Glial Research Articles

The causal relationship between 91 inflammatory cytokines and Gestational Diabetes Mmellitus: A bidirectional two-sample Mendelian randomization study

BackgroundGestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health, yet its precise etiology remains unclear. Observational studies have demonstrated a link between specific inflammatory cytokines and the occurrence of GDM, but the causal relationships remain uncertain. MethodsUtilizing publicly accessible genetic data, we performed a bidirectional two-sample mendelian randomization (MR) analysis to elucidate the causal association between 91 inflammatory cytokines and GDM. Sensitivity analysis was carried out to evaluate the robustness, heterogeneity, and potential presence of horizontal pleiotropy within the results. ResultsElevated levels of Interleukin-7 (IL7) and Neurturin (NRTN) (OR=1.104, 95 % CI=1.003–1.216, p = 0.042; OR=1.102, 95 % CI=1.023–1.187, p = 0.010), along with decreased levels of Glial cell line-derived neurotrophic factor (GDNF), Interleukin-12 subunit beta (IL12β), and Interleukin-20 (IL20) (OR=0.911, 95 % CI=0.849–0.979, p = 0.010;OR=0.955, 95 % CI=0.916–0.996, p = 0.033; OR=0.892, 95 % CI=0.819–0.971, p = 0.008), are associated with increased GDM risk. Additionally, GDM occurrence correlates with increased Matrix metalloproteinase-10 (MMP-10) and decreased Interleukin-20 receptor subunit alpha (IL-20Rα) levels (OR=1.042, 95 % CI=1.002–1.084, p = 0.038; OR=0.949, 95 % CI=0.909–0.992, p = 0.021). Sensitivity analyses detected no significant heterogeneity or pleiotropy. ConclusionThis study has clarified the causal link between inflammatory cytokines and GDM, thereby enhancing our comprehension of the potential mechanisms involved in GDM pathogenesis. These findings offer new insights into the etiology, diagnosis, and therapeutic strategies for GDM.

β-Hydroxybutyrate enhances astrocyte glutamate uptake through EAAT1 expression regulation

β-Hydroxybutyrate (BHB) has been reported to exert neuroprotective functions and is considered a promising treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's. Numerous studies have revealed BHB's multifaceted roles, including anti-senescence, anti-oxidative, and anti-inflammatory activities. However, the underlying mechanisms warrant further investigation. Astrocytes, the most abundant glial cells in the central nervous system, play a pivotal role in the development and progression of neurodegenerative diseases. While BHB is known to alter neuronal metabolism and function, its effects on astrocytes remain poorly understood. In this study, we conducted transcriptome sequencing analysis to identify differentially expressed genes induced by BHB in astrocytes and found that the gene Solute carrier family 1 member 3 (Slc1a3), encoding the glutamate transporter EAAT1, was significantly upregulated by BHB treatment. Cellular and animal-based experiments confirmed an increase in EAAT1 protein expression in primary astrocytes and the hippocampus of mice treated with BHB. This upregulation may be due to the activation of the Ca2+/CAMKII pathway by BHB. Furthermore, BHB improved astrocytes' glutamate uptake and partially restored neuronal viability impaired by glutamate-induced excitotoxicity when astrocytes were functionalized. Our results suggest that BHB may alleviate neuronal damage caused by excessive glutamate by enhancing the glutamate absorption and uptake capacity of astrocytes. This study proposes a novel mechanism for the neuroprotective effects of BHB and reinforces its beneficial impact on the central nervous system (CNS).

Multi-modal, Label-free, Optical Mapping of Cellular Metabolic Function and Oxidative Stress in 3D Engineered Brain Tissue Models.

Brain metabolism is essential for the function of organisms. While established imaging methods provide valuable insights into brain metabolic function, they lack the resolution to capture important metabolic interactions and heterogeneity at the cellular level. Label-free, two-photon excited fluorescence imaging addresses this issue by enabling dynamic metabolic assessments at the single-cell level without manipulations. In this study, we demonstrate the impact of spectral imaging on the development of rigorous intensity and lifetime label-free imaging protocols to assess dynamically metabolic functions over time in 3D engineered brain tissue models comprised of human induced neural stem cells, astrocytes, and microglia. Specifically, we rely on multi-wavelength spectral imaging to identify the excitation/emission profiles of key cellular fluorophores within human brain cells, including NAD(P)H, LipDH, FAD, and lipofuscin. These enable the development of methods to mitigate lipofuscin's overlap with NAD(P)H and flavin autofluorescence to extract reliable optical metabolic function metrics from images acquired at two excitation wavelengths over two emission bands. We present fluorescence intensity and lifetime metrics reporting on redox state, mitochondrial fragmentation, and NAD(P)H binding status in neuronal monoculture and the triculture systems to highlight the functional impact of metabolic interactions between different cell types. Our findings reveal significant metabolic differences between neurons and glial cells, shedding light on metabolic pathway utilization, including the glutathione pathway, OXPHOS, glycolysis, and fatty acid oxidation. Collectively, our studies establish a label-free, non-destructive approach to assess the metabolic function and interactions among different brain cell types relying on endogenous fluorescence and illustrate the complementary nature of the information that is gained by combining intensity and lifetime-based images. Such methods can improve understanding of physiological brain function and dysfunction that occurs at the onset of cancers, traumatic injuries and neurodegenerative diseases.

Neurological Impact of Respiratory Viruses: Insights into Glial Cell Responses in the Central Nervous System.

Respiratory viral infections pose a significant public health threat, particularly in children and older adults, with high mortality rates. Some of these pathogens are the human respiratory syncytial virus (hRSV), severe acute respiratory coronavirus-2 (SARS-CoV-2), influenza viruses (IV), human parvovirus B19 (B19V), and human bocavirus 1 (HBoV1). These viruses cause various respiratory symptoms, including cough, fever, bronchiolitis, and pneumonia. Notably, these viruses can also impact the central nervous system (CNS), leading to acute manifestations such as seizures, encephalopathies, encephalitis, neurological sequelae, and long-term complications. The precise mechanisms by which these viruses affect the CNS are not fully understood. Glial cells, specifically microglia and astrocytes within the CNS, play pivotal roles in maintaining brain homeostasis and regulating immune responses. Exploring how these cells interact with viral pathogens, such as hRSV, SARS-CoV-2, IVs, B19V, and HBoV1, offers crucial insights into the significant impact of respiratory viruses on the CNS. This review article examines hRSV, SARS-CoV-2, IV, B19V, and HBoV1 interactions with microglia and astrocytes, shedding light on potential neurological consequences.

Ghost cells: Wilder Penfield and the characterization of glia and glial pathology, 1924–1932

ABSTRACT Wilder Penfield is known for his contributions to the structure–function relationship of the brain and for the surgical treatment of focal epilepsy. Less well known are his contributions to the study of glial cells and his investigation of their role in human neuropathology. Penfield learned the gold and silver methods for staining neurons, glial cells, and their projections from Charles Sherrington and Pío del Río-Hortega. He and his colleague William Cone established a laboratory for the study of glial cells and human neuropathology using metallic stains, initially at the Presbyterian Hospital in New York City in 1925, and then at the Montreal Neurological Institute in 1928. Penfield, Cone, and their research fellows, building on the findings of Río-Hortega, confirmed the existence of oligodendrocytes and their relationship with myelin, and investigated the putative mesodermal origin of microglia. They discovered the reaction of oligodendrocytes to pathological stressors, and the phagocytic activity of microglia in human gliomas. In this article, we argue that Penfield’s studies of astrocytes, oligodendrocytes, and microglia, and their responses to craniocerebral trauma, epilepsy, malignant brain tumors, and other pathologies of the central nervous system inaugurated a new era in clinical neurocytology and neuropathology.

Abortive and productive infection of CNS cell types following in vivo delivery of VSV

