Transmembrane protein TMEM230, regulator of metalloproteins and motor proteins in gliomas and gliosis.

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis.

Pathological remodeling of reactive astrocytes: Involvement of DNA methylation and downregulation of homeostatic genes.

Astrocytes provide metabolic support to neurons, maintain ionic and water homeostasis, and uptake and recycle neurotransmitters. After exposure to the prototypical PAMP lipopolysaccharide (LPS), reactive astrocytes increase the expression of pro-inflammatory genes, facilitating neurodegeneration. In this study, we analyzed the expression of homeostatic genes in astrocytes exposed to LPS and identified the epigenetic factors contributing to the suppression of homeostatic genes in reactive astrocytes. Primary astrocytic cultures were acutely exposed to LPS and allowed to recover for 24, 72 h, and 7 days. As expected, LPS exposure induced reactive astrogliosis and increased the expression of pro-inflammatory IL-1B and IL-6. Interestingly, the acute exposure resulted in persistent hypermethylation of astroglial DNA. Similar hypermethylation was observed in highly reactive astrocytes from the traumatic brain injury (TBI) penumbra in vivo. Hypermethylation was accompanied by decreased expression of homeostatic genes including LDHA and Scl16a1 (MCT1) both involved in the lactate shuttle to neurons; glutamine synthase (GS) responsible for glutamate processing; Kcnj10 (Kir4.1) important for K+ homeostasis, and the water channel aquaporin-4 (Aqp4). Furthermore, the master regulator of DNA methylation, MAFG-1, as well as DNA methyl transferases DNMT1 and DNMT3a were overexpressed. The downregulation of homeostatic genes correlated with increased methylation of CpG islands in their promoters, as assessed by methylation-sensitive PCR and increased DNMT3a binding to the GS promoter. Treatment with decitabine, a DNMT inhibitor, prevented the LPS- and the HMGB-1-induced downregulation of homeostatic genes. Decitabine treatment also prevented the neurotoxic effects of these astrocytes in primary cortical cultures. In summary, our findings reveal that the pathological remodeling of reactive astrocytes encompasses not only the pro-inflammatory response but, significantly, also entails a long-term suppression of homeostatic gene expression with methylation of crucial CpG islands within their promoters.

Incidental Gliosis in the Central Nervous System of Control Nonhuman Primates and Rats.

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis ("not otherwise specified") of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.

Shortfalls of free autologous internal limiting membrane transplantation for highly myopic refractory macular holes in a long term follow-up.

BACKGROUND: The aim of this study is to evaluate long-term anatomical and functional outcomes of autologous internal limiting membrane (ILM) transplantation in refractory highly myopic macular holes (HMMHs). METHODS: Retrospective interventional analysis of 13 eyes with refractory HMMH undergoing autologous ILM transplantation with gas tamponade. Best-corrected visual acuity (BCVA, Snellen), optical coherence tomography and fundus photography were scheduled at baseline and every follow-up visit (1, 3, 6, 12, 18, 24 months and the most recent). Preoperatively, we collected minimum linear diameter (MLD) and basal diameter (BD). Post-operatively, rates of external limiting membrane (ELM)/ellipsoid zone (EZ) restoration, excessive gliosis and subfoveal retinal pigmented epithelium (RPE) atrophy were evaluated. RESULTS: Average AXL was 31.45 ± 2.07 mm and mean follow-up was 47.2 ± 31.4 months. Anatomical success was reached in 7/13 eyes (54%), while 2 cases showed persisting HMMH, 2 cases had early recurrence and 2 cases late recurrence. BCVA went from 0.19 ± 0.18 to 0.22 ± 0.20 at final follow-up (p = 0.64), improving in 5/13 eyes (38%). One eye showed continuous ELM and EZ lines, while another eye showed an irregular ELM but no EZ. Post-operatively, 5 eyes (71%) developed progressive atrophy of the subfoveal RPE, while excessive gliosis was reported in 3 eyes (43%). Furthermore, one patient developed post-operative chronic macular edema-like changes in the perifoveal area. CONCLUSION: Autologous ILM transplantation showed controversial anatomical outcomes and and poor visual results in refractory HMMH. Moreover, progressive subfoveal patchy atrophy and excessive gliosis are possible post-operative complications.

