also be used to predict the risk of AD and have good diagnostic efficacy. In addition, the mRNA expression levels of BDH1, TRAP1, OPA1, DLD in cell models and AD mice were consistent with the results of bioinformatics analysis, and expression levels of SPG7 showed a downward trend. Meanwhile, OPA1 overexpression alleviated mitochondrial damage and neuronal apoptosis induced by Aβ1-42. Conclusions: Five potential hub MitoDEGs most associated with AD were identified. Their interaction with immune microenvironment may play a crucial role in the occurrence and prognosis of AD, which provides a new insight for studying the potential pathogenesis of AD and exploring new targets. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia is the best predictor of developing cognitive decline and Alzheimer's disease progression in patients with obstructive sleep apnea. The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome has been poorly studied as a regulator of neuroinflammation in cognitive impairment caused by intermittent hypoxia. As critical inflammatory cells, exosomes secreted by microglia have been found to affect the spread of pathologic proteins and neuropathology in neurodegenerative diseases. However, the effects of microglial exosomes on neuroinflammation and cognitive outcomes after intermittent hypoxia remain unclear. In this study, the role of miRNAs in microglial exosomes in improving cognitive deficits in mice exposed to intermittent hypoxia was investigated. We demonstrated that miR-146a-5p fluctuated over time in microglial exosomes of mice exposed to intermittent hypoxia for different periods of time, which could regulate neuronal NLRP3 inflammasome and neuroinflammation. In primary neurons, we found that miR-146a-5p regulated mitochondrial reactive oxygen species by targeting HIF1α, thus affecting the NLRP3 inflammasome and secretion of inflammatory factors. Similarly, further studies showed that inhibition of NLRP3 by administering overexpressed miR-146a-5p in microglial exosomes and MCC950 has improved neuroinflammation and cognitive dysfunction in mice after intermittent hypoxia. In conclusion, NLRP3 inflammasome may be a regulatory target for ameliorating cognitive impairment caused by intermittent hypoxia, and microglial exosomal miR-146a-5p may be a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood–brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1+ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib's effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Neuroinflammation is an important mediator of secondary injury pathogenesis that exerts dual beneficial and detrimental effects on pathophysiology of the central nervous system (CNS) after traumatic brain injury (TBI). Fluvoxamine is a serotonin selective reuptake inhibitor (SSRI) and has been reported to have the anti-inflammatory properties. However, the mechanisms and therapeutic effects of fluvoxamine in neuroinflammation after TBI have not be defined. In this study, we showed that fluvoxamine inhibited peripheral immune cell infiltration and glia activation at 3 days in mice subjected to TBI. Fluvoxamine treatment promoted microglial/macrophage phenotypic transformation from pro-inflammatory M1-phenotype to anti-inflammatory M2-phenotype in in vivo and in vitro experiments. In addition, fluvoxamine treatment attenuated neuronal apoptosis, blood–brain barrier (BBB) disruption, cerebrovascular damage, and post-traumatic edema formation, thereby improving neurological function of mice subjected to TBI. These findings support the clinical evaluation of fluvoxamine as a neuroprotective therapy for TBI. [ABSTRACT FROM AUTHOR]

The incidence of repetitive mild traumatic brain injury (rmTBI), one of the main risk factors for predicting neurodegenerative disorders, is increasing; however, its underlying mechanism remains unclear. As suggested by several studies, ferroptosis is possibly related to TBI pathophysiology, but its effect on rmTBI is rarely studied. Mesenchymal stromal cells (MSCs), the most studied experimental cells in stem cell therapy, exert many beneficial effects on diseases of the central nervous system, yet evidence regarding the role of MSCs in ferroptosis and post-rmTBI neurodegeneration is unavailable. Our study showed that rmTBI resulted in time-dependent alterations in ferroptosis-related biomarker levels, such as abnormal iron metabolism, glutathione peroxidase (GPx) inactivation, decrease in GPx4 levels, and increase in lipid peroxidation. Furthermore, MSC treatment markedly decreased the aforementioned rmTBI-mediated alterations, neuronal damage, pathological protein deposition, and improved cognitive function compared with vehicle control. Similarly, liproxstatin-1, a ferroptosis inhibitor, showed similar effects. Collectively, based on the above observations, MSCs ameliorate cognitive impairment following rmTBI, partially via suppressing ferroptosis, which could be a therapeutic target for rmTBI. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI. Methods: Ten human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg/kg). Results: The expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047. Conclusions: ER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice. [ABSTRACT FROM AUTHOR]

