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PubMed2006

Signals for the induction of nitric oxide synthase in astrocytes.

Nitric oxide (NO), being a double-edged sword depending on its concentration in the microenvironment, is involved in both physiological and pathological processes of many organ systems including brain and spinal cord. It is now well-documented that once inducible nitric oxide synthase (iNOS) is expressed in CNS in a signal-dependent fashion, NO in excess of physiological thresholds is produced and this excess NO then plays a role in the pathogenesis of stroke, demyelination and other neurodegenerative diseases. Therefore, a keen interest has been generated in recent years in comprehending the regulation of this enzyme in brain cells. The present review summarizes our current understanding of signaling mechanisms leading to transcription of the iNOS gene in activated astrocytes. We attempt this comprehension with a hope to identify potential targets to intervene NO-mediated CNS disorders.

Animals↗
PubMed1997

Regeneration of neurosecretory axons into various types of intrahypothalamic graft is promoted by the absence of the blood-brain barrier: a neurophysin-immunohistochemical and horseradish peroxidase-histochemical study.

In order to test the hypothesis that neurosecretory axon regeneration occurs only in the presence of specific vascular, perivascular, and glial microenvironments, isografts of neural lobe and optic nerve and autografts of sciatic nerve were transplanted into the hypothalamo-neurohypophysial tract at the lateral retrochiasmatic area of adult male rats. The integrity of the blood-brain barrier (BBB) to intravenously administered horseradish peroxidase (HRP), the regenerative process of neurosecretory axons, and functional recovery from lesion-induced diabetes insipidus were analyzed at 18 hr, 36 hr, 10 days, 30 days, and 80 days postsurgery. Neurophysin-positive axons invaded all grafts, as well as perivascular spaces of the adjacent hypothalamus. Wherever neurosecretory axon regeneration occurred, the BBB was breached. Reestablishment of the BBB was paralleled by a decrease in both density and staining intensity of regenerated neurophysin-positive axons. These observations illustrate that neurosecretory axon regeneration is tributary of the absence of BBB. It is speculated that blood-borne factors, provided when the BBB is breached, initiate and sustain neurosecretory axon regeneration. In addition, products of glial elements may enhance or complement the above stimulatory processes.

Animals↗
PubMed2026

Mutational signatures in blood-brain barrier: mechanisms, computational insights, and clinical applications in precision oncology.

The blood - brain barrier (BBB) plays a central role in maintaining central nervous system (CNS) homeostasis, and its disruption is a defining feature of malignant brain tumors such as glioblastoma. Emerging evidence indicates that BBB dysfunction not only alters the tumor microenvironment but also shapes the mutational processes that drive genomic instability in CNS malignancies. This review synthesizes current understanding of the biological mechanisms linking BBB breakdown with distinct mutational signatures, including those arising from oxidative stress, hypoxia-induced replication stress, lipid peroxidation, inflammation, and metabolic reprogramming. Advances in next-generation sequencing, coupled with computational tools such as non-negative matrix factorization, Bayesian modeling, and deep learning, have enabled precise extraction of these signatures and their integration with multi-omics data. Clinically, BBB-associated mutational signatures offer significant promise for therapeutic stratification, prediction of treatment response, and noninvasive monitoring through cerebrospinal fluid - derived circulating tumor DNA. Despite these advances, challenges persist due to limited tissue accessibility, low-yield CSF samples, incomplete mechanistic models, and the lack of CNS-specific analytical frameworks. A deeper understanding of BBB-driven mutational processes, supported by improved computational approaches and integrative datasets, holds potential to advance precision oncology in neuro-oncology.

Humans↗
PubMed1998

Magnetoencephalography and magnetic source imaging.

Current brain imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), provide noninvasive, high-resolution images that depict fine anatomic structure and delineate pathology by control of image contrast and sensitivity to the physicochemical microenvironment. These methods, although invaluable for the identification, characterization, and localization of lesions, do not provide any assessment of the functional viability of brain tissues, nor of the spatial organization of sensory, motor, and cognitive systems. However, such additional functional information is of great significance to the clinician in the determination of treatment strategies and patient management.

Brain Mapping↗
PubMed2004

Biologic therapy for brain cancers--based on cellular and immunobiology.

The overall goal of our research projects is to develop effective immunotherapeutic regimens, particularly combining vaccine and gene therapy/ cell therapy strategies. For the development of clinically effective immunotherapy for brain cancers, the following issues are considered to be particularly important: 1) Induction of effective immune responses against tumors (afferent arm of the immune response), 2) Delivery of immune effector cells to the target tumor sites and maintaining the activity of the effector cells (efferent arm), 3) For specific and safe immunotherapy, specific brain tumor rejection antigens have to be identified, 4) Feasibility, safety and efficacy need to be tested in a series of clinical trials. The following presentation summarizes my research projects and demonstrates how each plan will fit in the whole schema of designing successful immunotherapeutic strategies for brain cancers. In this presentation, I would like to focus on our clinical and basic studies related to the vaccine strategies for patients with glioma, and modulation of tumor-microenvironment using bone-marrow derived stroma cells as vehicles for cytokine- gene delivery.

Biological Therapy↗
PubMed2004

How hematopoietic stem cells know and act in cardiac microenvironment for stem cell plasticity? Impact of local renin-angiotensin systems.

Bone marrow-derived hematopoietic stem cells (HSC) can exhibit tremendous differentiation activity in numerous non-hematopoietic organs. This enigmatic process is called as 'stem cell plasticity' (SCP). HSC may promote structural and functional repair in several organs such as heart, liver, brain, and skeletal muscle via the SCP. The differentiation capacity of HSC is dependent on the specific signals present in the local tissue microenvironment. Those specific molecular signals required for the interactions of HSC and host tissues are currently unknown. The aim of this report is to propose a hypothesis on how HSC reach, recognize, and function in cardiac tissues in the context of SCP. Locally signaling cardiac microenvironment is essential for the seeding, expansion, and 'cardiomyocyte differentiation' of the HSC in the heart. Our hypothesis is that the receptors, ligands, and signaling pathways of the tissue renin-angiotensin system (RAS) serve as the link between HSC and local cardiac microenvironment in SCP. The RAS is considered as a 'tissue-based system' exhibiting paracrine functions within many organs. The presence of local hematopoietic bone marrow RAS and local cardiac RAS have been suggested. Both local tissue RASs share similar angiotensin peptide-signaling pathways such as JAK-STAT and mitogen-activated protein kinases. HSC have angiotensin type I (AT1a) receptors for the binding of angiotensin II, the active component of the RAS. Binding of angiotensin II to AT1a can increase hematopoietic progenitor cell proliferation. Local cardiac RAS has critical (patho)biological functions in the cardiomyocyte survival, renewal, and growth, as well as in cardiac remodeling. Therefore, the components of the local cardiac RAS and hematopoietic RAS could interact with each other during the SCP through myocardial tissue repair. Activation of the local myocardial RAS after injury may be related to homing and engraftment of the HSC to the cardiac tissue. Regenerating myocardial tissue may exert regulatory functions on circulating or resident HSC via the locally active RAS. Understanding the exact molecular basis of SCP in relation to local tissue RAS could offer new frontiers in the better management of ischemic cardiac diseases.

Adaptation, Physiological↗
PubMed2002

Reactions of hemopoietic granulocytic stem in hypoxia of different severity.

We studied the reactions of granulocytic hemopoietic stem after acute hypoxia and during the development of posthypoxic encephalopathy. Damage to brain structures was associated with intensification of the bone marrow hemopoiesis due to activation of hemopoiesis-inducing microenvironment and more intense formation of hemopoietic islets, despite reduced proliferative capacity of granulocytic precursors.

Animals↗
PubMed1989

Interaction of rat brain cytidylate cyclase with phospholipids.

The interaction of rat brain cytidylate cyclase with some phospholipids such as L-alpha-phosphatidylcholine (PC), L-alpha-phosphatidylserine (PS), L-alpha-phosphatidylethanolamine (PE) and L-alpha-phosphatidic acid (PA) was studied. Cytidylate cyclase activity of Triton X-100 - solubilized fraction was inhibited by PS, PE and PA, but not with PC. The addition of PC to the incubation mixture containing PS, PE or PA dose - dependently reversed the inhibition of enzyme activity by these phospholipids. Phospholipids showed similar effect on the intact membrane - bound enzyme. PC could reactivate the enzyme which was inactivated by deoxycholate treatment, suggesting that PC may be an important factor to reconstitute an active conformation of the enzyme. These findings indicate that cytidylate cyclase could be regulated by phospholipids constituting its microenvironment of the membrane.

Animals↗
PubMed2004

Signal transduction pathways involved in the lineage-differentiation of NSCs: can the knowledge gained from blood be used in the brain?

Neural stem cells (NSC) are capable of differentiating toward neuronal, astrocytic, oligodendrocytic and glial lineages, depending on their spatial location within the central nervous system (CNS). Although, a lot of knowledge has been gained in the understanding of differentiation-specific signaling in hematopoietic (HSC) and mesenchymal (MSC) counterparts, the molecular mechanisms underlying lineage commitment in NSCs are just beginning to be understood. Furthermore, it is not well comprehended as to how the specification of one cell lineage can result in the suppression of parallel pathways in the NSCs. Thus, a thorough understanding of various signal transduction cascades activated via cytokines and growth factors, and the confounding effects of different CNS microenvironments are critically required to determine the full potential of NSCs. Our knowledge on the clonogenic ability, differentiation potential, and the inherent plasticity in both HSCs and MSCs may facilitate the understanding of lineage commitment in the NSCs as well. The information available from the marrow-derived stem cells may be extrapolated toward the similar signaling pathways in the neural precursors. From a number of previous studies, it is apparent that four distinctly different subsets of ligand-receptor superfamilies are involved in determining the fate of NSCs. These include 1) the transforming growth factor type-beta-1 (TGF-beta1) and bone morphogenetic protein (BMP) superfamily; 2) the platelet-derived and epidermal (PDGF/EGF) growth factors; 3) the interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor (IL-6/LIF/CNTF) superfamily; and 4) the EGF-like Notch/Delta group of extracellular ligands. Ligand binding to the cell surface receptor activates the receptor's cytosolic catalytic domain and/or the receptor-associated protein-kinases, which in turn activate intracellular second messengers and different sets of transcription factors. Transcription factor oligomerization, nuclear localization, followed by their recognition of DNA elements, leads to the expression of lineage-specific genes. Association between different groups of transcription factors can also regulate their ability to transcriptionally activate different genes. The limited availability of coactivators and cosuppressors, which can sequester the transcription factor complexes toward or away from a specific gene locus, further adds to the complexity in the cross talk between different signaling cascades. Both concerted actions of temporally regulated signals and convergent effects of different signaling cascades can thus ultimately precipitate the phenotypic changes. It is beginning to be realized that in addition to the cytokines and growth factors, cell-to-cell and cell-to-extracellular matrix (ECM) interactions, are also important within the molecular scenario linked to both proliferation and differentiation of the stem cells. The cell surface molecules, which include cell adhesion molecules (CAMs), integrins, selectins, and the immunoglobulins, are well known to regulate HSC and MSC commitment within different tissue microenvironments and may have direct implications in understanding the NSC cell fate determination within different regions of the brain.

Animals↗
PubMed1995

The unique characteristics of inflammatory responses in mouse brain are acquired during postnatal development.

The kinetics of leukocyte recruitment during acute inflammation in adult mouse brain differ from the stereotyped response occurring in non-CNS tissues; neutrophil recruitment is minimal and monocyte recruitment occurs after a 48 h delay. One aspect of the CNS microenvironment which may contribute to restricted leukocyte recruitment is the highly differentiated nature of resident CNS macrophages, the microglia. Thus we studied the inflammatory response to intracerebral injections of endotoxin in neonates in which microglia are less differentiated and resemble more closely macrophages of non-CNS tissues. Mice injected with endotoxin on the day of birth exhibited both neutrophil and monocyte recruitment to the parenchyma, but the response differed from that occurring in non-CNS tissues such as skin. Leukocyte recruitment was very slow, the mononuclear phagocyte response peaking 14 days after endotoxin injection. This sluggish inflammatory response was reminiscent of that previously described in fetal wounds. However, when endotoxin was injected into brains of 7-day-old neonates the inflammatory response resembled that seen in non-CNS tissues; i.e. prolific neutrophil recruitment and a brisk mononuclear phagocyte response. Thus the unusual inflammatory cell kinetics are a property of the mature CNS microenvironment; all signals necessary to support typical leukocyte recruitment are present in the brain by 7 days of age but the brain becomes able to restrict leukocyte immigration during subsequent postnatal development. Developmental changes in the host response to identical inflammatory challenges suggest a window during which the brain may be particularly vulnerable to inflammatory bystander damage.

Aging↗
PubMed1995

Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors.

Expression of the vitronectin gene was detected in advanced human astrocytoma by in situ hybridization, whereas vitronectin mRNA was undetectable in low grade tumors or in normal adult brain, indicating that vitronectin is a marker of malignant astrocytoma. We established a model of human astrocytoma by transplanting U-251MG human astrocytoma cells intracerebrally into acid mice (C.B.17 severe combined immunodeficient mice). In this model, tumors progressed rapidly and vitronectin mRNA was preferentially detected at the invading tumor margins, i.e. where tumor cells were adjacent to the normal brain tissue. Surprisingly, when U-251MG cells were injected subcutaneously into scid mice, vitronectin mRNA was undetectable throughout the tumor. Moreover, vitronectin mRNA or protein could not be detected among these cells in culture under a wide variety of growth conditions. These findings demonstrate that the cerebral microenvironment influences the expression of the vitronectin gene in malignant astrocytoma. Importantly, the vitronectin binding integrins alpha v beta 3 and alpha v beta 5 localized to distinct sites within these tumors, with beta 3 mRNA synthesized among invading cells, and alpha v and beta 5 mRNAs detected throughout the tumor. In vitro, both of these receptors were capable of promoting adhesion and invasion of astrocytoma cells on a vitronectin substratum. These findings implicate the expression of the vitronectin gene as a contributing factor to the biological behavior of astrocytomas within the cerebral microenvironment.

Animals↗
PubMed1978

Cellular microenvironment in relation to local blood flow.

The investigation was designed to identify microenvironmental factors that might be important in the regulation of local blood flow. Cellular microenvironment in terms of Po2, pH, [K+], [Cl-], [Ca2+] and lactate was measured in rat brain by means of specific microelectrodes. Vascular endothelium was stained in vivo with Thioflavine S. Local blood flow was measured with micro hydrogen electrodes. Some intracellular measurements of pH were made in conjunction with extracellular measurements. The main findings were that local autoregulation responses and blood flow changes in response to imposed hypoxic changes were very rapid (1-1.5 s). Microflow responses to changes in local cell activity were limited to a region not more than 250 micron in diameter. Increased blood flow in acute hypoxia occurred within 1-2 s of the fall in tissue Po2 and was much more rapid than changes in either pH or potassium. Intracellular pH changed within 10 s of the onset of severe hypoxia but in all cases the blood flow followed the Po2 much more closely than any other parameter. It is suggested that changes in capillary endothelium and local membrane transmission may play a part in autoregulatory mechanisms.

Animals↗
PubMed1999

A soluble factor produced by macrophages mediates the neurotoxic effects of HIV-1 Tat in vitro.

OBJECTIVES: There is now a strong consensus that the neurotoxic properties of HIV-1 are likely to be mediated by an indirect mechanism in which neurones are damaged by infected mononuclear cells. The aim of this study was to determine the ability of HIV-1 Tat to induce neurotoxic properties in a murine macrophage cell line RAW264.7. DESIGN: Simple culture systems using dissociated neurones may not provide the appropriate microenvironment in which to observe the complex cell-cell interactions that occur in the brain. We have therefore developed a more physiological model in which rat organotypic hippocampal slices are co-cultured with the murine macrophage cell line RAW264.7. Effects of Tat were studied by using a stable Tat expressing RAW264.7 cell line or by addition of recombinant Tat protein to co-cultures. METHODS: Organotypic hippocampal slices prepared from 8-10 day rat pups were grown on membrane inserts that were placed into six-well plates on which RAW264.7 cells were growing as an adherent monolayer. Cell death in the slices was assessed using propidium iodide. Specific astrocytic (glial fibrillary acidophilic protein; GFAP) and neuronal (microtubule-associated protein; MAP2) markers were visualized by immunocytochemistry. RESULTS: RAW264.7 cells that either expressed or were exposed to HIV-1 Tat protein, produced a soluble factor that caused profound degeneration in brain slice cultures involving loss of both glial cells and neurones. By contrast treatment of slice cultures with Tat in the absence of RAW264.7 cells was not neurotoxic. CONCLUSIONS: The neurotoxic properties previously attributed to HIV-1 Tat are likely to be mediated via induction of macrophage derived soluble factor(s).

Animals↗
PubMed2003

Intracranial extramedullary hematopoiesis associated with pilocytic astrocytoma: a case report.

Intracranial EMH is only occasionally found in primary brain tumors (mostly hemangioblastomas) and, to our knowledge, this is the first case of EMH associated with an astrocytoma. Intracranial extramedullary hematopoiesis (EMH) is described in a 29-year-old man with a recurrent pilocytic astrocytoma in the tectal region. Special stains confirmed the identities of erythroid, myeloid and megakaryocytic cells. The patient had no evidence of a predisposing bone marrow disorder or systemic EMH. Although the presence of multinucleated and blastic cells associated with a low-grade brain neoplasm is unusual, recognition of hematopoietic lineages allows EMH to be readily identified. Another tumor resection after a year of follow-up confirmed the absence of malignant progression in this recurrent astrocytoma. The small number of cases describing intracranial EMH in the absence of systemic hematologic abnormalities are correlated with the findings in this case. The low incidence of intracranial EMH indicates that cells with hematopoietic potential are seldom exposed to a supportive microenvironment within the central nervous system. However, intracranial EMH should be included as a potential, ancillary diagnosis when considering brain lesions. This may be particularly true if medical therapies involving growth factors or stem cells are found to promote hematopoiesis.

Adult↗
PubMed2003

The hypoxic response of tumors is dependent on their microenvironment.

To reveal the functional significance of hypoxia and angiogenesis in astrocytoma progression, we created genetically engineered transformed astrocytes from murine primary astrocytes and deleted the hypoxia-responsive transcription factor HIF-1alpha or its target gene, the angiogenic factor VEGF. Growth of HIF-1alpha- and VEGF-deficient transformed astrocytes in the vessel-poor subcutaneous environment results in severe necrosis, reduced growth, and vessel density, whereas when the same cells are placed in the vascular-rich brain parenchyma, the growth of HIF-1alpha knockout, but not VEGF knockout tumors, is reversed: tumors deficient in HIF-1alpha grow faster, and penetrate the brain more rapidly and extensively. These results demonstrate that HIF-1alpha has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor.

Animals↗
PubMed2004

Subependymal zone: immunohistochemically distinct compartment in the adult mammalian forebrain.

The subependymal zone (SEZ) lining lateral walls of the lateral cerebral ventricles represents the site of active neurogenesis in the brain of adult mammals. Peroxidase immunohistochemistry performed in paraffin-embedded sections reveals that structural organization of the SEZ differs from other regions in the brain. The SEZ is devoid of synapses that are abundant in the adjacent striatal neuropil. Therefore immunostaining of synaptophysin detects sharp borders of the SEZ. Using immunophenotypization, we identified cell types constituting the SEZ in the intact rat forebrain. The presence of neural progenitor/stem cells was confirmed by finding of nestin-immunopositive cells. Detection of the astroglial marker GFAP confirmed that astrocytes represented major supporting elements responsible for creating a unique microenvironment of the SEZ. One type of the astroglia participated in covering surfaces of the blood vessels and boundaries of the SEZ. The second astroglial cell type formed branched elongated tubes that enwrapped other SEZ cell types with their cytoplasmic extensions. The interior of astrocytic channels was occupied with small densely aggregated NCAM-immunoreactive neuroblasts. Bipolar morphology indicated that these cells probably underwent migration. Immunodetection of other neuronal markers like beta-III tubulin, MAP-2 and Pan neurofilaments identified positive cells in the neighbouring brain parenchyma but not in the SEZ. The rostral migratory stream (RMS) linked with the anterior SEZ had a similar structural arrangement. It contained a large amount of nestin+ and vimentin+ cells. The RMS consisted of GFAP+ astrocytic tubes ensheathing NCAM+ neuroblasts. On the contrary to the SEZ, the RMS neuroblasts expressed beta-III tubulin. However, markers of postmitotic neurons MAP-2, Pan neurofilaments and synaptophysin were not expressed in the RMS. Our study describes a complex histological structure of the rat SEZ, identifies its individual cell types and demonstrates a usefulness of immunohistochemical detection of cell-specific markers in a study of microenvironment forming neurogenic zones in the mammalian brain.

Animals↗
PubMed1994

Relationship between fatty acid accretion, membrane composition, and biologic functions.

Dietary fat affects metabolic pathways for phospholipid biosynthesis in tissues in a coordinated fashion. This may be important to aspects of development that concern phosphatidylcholine metabolism or regulatory processes that depend on signals from a changing milieu in the microenvironment of the membrane. Dietary fat influences the phosphatidylethanolamine (PE) composition in many membranes of the brain and retina and may by altered by small changes in the content of 20:4(6) and 22:6(3). Membrane PE fatty acids that contain one, four, or six double bonds and the ratio of 22:5(6) to 22:6(3) in PE that contains four to six double bonds are also affected. An increase in the omega 6 fatty acid content of membranes is associated with increased PE methyltransferase activity and decreased phosphocholine transferase activity, thus indicating a mechanism by which change in an exogenous factor (e.g., dietary fat intake) may alter neural phospholipid biosynthesis. Small changes in the composition of dietary fat intake change the composition of brain membranes during development. It is provocative to ponder whether diet could be used to induce formation of membrane structures that are more resistant to specific insults that cause degeneration of brain structural material, to ensure optimal functional compositions, or to reverse degenerative changes that occur in neural membrane structure and function.

Animals↗