Viral infection is frequently assayed by ongoing expression of viral genes. These assays fail to identify cells that have been exposed to the virus but limit or inhibit viral replication. To address this limitation, we used a dual-labeling vesicular stomatitis virus (DL-VSV), which has a deletion of the viral glycoprotein gene, to allow evaluation of primary infection outcomes. This virus encodes Cre, which can stably mark any cell with even a minimal level of viral gene expression. Additionally, the virus encodes GFP, which distinguishes cells with higher levels of viral gene expression, typically due to genome replication. Stereotactic injections of DL-VSV into the murine brain showed that different cell types had very different responses to the virus. Almost all neurons hosted high levels of viral gene expression, while glial cells varied in their responses. Astrocytes (Sox9+) were predominantly productively infected, while oligodendrocytes (Sox10+) were largely abortively infected. Microglial cells (Iba1+) were primarily uninfected. Furthermore, we monitored the early innate immune response to viral infection and identified unique patterns of interferon (IFN) induction. Shortly after infection, microglia were the main producers of IFNb, whereas later, oligodendrocytes were the main producers. IFNb+ cells were primarily abortively infected regardless of cell type. Last, we investigated whether IFN signaling had any impact on the outcome of primary infection and did not observe significant changes, suggesting that intrinsic factors are likely responsible for determining the outcome of primary infection.

Combined swimming with melatonin protects against behavioural deficit in cerebral ischemia-reperfusion injury induced rats associated with modulation of Mst1– MAPK ‐ERK signalling pathway

Background The inconvenience of social and behavioural deficits after cerebral ischaemia reperfusion (I/R) injury is still not well documented. Aim We aimed to study the protective effect of preconditioning swimming exercise combined with melatonin against cerebral I/R induced injury. Methodology Sixty rats were allocated into 6 groups; groups I and II served as control. Groups 3,4,5,6 subjected to bilateral carotid ligation for 30 minutes (min.) followed by reperfusion. Group 3 left untreated while groups 4 and 6; underwent swimming exercise 30 min/day, five days a week for three weeks before the surgery. Groups 5 and 6 treated with melatonin 30 minutes before the operation, then, all rats in groups 4, 5,6 were subjected to I/R. After that, groups 5 and 6 treated with 2nd dose of melatonin 30 minutes after reperfusion. Results Combined strategy exhibited the most neuroprotective effect through prevention of cerebral I/R induced inflammation, oxidative stress and apoptosis with subsequent improvement in socio behaviour deficits and enhanced Glial cell proliferative capacity. Conclusion The protective contribution of combined strategy is associated with modulation in Macrophage‐stimulating 1/mitogen-activated protein kinase/extracellular signal-regulated kinase (MST1/MAPK/ERK) pathway which may explain, at least in part, its protective potential.

Single-cell DNA methylation analysis tool Amethyst reveals distinct noncanonical methylation patterns in human glial cells.

Single-cell sequencing technologies have revolutionized biomedical research by enabling deconvolution of cell type-specific properties in highly heterogeneous tissue. While robust tools have been developed to handle bioinformatic challenges posed by single-cell RNA and ATAC data, options for emergent modalities such as methylation are much more limited, impeding the utility of results. Here we present Amethyst, a comprehensive R package for atlas-scale single-cell methylation sequencing data analysis. Amethyst begins with base-level methylation calls and expedites batch integration, doublet detection, dimensionality reduction, clustering, cell type annotation, differentially methylated region calling, and interpretation of results, facilitating rapid data interaction in a local environment. We introduce the workflow using published single-cell methylation human peripheral blood mononuclear cell (PBMC) and human cortex data. We further leverage Amethyst on an atlas-scale brain dataset to discover a noncanonical methylation pattern in human astrocytes and oligodendrocytes, challenging prior assumptions that this form of methylation is only biologically relevant to neurons in the brain.

Effects of exogenous hydrogen sulfide and honokiol intervention on the proliferation, apoptosis, and calcium signaling pathway of rat enteric glial cells

Hydrogen sulfide (H2S) is a gaseous signaling molecule that influences digestive and nervous system functions. Enteric glial cells (EGCs) are integral to the enteric nervous system and play a role in regulating gastrointestinal motility. This study explored the dual effects of exogenous H2S on EGCs and the influence of apoptosis-related pathways and ion channels in EGCs. We also administered honokiol for further interventional studies. The results revealed that low-concentration H2S increased the mitochondrial membrane potential (MMP) of EGCs, decreased the whole-cell membrane potential, downregulated BAX and caspase-3, upregulated Bcl2 expression, reduced apoptosis, and promoted cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also increased. A high concentration of H2S had the opposite effect. In addition, GFAP mRNA expression was upregulated in the test-low group, downregulated in the test-high group, and upregulated in the test-high + Hon group. Honokiol treatment increased MMP, reduced whole-cell membrane potential, inhibited BAX and caspase-3 expression, increased Bcl2 expression, decreased cell apoptosis, and increased cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also upregulated. In conclusion, our study showed that exogenous H2S can bidirectionally regulate EGC proliferation and apoptosis by affecting MMP and cell membrane potential via the Bcl2/BAX/caspase-3 pathway and modulate Cx43-mediated Ca2+ responses in EGCs to regulate colonic motility bidirectionally. Honokiol can ameliorate the damage to EGCs induced by high H2S concentrations through the Bcl2/BAX/caspase-3 pathway and improve colon motility by increasing Cx43 expression and Ca2+ concentration.

Neurological Damage Measured by S-100b and Neuron-Specific Enolase in Patients Treated with Electroconvulsive Therapy.

Electroconvulsive therapy (ECT) is considered one of the most effective treatments for psychiatric disorders. ECT has proven effective in the treatment of depression, mania, catatonia and psychosis. It is presumed that seizures induced during ECT administration cause toxicity and potentially neuronal and glial cell death. A broad range of neurological disorders increase cerebrospinal fluid and serum levels of neuron-specific enolase (NSE) and S-100b protein. This study aims to investigate the effect of ECT on NSE and S-100b levels, which, together, serve as a proxy for neuronal cell damage. Serum concentrations of S-100b and NSE of adult patients who received ECT were measured by immunoluminometric analysis before and after treatment. A two-way ANOVA test was used to estimate the statistical differences in marker concentrations between the subgroups of the study population. Results: A total of 55 patients were included in the analysis: 52.73% (n = 29) were diagnosed with depression, 21.82% (n = 12) with schizophrenia or other psychosis, 16.36% (n = 9) with mania and 9.09% (n = 5) with catatonia. There were no statistically significant changes in NSE (p = 0.288) and S-100b (p = 0.243) levels. We found no evidence that ECT induced neuronal damage based on NSE and S-100b protein levels measured in the serum of patients before and after treatment.

Hyperglycemia in a NOD Mice Model of Type-I Diabetes Aggravates Collagenase-Induced Intracerebral Hemorrhagic Injury.

Intracerebral hemorrhage (ICH) is a severe type of stroke with high mortality. Persistent hyperglycemia following ICH is linked to deteriorated neurological functions and death. However, the exacerbating effect of hyperglycemia on ICH injury at the molecular level is still unclear. Therefore, this study explores the impact of diabetes on ICH injury using a non-obese diabetic (NOD) mouse model of type I diabetes mellitus. NOD and non-diabetic (non-obese resistant) mice subjected to ICH by intrastriatal injection of collagenase were sacrificed three days following the ICH. Brains were collected for hematoma volume measurement and immunohistochemistry. Neurobehavioral assays were conducted 24 h before ICH and then repeated at 24, 48 and 72 h following ICH. NOD mice showed increased hematoma volume and impairment in neurological function, as revealed by rotarod and grip strength analyses. Immunohistochemical staining showed reduced glial cell activation, as indicated by decreased GFAP and Iba1 staining. Furthermore, the expression of oxidative/nitrosative stress markers represented by 3-nitrotyrosine and inducible nitric oxide synthase was reduced in the diabetic group. Overall, our findings support the notion that hyperglycemia exacerbates ICH injury and worsens neurological function and that the mechanism of injury varies depending on the type of diabetes model used.

Differential Expression of PACAP/VIP Receptors in the Post-Mortem CNS White Matter of Multiple Sclerosis Donors.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuroprotective and anti-inflammatory molecules of the central nervous system (CNS). Both bind to three G protein-coupled receptors, namely PAC1, VPAC1 and VPAC2, to elicit their beneficial effects in various CNS diseases, including multiple sclerosis (MS). In this study, we assessed the expression and distribution of PACAP/VIP receptors in the normal-appearing white matter (NAWM) of MS donors with a clinical history of either relapsing-remitting MS (RRMS), primary MS (PPMS), secondary progressive MS (SPMS) or in aged-matched non-MS controls. Gene expression studies revealed MS-subtype specific changes in PACAP and VIP and in the receptors' levels in the NAWM, which were partly corroborated by immunohistochemical analyses. Most PAC1 immunoreactivity was restricted to myelin-producing cells, whereas VPAC1 reactivity was diffused within the neuropil and in axonal bundles, and VPAC2 in small vessel walls. Within and around lesioned areas, glial cells were the predominant populations showing reactivity for the different PACAP/VIP receptors, with distinctive patterns across MS subtypes. Together, these data identify the differential expression patterns of PACAP/VIP receptors among the different MS clinical entities. These results may offer opportunities for the development of personalized therapeutic approaches to treating MS and/or other demyelinating disorders.

Benzopyrene represses mitochondrial fission factors and PINK1/Parkin-mediated mitophagy in primary astrocytes

Mitochondria are essential for various physiological functions in astrocytes in the brain, such as maintaining ion and pH homeostasis, regulating neurotransmission, and modulating neuroinflammation. Mitophagy, a form of autophagy specific to mitochondria, is essential for ensuring mitochondrial quality and function. Benzo[a]pyrene (BaP) accumulates in the brain, and exposure to it is recognized as an environmental risk factor for neurodegenerative diseases. However, while the toxic mechanisms of BaP have been investigated in neurons, their effects on astrocytes—the most prevalent glial cells in the brain—are not clearly understood. Therefore, this study aims to investigate the toxic effects of exposure to BaP on mitochondria in primary astrocytes. Fluorescent probes and genetically encoded indicators were utilized to visualize mitochondrial morphology and physiology, and regulatory factors involved in mitochondrial morphology and mitophagy were assessed. Additionally, the mitochondrial respiration rate was measured in BaP-exposed astrocytes. BaP exposure resulted in mitochondrial enlargement owing to the suppression of mitochondrial fission factors. Furthermore, BaP-exposed astrocytes demonstrated reduced mitophagy and exhibited aberrant mitochondrial function and physiology, such as altered mitochondrial respiration rates, increased mitochondrial superoxide, disrupted mitochondrial membrane potential, and dysregulated mitochondrial Ca2+. These findings offer insights into the underlying toxic mechanisms of BaP exposure in neurodegenerative diseases by inducing aberrant mitophagy and mitochondrial dysfunction in astrocytes.

Effects of acupuncture on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats

To observe the effects of acupuncture at "antihypertensive acupoint prescription" on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats, and explore the vascular regulation and central regulation mechanisms of acupuncture for anti-hypertension. Thirty SPF grade male spontaneous hypertension rats were randomly divided into a model group (15 rats) and an acupuncture group (15 rats). Besides, 15 Wistar Kyoto rats were collected as a blank control group (normal group). In the acupuncture group, acupuncture was delivered at the "antihypertensive acupoint prescription" (bilateral "Renying" [ST 9], "Quchi" [LI 11], "Zusanli" [ST 36], "Taichong" [LR 3] and "Neiguan" [PC 6]), with needles retained for 30 min, once daily. The duration of intervention was 28 days. Every week, using the the irritation scale, the sign of sympathetic irritation was evaluated dynamically. The arterial blood pressure of the rats tail was determined, using non-invasive blood pressure measurement system. ELISA was adopted to detect the levels of calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1 (ET-1), neuropeptide Y (NPY) in the serum. DAB chromogenic in situ hybridization (CISH) was provided to detect the mRNA expression of endothelial nitric oxide synthase (eNOS) in the internal carotid artery and the arcuate nucleus (ARC), and that of CGRP in the paraventricular nucleus posterior (PVP) and the ventrolateral medulla (VLM). Liquid chromatography-mass spectrometry (LC-MS) was used to detect the levels of epinephrine (E) and norepinephrine (NE) in the paraventricular nucleus anterior (PVA). Compared with the normal group, the irritation scores, systolic blood pressure and diastolic blood pressure were increased at each time point in the model group (P<0.05). When compared with the model group, the irritation scores after the intervention for 3 and 4 weeks, and systolic and diastolic blood pressure after intervention for 2, 3 and 4 weeks were reduced in the acupuncture group (P<0.05). In comparison with the normal group, the serum CGRP and NO levels of the rats were decreased (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels in PVA were increased (P<0.05) in the model group. The levels of serum CGRP and NO were elevated (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels of PVA were reduced (P<0.05) in the acupuncture group when compared with those of the model group. In the model group, the media of internal carotid artery exhibited thickening and remodeling, while the neuron volume in ARC was small. In the acupuncture group, every layer of internal carotid artery was acceptably arranged, and the parvicellular neuron of ARC was moderate in volume. For the in situ hybridization of eNOS mRNA for the rats of each group, the smooth muscle cells were predominantly expressed in each layer of the internal carotid artery, whereas the expression of parvicellular neurons was dominated in ARC. In the model group, the large and small neurosecretory cells were distributed sparsely in the nerves of PVP; in the acupuncture group, the cells of these two species were distributed regularly; and there were few species of glial cell in the VLM of either the model group or the acupuncture group. In each group, for the in situ hybridization of CGRP mRNA, the small neurosecretory cells were expressed predominately in the PVP, while, the expression of glial cell nuclei and the cell cytoplasm was dominated in the VLM. Compared with the normal group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP mRNA in the PVP and VLM was decreased in the model group (P<0.05). In the acupuncture group, when compared with the model group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP in the PVP and VLM was increased in the acupuncture group (P<0.05). Acupuncture at "antihypertensive acupoint prescription" can upregulate the level of vascular relaxing factors, downregulate the level of contracting factors, enhance the response of relaxing factors in targeting blood vessels and regulating the center. The mechanism may be related to the modulation of the sympathetic-adrenergic autonomic neurotransmitters in the paraventricular nucleus in spontaneous hypertension rats.

Lipidomic and Proteomic Insights from Extracellular Vesicles in Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes.

Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to glial activation and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmann's area 9 (BA9) in postmortem subjects. We isolated BA9-derived EVs from postmortem brain tissues of eight individuals (controls: n=4, SUD: n=4). The EVs were analyzed for physical properties (concentration, size, zeta potential, morphology) and subjected to integrative multi-omics analysis to profile the lipidomic and proteomic characteristics. We assessed the interactions and bioactivity of EVs by evaluating their uptake by glial cells. We further assessed the effects of EVs on complement mRNA expression in glial cells as well as their effects on microglial migration. No significant differences in EV concentration, size, zeta potential, or surface markers were observed between SUD and control groups. However, lipidomic analysis revealed significant enrichment of glycerophosphoinositol bisphosphate (PIP2) in SUD EVs. Proteomic analysis indicates downregulation of SERPINB12, ACYP2, CAMK1D, DSC1, and FLNB, and upregulation of C4A, C3, and ALB in SUD EVs. Gene ontology and protein-protein interactome analyses highlight functions such as cell motility, focal adhesion, and acute phase response signaling that is associated with the identified proteins. Both control and SUD EVs increased C3 and C4 mRNA expression in microglia, but only SUD EVs upregulated these genes in astrocytes. SUD EVs also significantly enhanced microglial migration in a wound healing assay.This study successfully isolated EVs from postmortem brains and used a multi-omics approach to identify EV-associated lipids and proteins in SUD. Elevated C3 and C4 in SUD EVs and the distinct effects of EVs on glial cells suggest a crucial role in acute phase response signaling and neuroinflammation.

Nakagami-fuzzy imaging for grading brain tumors by analyzing fractal complexity

Gliomas are the brain tumors in glial cells, which are categorized into four numerical grades, I-II-III-IV, to quantize the aggressiveness and severity of the tumors; while divided into two major groups, high-grade (HG) and low-grade (LG), in general. Among many differences between these groups, one of the most distinct and characteristic features could be seen in the shape of the tumor boundaries by magnetic resonance imaging (MRI). Due to aggressive nature of the HG tumors in proliferation phase, the boundaries of HG tumors become more shape-wise complex compared to the LG tumors, which could be differentiated by analyzing the fractal complexity of the cell membranes. However, the complexity cannot be either manually calculated or estimated by eye inspection without a reference point with one single image or sometimes even with an image set. Therefore, we present an automated glioma grading framework to provide an insight on the grades with a novel contouring and fractal dimension analysis system. The primary component of the proposed system is an automated Nakagami imaging module with a specialized fuzzy c-means algorithm to contour the boundaries of the whole tumors. The contoured images, afterwards, are analyzed by the Minkowski–Bouligand and Hausdorff methods for two panning options to generate the fractal dimensions and to estimate the fractal complexities for classifying the gliomas The results are greatly encouraging that the overall classification accuracy is computed as 88.31 % using the basic support vector machines (SVM) classifier; while as 91.96 % with the arbitrary thresholding appended. The outcomes of this paper with implementable mathematical infrastructure would be very useful and beneficial as an expert system in intelligent and automatic glioma grading, for researchers and medical experts.

Transient impairment in microglial function causes sex-specific deficits in synaptic maturity and hippocampal function in mice exposed to early adversity

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early-life adversity (ELA), with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of ELA, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the rodent hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21 in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. These findings suggest a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, our study highlights a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of ELA.

Endoplasmic Reticulum Stress Differently Modulates the Release of IL-6 and IL-8 Cytokines in Human Glial Cells.

Endoplasmic reticulum (ER) stress is a significant player in the pathophysiology of various neurodegenerative and neuropsychiatric disorders. Despite the established link between ER stress and inflammatory pathways, there remains a need for deeper exploration of the specific cellular mechanisms underlying ER stress-mediated neuroinflammation. This study aimed to investigate how the severity of ER stress (triggered by different concentrations of tunicamycin) can impact the release of proinflammatory cytokines IL-6 and IL-8 from astrocytes and microglia, comparing the effects with those induced by well-known immunostimulants-tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Mild ER stress has a distinct effect on the cytokine release compared to more intense stress levels, i.e., diminished IL-6 production was accompanied by an increase in IL-8 level, which was significantly more pronounced in astrocytes than in microglia. On the contrary, prolonged or more severe ER stress induced inflammation in glial cells, leading to a time- and concentration-dependent buildup of proinflammatory IL-6, but unlike inflammatory agents, an ER stress inducer diminished IL-8 secretions by glial cells. The differences could hold importance in identifying ER stress markers as potential drug targets for the treatment of neurodegenerative diseases or mood disorders, yet this requires confirmation in more complex animal studies.

Assessment of the potential protective effectsof culture filtrate ofTrichoderma harzianum to ameliorate the damagedhistoarchitecture of brain in epileptic rats.

The simultaneous hyperexcitability of the neural network is the most well-known manifestation of epilepsy that causes recurrent seizures. The current study was aimed to examine any potential safety benefits of the culture filtrate of Trichoderma harzianum (ThCF) to ameliorate damaged histoarchitecture of the brain in epileptic rats by assessing seizure intensity scale and behavioral impairments and follow up the spontaneous motor seizures during status epilepticus phases in rats. Twenty-four rats were divided into four groups; control (C), epileptic (EP) valproic acid-treated epileptic (EP-VPA), and epileptic treated with T. harzianum cultured filtrate (ThCF). In addition to a seizure intensity score and behavioral tests, routine H&E and Golgi-Copsch histopathology, were used to examine the cell somas, dendrites, axons, and neural spines. ThCF treatment increased activity and recorded movements during grooming, rearing, and ambulation frequency. Brain tissues of epileptic rats exhibited detached meninges, hypercellularity, mild edema in the cortex and markedly degenerated neurons, degenerated glial cells, and microcyst formation in the hippocampus. Moreover, brains of EP-ThCF were noticed with average blood vessels, and increased dendritogenesis. The current data revealed some of negative effects of epileptogenesis brought on by seizure intensity score and retarded histopathological alterations in the hippocampus. Therefore, the study is forecasting to identify novel active components from the metabolites of T. harzianum with a crucial therapeutic role in various disorders.

A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution.

The definition of molecular and cellular mechanisms contributing to brain ontogenetic trajectories is essential to investigate the evolution of our species. Yet their functional dissection at an appropriate level of granularity remains challenging. Capitalizing on recent efforts that have extensively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework to perform (i) trajectory inference and gene regulatory network reconstruction, (ii) (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and (iii) paleogenomic analysis for a higher-resolution mapping of derived regulatory variants in our species in comparison to our closest relatives. We provide evidence for cell type-specific regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a key role for a cholesterol program in outer radial glia, regulated by zinc-finger transcription factor KLF6. A cartography of the regulatory landscape impacted by Homo sapiens-derived variants reveals signals of selection clustering around regulatory regions associated with GLI3, a well-known regulator of radial glial cell cycle, and impacting KLF6 regulation. Our study contributes to the evidence of significant changes in metabolic pathways in recent human brain evolution.