Our recent studies have identified increased expression of miR-21 in brain following traumatic brain injury (TBI), which alleviated brain edema that related to the blood–brain barrier (BBB) leakage. To analyze the potential effect of miR-21 on secondary BBB damage after TBI, we employed the fluid percussion injury rat model and manipulated the expression level of miR-21 in brain. We found that miR-21 level in brain microvascular endothelial cells (BMVECs) in lesioned cerebral cortex can be upregulated or downregulated by intracerebroventricular infusion of miR-21 agomir or antagomir. Upregulated miR-21 level conferred a better neurological outcome of TBI, and alleviated TBI-induced secondary BBB damage and loss of tight junction proteins. To explore the molecular mechanism underlying this protective effect, we detected the impact of miR-21 on the expression of Angiopoietin-1(Ang-1) and Tie-2, which can promote the expression of tight junction proteins and amplify BBB stabilization. We found that miR-21 exerts the protective effect on BBB by activating the Ang-1/Tie-2 axis in BMVECs. Thus, miR-21 could be a potential therapeutic target for interventions of secondary BBB damage after TBI. [ABSTRACT FROM AUTHOR]

Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain the viability of cells. This communication is mediated and maintained by the mitochondria-associated membranes and may be disrupted during acute traumatic brain injury (TBI), leading to structural and functional damage of neurons and supporting cells. To test this hypothesis, we subjected male C57BL/6 mice to severe TBI (sTBI) using a controlled cortical impact device. We analyzed the physical ER-mitochondrion contacts in the perilesional cortex using transmission electron microscopy, Western blot, and immunofluorescence. We specifically measured changes in the production of reactive oxygen species (ROS) in mitochondria, the unfolded protein response (UPR), the neuroinflammatory response, and ER stress-mediated apoptosis in the traumatic injured cerebral tissue. A modified neurological severity score was used to evaluate neurological function in the sTBI mice. We found that sTBI induced significant reorganizations of mitochondria-associated ER membranes (MAMs) in the cerebral cortex within the first 24 h post-injury. This ER-mitochondrion coupling was enhanced, reaching its peak level at 6 h post-sTBI. This enhanced coupling correlated closely with increases in the expression of the Ca2+ regulatory proteins (inositol 1,4,5-trisphosphate receptor type 1 [IP3R1], voltage-dependent anion channel 1 [VDAC1], glucose-regulated protein 75 [GRP75], Sigma 1 receptor [Sigma-1R]), production of ROS, degree of ER stress, levels of UPR, and release of proinflammatory cytokines. Further, the neurological function of sTBI mice was significantly improved by silencing the gene for the ER-mitochondrion tethering factor PACS2, restoring the IP3R1-GRP75-VDAC1 axis of Ca2+ regulation, alleviating mitochondria-derived oxidative stress, suppressing inflammatory response through the PERK/eIF2α/ATF4/CHOP pathway, and inhibiting ER stress and associated apoptosis. These results indicate that dysfunctional ER-mitochondrion coupling might be primarily involved in the neuronal apoptosis and neurological deficits, and modulating the ER-mitochondrion crosstalk might be a novel therapeutic strategy for sTBI. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD), the second most prevalent type of dementia, lacks a well-defined cause and effective treatment. Our objective was to utilize bioinformatics analysis to discover the fundamental disease-causing genes and pathological mechanisms in individuals diagnosed with VaD. To identify potential pathogenic genes associated with VaD, we conducted weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein–protein interaction (PPI) analysis. The exploration of potential biological mechanisms involved the utilization of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Moreover, a bilateral common carotid artery stenosis (BCAS) mouse model of VaD was established, and the expression of the hub gene, its relationship with cognitive function and its potential pathogenic mechanism were verified by cognitive behavior tests, cerebral blood flow measurement, Western blotting, and immunofluorescence experiments. This study identified 293 DEGs from the brain cortex of VaD patients and healthy controls, among these genes, the Toll-like receptor 2 (TLR2) gene was identified as hub gene, and it was associated with the apoptosis-related pathway PI3K/AKT.The BCAS model demonstrated that the use of TLR2 inhibitors greatly enhanced the cognitive function of the mice (p < 0.05). Additionally, there was a notable decrease in the number of apoptotic cells in the brain cortex of the mice (p < 0.01). Moreover, significant alterations in the levels of proteins related to the PI3K/AKT pathway and cleaved-caspase3 proteins were detected (p < 0.05). TLR2 plays a role in the pathophysiology of VaD by enhancing the neuronal apoptotic pathway, suggesting it could be a promising therapeutic target. • Identified Toll-like receptor 2 (TLR2) as a hub gene in VaD pathology • TLR2 inhibition improved cognitive function in a VaD mouse model. • Decreased apoptotic cells in mouse brain cortex with TLR2 inhibition • TLR2's association with apoptosis via the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

• Brain-derived EVs induce inflammation and coagulopathy after traumatic brain injury. • Brain-derived EVs induce leukocytes and platelets dysfunction. • Brain-derived EVs activate and stimulate leukocytes and platelets release EVs. • Removing brain-derived EVs alleviate systemic coagulopathy and inflammation. Traumatic brain injury (TBI) can induce systemic coagulopathy and inflammation, thereby increasing the risk of mortality and disability. However, the mechanism causing systemic coagulopathy and inflammation following TBI remains unclear. In prior research, we discovered that brain-derived extracellular vesicles (BDEVs), originating from the injured brain, can activate the coagulation cascade and inflammatory cells. In this study, we primarily investigated how BDEVs affect systemic coagulopathy and inflammation in peripheral circulation. The results of cytokines and coagulation function indicated that BDEVs can lead to systemic coagulopathy and inflammation by influencing inflammatory factors and chemokines within 24 h. Furthermore, according to flow cytometry and blood cell counter results, we found that BDEVs induced changes in the blood count such as a reduced number of platelets and leukocytes and an increased percentage of neutrophils, macrophages, activated platelets, circulating platelet-EVs, and leukocyte-derived EVs. We also discovered that eliminating circulating BDEVs with lactadherin helped improve coagulopathy and inflammation, relieved blood cell dysfunction, and decreased the circulating platelet-EVs and leukocyte-derived EVs. Our research provides a novel viewpoint and potential mechanism of TBI-associated secondary damage. [ABSTRACT FROM AUTHOR]

Prognosis evaluation is crucial for the effective management of patients with acute traumatic brain injury (TBI). However, there is still a lack of routinely available blood indicators for mortality risk in clinical practice. To investigate whether blood red cell distribution width to platelet count ratio (RPR) correlates with hospital mortality of TBI, clinical data of 2220 patients with TBI were extracted from two large intensive care unit cohorts (MIMIC-III and eICU Database), and were integratively analyzed using our developed method named MeDICS. We found that higher RPR can be observed among non-survivors than survivors of TBI (p < 0.001). It had a moderately good prognostic performance for mortality with an area under receiver-operating characteristic curve (AUC) of 0.7367, which was greater than that of Glasgow Coma Scale (GCS; AUC = 0.6022). Besides, the nomogram consisting of RPR, GCS, and other risk factors was developed, where 10-fold cross-validation was performed to protect it against overfitting. A Harrell's C-index of 0.8523 was determined, suggesting an improved prognostic value based on RPR. The in vivo experiments further confirmed the association between RPR and neuro-outcome after TBI. It indicated that the continuous change in RPR post-injury is attributed to the development of inflammation, which emphasized the importance of controlling inflammatory response in clinical treatment. Taken together, RPR is a promising routinely available predictor of mortality for acute TBI. The nomogram generated from it can be used in resource-limited settings, thus be proposed as a prognosis evaluation aid for patients with TBI in all levels of medical system. [ABSTRACT FROM AUTHOR]

