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PubMed1987

Effect of rat serum albumin-cholesterol on the physical properties of biomembranes.

Affinity chromatography, using Cibacron blue F3GA bound to Sepharose 4B, and Sephadex G-150 column chromatography, permit the isolation of large quantities of non-esterified cholesterol loaded albumin from rat serum. Unlabeled cholesterol and cholesterol oxides displaced 14C-cholesterol bound to albumin in a dose-dependent manner. Binding of 14C-cholesterol to rat serum albumin in vitro follows a sigmoid curve. Ca2+ ions (up to 10 mM) inhibited the cholesterol binding to albumin in vitro. Fluorescence anisotropy of diphenyl-hexatriene (DPH) embedded in the lipid core of rat brain synaptosomal plasma membranes (SPM) increased with albumin-cholesterol incorporation and decreased in parallel to cholesterol removal. The allosteric properties of the SPM-bound (Na+ + K+)ATPase by fluoride (F-) (as reflected by changes in the Hill coefficient) were modulated by albumin-cholesterol, suggesting that the physical state of the (Na+ + K+)ATPase lipid microenvironment changed from a liquid-crystalline to gel phase. The present studies concerning albumin-cholesterol complex, its behavior and its role in the structure of biomembranes, provide important new clues to the role of this fascinating molecule in normal and pathological states.

Albumins↗
PubMed1999

Differential expression of inflammatory mediators in rat microglia cultured from different brain regions.

Microglial cells show a rather uniform distribution of cell numbers throughout the brain with only minor prevalences in some brain regions. Their in situ morphologies, however, may vary markedly from elongated forms observed in apposition with neuronal fibers to spherical cell bodies with sometimes extremely elaborated branching. This heterogeneity gave rise to the hypothesis that these cells are differentially conditioned by their microenvironment and, therefore, also display specific patterns of differential gene expression. In this study, microglia were isolated from 2-4 week-old mixed CNS cultures that had been prepared from neonatal rat diencephalon, tegmentum, hippocampus, cerebellum and cerebral cortex, and were investigated 24 h later. Messenger RNA levels of proteins involved in crucial immune functions of this cell type (TNF-alpha, CD4, Fcgamma receptor II, and IL-3 receptor beta-subunit) have been determined by semi-quantitative RT-PCR. The results clearly show, that three of these mRNAs (TNF-alpha, CD4, Fcgamma receptor II) are differentially expressed in microglia with hippocampal microglia displaying the highest levels of these mRNAs. The data strongly support the notion that the status of microglial gene expression depends on their localization in brain and on specific interactions with other neural cell types. Consequently, it is hypothesized that their responsiveness to signals arising in injury or disease may vary from one brain region to another.

Animals↗
PubMedDate not supplied

Cells encapsulated in alginate: a potential system for delivery of recombinant proteins to malignant brain tumours.

Growth and progression of malignant brain tumours occurs in a micromilieu consisting of both tumour and normal cells. Several proteins have been identified with the potential of interfering directly with tumour cells or with the neovascularisation process, thereby inhibiting tumour growth. A continuous delivery of such inhibitory proteins to the tumour microenvironment by genetically engineered cells could theoretically be of considerable therapeutic importance. In this study we have investigated the growth characteristics of cells encapsulated in alginate, which represents a potential delivery system for recombinant proteins that may have antitumour effects. Three different cell lines, NHI 3T3, 293 and BT4C were encapsulated in alginate, which is an immuno-isolating substance extracted from brown seaweed. The encapsulated cells were observed at specific intervals during a 4-month period after in vitro propagation and as transplants into the cortex of BD-IX rats. Morphological studies showed that encapsulated cells proliferated and formed spheroids within the alginate in the in vitro cultures and after implantation into the brain. Even after 4 months in vivo a substantial amount of living cells were observed within the alginate beads. A vigorous infiltration of mononuclear cells was observed in the brain bordering the alginate beads, one week after implantation. However, there was a gradual decrease of mononuclear cells at the border zone beyond the first week of implantation. The majority of inflammatory cells were reactive microglia and invading monocytes, as verified by immunohistochemistry. The data further shows that alginate encapsulated cells can be frozen in liquid N2 and will retain their viability and proliferative capacity.

3T3 Cells↗
PubMed2007

S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage.

During the postnatal development, astrocytic cells in the neocortex progressively lose their neural stem cell (NSC) potential, whereas this peculiar attribute is preserved in the adult subventricular zone (SVZ). To understand this fundamental difference, many reports suggest that adult subventricular GFAP-expressing cells might be maintained in immature developmental stage. Here, we show that S100B, a marker of glial cells, is absent from GFAP-expressing cells of the SVZ and that its onset of expression characterizes a terminal maturation stage of cortical astrocytic cells. Nevertheless, when cultured in vitro, SVZ astrocytic cells developed as S100B expressing cells, as do cortical astrocytic cells, suggesting that SVZ microenvironment represses S100B expression. Using transgenic s100b-EGFP cells, we then demonstrated that S100B expression coincides with the loss of neurosphere forming abilities of GFAP expressing cells. By doing grafting experiments with cells derived from beta-actin-GFP mice, we next found that S100B expression in astrocytic cells is repressed in the SVZ, but not in the striatal parenchyma. Furthermore, we showed that treatment with epidermal growth factor represses S100B expression in GFAP-expressing cells in vitro as well as in vivo. Altogether, our results indicate that the S100B expression defines a late developmental stage after which GFAP-expressing cells lose their NSC potential and suggest that S100B expression is repressed by adult SVZ microenvironment.

Animals↗
PubMedDate not supplied

Hyperphosphorylated protein tau is restricted to neurons devoid of perineuronal nets in the cortex of aged bison.

Hyperphosphorylated tau in the cortex and hippocampal formation of two aged bisons was characterized by its immunoreactivity to the phospho-epitope-recognizing monoclonal antibodies AT8, AT100, PHF-1 and TG-3. Gallyas silver staining revealed sparsely scattered cortical tangles and neuropil threads. In dual-peroxidase staining experiments, the immunocytochemical detection of vulnerable neurons was combined with the demonstration of chondroitin sulphate proteoglycan-rich perineuronal nets of the extracellular matrix. Such polyanionic lattice-like neuronal coatings were revealed lectin- and immunocytochemically. Hyperphosphorylated tau was exclusively observed in neurons devoid of perineuronal nets. The present findings in the aged bison parallel previously obtained results from a quantitative study of human brains affected by Alzheimer's disease. In conclusion, the low susceptibility of different types of neurons to the abnormal phosphorylation of tau corresponds to high proportions of certain chondroitin sulphate proteoglycans in their microenvironment.

Age Factors↗
PubMed2025

Population analysis and immunologic landscape of melanoma in people living with HIV.

PURPOSE: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer. EXPERIMENTAL DESIGN: We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). RESULTS: PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8+ T cell compartment in PLWH, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). CONCLUSIONS: Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.

HIV↗
PubMed1994

Thyroid hormones influence the astroglial plasticity: changes in the expression of glial fibrillary acidic protein (GFAP) and of its encoding message.

Normal development of the brain requires the presence of thyroid hormones. To progress in the understanding of the contribution of astrocytes to brain pathophysiology we investigated the effect of T3, on the astroglial plasticity through the expression of two astroglial proteins: the Glial fibrillary acidic protein (GFAP) and the glutamine synthetase (GS). Western and northern blots were performed using astroglial primary cultures initiated from neocortex and cerebellum of new-born mice. Treatment with T3 caused a decrease of GFAP and of its encoding message level in both areas, suggesting a transcriptional regulation of its expression, whereas it had no apparent effect on GS expression. This reduction in GFAP expression was developmentally regulated; it was significant in proliferating but not in more mature astrocytes. T3 effect on astrocytes was higher in the cerebellum compared to the neocortex, suggesting the presence of astroglial subpopulations differing by their sensitivity to T3. The astroglial specific response to T3, corresponds to a precise, targetted and regulated adaptation of the cell. Factors of the microenvironment may modulate this specific astroglial response in vivo.

Animals↗
PubMed2006

Blood-neural barrier: intercellular communication at glio-vascular interface.

The blood-neural barrier (BNB), including blood-brain barrier (BBB) and blood-retinal barrier (BRB), is an endothelial barrier constructed by an extensive network of endothelial cells, astrocytes and neurons to form functional "neurovascular units", which has an important role in maintaining a precisely regulated microenvironment for reliable neuronal activity. Although failure of the BNB may be a precipitating event or a consequence, the breakdown of BNB is closely related with the development and progression of CNS diseases. Therefore, BNB is most essential in the regulation of microenvironment of the CNS. The BNB is a selective diffusion barrier characterized by tight junctions between endothelial cells, lack of fenestrations, and specific BNB transporters. The BNB have been shown to be astrocyte dependent, for it is formed by the CNS capillary endothelial cells, surrounded by astrocytic end-foot processes. Given the anatomical associations with endothelial cells, it could be supposed that astrocytes play a role in the development, maintenance, and breakdown of the BNB. Therefore, astrocytes-endothelial cells interaction influences the BNB in both physiological and pathological conditions. If we better understand mutual interactions between astrocytes and endothelial cells, in the near future, we could provide a critical solution to the BNB problems and create new opportunities for future success of treating CNS diseases. Here, we focused astrocyte-endothelial cell interaction in the formation and function of the BNB.

Animals↗
PubMed1991

How do retinal axons find their targets in the developing brain?

Tissue culture studies show that cell survival and process outgrowth from retinal ganglion cells depend on the molecular composition of the substrates over which the neurites grow, and on diffusible factors present in the medium. Recent work has begun to show that at least some of these components might be interactive. Since the conditions in a culture dish, as well as the patterns of antigen expression on cells in vitro, can differ considerably from those encountered in vivo, it is important to design experiments in vivo that examine how growing neurites relate to their natural microenvironment. By the use of transplantation techniques, it has been possible to provide evidence for a comparable duality of substrate-dependent and target-derived controls of optic axon growth, which might provide insight into the normal developmental process.

Animals↗
PubMedDate not supplied

Neurodevelopmental influences on the immune system reflecting brain pathology.

A number of studies have shown that early life events can affect the development of the nervous system, contributing to particular individual differences in later vulnerability to different forms of psychosocial stress related to the environment and lifestyle. Neuropeptides, chemokines (CKs), neurotrophins (NTs) belong to the chemical microenvironment of the cells of the central nervous system (CNS). This paper reviews research performed in our and other laboratories indicating that mass spectrometry should play a significant role in future studies of the structures of proteins/peptides in neuroscience. These applications include peptide metabolism associated with normal and impaired neurone/immune function. Detailed information about peptide/protein processing in the CNS may be studied by using the lymphocyte as a model reflecting different chemical modifications of peptides/proteins related to various psychosomatic disturbances reflecting disorders of environment and lifestyle.

Journal Article↗
PubMed2001

Cerebral abscesses: investigation using apparent diffusion coefficient maps.

The combination of high signal and reduced apparent diffusion coefficients (ADC) within abscesses on diffusion-weighted MRI (DWI) has been reported as characteristic of abscesses, and useful for distinguishing them from cystic or necrotic neoplasms. To assess whether these are consistent findings in abscesses, we used DWI-derived ADC to investigate changes in water diffusibility in cerebral abscesses. We reviewed the MRI studies and clinical records of five patients with brain abscesses, who underwent DWI. Regions of interest were drawn within the abscesses on ADC maps, to obtain the ADC. The center of all five abscesses gave signal higher than that of white matter on DWI. The three largest also appeared bright on ADC maps, i. e., showed ADC substantially lower than those of normal white matter, consistent with restricted diffusion. However, the two smaller abscesses were not visible on ADC maps because their ADC were essentially the same as that of white matter; they did not show restricted diffusion. The absence of restricted diffusion within small abscesses may be related to intrinsic differences in molecular microenvironment between small and large abscesses, or to greater influence of volume averaging with surrounding edema on the ADC in smaller abscesses.

Brain Abscess↗
PubMedDate not supplied

Effects of aging and vincamine derivatives on pericapillary microenvironment: stereological characterization of the cerebral capillary network.

Changes in the pericapillary microenvironment of adult (18-month-old) and senescent (27 1/2-month-old) Fischer-344 rats treated for 6 weeks with daily IP injections of brovincamine or apovincamine (0, 2.5, 5, 10 mg/kg) were correlated with spontaneous locomotor activity and [14C]-2-deoxyglucose uptake of the brain. The animals were tested for spontaneous locomotor activity in a tunnel maze. Twenty-four hr after behavioral testing and subsequently after a [14C]-2-deoxyglucose injection, brains were removed and capillaries stained with alkaline phosphatase reaction, being later measured with an optical-electronic image analysis technique. Results revealed an increase in intercapillary distance, as a sensitive parameter for capillary density, in the hippocampus (CA1) and in the parietal cortex (area 39) in association with aging. Capillary diameter in the parietal cortex was found to be increased age dependently. A similar age-related increase was also observed in the CA1 field but this age trend was not significant. Chronic treatment with the vincamines produced a dose-dependent reduction in intercapillary distance in senescent animals which approached the level of untreated adult control rats. Significant negative correlations were found between maze locomotion and intercapillary distance among senescent rats. Furthermore, intercapillary distance and local relative 2-deoxyglucose uptake tended to be negatively correlated in both age groups. These findings provide evidence for the working hypothesis that mean intercapillary distance can be considered as an indicator of neuronal activity in the pericapillary microenvironment.

Aging↗
PubMed1990

Synaptic aging as revealed by changes in membrane potential and decreased activity of Na+,K(+)-ATPase.

Age-related changes in the membrane potential of nerve terminals were investigated by monitoring the accumulation of tritium-labeled triphenylmethylphosphonium ion, [3H]TPMP+, in mouse cortical synaptosomes. The resting membrane potential became less negative with advancing age, that is, it changed from -64.5 +/- 0.8 to -58.1 +/- 2.3 mV between 6 and 27 months of age. The intrasynaptosomal potassium concentration was found to decrease concomitantly by 13% in aged mice (56.6 +/- 0.9 mM) as compared to young-adult mice (64.9 +/- 0.5 mM). The ouabain-sensitive Na+,K(+)-ATPase activity of synaptic plasma membranes decreased in late senescence to 82% of the adult level. To examine the correlation with the decreased Na+,K(+)-ATPase activity, the membrane lipid composition was analyzed. Among the membrane phospholipids, only the content of phosphatidylcholine decreased in the course of senescence. The changes in the Na+,K(+)-ATPase activity were found to be positively correlated with the changes in the phospholipid content, and more specifically with the changes in the phosphatidyl-choline content. These results suggest that age-related alterations in the microenvironment constructed by phospholipids may decrease the activity of Na+,K+-ATPase, resulting in neuronal ion imbalance and decreased membrane potential. This might be responsible in part for altered functions of nerve terminals in aging brain.

Aging↗
PubMed2026

DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer's disease.

Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer's disease (AD), characterized by beta-amyloid (Aβ) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of Aβ plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed "DeepPlaque", an integrated system featuring "PlaqueNet", a deep learning model for automated classification of Aβ plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC > 90%) in classifying the 3 major Aβ plaque species, supporting consistent and large-scale annotation. By integrating spatial cellular phenotyping with laser microdissection, DeepPlaque enables high-throughput proteomic analysis of Aβ plaque niches, revealing that microglia are more abundant around core and fibrillar Aβ plaques, with increased expression of apolipoprotein E and amyloid precursor protein in core Aβ plaques. This customizable platform enhances the molecular and cellular characterization of Aβ plaque-associated environments, providing critical insights into AD pathology.

Alzheimer Disease↗
PubMedDate not supplied

Enkephalins, brain and immunity: modulation of immune responses by methionine-enkephalin injected into the cerebral cavity.

There is a large number of interactions at molecular and cellular levels between the nervous system and the immune system. It has been demonstrated that the opioid neuropentapeptide methionine-enkephalin (Met-Enk) is involved in humoral and cell-mediated immune reactions. Met-Enk injected peripherally produces a dual and dose-dependent immunomodulatory effect: high doses suppress, whereas low doses potentiate the immune reactivity. The present mini-review concerns the immunological activity of Met-Enk after its administration into the lateral ventricles of the rat brain, and describes the extraordinary capacity of centrally applied Met-Enk to regulate/modulate the immune function. This survey is composed of sections dealing with (a) the role of opioid peptides in the central nervous system (CNS); (b) the activity of opioid peptides in the immune system; (c) the application of Met-Enk into the cerebral cavity; (d) the influence of centrally administered Met-Enk on nonspecific local inflammatory reaction; (e) the effect of Met-Enk injected intracerebroventricularly (i.c.v.) on specific delayed hypersensitivity skin reaction, experimental allergic encephalomyelitis, anaphylactic shock, plaque-forming cell response, and hemagglutinin production; (f) the central antagonizing action of quaternary naltrexone, an opioid antagonist that does not cross the brain-blood barrier, on Met-Enk-induced immunomodulation; (g) the alteration of immune responsiveness by i.c.v. injection of enkephalinase-degrading enzymes; (h) the participation of the brain-blood/blood-brain barrier in the CNS-immune system interaction; and (i) the role of opioid receptors in immunological activity of Met-Enk. A hypothesis has been advanced for the reaction of Met-Enk and opioid receptor sitting on the cell membrane. This concept suggests that the constellation of chemical residues of enkephalin and receptor in the microenvironment determines the binding between the opioid partners. The plurality of conformational structures of enkephalins and receptors makes possible their involvement in a variety of processes which occur in different physiological systems, including the nervous system and the immune system, and intercommunications between the two systems.

Animals↗
PubMed1999

A new model of the blood--brain barrier: co-culture of neuronal, endothelial and glial cells under dynamic conditions.

Developing in vitro blood-brain barrier (BBB) models that closely mimic the natural state is important for theoretical and practical applications, including drug development. We previously developed an in vitro BBB model based on co-culturing endothelial cells with glia in the presence of flow on hollow fiber tube culture substrates. We now report that this dynamic in vitro BBB (DIV-BBB) can be successfully used to co-culture differentiated serotonergic neurons in the presence of a BBB. These neurons demonstrated fluoxetine-sensitive serotonin (5HT) uptake and depolarization-induced release of [3H]5HT. Our results demonstrate that the DIV-BBB is a suitable model for culturing of neurons in a quasi-physiological microenvironment and in the presence of a high-resistance, stereoselective BBB.

Animals↗
PubMed2005

Clinically relevant metastatic breast cancer models to study chemosensitivity.

Metastatic disease, notably to the lungs, liver, bone, and brain, is the most common cause of death from breast cancer, despite advances in surgical and clinical management. Two basic principles govern the process of metastasis: first, that tumors are heterogeneous populations of cells; and second, that the process of metastasis is a sequence of events that depends on tumor cell properties and interactions with the microenvironment at the sites of metastasis. In theory, inhibitors targeted at any of the steps of metastasis have the potential to inhibit metastatic progression. In vitro assays cannot simulate accurately the complex process of metastasis, and the use of appropriate animal models is necessary to model the process, and for testing the impact of targeted inhibitors on the growth and development of breast cancer metastasis. Animal models of the growth and metastasis of rodent and human breast cancer cells have been developed, including models that target the metastatic growth in key organs sites such as the bone and brain.

Animals↗
PubMed1984

Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies.

Mononuclear cell infiltrates are found to varying degrees in 30% to 60% of primary human central nervous system (CNS) gliomas. To explore the immunological importance of this, six operative glial tumors, eight non-glial tumors, and three normal brain specimens were studied. Utilizing an immunoperoxidase method, the authors examined frozen sections for lymphoid infiltrates expressing suppressor/cytotoxic and helper phenotypes, as identified with the Leu-1,2,3 monoclonal antibodies. Four of six gliomas demonstrated lymphoid infiltrates: three tumors exhibited a predominant suppressor/cytotoxic cell phenotype and the fourth showed mixed staining of suppressor/cytotoxic and helper cell phenotypes. Varying degrees of lymphoid infiltration characterized four out of eight non-glial primary CNS tumors. Two cases exhibited a prevalence of suppressor/cytotoxic phenotype cells, while two cases demonstrated a more heterogeneous pattern of phenotype expression. Normal brain sections revealed little or no evidence of mononuclear infiltrates. The immunobiological significance of these findings is discussed in the context of tumor-host interaction within the CNS.

Antibodies, Monoclonal↗