Prognostic Factors for Recurrent Glioma: A Population-Based Analysis.

Background: The overall survival (OS) for patients with recurrent glioma is meager. Also, the effect of radionecrosis and prognostic factors for recurrent glioma remains controversial. In this regard, developing effective predictive models and guiding clinical care is crucial for these patients. Methods: We screened patients with recurrent glioma after radiotherapy and those who received surgery between August 1, 2013, and December 31, 2020. Univariate and multivariate Cox regression analyses determined the independent prognostic factors affecting the prognosis of recurrent glioma. Moreover, nomograms were constructed to predict recurrent glioma risk and prognosis. Statistical methods were used to determine the prediction accuracy and discriminability of the nomogram prediction model based on the area under the curve (AUC), the C-index, the decision curve analysis (DCA), and the calibration curve. In order to distinguish high-risk and low-risk groups for OS, the X-Tile and Kaplan-Meier (K-M) survival curves were employed, and the nomogram prediction model was further validated by the X-Tile and K-M survival curves. Results: According to a Cox regression analysis, independent prognostic factors of recurrent glioma after radiotherapy with radionecrosis were World Health Organization (WHO) grade and gliosis percentage. We utilized a nomogram prediction model to analyze results visually. The C-index was 0.682 (95% CI: 0.616-0.748). According to receiver operating characteristic (ROC) analysis, calibration plots, and DCA, the nomogram prediction model was found to have a high-performance ability, and all patients were divided into low-risk and high-risk groups based on OS (P < .001). Conclusion: WHO grade and gliosis percentage are prognostic factors for recurrent glioma with radionecrosis, and a nomogram prediction model was established based on these two variables. Patients could be divided into high- and low-risk groups with different OS by this model, and it will provide individualized clinical decisions for future treatment.

Microglial proliferation and astrocytic protein alterations in the human Huntington's disease cortex.

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.

Omega-3 fatty acid diglyceride emulsions as a novel injectable acute therapeutic in neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic encephalopathy (HIE), resulting from a lack of blood flow and oxygen before or during newborn delivery, is a leading cause of cerebral palsy and neurological disability in children. Therapeutic hypothermia (TH), the current standard of care in HIE, is only beneficial in 1 of 7-8 cases. Therefore, there is a critical need for more efficient treatments. We have previously reported that omega-3 (n-3) fatty acids (FA) carried by triglyceride (TG) lipid emulsions provide neuroprotection after experimental hypoxic-ischemic (HI) injury in neonatal mice. Herein, we propose a novel acute therapeutic approach using an n-3 diglyceride (DG) lipid emulsions. Importantly, n-3 DG preparations had much smaller particle size compared to commercially available or lab-made n-3 TG emulsions. We showed that n-3 DG molecules have the advantage of incorporating at substantially higher levels than n-3 TG into an in vitro model of phospholipid membranes. We also observed that n-3 DG after parenteral administration in neonatal mice reaches the bloodstream more rapidly than n-3 TG. Using neonatal HI brain injury models in mice and rats, we found that n-3 DG emulsions provide superior neuroprotection than n-3 TG emulsions or TH in decreasing brain infarct size. Additionally, we found that n-3 DGs attenuate microgliosis and astrogliosis. Thus, n-3 DG emulsions are a superior, promising, and novel therapy for treating HIE.

Age-related dysregulation of the retinal transcriptome in African turquoise killifish.

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNAseq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Choline chloride shows gender-dependent positive effects on social deficits, learning/memory impairments, neuronal loss and neuroinflammation in the lipopolysaccharide-induced rat model of autism.