Small extracellular vesicles(sEVs), a subset of extracellular vesicles with a bilateral membrane structure, contain biological cargoes, such as lipids, nucleic acids, and proteins. sEVs are crucial mediators of intercellular communications in the physiological and pathological processes of the central nervous system. Because of the special structure and complex pathogenesis of the brain, central nervous system disorders are characterized by high mortality and morbidity. Increasing evidence has focused on the potential of sEVs in clinical application for central nervous system disorders. sEVs are emerging as a promising diagnostic and therapeutic tool with high sensitivity, low immunogenicity, superior safety profile, and high transfer efficiency. This review highlighted the development of sEVs in central nervous system disorder clinical application. We also outlined the role of sEVs in central nervous system disorders and discussed the limitations of sEVs in clinical translation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a primary focus of human healthcare due to the lack of achieved lasting and complete remission strategies to treat AD with the characteristics of heterogeneity and complexity. Exosomes, which is the new emerging approach to intercellular communication, provide novel perspective on identified therapeutic strategies of AD. Mesenchymal stem cell-derived exosomes (MSC-exos) are emerging to be an appealing therapeutic tool for AD, with the donor-derived properties and the characteristics of minimal immunogenicity, effortless storage, nature delivery vehicles, and low risks of tumor formation based on the previous researches. In this review, we elaborate the mechanism of MSC-exos in the treatment of AD and discuss limitations in the clinical application. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a primary focus of human healthcare due to the lack of achieved lasting and complete remission strategies to treat AD with the characteristics of heterogeneity and complexity. Exosomes, which is the new emerging approach to intercellular communication, provide novel perspective on identified therapeutic strategies of AD. Mesenchymal stem cell-derived exosomes (MSC-exos) are emerging to be an appealing therapeutic tool for AD, with the donor-derived properties and the characteristics of minimal immunogenicity, effortless storage, nature delivery vehicles, and low risks of tumor formation based on the previous researches. In this review, we elaborate the mechanism of MSC-exos in the treatment of AD and discuss limitations in the clinical application. [ABSTRACT FROM AUTHOR]

• Nerves injury can induce the upregulation of miR-21-5p in neuron. • Neuron-exosomes with high miR-21-5p expression induced microglia polarization. • Inflammation factors released by polarized microglia further aggravated nerves injury. Neuroinflammation is a characteristic pathological change of acute neurological deficit and chronic traumatic encephalopathy (CTE) after traumatic brain injury (TBI). Microglia are the key cell involved in neuroinflammation and neuronal injury. The type of microglia polarization determines the direction of neuroinflammation. MiR-21-5p elevated in neurons and microglia after TBI in our previous research. In this study, we explore the influence of miR-21-5p for neuroinflammation by regulating microglia polarization. In this study, PC12 and BV2 used to instead of neuron and microglia respectively. The co-cultured transwell system used to simulate interaction of PC12 and BV2 cells in vivo environment. We found that PC12-derived exosomes with containing miR-21-5p were phagocytosed by microglia and induced microglia polarization, meanwhile, the expression of miR-21-5p was increased in M1 microglia cells. Polarization of M1 microglia aggravated the release of neuroinflammation factors, inhibited the neurite outgrowth, increased accumulation of P-tau and promoted the apoptosis of PC12 cells, which formed a model of cyclic cumulative damage. Simultaneously, we also got similar results in vivo experiments. PC12-derived exosomes with containing miR-21-5p is the essential of this cyclic cumulative damage model. Therefore, regulating the expression of miR-21-5p or the secretion of exosomes may be an important novel strategy for the treatment of neuroinflammation after TBI. [ABSTRACT FROM AUTHOR]

In our recent study, we observed consistent increases in miR-124-3p levels in exosomes derived from cultured BV2 microglia which was treated with repetitive traumatic brain injury (rTBI) mouse model brain extracts. To clarify the mechanisms underlying increases in microglia-derived exosomal miR-124-3p and their role in regulating neuronal autophagy after TBI, we investigated the impact of exosomal miR-124-3p on neuronal autophagy in scratch-injured HT22 neurons and rTBI mice. We harvested injured brain extracts from rTBI mice at 3 to 21 days post injury (DPI) for the treatment of cultured BV2 microglia in vitro. We observed significant induction of autophagy following TBI in vitro, and that inhibition of activated neuronal autophagy could protect against trauma-induced injury. Our results indicated that co-culture of injured HT22 neurons with miR-124-3p overexpressing BV2 microglia exerted a protective effect by inhibiting neuronal autophagy in scratch-injured neurons. Further research revealed that these effects were achieved mainly via upregulation of exosomal miR-124-3p, and that Focal adhesion kinase family-interacting protein of 200 kDa (FIP200) plays a key role in trauma-induced autophagy. Injection of exosomes into the vena caudalis in in vivo experiments revealed that exosomal miR-124-3p was associated with decreases in the modified neurological severity score (mNSS) and improvements in Morris water maze (MWM) test results in rTBI mice. Altogether, our results indicate that increased miR-124-3p in microglial exosomes following TBI may inhibit neuronal autophagy and protect against nerve injury via their transfer into neurons. Thus, treatment with microglial exosomes enriched with miR-124-3p may represent a novel therapeutic strategy for the treatment of nerve injury after TBI. [ABSTRACT FROM AUTHOR]

[Display omitted] • TBI causes oxidative stress and neuroinflammation in brain tissue, which in turn causes ferroptosis. • DFO can reduce oxidative stress and iron death levels after TBI. • GSNO reduces TBI-induced neurodegeneration and aids in functional recovery. • DFO can reduce NF-kb pathway expression after TBI, which in turn reduces pyroptosis and attenuates neuroinflammation. Traumatic brain injury (TBI) is an important reason of neurological damage and has high morbidity and mortality rates. The secondary damage caused by TBI leads to a poor clinical prognosis. According to the literature, TBI leads to ferrous iron aggregation at the site of trauma and may be a key factor in secondary injury. Deferoxamine (DFO), which is an iron chelator, has been shown to inhibit neuron degeneration; however, the role of DFO in TBI is unclear. The purpose of this study was to explore whether DFO can ameliorate TBI by inhibiting ferroptosis and neuroinflammation. Here, our findings suggest that DFO can reduce the accumulation of iron, lipid peroxides, and reactive oxygen species (ROS) and modulate the expression of ferroptosis-related indicators. Moreover, DFO may reduce NLRP3 activation via the ROS/NF-κB pathway, modulate microglial polarization, reduce neutrophil and macrophage infiltration, and inhibit the release of inflammatory factors after TBI. Additionally, DFO may reduce the activation of neurotoxic responsive astrocytes. Finally, we demonstrated that DFO can protect motor memory function, reduce edema and improve peripheral blood perfusion at the site of trauma in mice with TBI, as shown by behavioral experiments such as the Morris water maze test, cortical blood perfusion assessment and animal MRI. In conclusion, DFO ameliorates TBI by reducing iron accumulation to alleviate ferroptosis and neuroinflammation, and these findings provide a new therapeutic perspective for TBI. [ABSTRACT FROM AUTHOR]

Pyroptosis is a highly specific type of inflammatory programmed cell death that different from necrosis or apoptosis. It is initiated by cellular detection of acute damage via recognizing pathogen-associated molecular patterns (PAMPs) by NOD-like receptors (NLRs) or AIM2-like receptor (AIM2). NLRs and AIM2 could trigger the formation of a multi-protein complex, known as inflammasome. It also contains apoptotic speck-containing protein (ASC) and pro-Caspase-1, and could process the signals to induce a cascade of inflammatory response. Recently, growing evidence showed that inflammasome-mediated pyroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to their particular roles in regulating blood-brain barrier (BBB) damage, the central pathological change in secondary brain damage of TBI. Thus, we designed this research to explore the impact and mechanism of NLRs and AIM2 inflammasome-mediated pyroptosis in BBB after TBI. We employed the controlled cortical impact (CCI) mice model and manipulated the severity of pyroptosis in BBB using Caspase-1 inhibitor, Ac-YVAD-cmk. We found that TBI led to NLRs and AIM2 inflammasome-mediated pyroptosis in brain microvascular endothelial cells (BMVECs) from injured cerebral cortex. Ac-YVAD-cmk treatment inhibited pyroptosis in injured BMVECs by suppressing the expression of essential inflammasome subunit – Caspase-1 and pivotal downstream pro-inflammatory cytokines (IL-1β and IL-18), as well as hindering GSDMD cleavage and ASC oligomerization. In addition, inhibiting pyroptosis could alleviate TBI-induced BBB leakage, brain edema, loss of tight junction proteins, and the inflammatory response in injured BMVECs. These effects contributed to improving the neurological outcome of CCI mice. In conclusion, NLRs and AIM2 inflammasome-mediated pyroptosis could aggravate BBB damage after TBI. Targeting and controlling pyroptosis in injured BBB would be a promising therapeutic strategy for TBI in the future. [ABSTRACT FROM AUTHOR]

