Neuroglia (Basel, Switzerland)最新文献

{"title":"Targeting Bioinformatics Predicted Biomarkers Associated with Cell Proliferation and Migration for Treating Gliomas: Preclinical Studies in a GL261 Mouse Model","authors":"R. Towner, N. Smith, D. Saunders, M. Lerner, Randy L. Jensen, J. Battiste, Marya Ahmed, J. Wren","doi":"10.3390/neuroglia4010006","DOIUrl":"https://doi.org/10.3390/neuroglia4010006","url":null,"abstract":"We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43168406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modest Reduction in CAG Repeat Length Rescues Motor Deficits but Not Purkinje Cell Pathology and Gliosis in Spinocerebellar Ataxia Type 1 Mice.","authors":"Stephen Gilliat, Juao-Guilherme Rosa, Genevieve Benjamin, Kaelin Sbrocco, Wensheng Lin, Marija Cvetanovic","doi":"10.3390/neuroglia4010005","DOIUrl":"10.3390/neuroglia4010005","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the <i>Ataxin-1</i> (<i>ATXN1</i>) gene. SCA1 is characterized by the early and prominent pathology of the cerebellar Purkinje cells that results in balance and coordination deficits. We previously demonstrated that cerebellar astrocytes contribute to SCA1 pathogenesis in a biphasic, stage of disease-dependent manner. We found that pro-inflammatory transcriptional regulator nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in astrocytes has a neuroprotective role during early-stage SCA1. Here, we sought to examine whether further inducing NF-κB activation in astrocytes of SCA1 model mice at an early stage of the disease has therapeutic benefits. To perform this task, we created a novel Slc1a3-CreER^T/IKKβ_CA/<i>ATXN1[82Q]</i> triple transgenic mouse model in which TMX injection at 4 weeks of age results in the expression of constitutively active inhibitor of kB kinase beta (IKKβ_CA), the main activator of NF-κB signaling. As we evaluated SCA1-like phenotypes, we noticed that <i>ATXN1[82Q]</i> mice did not exhibit motor deficits anymore, even at very late stages of the disease. We sequenced the mutant <i>ATXN1</i> gene and discovered that the CAG repeat number had decreased from 82 to 71. However, despite the loss of motor phenotype, other well-characterized SCA1-changes, including atrophy of Purkinje cell dendrites, hallmarks of cerebellar astrogliosis and microgliosis, and Purkinje cell disease-associated gene expression changes, were still detectable in <i>ATXN1[71Q]</i> mice. We found delayed PC atrophy and calbindin reduction in SCA1 mice expressing IKKβ_CA in astrocytes implicating beneficial effects of increased NF-κB signaling on Purkinje cell pathology. The change in the motor phenotype of SCA1 mice with CAG reduction prevented us from evaluating the neuroprotective potential of IKKβ_CA on motor deficits in these mice.</p>","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":"52-68"},"PeriodicalIF":2.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46579687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System","authors":"A. Loonen","doi":"10.3390/neuroglia4010004","DOIUrl":"https://doi.org/10.3390/neuroglia4010004","url":null,"abstract":"Astrocytes and microglia play important roles in organizing the structure and function of neuronal networks in the central nervous system (CNS). The dorsal diencephalic connection system (DDCS) is a phylogenetically ancient regulatory system by which the forebrain influences the activity of cholinergic and ascending monoaminergic pathways in the midbrain. The DDCS is probably important in inducing aspects of mental disorders, such as depression and addiction. The habenula is the small but highly complex connecting center of the DDCS in the epithalamus that consists of a medial (MHb) and lateral (LHb) division. MHb and LHb are built differently and connect different brain structures. Studies in animal models and human biomarker research provide good evidence that astroglia and microglia also affect the symptoms of mental disorders (such as depression). The significance of these neuroglia in habenular neurotransmission has not been extensively studied. This review article provides arguments for doing so more thoroughly.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47551404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ONC201 for Glioma Treatment: Adding an Important Weapon to Our Arsenal","authors":"Athina-Maria Aloizou, Dimitra Aloizou","doi":"10.3390/neuroglia4010003","DOIUrl":"https://doi.org/10.3390/neuroglia4010003","url":null,"abstract":"Glioma, specifically gliobastoma, represents the commonest central nervous system malignancy and is notoriously challenging to treat, with only a minimal number of patients surviving beyond a year after diagnosis. The available treatment options include surgical resection, radiotherapy, and chemotherapy, mainly with temozolomide. However, gliomas can be particularly treatment resistant and novel options are currently being researched. One such agent is ONC201, the first member of the imipridone class and a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound, which has shown positive results in the first preliminary clinical reports about its application in glioma patients, while also being safe and well-tolerated. Particular promise has been shown for the H3K27M mutated glioblastomas, with more trials focusing on this patient subset. It is likely that this compound will be added in the treatment algorithms of glioma in the future, although more research is still needed.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47252521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of Central and Peripheral Glial Cells in the Development and Persistence of Itch: Therapeutic Implication of Glial Modulation","authors":"P. Gazerani","doi":"10.3390/neuroglia4010002","DOIUrl":"https://doi.org/10.3390/neuroglia4010002","url":null,"abstract":"Chronic itch (CI) is an unpleasant skin sensation accompanied by an intense scratching desire that lasts 6 weeks or longer. Despite the high prevalence and negative impact on affected individuals and a huge healthcare burden, CI mechanisms are only partially understood, and consequently, treatment of CI remains sub-optimal. The complexity of CI treatment also stems from the comorbid existence of persistent itch with other somatic and psychological disorders. Etiologies of CI are multiple and diverse, although CI is often a result of dermatologically related conditions such as atopic dermatitis and psoriasis. Unfolding the pathophysiology of CI can provide possibilities for better therapy. Itch signaling is complex and neurons and non-neuronal cells play a role. This review focuses on recent findings on the role of glial cells in itch. Central glia (astrocytes and microglia) and peripheral glia (satellite glial cells and Schwann cells) are found to contribute to the development or persistence of itch. Hence, glial modulation has been proposed as a potential option in CI treatment. In experimental models of itch, the blockade of signal transducer and the activator of transcription (STAT) 3-mediated reactive astrogliosis have been shown to suppress chronic itch. Administration of a microglial inhibitor, minocycline, has also been demonstrated to suppress itch-related microglial activation and itch. In sensory ganglia, gap-junction blockers have successfully blocked itch, and hence, gap-junction-mediated coupling, with a potential role of satellite glial cells have been proposed. This review presents examples of glial involvement in itch and opportunities and challenges of glial modulation for targeting itch.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48882730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the Potential Therapeutic Roles of Taurine in Autism Spectrum Disorder","authors":"Alberto Rubio-Casillas, E. Redwan, V. Uversky","doi":"10.3390/neuroglia4010001","DOIUrl":"https://doi.org/10.3390/neuroglia4010001","url":null,"abstract":"Contemporary research has found that people with autism spectrum disorder (ASD) exhibit aberrant immunological function, with a shift toward increased cytokine production and unusual cell function. Microglia and astroglia were found to be significantly activated in immuno-cytochemical studies, and cytokine analysis revealed that the macrophage chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and transforming growth factor β-1 (TGFB-1), all generated in the neuroglia, constituted the most predominant cytokines in the brain. Taurine (2-aminoethanesulfonic acid) is a promising therapeutic molecule able to increase the activity of antioxidant enzymes and ATPase, which may be protective against aluminum-induced neurotoxicity. It can also stimulate neurogenesis, synaptogenesis, and reprogramming of proinflammatory M1 macrophage polarization by decreasing mitophagy (mitochondrial autophagy) and raising the expression of the markers of the anti-inflammatory and pro-healing M2 macrophages, such as macrophage mannose receptor (MMR, CD206) and interleukin 10 (IL-10), while lowering the expression of the M1 inflammatory factor genes. Taurine also induces autophagy, which is a mechanism that is impaired in microglia cells and is critically associated with the pathophysiology of ASD. We hypothesize here that taurine could reprogram the metabolism of M1 macrophages that are overstimulated in the nervous system of people suffering from ASD, thereby decreasing the neuroinflammatory process characterized by autophagy impairment (due to excessive microglia activation), neuronal death, and improving cognitive functions. Therefore, we suggest that taurine can serve as an important lead for the development of novel drugs for ASD treatment.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44222145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine.","authors":"Prabhat R Napit,&nbsp;Abdulrahman Alhamyani,&nbsp;Khaggeswar Bheemanapally,&nbsp;Paul W Sylvester,&nbsp;Karen P Briski","doi":"10.3390/neuroglia3040010","DOIUrl":"https://doi.org/10.3390/neuroglia3040010","url":null,"abstract":"<p><p>Astrocyte glycogen is a critical metabolic variable that impacts hypothalamic control of glucostasis. Glucocorticoid hormones regulate peripheral glycogen, but their effects on hypothalamic glycogen are not known. A hypothalamic astrocyte primary culture model was used to investigate the premise that glucocorticoids impose sex-dimorphic independent and interactive control of glycogen metabolic enzyme protein expression and glycogen accumulation. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) down-regulated glycogen synthase (GS), glycogen phosphorylase (GP)-brain type (GPbb), and GP-muscle type (GPmm) proteins in glucose-supplied male astrocytes, but enhanced these profiles in female. The catecholamine neurotransmitter norepinephrine (NE) did not alter these proteins, but amplified DEX inhibition of GS and GPbb in male or abolished GR stimulation of GPmm in female. In both sexes, DEX and NE individually increased glycogen content, but DEX attenuated the magnitude of noradrenergic stimulation. Glucoprivation suppressed GS, GPbb, and GPmm in male, but not female astrocytes, and elevated or diminished glycogen in these sexes, respectively. Glucose-deprived astrocytes exhibit GR-dependent induced glycogen accumulation in both sexes, and corresponding loss (male) or attenuation (female) of noradrenergic-dependent glycogen build-up. Current evidence for GR augmentation of hypothalamic astrocyte glycogen content in each sex, yet divergent effects on glycogen enzyme proteins infers that glucocorticoids may elicit opposite adjustments in glycogen turnover in each sex. Results document GR modulation of NE stimulation of glycogen accumulation in the presence (male and female) or absence (female) of glucose. Outcomes provide novel proof that astrocyte energy status influences the magnitude of GR and NE signal effects on glycogen mass.</p>","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"3 4","pages":"144-157"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9850496/pdf/nihms-1853554.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10666985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactory Ensheathing Cells for Spinal Cord Injury: The Cellular Superpowers for Nerve Repair","authors":"Francesca Oieni, Ronak Reshamwala, J. S. St John","doi":"10.3390/neuroglia3040009","DOIUrl":"https://doi.org/10.3390/neuroglia3040009","url":null,"abstract":"Neurotrauma injuries are notoriously difficult to deal with both clinically as well as experimentally, as the cellular and molecular events ensuing after injury complicate the neuroinflammatory processes. Spinal cord injuries are further complicated by the formation of scars at the injury sites, which can provide a physical barrier to repair. The lack of effective clinical therapy for spinal cord injury underscores the need for experimental approaches to generate effective therapies. To repair the injury, cell transplantation offers the potential to replace lost cells and create a permissive bridge to promote neural regeneration across the injury site. Olfactory ensheathing cells (OECs), which are the glia of the olfactory nerve, stand apart from other candidate cell types due to their innate natural abilities to manage nerve injury and promote repair and regeneration. This is evidenced by their physiological role in the daily repair and maintenance of the olfactory nerve. Here, we explain their properties in relation to their physiological role and their most relevant cellular attributes, including cellular interactions, phagocytosis, migration, axonal guidance and support, and modulation of neuroinflammation. We highlight some critical drawbacks in the current approaches and identify some ways to address them.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43902157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overview of Neuroglia Activation, Chronic Neuroinflammation, Remodeling, and Impaired Cognition Due to Perivascular Adipose Tissue-Derived Extracellular Vesicle Exosomes in Obesity and Diabetes","authors":"M. Hayden","doi":"10.3390/neuroglia3040008","DOIUrl":"https://doi.org/10.3390/neuroglia3040008","url":null,"abstract":"Perivascular adipose tissue (PVAT)-derived extracellular vesicles (EVs) with small exosome(s) (PVAT-dEVexos) from the descending aorta are capable of entering capillaries and systemic circulation. These PVAT-dEVexos are delivered to the central nervous system (CNS) in preclinical, obese, insulin and leptin resistant, diabetic, db/db mouse models and humans with T2DM. Once within the CNS, these exosomes are capable of traversing the blood–brain barrier and the blood-cerebrospinal fluid barrier resulting in activation of the neuroglia microglia cell(s) (aMGCs) and the formation of reactive astrocytes (rACs). The chronic peripheral inflammation in the PVAT via crown-like structures consists of activated macrophages and mast cells, which harbor peripheral adipokines, cytokines, and chemokines (pCC) in addition to the EV exosomes. These pCC are transported to the systemic circulation where they may act synergistically with the PVAT-dEVexos to amplify the activation of neuroglia and result in chronic neuroinflammation. Once activated, the MGCs and ACs will contribute to even greater neuroinflammation via central nervous cytokines/chemokines (cnsCC). Activated neuroglia results in an increase of cnsCC and the creation of a vicious cycle of ongoing chronic neuroinflammation and increased redox stress. The increase in reactive oxygen species (ROS) involves the reactive species interactome that not only include reactive oxygen but also reactive nitrogen and sulfur species wherein a vicious cycle of ROS begetting inflammation and inflammation begetting ROS develops. Thus, the CNS perceives peripheral systemic inflammation from the obese PVAT depots as an injury and a response to injury wound healing mechanism develops with activation of neuroglia, cellular remodeling, neurodegeneration, and impaired cognition.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45663107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal Profile of Reactive Astrocytes after Ischemic Stroke in Rats","authors":"Justin Stadler, Harrison Schurr, D. Doyle, Lucas Garmo, B. Srinageshwar, Marc R. Spencer, Robert B Petersen, G. Dunbar, J. Rossignol","doi":"10.3390/neuroglia3030007","DOIUrl":"https://doi.org/10.3390/neuroglia3030007","url":null,"abstract":"Ischemic stroke is a debilitating neurological disease most commonly resulting from an occlusion within the cerebral vasculature. Ischemia/reperfusion injury is oftentimes a consequence of stroke, characterized by oxidative stress, neuroinflammation, and the activation of surrounding glial cells following restoration of blood supply. Astrocytes are regarded as the most prominent glial cell in the brain and, under pathologic conditions, display, among other pathologies, activated (GFAP) relatively proportional to the degree of reactivity. The primary objective of the study was to determine the temporal profile of astrocyte reactivity following ischemic stroke. Thirty-four Sprague-Dawley rats were assigned to surgery consisting of either 90-min middle cerebral artery occlusion (MCAo) or sham surgery. Animals were sub-grouped by postoperative euthanization day; 2 days (n = 10), 4 days (n = 11), and 7 days (n = 13). Fluorescence microscopy and densitometry were utilized to quantify GFAP immunoreactivity, which indicated a non-linear relationship following ischemia/reperfusion. Results demonstrated substantially higher GFAP levels in MCAo groups than in sham, with peak GFAP reactivity being shown in the brains of rats euthanized on day 4. These findings are applicable to future research, especially in the investigation of interventions that target reactive astrocytes following ischemic injury.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47952830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}