The neuroprotective effects of choline chloride, an essential nutrient, a precursor for the acetylcholine and synthesis of membrane phospholipids, have been associated with neurological and neurodegenerative diseases. Its contribution to autism spectrum disorder, a neurodevelopmental disorder, remains unknown. Thus, we aimed to evaluate the effects of choline chloride on social behaviours, and histopathological and biochemical changes in a rat autism model. The autism model was induced by administration of 100 µg/kg lipopolysaccharide (LPS) on the 10th day of gestation. Choline chloride treatment (100 mg/kg/day) was commenced on PN5 and maintained until PN50. Social deficits were assessed by three-chamber sociability, open field, and passive avoidance learning tests. Tumour necrosis factor alpha (TNF-α), interleukin-2 (IL) and IL-17, nerve growth factor (NGF), and glutamate decarboxylase 67 (GAD67) levels were measured to assess neuroinflammatory responses. In addition, the number of hippocampal and cerebellar neurons and glial fibrillary acidic protein (GFAP) expression were evaluated. Social novelty and passive avoidance learning tests revealed significant differences in choline chloride-treated male rats compared with saline-treated groups. TNF-α, IL-2, and IL-17 were significantly decreased after choline chloride treatment in both males and females. NGF and GAD67 levels were unchanged in females, while there were significant differences in males. Histologically, significant changes in terms of gliosis were detected in hippocampal CA1 and CA3 regions and cerebellum in choline chloride-treated groups. The presence of ameliorative effects of choline chloride treatment on social behaviour and neuroinflammation through neuroinflammatory, neurotrophic, and neurotransmission pathways in a sex-dependent rat model of LPS-induced autism was demonstrated.

Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine ß-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy.

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine ß-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

Functional Recovery in a Patient of Abnormal Left Parieto-Occipital Encephalomalacia With Gliosis-Associated Genu Varum Deformity: A Case Report.

Parieto-occipital encephalomalacia is a macroscopic appearance of the brain with loss of cerebral parenchyma associated with gliosis in the brain's anatomical structures. It occurs because of the liquefaction of brain parenchymal necrosis after cerebral ischemia, infection, and haemorrhages. It is often surrounded by glial cell proliferation in response to damage. Rehabilitation after the manifestation of neurological function must be tailored, and well-coordinated intervention must be formulated. We present a case study of a 77-year-old male with parieto-occipital encephalomalacia associated with genu varum deformity with a complaint of generalized weakness, vertigo, giddiness, and fall with one episode of a seizure attack. Further, bilateral genu varum deformity was noted on the knees. Encephalomalcia is associated with vitamin D deficiency. The physiotherapy rehabilitation consisted of resolving the symptoms of the patient, along with working on strengthening weak muscles of the genu varum deformity of the patient. The proprioceptive neuromuscular facilitation (PNF) method is a popular rehabilitation strategy for regaining motor function. Numerous outcome measures were used to monitor the patient's progress. Outcome measures such as the tone grading scale (TGS), motor assessment scale (MAS), dynamic gait index (DGI), Barthel index (BI), and world health-related quality-of-life (WHORQOL) scales were used. The rehabilitation lasted for six weeks. Tele-rehabilitation also plays a crucial impact in the recovery of patients. By the end of our rehabilitation, the patient significantly improved in performing activities of daily living and improved his quality of life. Tele-rehabilitation helped us stay connected with the patient.

Retinal Neurodegeneration in an Intraocular Pressure Fluctuation Rat Model.

Increased intraocular pressure (IOP) is the most important risk factor for glaucoma. The role of IOP fluctuation, independently from elevated IOP, has not yet been confirmed in glaucoma. We investigated the effects of IOP fluctuation itself on retinal neurodegeneration. Male rats were treated with IOP-lowering eyedrops (brinzolamide and latanoprost) on Mondays and Thursdays (in the irregular instillation group) or daily (in the regular instillation group), and saline was administered daily in the normal control group for 8 weeks. The IOP standard deviation was higher in the irregular instillation group than the regular instillation group or the control group. The degree of oxidative stress, which was analyzed by labeling superoxide, oxidative DNA damage, and nitrotyrosine, was increased in the irregular instillation group. Macroglial activation, expressed by glial fibrillary acidic protein in the optic nerve head and retina, was observed with the irregular instillation of IOP-lowering eyedrops. Microglial activation, as indicated by Iba-1, and the expression of TNF-α did not show a significant difference between the irregular instillation and control groups. Expression of cleaved caspase-3 was upregulated and the number of retinal ganglion cells (RGCs) was decreased in the irregular instillation group. Our findings indicate that IOP fluctuations could be induced by irregular instillation of IOP-lowering eyedrops and this could lead to the degeneration of RGCs, probably through increased oxidative stress and macrogliosis.

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.

Age-related dysregulation of the retinal transcriptome in African turquoise killifish.

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

Metabolic disorders exacerbate the formation of glial scar after stroke.

Metabolic disorders are risk factors for stroke exacerbating subsequent complications. Rapidly after brain injury, a glial scar forms, preventing excessive inflammation and limiting axonal regeneration. Despite the growing interest in wound healing following brain injury, the formation of a glial scar in the context of metabolic disorders is poorly documented. In this study, we used db/db mice to investigate the impact of metabolic perturbations on brain repair mechanisms, with a focus on glial scarring. First, we confirmed the development of obesity, poor glucose regulation, hyperglycaemia and liver steatosis in these mice. Then, we observed that 3 days after a 30-min middle cerebral artery occlusion (MCAO), db/db mice had larger infarct area compared with their control counterparts. We next investigated reactive gliosis and glial scar formation in db/+ and db/db mice. We demonstrated that astrogliosis and microgliosis were exacerbated 3 days after stroke in db/db mice. Furthermore, we also showed that the synthesis of extracellular matrix (ECM) proteins (i.e., chondroitin sulphate proteoglycan, collagen IV and tenascin C) was increased in db/db mice. Consequently, we demonstrated for the first time that metabolic disorders impair reactive gliosis post-stroke and increase ECM deposition. Given that the damage size is known to influence glial scar, this study now raises the question of the direct impact of hyperglycaemia/obesity on reactive gliosis and glia scar. It paves the way to promote the development of new therapies targeting glial scar formation to improve functional recovery after stroke in the context of metabolic disorders.

Associations of radiologic characteristics of the neonatal hypothalamus with early life adiposity gain.

BACKGROUND: The mediobasal hypothalamus (MBH) is a key brain area for regulation of energy balance. Previous neuroimaging studies suggest that T2-based signal properties indicative of cellular inflammatory response (gliosis) are present in adults and children with obesity, and predicts greater adiposity gain in children at risk of obesity. OBJECTIVES/METHODS: The current study aimed to extend this concept to the early life period by considering if, in full-term healthy neonates (up to n = 35), MRI evidence of MBH gliosis is associated with changes in early life (neonatal to six months) body fat percentage measured by DXA. RESULTS: In this initial study, neonatal T2 signal in the MBH was positively associated with six-month changes in body fat percentage. CONCLUSION: This finding supports the notion that underlying processes in the MBH may play a role in early life growth and, by extension, childhood obesity risk.

Neuroprotective Effects of Aucubin against Cerebral Ischemia and Ischemia Injury through the Inhibition of the TLR4/NF-κB Inflammatory Signaling Pathway in Gerbils.

Aucubin, an iridoid glycoside, possesses beneficial bioactivities in many diseases, but little is known about its neuroprotective effects and mechanisms in brain ischemia and reperfusion (IR) injury. This study evaluated whether aucubin exhibited neuroprotective effects against IR injury in the hippocampal CA1 region through anti-inflammatory activity in gerbils. Aucubin (10 mg/kg) was administered intraperitoneally once a day for one week prior to IR. Neuroprotective effects of aucubin were assessed by neuronal nuclei (NeuN) immunofluorescence and Floro-Jade C (FJC) histofluorescence. Microgliosis and astrogliosis were evaluated using immunohistochemistry with anti-ionized calcium binding adapter protein 1 (Iba1) and glial fibrillary acidic protein (GFAP). Protein levels of proinflammatory cytokines interleukin1 beta (IL1ß) and tumor necrosis factor alpha (TNFα) were assayed using enzyme-linked immunosorbent assay and Western blot. Changes in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway were assessed by measuring levels of TLR4, inhibitor of NF-κB alpha (IκBα), and NF-κB p65 using Western blot. Aucubin treatment protected pyramidal neurons from IR injury. IR-induced microgliosis and astrogliosis were suppressed by aucubin treatment. IR-induced increases in IL1ß and TNFα levels were significantly alleviated by the treatment. IR-induced upregulation of TLR4 and downregulation of IκBα were significantly prevented by aucubin treatment, and IR-induced nuclear translocation of NF-κB was reversed by aucubin treatment. Briefly, aucubin exhibited neuroprotective effects against brain IR injury, which might be related to the attenuation of neuroinflammation through inhibiting the TLR-4/NF-κB signaling pathway. These results suggest that aucubin pretreatment may be a potential approach for the protection of brain IR injury.

Cytokine profiling in senescent and reactive astrocytes: A systematic review.

Astrocytes play an important role in neuroinflammation by producing proinflammatory molecules. In response to various stressful stimuli, astrocytes can become senescent or reactive, both are present in age-associated cognitive impairment and other neurodegenerative diseases, and contribute to neuroinflammation. However, there are no studies that compare the cytokines secreted by these types of astrocytes in the brain during aging. Hence, we aimed to broaden the picture of the secretory profiles and to differentiate the variability between them. Therefore, a systematic review was conducted following the guidelines of the "Reporting Items for Systematic Review and Meta-Analyses". Only three studies that met the inclusion terms evaluated age-related cytokine secretion, however, no evaluation of senescence or gliosis was performed. Consequently, to increase the spectrum of the review, studies where those phenotypes were induced and cytokines determined were included. Although some cytokines were common for gliosis and senescence, some interesting differences were also found. The dissimilarities in cytokines secretion between these phenotypes could be studied in the future as potential markers.

A Retrospective Analysis of Temporal Lobe Gliosis after Middle Fossa Resection of Small Vestibular Schwannomas.

INTRODUCTION: The middle cranial fossa (MCF) approach is a well-established procedure in surgery of the internal auditory canal, as well as with the retrosigmoid and translabyrinthine approaches. It is commonly used in the hearing-preserving microsurgery of small vestibular schwannomas (VS). The debate about the "best" approach for the microsurgery of small VS without contact to the brainstem is controversial. It has been stated that the MCF approach leads to irreversible damage to the temporal lobe, which may be evident in follow-up magnet resonance imaging (MRI) as gliosis in up to 70% of patients. MATERIALS AND METHODS: This study represents a retrospective chart analysis conducted at a tertiary university hospital. Here, 76 postoperative MRIs were re-evaluated by an experienced neuroradiologist and compared with the preoperative images. Temporal lobe gliosis was classified on an ordinal scale as absent, slight, moderate or severe. Occurrence of gliosis was matched to the clinical predictors (tumor stage, tumor volume, sex, age, and side). RESULTS: No case of severe or moderate gliosis was found in the patient group. Slight gliosis of the temporal lobe was rare and was only detected in four patients (5%). There was no relation between clinical predictors and the incidence of gliosis. CONCLUSIONS: In our cohort, postoperative MR imaging did not reveal relevant damage to the temporal lobe parenchyma. This confirms the safe concept of microsurgery of small tumors via the middle fossa approach. The severe glioses described in other studies may be caused by a forced insertion of the retractor or by more extended approaches. However, further prospective neurocognitive studies seem to be necessary in order to assess functional changes in the temporal lobe.