Highlights • We develop a novel rmTBI model that represents clinical settings of mild TBI & CTE. • The model does not induce any adverse effects as described in existing rmTBI models. • A short research period of 5 w post-injury was allowed for observing chronic changes. • Self-designed molded acrylic cast and concave metal disc are used in modeling. • Chronic neuroinflammation, neurodegeneration and cognitive dysfunction are observed. Abstract Background Athletes, military personnel and mobility-declined elderly people are prone to repetitive mild traumatic brain injury (rmTBI). The injury does not cause acute pathological changes, but leads to chronic neurodegeneration, long-term cognitive dysfunction and even chronic traumatic encephalopathy (CTE). Many existing rmTBI animal models reported uncontrollable adverse effects and long experiment period. Therefore, an improved model needs to be designed. New method Our rmTBI mouse model is a modification of the closed head injury method using electronic controlled cortical impact system. Discontinuous 4 impacts with 48-h interval were performed. A key facet of the model is the use of our designed molded acrylic cast and concave metal disc (as a helmet). They could scatter and transmit hitting power to the whole brain, thus produced a mild diffused injury. The procedure does not require scalp incision or craniotomy, which allows the impacting to be completed in 2 min. Results Our model did not induce acute macroscopic brain damage and brain edema. It could lead to sustained neuroinflammation and chronic neurodegeneration in injured brain, and resulted in cognitive dysfunction within 5 weeks post-injury. Comparison with existing methods Previously reported adverse effects including skull fractures, hemorrhage and brain tissue loss were not observed in our model. An experiment period of 5 weeks was allowed for observing chronic neurodegeneration and cognitive dysfunction. Conclusions Our model is beneficial to use for simplicity, reproducibility and time saver. It could serve as a platform for research on the pathogenesis, diagnosis and potential therapeutics for rmTBI and CTE. [ABSTRACT FROM AUTHOR]

To date, the pathogenesis of Alzheimer's disease (AD) remains unclear. It is well-known that excessive deposition of Aβ in the brain is a crucial part of the pathogenesis of AD. In recent years, the AD neurovascular unit hypothesis has attracted much attention. Impairment of the blood-brain barrier (BBB) leads to abnormal amyloid-β (Aβ) transport, and chronic cerebral hypoperfusion causes Aβ deposition throughout the onset and progression of AD. Endothelial progenitor cells (EPCs) are the universal cells for repairing blood vessels. Our previous studies have shown that a reduced number of EPCs in the peripheral blood results in cerebral vascular repair disorder, cerebral hypoperfusion and neurodegeneration, which might be related to the cognitive dysfunction of AD patients. This study was designed to confirm whether EPCs transplantation could repair the blood-brain barrier, stimulate angiogenesis and reduce Aβ deposition in AD. The expression of ZO-1, Occludin and Claudin-5 was up-regulated in APP/PS1 transgenic mice after hippocampal transplantation of EPCs. Consistent with previous studies, EPC transplants also increased the microvessel density. We observed that Aβ senile plaque deposition was decreased and hippocampal cell apoptosis was reduced after EPCs transplantation. The Morris water maze test showed that spatial learning and memory functions were significantly improved in mice transplanted with EPCs. Consequently, EPCs could up-regulate the expression of tight junction proteins, repair BBB tight junction function, stimulate angiogenesis, promote Aβ clearance, and decrease neuronal loss, ultimately improve cognitive function. Taken together, these data demonstrate EPCs may play an important role in the therapeutic implications for vascular dysfunction in AD. [ABSTRACT FROM AUTHOR]

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neu‐ronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR‐124‐3p increased most apparently in the miRNAs. We found that miR‐124‐3p promoted the anti‐inflamed M2 polarization in microglia, and microglial exosomal miR‐124‐3p inhibited neuronal inflammation in scratch‐injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR‐124‐3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR‐124‐3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR‐124‐3p by pathway analysis. We proved that it was directly targeted by miR‐124‐3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR‐124‐3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR‐124‐3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreasedexpressiononRhoAand neurodegenerative proteins [Aß‐peptide and p‐Tau]. It also improved the neurologic outcome and inhibited neuro‐inflammation in mice with rTBI. Taken together, increased miR‐124‐3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR‐124‐3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR‐124‐3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.—Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J. 32, 512‐528 (2018). www.fasebj.org [ABSTRACT FROM AUTHOR]

Although, there is growing awareness in the progressive neurodegeneration of chronic traumatic encephalopathy, changes of immune reactions remain equivocal at best. Thus, in a clinically relevant rat repetitive mild traumatic brain injury (rmTBI) model, some immunologic cells (T cell subsets, microglia) in the injured brain and peripheral blood were analyzed by flow cytometry and immunofluorescence. In the injured brain, CD3 T cells showed a bimodal increase during 42 days post-injury (dpi). CD3CD4 T cells firstly increased and then decreased, while CD3CD8 T cells had reversed tendency. CD86/CD11b M1-like microglia increased at 42 dpi and CD206/CD11b M2-like microglia peaked at 7 dpi. In addition, peripheral immune suppression was implicated in the chronic phase after rmTBI. Taken together, the study provided useful information on long-term dynamic changes of some immune cells after rmTBI in rats. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is a characteristic pathophysiological change of obstructive sleep apnea (OSA), a commonly diagnosed chronic sleep disorder. With the process of OSA, patients will suffer from the nervous system damage and appear to multiple cognitive dysfunction. The mechanism that how IH causes cognitive impairment is still unknown. Both control and experimental rats were placed in conditions absence and presence of intermittent hypoxia (IH) for 8 h a day for a week, two weeks and four weeks, and then followed by behavioral assessments with Morris Water Maze (MWM) test. The results showed that the escape latency of the tested animals to IH significantly increased the escape latency on the last four training days in comparison to the control group. Consistent with this, the expressions of apoptosis/anti-apoptosis proteins were both changed in the hippocampus. Then we utilized the miRNA microarray assay to investigate the level of miRNA expression in rat hippocampus which suffered from intermittent hypoxia. It is noteworthy that the expressions of miR-26b and miR-207 were consistently dysregulated in all the experimental groups post IH. And we utilized qRT-PCR methods to verify the microarray results. Our results showed that microarray based analysis of microRNA expression in rat hippocampus after IH has shown that some microRNAs such as miR-26b and miR-207 could be involved in the OSA-induced cognitive impairments. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major public health problem with long-term neurobehavioral sequela. The evidences have revealed that TBI is a risk factor for later development of neurodegenerative disease and both the single and repetitive brain injury can lead to the neurodegeneration. But whether the effects of accumulation play an important role in the neurodegenerative disease is still unknown. We utilized the Sprague Dawley (SD) rats to develop the animal models of repetitive mild TBI and single mild TBI in order to detect the neurobehavioral changes. The results of neurobehavioral test revealed that the repetitive mild TBI led to more severe behavioral injuries than the single TBI. There were more activated microglia cells and astrocytes in the repetitive mild TBI group than the single TBI group. In consistent with this, the levels of TNF-α and IL-6 were higher and the expression of IL-10 was lower in the repetitive mild TBI group compared with the single TBI group. The expression of amyloid precursor protein (APP) increased in the repetitive TBI group detected by ELISA and western blot. But the levels of total tau (Tau-5) and P-tau (ser202) seem no different between the two groups in most time point. In conclusion, repetitive mild TBI could lead to more severe neurobehavioral impairments and the effects of accumulation may be associated with the increased inflammation in the brain. [ABSTRACT FROM AUTHOR]

Our recent researches have identified increased expression of miR-21-5p in rats brain following traumatic brain injury (TBI), which protected against blood-brain barrier (BBB) damage. To further study the mechanism underlying the role of miR-21-5p on alleviating BBB damage after TBI, we performed the scratch injury model on cultured brain microvascular endothelial cells (BMVECs), which formed the microvascular endothelial barrier – an integral part of the highly specialized BBB. The expression level of miR-21-5p in BMVECs was observed to be increased after scratch injury, and could be further up-regulated by transfecting miR-21-5p mimics. We found that up-regulation of miR-21-5p level in BMVECs can alleviate endothelial barrier damage and loss of tight junction proteins. To further investigate the mechanism of this protective effect, we evaluated the impact of miR-21-5p on inflammation and apoptosis in injured BMVECs. On one hand, miR-21-5p suppressed inflammation by regulating the expression of inflammatory cytokines and NF-kB signaling. On the other hand, miR-21-5p inhibited cellular apoptosis by regulating the expression of apoptosis factors and Akt signaling. In addition, we also detected the activity of Ang-1/Tie-2 axis (associated with BBB stabilization) in BMVECs after scratch injury, and found that miR-21-5p can promote its activation. Taken together, miR-21-5p alleviates leakage of injured brain microvascular endothelial barrier through suppressing inflammation and apoptosis, while impacting the activities of NF-kB, Akt and Ang-1/Tie-2 signaling. Thus, miR-21-5p could be a potential therapeutic target for interventions of BBB damage after TBI. [ABSTRACT FROM AUTHOR]

Dysregulated microRNAs in neurons could cause many nervous system diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNA modulators targeting neurons with minimal off-target effects. The study aimed to establish a lipofection protocol to upregulate expression levels of miR-21 in neurons under different conditions, including different serum-free medium, transfection conditions, and reagent concentration, by evaluating the expression levels of miR-21 and neuron injury. The expression levels of miR-21 were higher in neurons transfected by Neurobasal-A than by DMEM. Expression levels of miR-21 were already the highest at the ratio RNAiMAX:miR-21 = 3:5, but the increase of RNAiMAX's concentration had not caused the further upregulation of expression level of miR-21. Neuron injury was condition dependent and dose dependent after transfection. Compared to S-Neurobasal groups, neurons have a smaller injury in N-Neurobasal groups, and compared to ratios RNAiMAX:miR-21 = 4:5, 5:5, neuron injury was smaller at ratios of RNAiMAX:miR-21 = 1:5, 2:5, 3:5. Without the pretreatment of starvation in vitro, the lipofection protocol was that RNAiMAX/miR-21 agomir complexes were diluted in Neurobasal-A at the ratio of RNAiMAX:miR-21 = 3:5. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the correlations between intraocular pressure (IOP) and circulating endothelial progenitor cells (EPCs), retinal ganglion cells (RGC) apoptosis and EPCs, and explore the possible role of EPCs in the elevated IOP-induced RGC apoptosis. Materials and methods: A rat model of IOP elevation was induced by photocoagulation of the limbus vein and episcleral veins using a 532-nm green laser. Twenty rats were randomly assigned to normal control (NC) group, 30 rats were randomly assigned to sham-treated control (STC) group and 50 rats were randomly assigned to laser-treated (LT) group. The IOPs were measured with a Tono-pen XL tonometer. Hematoxylin-eosin staining was performed to observe the effects of IOP elevation on the structure of retina. Retinal apoptotic cells were determined by in situ TUNEL staining, and peripheral blood EPCs (CD34+/CD133+) were detected by flow cytometry. Results: Compared with the NC group (9.9 ± 1.2 mmHg), the IOPs in the LT group were 37.4 ± 1.5, 31.8 ± 4.1, 25.9 ± 2.2, 23.1 ± 3.6 and 22.4 ± 3.0 mmHg on the third day, seventh day, third week, second month and third month, respectively, after the laser photocoagulation. There were significant differences in IOPs between the groups at the different time points ( F = 110.02, p < 0.001). TUNEL analysis showed that only few apoptotic RGCs were found on the third and the seventh day after the laser treatment, and then many more apoptotic RGCs were found beginning on the third week after the laser treatment. The EPC counts were 121.3 ± 22.4, 81.3 ± 23.7, 46.1 ± 15.8, 54.4 ± 19.1 and 54.7 ± 15.9 /2 × 105 mononuclear cells (MNCs) on the third day, seventh day, third week, second month and third month, respectively, after the laser photocoagulation, compared with the NC group (62.1 ± 13.1)/2 × 105 MNCs. There were significant differences in EPC counts between the groups at the different time points ( F = 22.09, p < 0.001). Conclusions: Elevated IOP-induced RGC apoptosis is associated with the reduced circulating EPC counts. [ABSTRACT FROM AUTHOR]

Abstract: Background: Endothelial progenitor cells (EPCs) are critical for repairing injured tissue. Endothelial colony-forming cells (ECFCs) are a homogeneous subtype of EPCs. We investigated whether intravenously infused human ECFCs homed to injured brain promoted angiogenesis and ameliorate neurologic disabilities in a mouse model of traumatic brain injury. Materials and methods: ECFCs were generated by in vitro propagation of EPCs from human umbilical cord blood. Young female nude mice received intravenously ECFCs from human newborns (1 × 106) 1 h after they were exposed to lateral fluid percussion injury. Neurologic function was evaluated by a modified neurologic severity score and Morris water maze. ECFC homing and neovascularization at the site of injury were examined by fluorescence in situ hybridization and histochemistry on days 2 and 14 after injury, respectively. Results: Donor ECFCs were detected in injured brain 24 h after infusion. The modified neurologic severity score and Morris water maze tests were used to evaluate neurologic disability, and found the rate of neurologic disability was improved in mice that received ECFCs. Microvessel density and expression of the proangiogenic growth factors stromal cell–derived factor-1 and vascular endothelial growth factor were also increased in the region of injured brain from mice that received ECFCs compared with those received vehicle control. Conclusions: These data suggest that ECFCs are effective in promoting neovascularization and improving neurologic functions after traumatic brain injury. [Copyright &y& Elsevier]