Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

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Jessica L Williams

2014-05-01

Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

Endovascular transplantation of stem cells to the injured rat CNS

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Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan [Karolinska University Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Department of Neuroradiology, Stockholm (Sweden); Le Blanc, Katarina [Karolinska University Hospital, Department of Stem Cell Research, Karolinska Institutet, Department of Clinical Immunology, Stockholm (Sweden)

2009-10-15

Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p<0.01) and 5 days (p<0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases. (orig.)

Endovascular transplantation of stem cells to the injured rat CNS

International Nuclear Information System (INIS)

Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan; Le Blanc, Katarina

2009-01-01

Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p<0.01) and 5 days (p<0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases. (orig.)

X-linked inhibitor of apoptosis regulates T cell effector function

DEFF Research Database (Denmark)

Zehntner, Simone P; Bourbonnière, Lyne; Moore, Craig S

2007-01-01

To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice with exper......To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice...... dramatically reduced within the CNS. Flow cytometry showed an 88-93% reduction in T cells. The proportion of TUNEL(+) apoptotic CD4(+) T cells in the CNS was increased from Neurons...... and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function...

Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

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Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

2013-01-01

Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

microRNAs in CNS disorders

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Kocerha, Jannet; Kauppinen, Sakari; Wahlestedt, Claes

2009-01-01

RNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact...

Radioprotection of mouse CNS endothelial cells in vivo

International Nuclear Information System (INIS)

Lyubimova, N.; Coultas, P.; Martin, R.

1996-01-01

Full text: Radioprotection using the minor groove binding DNA ligand Hoechst 33342 has been demonstrated in vitro, and more recently in vivo, in mouse lung. Intravenous administration was used for the lung studies, and both endothelial and alveolar epithelial cells-showed good up-take. Radiation damage to the endothelial cell population has also been postulated as important in late developing radionecrosis of spinal cord and brain. Endothelial cell density in brain can be readily determined by a fluorescent-histochemical technique. Treatment with a monoamine oxidase inhibitor and subsequent injection with L-DOPA results in an accumulation of dopamine (DA) in CNS endothelial cells. DA is converted to a fluorophore by exposure to paraformaldehyde, and cell numbers assayed by fluorescence microscopy. Earlier studies used this technique to monitor post-irradiation changes in endothelial cell density in rodent brain and showed the loss, within 24 hours, of a sensitive subpopulation comprising about 15% of the endothelial cells. Ten minutes after intravenous injection of Hoechst 33342 (80mg/kg) the ligand is confined by its limited penetration to the endothelial cells in mouse brain. When we irradiated at this time, there was protection against early endothelial cell loss. Ablation of the sensitive subpopulation in unprotected mice takes place over a dose range of 1 to 3 Gy γ-rays, but doses between 12 to 20 Gy are required in the presence of ligand. This protection equates to a very high dose modification factor of about 7 and possibly reflects a suppression of apoptosis in the sensitive endothelial subpopulation. The extent to which there is enhanced survival in the endothelial population as a whole and how the observed protection affects late CNS necrosis development has yet to be determined. However present results clearly show potential for the use of DNA-binding radioprotectors with limited penetration for investigations into the relative significance of

Electrical Stimulation Elicit Neural Stem Cells Activation：New Perspectives in CNS Repair

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Ratrel eHuang

2015-10-01

Full Text Available Researchers are enthusiastically concerned about neural stem cell (NSC therapy in a wide array of diseases, including stroke, neurodegenerative disease, spinal cord injury (SCI and depression. Although enormous evidences have demonstrated that neurobehavioral improvement may benefit from NSC-supporting regeneration in animal models, approaches to endogenous and transplanted NSCs are blocked by hurdles of migration, proliferation, maturation and integration of NSCs. Electrical stimulation (ES may be a selective nondrug approach for mobilizing NSCs in the central nervous system (CNS. This technique is suitable for clinic application, because it is well established and its potential complications are manageable. Here, we provide a comprehensive review of the emerging positive role of different electrical cues in regulating NSC biology in vitro and in vivo, as well as biomaterial-based and chemical stimulation of NSCs. In the future, ES combined with stem cell therapy or other cues probably becomes an approach for promoting brain repair.

Inflammatory cytokines in the brain: does the CNS shape immune responses?

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Owens, T; Renno, T; Taupin, V; Krakowski, M

1994-12-01

Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far from being an immunologically privileged organ, T lymphocytes may be regular and frequent visitors to the CNS, for purposes of immune surveillance. Here, Trevor Owens and colleagues propose that the brain itself can regulate or shape immune responses therein. Furthermore, given that the immune cells may be subverted to autoimmunity, they suggest that the study of inflammatory autoimmune disease in the brain may shed light on the ability of the local environment to regulate immune responses.

Neutrophils that infiltrate the central nervous system regulate T cell responses

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Zehntner, Simone P; Brickman, Cristina; Bourbonnière, Lyne

2005-01-01

Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high ...

Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

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Kate Kosmac

2013-03-01

Full Text Available Infection of the developing fetus with human cytomegalovirus (HCMV is a major cause of central nervous system disease in infants and children; however, mechanism(s of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.

Gut-derived factors promote neurogenesis of CNS-neural stem cells and nudge their differentiation to an enteric-like neuronal phenotype.

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Kulkarni, Subhash; Zou, Bende; Hanson, Jesse; Micci, Maria-Adelaide; Tiwari, Gunjan; Becker, Laren; Kaiser, Martin; Xie, Xinmin Simon; Pasricha, Pankaj Jay

2011-10-01

Recent studies have explored the potential of central nervous system-derived neural stem cells (CNS-NSC) to repopulate the enteric nervous system. However, the exact phenotypic fate of gut-transplanted CNS-NSC has not been characterized. The aim of this study was to investigate the effect of the gut microenvironment on phenotypic fate of CNS-NSC in vitro. With the use of Transwell culture, differentiation of mouse embryonic CNS-NSC was studied when cocultured without direct contact with mouse intestinal longitudinal muscle-myenteric plexus preparations (LM-MP) compared with control noncocultured cells, in a differentiating medium. Differentiated cells were analyzed by immunocytochemistry and quantitative RT-PCR to assess the expression of specific markers and by whole cell patch-clamp studies for functional characterization of their phenotype. We found that LM-MP cocultured cells had a significant increase in the numbers of cells that were immune reactive against the panneuronal marker β-tubulin, neurotransmitters neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and neuropeptide vasoactive intestinal peptide (VIP) and showed an increase in expression of these genes, compared with control cells. Whole cell patch-clamp analysis showed that coculture with LM-MP decreases cell excitability and reduces voltage-gated Na(+) currents but significantly enhances A-current and late afterhyperpolarization (AHP) and increases the expression of the four AHP-generating Ca(2+)-dependent K(+) channel genes (KCNN), compared with control cells. In a separate experiment, differentiation of LM-MP cocultured CNS-NSC produced a significant increase in the numbers of cells that were immune reactive against the neurotransmitters nNOS, ChAT, and the neuropeptide VIP compared with CNS-NSC differentiated similarly in the presence of neonatal brain tissue. Our results show that the gut microenvironment induces CNS-NSC to produce neurons that share some of the

Immune cell entry to the CNS--a focus for immunoregulation of EAE

DEFF Research Database (Denmark)

Owens, T; Tran, E; Hassan-Zahraee, M

1999-01-01

-requirement then to prove such a role. The point that emerges is that cytokine production in the CNS parenchyma is itself dependent on the prior infiltration of immune cells, and that without immune cell entry, EAE does not occur. This identifies events at the BBB, and in particular in the perivascular space, as critical...

CNS Damage Classification in Newborn Infants by Neural Network Based Cry Analysis

NARCIS (Netherlands)

Poel, Mannes; Ekkel, T.

2002-01-01

The central nervous system (CNS) of the human body is the whole system of brain, spinal marrow and nerve cells throughout the body that correlates and regulates the internal reactions of the body and controls its adjustment to the environment. It controls muscles and processes sensory information

The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

Science.gov (United States)

Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

2016-09-01

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

Science.gov (United States)

Blachère, Nathalie E; Orange, Dana E; Santomasso, Bianca D; Doerner, Jessica; Foo, Patricia K; Herre, Margaret; Fak, John; Monette, Sébastien; Gantman, Emily C; Frank, Mayu O; Darnell, Robert B

2014-11-01

Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inflammation in the CNS and Th17 Responses Are Inhibited by IFN-{gamma}-Induced IL-18 Binding Protein

DEFF Research Database (Denmark)

Millward, Jason M; Pedersen, Morten Løbner; Wheeler, Rachel D

2010-01-01

Inflammatory responses are essential for immune protection but may also cause pathology and must be regulated. Both Th1 and Th17 cells are implicated in the pathogenesis of autoimmune inflammatory diseases, such as multiple sclerosis. We show in this study that IL-18-binding protein (IL-18bp......), the endogenous inhibitor of the Th1-promoting cytokine IL-18, is upregulated by IFN-gamma in resident microglial cells in the CNS during multiple sclerosis-like disease in mice. Test of function by overexpression of IL-18bp in the CNS using a viral vector led to marked reduction in Th17 responses and robust...... inhibition of incidence, severity, and histopathology of disease, independently of IFN-gamma. The disease-limiting action of IL-18bp included suppression of APC-derived Th17-polarizing cytokines. IL-18bp thus acts as a sensor for IFN-gamma and can regulate both Th1 and Th17 responses in the CNS....

Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

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Qian-Kun Yang

2013-01-01

Full Text Available NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

Suppressors of cytokine signaling 1 and 3 are up-regulated in brain resident cells in response to virus induced inflammation of the CNS via at least two distinctive pathways

DEFF Research Database (Denmark)

Steffensen, Maria Abildgaard; Fenger, Christina; Christensen, Jeanette Erbo

2014-01-01

underlie a virus induced up-regulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual up-regulation of SOCS1/3 mRNA expression peaking at day 7 post infection (p.i.). In the LCMV model, SOCS m...

Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease.

Science.gov (United States)

Lepoutre, Veronique; Jain, Pooja; Quann, Kevin; Wigdahl, Brian; Khan, Zafar K

2009-01-01

Human T cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiologic agent for a number of disorders; the two most common pathologies include adult T cell leukemia (ATL) and a progressive demyelinating neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The neurologic dysfunction associated with HAM/TSP is a result of viral intrusion into the central nervous system (CNS) and the generation of a hyperstimulated host response within the peripheral and central nervous system that includes expanded populations of CD4+ and CD8+ T cells and proinflammatory cytokines/chemokines in the cerebrospinal fluid (CSF). This robust, yet detrimental immune response likely contributes to the death of myelin producing oligodendrocytes and degeneration of neuronal axons. The mechanisms of neurological degeneration in HAM/TSP have yet to be fully delineated in vivo and may involve the immunogenic properties of the HTLV-1 transactivator protein Tax. This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP.

Analysis of perfusion weighted image of CNS lymphoma

International Nuclear Information System (INIS)

Lee, In Ho; Kim, Sung Tae; Kim, Hyung-Jin; Kim, Keon Ha; Jeon, Pyoung; Byun, Hong Sik

2010-01-01

Purpose: It is difficult to differentiate CNS lymphoma from other tumors such as malignant gliomas, metastases, or meningiomas with conventional MR imaging, because the imaging findings are overlapped between these tumors. The purpose of this study is to investigate the perfusion weighted MR imaging findings of CNS lymphomas and to compare the relative cerebral blood volume ratios between CNS lymphomas and other tumors such as high grade gliomas, metastases, or meningiomas. Materials and methods: We retrospectively reviewed MRI findings and clinical records in 13 patients with pathologically proven CNS lymphoma between January 2006 and November 2008. We evaluated the relative cerebral blood volume ratios of tumor, which were obtained by dividing the values obtained from the normal white matter on MRI. Results: Total 13 patients (M:F = 8:5; age range 46-67 years, mean age 52.3 years) were included. The CNS lymphomas showed relatively low values of maximum relative CBV ratio in most patients regardless of primary or secondary CNS lymphoma. Conclusion: Perfusion weighted image may be helpful in the diagnosis of CNS lymphoma in spite of primary or secondary or B cell or T cell.

EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

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Florian Wanke

2017-01-01

Full Text Available Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE, the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23 and interleukin-1 beta (IL-1β, maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

The Effect of the Uncariae Ramulus et Uncus on the Regeneration Following CNS Injury

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Lee Jin-Goo

2009-03-01

Full Text Available Objective : Following central nervous system(CNS injury, inhibitory influences at the site of axonal damage occur. Glial cells become reactive and form a glial scar, gliosis. Also myelin debris such as MAG inhibits axonal regeneration. Astrocyte-rich gliosis relates with up-regulation of GFAP and CD81, and eventually becomes physical and mechanical barrier to axonal regeneration. MAG is one of several endogenous axon regeneration inhibitors that limit recovery from CNS injury and disease. It was reported that molecules that block such inhibitors enhanced axon regeneration and functional recovery. Recently it was reported that treatment with anti-CD81 antibodies enhanced functional recovery in the rat with spinal cord injury. So in this current study, the author investigated the effect of the water extract of Uncariae Ramulus et Uncus on the regulation of CD81, GFAP and MAG that increase when gliosis occurs. Methods : MTT assay was performed to examine cell viability, and cell-based ELISA, western blot and PCR were used to detect the expression of CD81, GFAP and MAG. Then also immunohistochemistry was performed to confirm in vivo. Results : Water extract of Uncariae Ramulus et Uncus showed relatively high cell viability at the concentration of 0.05%, 0.1% and 0.5%. The expression of CD81, GFAP and MAG in astrocytes was decreased after the administration of Uncariae Ramulus et Uncus water extract. These results was confirmed in the brain sections following cortical stab injury by immunohistochemistry. Conclusion : The authors observed that Uncariae Ramulus et Uncus significantly down-regulates the expression of CD81, GFAP and MAG. These results suggest that Uncariae Ramulus et Uncus can be a candidate to regenerate CNS injury.

The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury

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Forbes, Lindsey H.

2018-01-01

The extracellular environment of the central nervous system (CNS) becomes highly structured and organized as the nervous system matures. The extracellular space of the CNS along with its subdomains plays a crucial role in the function and stability of the CNS. In this review, we have focused on two components of the neuronal extracellular environment, which are important in regulating CNS plasticity including the extracellular matrix (ECM) and myelin. The ECM consists of chondroitin sulfate proteoglycans (CSPGs) and tenascins, which are organized into unique structures called perineuronal nets (PNNs). PNNs associate with the neuronal cell body and proximal dendrites of predominantly parvalbumin-positive interneurons, forming a robust lattice-like structure. These developmentally regulated structures are maintained in the adult CNS and enhance synaptic stability. After injury, however, CSPGs and tenascins contribute to the structure of the inhibitory glial scar, which actively prevents axonal regeneration. Myelin sheaths and mature adult oligodendrocytes, despite their important role in signal conduction in mature CNS axons, contribute to the inhibitory environment existing after injury. As such, unlike the peripheral nervous system, the CNS is unable to revert to a “developmental state” to aid neuronal repair. Modulation of these external factors, however, has been shown to promote growth, regeneration, and functional plasticity after injury. This review will highlight some of the factors that contribute to or prevent plasticity, sprouting, and axonal regeneration after spinal cord injury. PMID:29849554

Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARγ/RORγt Pathway.

Science.gov (United States)

Zhang, Kai; Guo, Yawei; Ge, Zhenzhen; Zhang, Zhihui; Da, Yurong; Li, Wen; Zhang, Zimu; Xue, Zhenyi; Li, Yan; Ren, Yinghui; Jia, Long; Chan, Koon-Ho; Yang, Fengrui; Yan, Jun; Yao, Zhi; Xu, Aimin; Zhang, Rongxin

2017-09-01

T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

Histological characterization and quantification of cellular events following neural and fibroblast(-like) stem cell grafting in healty and demyelinated CNS tissue

OpenAIRE

Praet, J.; SANTERMANS, Eva; Reekmans, K.; de Vocht, N.; Le Blon, D.; Hoornaert, C.; Daans, J.; Goossens, H.; Berneman, Z.; HENS, Niel; Van der Linden, A.; Ponsaerts, P.

2014-01-01

Preclinical animal studies involving intracerebral (stem) cell grafting are gaining popularity in many laboratories due to the reported beneficial effects of cell grafting on various diseases or traumata of the central nervous system (CNS). In this chapter, we describe a histological workflow to characterize and quantify cellular events following neural and fibroblast(-like) stem cell grafting in healthy and demyelinated CNS tissue. First, we provide standardized protocols to isolate and cult...

Management and Outcome of Patients With Langerhans Cell Histiocytosis and Single-Bone CNS-Risk Lesions: A Multi-Institutional Retrospective Study

NARCIS (Netherlands)

Chellapandian, Deepak; Shaikh, Furqan; van den Bos, Cor; Somers, Gino R.; Astigarraga, Itziar; Jubran, Rima; Degar, Barbara; Carret, Anne-Sophie; Mandel, Karen; Belletrutti, Mark; Dix, David; Visser, Johannes; Abuhadra, Nour; Chang, Tiffany; Rollins, Barret; Whitlock, James; Weitzman, Sheila; Abla, Oussama

2015-01-01

Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or

Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

Science.gov (United States)

Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

2016-10-01

Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection. Published by Elsevier B.V.

Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

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Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A

2016-09-01

Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

Transplantation of autologous bone marrow stromal cells (BMSC for CNS disorders – Strategy and tactics for clinical application

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Satoshi Kuroda

2010-01-01

Full Text Available Background – There is increasing evidence that the transplanted bone marrow stromal cells (BMSC significantly promote functional recovery after central nervous system (CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, brain contusion and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with neurological disorders. In this paper, therefore, we discuss what we should clarify to establish cell transplantation therapy in clinical situation and describe our recent works for this purpose.Methods and Results – The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. Using optical imaging and MRI techniques, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. Functional imaging such as PET scan may have the potential to assess the beneficial effects of BMSC transplantation. The BMSC can be expanded using the animal protein-free culture medium, which would maintain their potential of proliferation, migration, and neural differentiation.Conclusion – It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future

Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation

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Ribeiro-da-Silva Alfredo

2010-11-01

Full Text Available Abstract Oro-facial pain following injury and infection is frequently observed in dental clinics. While neuropathic pain evoked by injury associated with nerve lesion has an involvement of glia/immune cells, inflammatory hyperalgesia has an exaggerated sensitization mediated by local and circulating immune mediators. To better understand the contribution of central nervous system (CNS glial cells in these different pathological conditions, in this study we sought to characterize functional phenotypes of glial cells in response to trigeminal nerve injury (loose ligation of the mental branch, infection (subcutaneous injection of lipopolysaccharide-LPS and to sterile inflammation (subcutaneous injection of complete Freund's adjuvant-CFA on the lower lip. Each of the three insults triggered a specific pattern of mechanical allodynia. In parallel with changes in sensory response, CNS glial cells reacted distinctively to the challenges. Following ligation of the mental nerve, both microglia and astrocytes in the trigeminal nuclear complex were highly activated, more prominent in the principal sensory nucleus (Pr5 and subnucleus caudalis (Sp5C area. Microglial response was initiated early (days 3-14, followed by delayed astrocytes activation (days 7-28. Although the temporal profile of microglial and astrocyte reaction corresponded respectively to the initiation and chronic stage of neuropathic pain, these activated glial cells exhibited a low profile of cytokine expression. Local injection of LPS in the lower lip skin also triggered a microglial reaction in the brain, which started in the circumventricular organs (CVOs at 5 hours post-injection and diffused progressively into the brain parenchyma at 48 hours. This LPS-induced microglial reaction was accompanied by a robust induction of IκB-α mRNA and pro-inflammatory cytokines within the CVOs. However, LPS induced microglial activation did not specifically occur along the pain signaling pathway. In

Ascl1 (Mash1) lineage cells contribute to discrete cell populations in CNS architecture.

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Kim, Euiseok J; Battiste, James; Nakagawa, Yasushi; Johnson, Jane E

2008-08-01

Ascl1 (previously Mash1) is a bHLH transcription factor essential for neuronal differentiation and specification in the nervous system. Although it has been studied for its role in several neural lineages, the full complement of lineages arising from Ascl1 progenitor cells remains unknown. Using an inducible Cre-flox genetic fate-mapping strategy, Ascl1 lineages were determined throughout the brain. Ascl1 is present in proliferating progenitor cells but these cells are actively differentiating as evidenced by rapid migration out of germinal zones. Ascl1 lineage cells contribute to distinct cell types in each major brain division: the forebrain including the cerebral cortex, olfactory bulb, hippocampus, striatum, hypothalamus, and thalamic nuclei, the midbrain including superior and inferior colliculi, and the hindbrain including Purkinje and deep cerebellar nuclei cells and cells in the trigeminal sensory system. Ascl1 progenitor cells at early stages in each CNS region preferentially become neurons, and at late stages they become oligodendrocytes. In conclusion, Ascl1-expressing progenitor cells in the brain give rise to multiple, but not all, neuronal subtypes and oligodendrocytes depending on the temporal and spatial context, consistent with a broad role in neural differentiation with some subtype specification.

CNS β3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight.

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Richard, Jennifer E; López-Ferreras, Lorena; Chanclón, Belén; Eerola, Kim; Micallef, Peter; Skibicka, Karolina P; Wernstedt Asterholm, Ingrid

2017-09-01

Pharmacological β 3 -adrenergic receptor (β 3 AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of β 3 AR agonists is mediated solely through activation of β 3 ARs in adipose tissue. However, β 3 ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus, contrary to the current adipocentric view, the central nervous system (CNS) may also have the ability to regulate energy balance and metabolism through actions on central β 3 ARs. Therefore, this study aimed to elucidate whether CNS β 3 ARs can regulate browning of WAT and other aspects of metabolic regulation, such as food intake control and insulin release. We found that acute central injection of β 3 AR agonist potently reduced food intake, body weight, and increased hypothalamic neuronal activity in rats. Acute central β 3 AR stimulation was also accompanied by a transient increase in circulating insulin levels. Moreover, subchronic central β 3 AR agonist treatment led to a browning response in both inguinal (IWAT) and gonadal WAT (GWAT), along with reduced GWAT and increased BAT mass. In high-fat, high-sugar-fed rats, subchronic central β 3 AR stimulation reduced body weight, chow, lard, and sucrose water intake, in addition to increasing browning of IWAT and GWAT. Collectively, our results identify the brain as a new site of action for the anorexic and browning impact of β 3 AR activation. Copyright © 2017 the American Physiological Society.

An in vitro clonogenic assay to assess radiation damage in rat CNS glial progenitor cells

International Nuclear Information System (INIS)

Maazen, R.W.M. van der; Verhagen, I.; Kogel, A.J. van der

1990-01-01

Normal glial progenitor cells can be isolated from the rat central nervous system (CNS) and cultured in vitro on a monolayer of type-1 astrocytes. These monolayers are able to support and stimulate explanted glial progenitor cells to proliferate. Employing these in vitro interactions of specific glial cell types, an in vivo-in vitro clonogenic assay has been developed. This method offers the possibility to study the intrinsic radiosensitivity, repair and regeneration of glial progenitor cells after in vitro or in vivo irradiation. (author)

PEG minocycline-liposomes ameliorate CNS autoimmune disease.

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Wei Hu

Full Text Available Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS. Minocycline, a potent inhibitor of matrix metalloproteinase (MMP-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG minocycline liposomes are effective in treating EAE.Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs, we determined that PEG minocycline-liposome preparations stabilized with CaCl(2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number.Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

Cell fate control in the developing central nervous system

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Guérout, Nicolas; Li, Xiaofei; Barnabé-Heider, Fanie, E-mail: Fanie.Barnabe-Heider@ki.se

2014-02-01

The principal neural cell types forming the mature central nervous system (CNS) are now understood to be diverse. This cellular subtype diversity originates to a large extent from the specification of the earlier proliferating progenitor populations during development. Here, we review the processes governing the differentiation of a common neuroepithelial cell progenitor pool into mature neurons, astrocytes, oligodendrocytes, ependymal cells and adult stem cells. We focus on studies performed in mice and involving two distinct CNS structures: the spinal cord and the cerebral cortex. Understanding the origin, specification and developmental regulators of neural cells will ultimately impact comprehension and treatments of neurological disorders and diseases. - Highlights: • Similar mechanisms regulate cell fate in different CNS cell types and structures. • Cell fate regulators operate in a spatial–temporal manner. • Different neural cell types rely on the generation of a diversity of progenitor cells. • Cell fate decision is dictated by the integration of intrinsic and extrinsic signals.

Cell fate control in the developing central nervous system

International Nuclear Information System (INIS)

Guérout, Nicolas; Li, Xiaofei; Barnabé-Heider, Fanie

2014-01-01

The principal neural cell types forming the mature central nervous system (CNS) are now understood to be diverse. This cellular subtype diversity originates to a large extent from the specification of the earlier proliferating progenitor populations during development. Here, we review the processes governing the differentiation of a common neuroepithelial cell progenitor pool into mature neurons, astrocytes, oligodendrocytes, ependymal cells and adult stem cells. We focus on studies performed in mice and involving two distinct CNS structures: the spinal cord and the cerebral cortex. Understanding the origin, specification and developmental regulators of neural cells will ultimately impact comprehension and treatments of neurological disorders and diseases. - Highlights: • Similar mechanisms regulate cell fate in different CNS cell types and structures. • Cell fate regulators operate in a spatial–temporal manner. • Different neural cell types rely on the generation of a diversity of progenitor cells. • Cell fate decision is dictated by the integration of intrinsic and extrinsic signals

Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

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Elkington Paul T

2011-05-01

Full Text Available Abstract Tuberculosis (TB of the central nervous system (CNS is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2 which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb, but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis.

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Maricic, Igor; Halder, Ramesh; Bischof, Felix; Kumar, Vipin

2014-08-01

CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139-151/I-A(s)-tetramer(+) cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases. Copyright © 2014 by The American Association of Immunologists, Inc.

CD8+ T cells in inflammatory demyelinating disease

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Weiss, Hanne A; Millward, Jason M; Owens, Trevor

2007-01-01

We review the contribution made by CD8+ T cells to inflammation in the central nervous system (CNS) in Multiple Sclerosis (MS), and discuss their role in the animal model Experimental Autoimmune Encephalomyelitis (EAE). We show that the inflammatory cytokines interferon-gamma and interleukin-17...... are differentially regulated in CNS-infiltrating CD4+ and CD8+ T cells in EAE, and that CD8+ T cells regulate disease. In MS, CD8+ T cells appear to play a role in promotion of disease, so cytokine regulation is likely different in CD8+ T cells in MS and EAE...

Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3

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Christensen, Jeanette Erbo; Nansen, Anneline; Moos, Torben

2004-01-01

T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis......-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3...

Insulin/IGF-regulated size scaling of neuroendocrine cells expressing the bHLH transcription factor Dimmed in Drosophila.

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Jiangnan Luo

Full Text Available Neurons and other cells display a large variation in size in an organism. Thus, a fundamental question is how growth of individual cells and their organelles is regulated. Is size scaling of individual neurons regulated post-mitotically, independent of growth of the entire CNS? Although the role of insulin/IGF-signaling (IIS in growth of tissues and whole organisms is well established, it is not known whether it regulates the size of individual neurons. We therefore studied the role of IIS in the size scaling of neurons in the Drosophila CNS. By targeted genetic manipulations of insulin receptor (dInR expression in a variety of neuron types we demonstrate that the cell size is affected only in neuroendocrine cells specified by the bHLH transcription factor DIMMED (DIMM. Several populations of DIMM-positive neurons tested displayed enlarged cell bodies after overexpression of the dInR, as well as PI3 kinase and Akt1 (protein kinase B, whereas DIMM-negative neurons did not respond to dInR manipulations. Knockdown of these components produce the opposite phenotype. Increased growth can also be induced by targeted overexpression of nutrient-dependent TOR (target of rapamycin signaling components, such as Rheb (small GTPase, TOR and S6K (S6 kinase. After Dimm-knockdown in neuroendocrine cells manipulations of dInR expression have significantly less effects on cell size. We also show that dInR expression in neuroendocrine cells can be altered by up or down-regulation of Dimm. This novel dInR-regulated size scaling is seen during postembryonic development, continues in the aging adult and is diet dependent. The increase in cell size includes cell body, axon terminations, nucleus and Golgi apparatus. We suggest that the dInR-mediated scaling of neuroendocrine cells is part of a plasticity that adapts the secretory capacity to changing physiological conditions and nutrient-dependent organismal growth.

Bovine-associated CNS species resist phagocytosis differently

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2013-01-01

Background Coagulase-negative staphylococci (CNS) cause usually subclinical or mild clinical bovine mastitis, which often remains persistent. Symptoms are usually mild, mostly only comprising slight changes in the appearance of milk and possibly slight swelling. However, clinical mastitis with severe signs has also been reported. The reasons for the differences in clinical expression are largely unknown. Macrophages play an important role in the innate immunity of the udder. This study examined phagocytosis and killing by mouse macrophage cells of three CNS species: Staphylococcus chromogenes (15 isolates), Staphylococcus agnetis (6 isolates) and Staphylococcus simulans (15 isolates). Staphylococcus aureus (7 isolates) was also included as a control. Results All the studied CNS species were phagocytosed by macrophages, but S. simulans resisted phagocytosis more effectively than the other CNS species. Only S. chromogenes was substantially killed by macrophages. Significant variations between isolates were seen in both phagocytosis and killing by macrophages and were more common in the killing assays. Significant differences between single CNS species and S. aureus were observed in both assays. Conclusion This study demonstrated that differences in the phagocytosis and killing of mastitis-causing staphylococci by macrophages exist at both the species and isolate level. PMID:24207012

TAM receptors regulate multiple features of microglial physiology.

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Fourgeaud, Lawrence; Través, Paqui G; Tufail, Yusuf; Leal-Bailey, Humberto; Lew, Erin D; Burrola, Patrick G; Callaway, Perri; Zagórska, Anna; Rothlin, Carla V; Nimmerjahn, Axel; Lemke, Greg

2016-04-14

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

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Clara Penas

2015-04-01

Full Text Available Although casein kinase 1δ (CK1δ is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1 ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

Thermal hydraulic considerations and mock-up tests for developing two-phase thermo-siphon loop of CARR-CNS

International Nuclear Information System (INIS)

Shejiao, Du; Qincheng, Bi; Tingkuan, Chen; Quanke, Feng

2005-01-01

The main component of the China Advanced Research Reactor Cold Neutron Source (CARR-CNS), which is under design, is a two-phase thermo-siphon loop of hydrogen. It consists of a condenser, a single tube with counter current flow avoiding flooding and a cylindrical-annulus moderator cell. The mockup tests were carried out using a full-scale loop with Freon-113, to validate the self-regulating characteristics of the loop, void fraction less than 20% in the liquid of the moderator cell and the requirements for establishing the condition under which the inner shell of the moderator cell has only vapor and the outer shell liquid. In the case of these mockup tests the density ratio of liquid to vapor and the volumetric vapor evaporation rate due to heat load are kept the same as those in normal operation of the CARR-CNS. The results show that the loop has the self-regulating characteristics and the inner shell of the moderator cell contains only vapor, the outer shell liquid. The average void fraction of the moderator cell was verified less than 20% under the volumetric vapor generation of 0.65 l/s corresponding to the nuclear heating of 800 W in the case of the liquid hydrogen. The local void fraction in the liquid hydrogen increases with the increase of the loop pressure under the condition of a constant volumetric evaporation

Supratentorial CNS malformations

International Nuclear Information System (INIS)

Zlatareva, D.

2012-01-01

Full text: Clinical suspicion of a developmental anomaly of the central nervous system (CNS) is a frequent indication for performing and magnetic resonance imaging (MRI) examination of the brain. Classification systems for malformation of the CNS are constantly revised according to newer scientific research. Developmental abnormalities can be classified in two main types. The first category consists of disorders of organogenesis in which genetic defects or any ischemic, metabolic, toxic or infectious insult to the developing brain can cause malformation. These malformations result from abnormal neuronal and glial proliferation and from anomalies of neuronal migration and or cortical organization. They are divided into supra- and infratentorial and may involve grey or white matter or both. The second category of congenital brain abnormalities is disorders of histogenesis which result from abnormal cell differentiation with a relatively normal brain appearance. Supratentorial CNS malformations could be divided into anomalies in telencephalic commissure, holoprosencephalies and malformations in cortical development. There are three main telencephalic commissures: the anterior commissure, the hippocampal commissure and the corpus callosum. Their morphology (hypoplasia, hyperplasia, agenesis, dysgenesis, even atrophy) reflects the development of the brain. Their agenesis, complete or partial, is one of the most commonly observed features in the malformations of the brain and is a part of many syndromes. Malformations of cortical development (MCD) are heterogeneous group of disease which result from disruption of 3 main stages of cortical development. The common clinical presentation is refractory epilepsy and or developmental delay. The most common MCD are heterotopias, focal cortical dysplasia, polymicrogyria, schizencephaly, pachygyria and lizencephaly. The exact knowledge of the brain anatomy and embryology is mandatory to provide a better apprehension of the

Observations at the CNS-PNS border of ventral roots connected to a neuroma

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Sten Remahl

2010-10-01

Full Text Available Previous studies have shown that numerous sprouts originating from a neuroma, after nerve injury in neonatal animals, can invade spinal nerve roots. In this study the border between the central and peripheral nervous system (CNS-PNS border of ventral roots in kittens was examined with both light and electron microscopy after early postnatal sciatic nerve resection. A transient ingrowth of substance P positive axons was observed into the CNS, but no spouts remained 6 weeks after the injury. Using serial sections and electron microscopy it was possible to identify small bundles of unmyelinated axons that penetrated from the root fascicles for a short distance into the CNS. These axons ended blindly, sometimes with a growth cone-like terminal swelling filled with vesicles. The axon bundles were accompanied by p75 positive cells in both the root fascicles and the pia mater, but not in the CNS. It may thus be suggested that neurotrophin presenting p75 positive cells could facilitate axonal growth into the pia mater and that the lack of such cells in the CNS compartment might contribute to the failure of growth into the CNS. A maldevelopment of myelin sheaths at the CNS-PNS border of motor axons was observed and it seems possible that this could have consequences for the propagation of action potential across this region after neonatal nerve injury.

Melanocortin signaling in the CNS directly regulates circulating cholesterol

OpenAIRE

Perez-Tilve, Diego; Hofmann, Susanna M; Basford, Joshua; Nogueiras, Ruben; Pfluger, Paul T; Patterson, James T; Grant, Erin; Wilson-Perez, Hilary E; Granholm, Norman A; Arnold, Myrtha; Trevaskis, James L; Butler, Andrew A; Davidson, William S; Woods, Stephen C; Benoit, Stephen C

2010-01-01

Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an impo...

The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma

DEFF Research Database (Denmark)

El-Galaly, