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At least 217 records · Page 12Linked to original sources
PubMed2000

Synaptic microenvironments--structural plasticity, adhesion molecules, proteases and their inhibitors.

Proteolytic regulation might be essential in neural plasticity in mature brain as well as the developing brain. An increasing number of studies support the idea that structural changes in the synapses are closely associated with synaptic plasticity. Proteases and their inhibitors in a synaptic microenvironment are important in the regulation of dynamic changes in the extracellular matrix components associated with synaptic plasticity. In the present article, the possible roles of neuronal proteases, protease inhibitors and extracellular macromolecules are reviewed.

Animals↗
PubMed2002

Innate differences between simian-human immunodeficiency virus (SHIV)(KU-2)-infected rhesus and pig-tailed macaques in development of neurological disease.

Neurological disease associated with HIV infection results from either primary replication of the virus or a combination of virus infection and replication of opportunistic pathogens in the CNS. Recent studies indicate that the primary infection is mediated mainly by viruses that utilize CCR5 as the coreceptor; it is not known whether the syndrome can be mediated by viruses that use the CXCR4 coreceptor. The macaque model of the disease using simian immunodeficiency virus (SIV) has confirmed that CCR5-using viruses such as SIV(mac)251 can cause primary disease in the CNS. In this report we have examined the role of simian-human immunodeficiency virus (SHIV)(KU-2), a CXCR4 virus which replicates productively in rhesus macrophages, in causing CNS disease. A survey of archival brain tissues from SHIV(KU-2)-infected rhesus and pig-tailed macaques that succumbed to AIDS showed productive viral replication in the CNS of 10 of 14 rhesus animals. Eight of these 10 had additional infections with opportunistic pathogens. In contrast, 21 of 22 pig-tailed macaques had no evidence of productive viral infection in the brain. In an earlier study we had shown that inoculation of SHIV-infected rhesus macaques with eggs of Schistosoma mansoni, a potent inducer of IL-4, resulted in enhanced replication of the virus in tissue macrophages. In the present study, we compared the replication of the virus in macrophages from normal rhesus and pig-tailed macaques and determined further whether exogenous IL-4 could cause enhancement of virus replication in these cells. These studies showed that the virus replicated productively in rhesus macrophages, and this was enhanced significantly after recombinant macaque IL-4 was added to the medium. IL-4 also caused enhancement of virus production in macrophages isolated from virus-infected animals. In contrast, the virus replicated only minimally in pig-tailed macaque macrophages and supplemental IL-4 had negligible effects. The data thus suggested that failure of pig-tailed macaques to develop encephalitis was due to the innate resistance of macrophages from this species of macaque to support replication of SHIV(KU-2). The ability of the virus to replicate in the brains of rhesus macaques was dependent on coinfection in the brain with opportunistic pathogens which presumably induced both macrophages and IL-4 in the CNS microenvironment. A supportive role for IL-4 in the CNS disease was suggested by the presence of IL-4 RNA in the encephalitic brains of rhesus macaques and reduced levels of this cytokine in the brains from pig-tailed macaques.

Acquired Immunodeficiency Syndrome↗
PubMed2006

mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging.

In normal brain aging, CNS resident macrophages exhibit increased expression of major histocompatibility complex (MHC) II expression. However, the transcriptional basis for this observation has not been clarified nor have age-related alterations in pivotal pro-inflammatory genes been characterized. Age-related mRNA alterations in MHC II, MHC II accessory molecules and several pro-inflammatory mediators were measured in older (24 months) and younger (3 months) male F344xBN F1 rats. Real time RT-PCR was utilized to measure steady state mRNA levels in hippocampus. Older as compared to younger animals exhibited increased mRNA levels of MHC II, CD86, CIITA and IFN-gamma. Furthermore, IL-10 and CD200 mRNA, molecules that down-regulate macrophage activation, was decreased in older animals. The present results indicate that normal brain aging is characterized by a shift towards a pro-inflammatory microenvironment in the CNS.

Aging↗
PubMed2026

Immunopeptidomics in gliomas: Decoding antigen presentation for precision immunotherapy.

Gliomas and particularly glioblastomas, represent the most aggressive and treatment-resistant brain tumours. Current standard treatments, including surgical resection, radiotherapy and chemotherapy, offer only limited long-term survival benefits. The highly immunosuppressive tumour microenvironment that characterizes gliomas enables immune evasion and limits the effectiveness of anti-tumour immune response, indicating the urgent need for identification of tumour antigens with clinical relevance to improve current immunotherapeutic strategies and enhance glioma immunogenicity. Immunopeptidomics, a mass spectrometry-based identification of peptides presented by HLA molecules, is a growing field of research for understanding the immunosurveillance of gliomas. By enabling the direct identification of naturally presented HLA-bound peptides from tumour tissue for T cell recognition, immunopeptidomics provide valuable insights into tumour antigen presentation and immune targeting. This review highlights the emerging role of immunopeptidomics in gliomas, covering the mechanisms of antigen processing and presentation by HLA class I and II molecules, the identification of glioma-associated antigens, the development of personalised peptide vaccines and the discovery of new targets for T cell-based immunotherapies. The potential of plasma-derived soluble HLA (sHLA) peptidomes as minimally invasive liquid-biopsy biomarkers is further discussed for disease monitoring and response to treatment. Overall, immunopeptidomics are foreseen as a powerful tool for the discovery of new tumour antigens leading to the development of more effective personalised glioma immunotherapies.

Humans↗
PubMed1999

Gangliosides influence angiogenesis in an experimental mouse brain tumor.

Gangliosides are sialated glycosphingolipids present on the plasma membranes of all vertebrate cells. Tumors shed gangliosides into the extracellular microenvironment, which may influence tumor-host cell interactions. We have investigated the role of gangliosides on the growth and angiogenesis of the EPEN experimental mouse brain tumor. EPEN cells express only ganglioside G(M3), and the solid tumors formed in vivo are sparsely vascularized with extensive necrosis. We stably transfected the EPEN cells with the cDNA for N-acetylgalactosaminyl transferase, a key enzyme for the synthesis of complex gangliosides. In addition to G(M3), the transfected cell line (EPEN-GNT) expressed complex gangliosides G(M2), G(M1), and G(D1a). The EPEN-GNT tumor was more densely vascularized with less necrosis and grew more rapidly than the nontransfected EPEN or mock-transfected (EPEN-V) control tumors. Also, VEGF gene expression was higher in the EPEN-GNT tumor than in the control tumors. The synthesis of complex gangliosides in the EPEN-GNT tumor cells also stimulated vascularization in an in vivo Matrigel assay for angiogenesis. These results indicate that the ratio of G(M3) to complex gangliosides can influence the growth and angiogenic properties of the EPEN experimental brain tumor and are consistent with previous findings in other systems. We conclude that gangliosides may be important modulators of brain tumor angiogenesis.

Animals↗
PubMed1989

Developmental profile of glutamine synthetase in lines of mice bred for ethanol sensitivity.

Glutamine synthetase (GS) activity was used as a marker to examine differences in astrocyte development in mice selectively bred for ethanol sensitivity: long sleep (LS), short sleep (SS), mild ethanol withdrawal (MEW), severe ethanol withdrawal (SEW) and control ethanol withdrawal (CEW). We found that 1) GS activity in MEW and SEW was higher than in LS and SS during the first 2 weeks of postnatal development, in the forebrain but not in the cerebellum; 2) lower GS activity was observed consistently in all areas examined with the SS mice as compared to the LS; 3) glutamine synthetase activity in MEW and SEW differed significantly from their controls (CEW) during the early developmental period regardless of the brain region examined; however, after 30 days of maturation, GS activity in SEW was higher than that in MEW and CEW in the forebrain. Astrocytes are known to contribute in the regulation of the neuronal microenvironment. Therefore, we interpret the differences we found in astrocytic function during early brain development among these lines of mice to account in part for the neuronal predisposition to ethanol sensitivity.

Aging↗
PubMed2006

Cannabinoids in microglia: a new trick for immune surveillance and neuroprotection.

Microglia are the resident immune cells of the brain, and they are under permanent activity to patrol the cerebral microenvironment. A proper inhibitory feedback onto these cells is critical during both intact and injury conditions. In this issue of Neuron, Eljaschewitsch and colleagues report that such feedback is provided by the endogenous cannabinoid anandamine and CB(1/2) receptor signaling, which ultimately leads to mitogen-activated protein kinase phosphatase-1 (MKP-1) induction. MKP-1 interferes with lipopolysaccharide-induced toll-like receptor 4 signaling and limits brain damage due to exaggerated microglial reactivity following acute NMDA injury.

Animals↗
PubMed2002

Isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors.

Brain tumor formation and growth is accompanied by the proliferation and infiltration of blood capillaries. The phenotypes of endothelial cells that make up capillaries are known to differ not only in the tissues in which endothelial cells are located but also as a result of the microenvironment to which they are exposed. For this reason, primary cultures of brain endothelial cells were isolated from human brain tumors removed by surgery and compared with cells from normal tissue. The primary confluent monolayers that grew out of isolated capillary fragments consisted of closely associated, elongated, fusiform-shaped cells. But brain tumor-derived endothelial cells in culture exhibited significantly less expression of endothelial-specific Factor VIII-related antigen compared with cells isolated from normal tissue. Cultured cells that exhibited binding of Ulex europaeus lectin were shown to take up Dil-Ac-Ldl and formed continuous monolayers that were joined together by tight junctions. The cells also exhibited characteristics of the cells of the brain microvasculature in vitro as seen by the presence of large numbers of mitochondria and few pinocytotic vesicles and by the absence of Weibel-Palade bodies within the cells. The expression of vascular cell adhesion molecule-1, E-Selectin, and the tight junction associated protein ZO-1 but not intercellular adhesion molecule-1 was demonstrated by immunohistological staining or reverse transcriptase-polymerase chain reaction methodologies. Comparative studies of these endothelial cells with endothelial cells from normal tissue will be useful for determining and understanding how the blood-brain barrier differs and functions in tumor and healthy tissues and may lead to strategies for brain tumor therapeutic approaches.

Blood-Brain Barrier↗
PubMed2026

Spatial Omics in High-Grade Gliomas: Mapping Immune-Tumor Niches for Precision Therapy.

High-grade gliomas (HGGs), particularly glioblastoma (GBM), remain among the most lethal human cancers despite decades of molecular profiling and therapeutic innovation. A primary reason for treatment failure is that HGG biology is spatial: malignant cell states, immune suppression, metabolic stress, and therapeutic resistance are organized into distinct anatomical and functional niches. Spatial omics technologies now enable high-dimensional mapping of gene expression, protein signaling, immune architecture, and metabolic activity within intact tumor tissue. These approaches reveal how proneural and mesenchymal transcriptional states coexist yet localize to distinct regions, alongside hypoxic, invasive, and stem-enriched niches. Spatial analyses show that key clinical determinants, including O6-methylguanine-DNA methyltransferase (MGMT)-associated temozolomide resistance, radiotherapy tolerance in hypoxic regions, and immunotherapy failure driven by myeloid-dominated immune exclusion, are influenced not only by molecular programs but also by cellular location. Beyond biological insight, spatial omics is reshaping clinical paradigms by enabling region-specific patient stratification, early assessment of treatment response, and identification of therapy-resistant reservoirs that seed recurrence. Prior bulk and single-cell studies defined HGG cell states and pathways but often treated resistance as tumor-wide. This review presents a spatially explicit framework that synthesizes spatial transcriptomic and immune-profiling studies to identify tumor-immune niches and spatial bottlenecks that drive therapeutic failure and recurrence.

Humans↗
PubMed1987

Neuroimmune interactions: experimental and clinical strategies.

This historical mini-review is devoted to the 30th Anniversary of the research activities of the Neuroimmunomodulation Group at the Immunology Research Center of Belgrade. During the past 30 years, these scientists have contributed to: (a) the definition of the structural and functional complexity and the lymphoneuroendocrine web of the immune microenvironment; (b) the structural and functional dissection of the neuron, brain and mind by means of anti-neural antibodies; (c) the antigenic relationship among the multiple components of the nervous and lymphoid tissues; (d) the methodological and conceptual aspects of the influence of lesioning and stimulation of various brain structures on immune responsiveness; (e) the lymphoneuroendocrine relationships during embryonic development; (f) the definition of immunopsychiatric diseases, i.e., neural tissue immunologic hypersensitivity in psychiatric diseases; (g) the immunomodulating and regulating activity of methionine-enkephalin and leucine-enkephalin; (h) the correlations between associative learning and immunity (behavioral immunology). The theoretical, experimental and clinical devices created, and observations collected from 1957 to 1987 by the Belgrade group of neuroimmunologists proved to be useful for elucidation of the complex interactions between the immune system and the nervous system, and provided a broad perspective for research in neuroimmunomodulation.

Allergy and Immunology↗
PubMed1990

Cellular expression of lymphocyte function associated antigens and the intercellular adhesion molecule-1 in normal tissue.

A detailed immunohistological analysis of normal tissues for the distribution of lymphocyte function-associated antigens (LFA) and the intercellular adhesion molecule-1 (ICAM-1) showed several hitherto unrecognised patterns of LFA-3 and ICAM-1 expression. The widespread, but not ubiquitous, distribution of LFA-3 contrasted with the more restricted distribution of ICAM-1. Among epithelial cells, all tissues which were ICAM-1 positive were also LFA-3 positive with the single exception that thymic cortical epithelium, in contrast to previous reports, expressed only ICAM-1. It was striking that LFA-3 molecules were absent in some tissues which are considered to be sites of immunological privilege (such as brain and testis), suggesting an additional mechanism by which these microenvironments maintain immunological autonomy. Furthermore, the unexpected finding that LFA-3 is strongly expressed on intercalated discs of cardiac muscle may possibly be related to a non-immune function, or indicate a structurally similar epitope expressed by an unrelated molecule within this tissue.

Antigens, Surface↗
PubMed2002

[Immunotherapy of gliomas].

There has been little change in the average survival of patients with malignant glioma these past two decades, despite extensive treatment including surgical resection, radiotherapy and chemotherapy. Immunotherapy has attracted the attention of many investigators as a new adjuvant therapy, but early approaches were largely unsuccessful. This seems to have been related to the immunological microenvironment within the central nervous system in which the blood brain barrier exists, and where no dendritic cells, potent antigen-presenting cells, are distributed. Furthermore, the immunobiological characters of glioma, which have many mechanisms to escape host's immunological surveillance, are the reason for the difficulty of immunotherapy. However, the modern advanced understanding of immunology and molecular biology has yielded novel immunostimulatory strategies such as immunogene therapy and dendritic cell manipulations, which have caused dramatic preclinical results in glioma models. Although definitive clinical results and solutions to side effects remain to be seen, immunotherapy shows great promise for the future.

Glioma↗
PubMed1991

Partial (coherence & correlation) estimates of brain autorhythmicity.

These experiments try to exhibit the interactions of the electrical activity of the microenvironment of a neuronal population spatially distant from the microenvironment of a different neuronal population. These experiments involve 18 cats with chronic electrodes surgically implanted into cerebral cortex, septal nuclei and amygdala. The Fast Fourier Transform (FFT) algorithm is done to process frequency domain data. In order to compare the phase relations between two channels, x(t) and y(T), use is often made of the coherence function. Computing partial coherence implies first eliminating from each two signals, that part which can be considered as being determined by, or predictable, on the basis of a third signal. It is assumed that there are three stochastic signals Y1, Y2, Y3. These variables can be considered as spectral components for a particular frequency. We assume that the correlations can be interpreted as square root of the coherence. For simplicity we use, in the partial correlations analyses.

Animals↗
PubMed1992

Early and late meningeal reaction to trauma after long-term brain death.

We examined histologically the meninges adherent to traumatic lesions of a patient with brain death sustained for 101 days and observed both early and late reactions of wound healing at the same site of the dura mater. Some parts of the dura mater were thick and histological examinations revealed formation of new vessels and fibrosis with strong positive reaction for iron and fat staining. We also observed fresh haemorrhage and some cell infiltration in the dura and fresh haemorrhage in a small piece of necrotic brain tissue adhered to the dura mater, while other areas of the brain tissue were completely necrotic, enabling the sites of head injury to be localised. These observations suggested that the blood flow in the dura mater fluctuates due to a change of microenvironment, which probably causes repeated secondary petechial haemorrhages in the dura and its adherent necrotic brain tissue, even 101 days after brain death.

Brain Death↗
PubMed2004

Microglia phagocytose alloreactive CTL-damaged 9L gliosarcoma cells.

Intracranial adoptive transfers of alloreactive cytotoxic T lymphocytes (aCTL) for brain tumor treatment were safe and showed promise in preclinical and early clinical trials. To better understand the endogenous immune responses that may ensue following cellular therapy with aCTL, we examined the ability of microglia to phagocytose aCTL-damaged and undamaged rat 9L gliosarcoma cells in vitro and in vivo. In vitro, 5.5+/-0.9% of microglial cells isolated from adult tumor-bearing rat brains phagocytosed aCTL-damaged 9L cells, whereas microglia did not bind to or ingest undamaged 9L cells. Addition of supernates from either 9L cell cultures or from aCTL+9L co-incubate cell cultures to microglia did not significantly alter their ability to bind to or phagocytose damaged glioma cells even though the latter contained T helper 1 and 2 cytokines. At 3 days following intracranial 9L cell infusion, 17.5+/-0.1% of the microglia phagocytosed CFSE-labeled aCTL-damaged 9L tumor cells within the adult rat brain, confirming the in vitro data. The results suggest that microglia within the tumor microenvironment of the adult rat glioma model selectively remove damaged, but not undamaged, glioma cells.

Animals↗
PubMed2004

Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression.

Insulin-like growth factor-I (IGF-I) is widely expressed in the central nervous system (CNS). Whereas during normal development IGF-I is expressed predominantly by neurons and to a much lesser degree by glial cells, its expression in astrocytes, and often in microglia, is increased during and/or after variety of CNS injuries. Recently we have generated a new line of IGF-I Tg mice, called IGF-I(Ast/Tet-Off) Tg mice, in which IGF-I transgene is expressed specifically in astrocytes and is tightly controlled by the tetracycline analog doxycycline. In this study we examined whether IGF-I derived from astrocytes is capable of promoting neural cell growth during development. When the IGF-I transgene is allowed to be expressed, IGF-I(Ast/Tet-Off) Tg mice exhibit markedly increases in 1) brain weight; 2) brain DNA and protein abundance; and 3) number of neurons, oligodendrocytes, and astrocytes, as well as myelination, findings similar to those observed in our other lines of Tg mice that express IGF-I transgene predominantly in neurons. Unlike Tg mice with neuron-specific IGF-I expression, which manifest marked increases in the concentrations of oligodendrocyte/myelin-specific proteins, however, IGF-I(Ast/Tet-Off) Tg mice exhibit an increase in the concentration of glial fibrillary acidic protein, an astrocyte-specific protein. Furthermore, when transgene expression is blunted, brain overgrowth in IGF-I(Ast/Tet-Off) Tg mice ceases. Our data indicate that astrocyte-derived IGF-I is capable of promoting neural cells growth in vivo. Our data also suggest that IGF-I's actions in CNS depend in part on the location of its expression and cellular microenvironment and that continuous presence of IGF-I expression is necessary for brain overgrowth.

Age Factors↗
PubMed1996

A systematic histochemical investigation in mammals of the dense glycocalyx glycosylations common to all cells bordering the interstitial fluid compartment of the brain.

Microanatomical evidence is presented that the intercellular fluid (ICF) compartment of the central nervous tissue is lined entirely and exclusively by heavily glycosylated cells, with glycoconjugates exposed primarily at the apical cell surface, fronting the CSF or blood. On both common ependymal cells and on those specialised to form the choroid plexus epithelium, oligosaccharides coat the cilia and microvilli at the apical surface, and also the smoother lateral and basal cell surfaces. In the ependyma, folded and wrinkled structures seem especially associated with freely exposed carbohydrates. On cerebral endothelial cells, oligosaccharides coat the luminal surface densely and the basal surface lightly. The patterns of carbohydrate distribution thus vary from one cell type to another, but the different cell types all bear essentially the same set of oligosaccharides, variations being due largely to degree of terminal sialylation. Furthermore, the same set of oligosaccharides borders the brain in a broad spectrum of mammals, including pouched and placental mammals. In both epithelia and endothelia, the lectin binding sites visualised in fixed and embedded preparations were shown to be exposed likewise at the cell surfaces in unfixed tissues and so able to bind molecules present in the fluid (CSF or blood) bathing the cells in vivo. This phylogenetically ancient enclosure of the ICF compartment in a "ring of sugars" is suggested to relate to regulation of the central neuronal microenvironment.

Animals↗
PubMed2006

Purinergic receptors modulate MAP kinases and transcription factors that control microglial inflammatory gene expression.

Following many types of brain injury, microglial cell hyperactivation, and the subsequent release of neurotoxic mediators into the CNS contributes to inflammation and neuronal death. Among the proteins important for modulating the inflammatory function of microglia are the P2 purinergic receptors for which extracellular adenine nucleotides, such as ATP, are ligands. Because adenine nucleotides are abundant in the extracellular fluid following brain injury, ATP may represent an important component of the inflammatory microenvironment controlling microglial cell function. Although much work has been done examining the mechanisms whereby adenine nucleotides stimulate inflammatory mediator production, little is known concerning their complementary inhibitory effects. In this review we will focus on what is currently known about the microglial inhibitory effects of adenine nucleotides in the context of inflammation and summarize the current knowledge of their effects via purinergic receptors on microglial signal transduction pathways including transcription factors important for controlling inflammatory gene expression. The relevance of these mechanisms to microglial inflammatory function and physiology will be discussed. Further, we present data here illustrating that MAP kinase signal transduction pathways are altered in activated microglia that have been primed with or co-exposed to adenine nucleotides; effects that are stimulus- and MAPK pathway-specific. We also demonstrate the ability of P2X7 receptors to stimulate the phosphorylation of CREB, a putative inhibitory transcription factor in microglia. Together, these data indicate that ATP may be an endogenous inhibitor or neuroprotective molecule decreasing the inflammatory capacity of microglia.

Adenosine Triphosphate↗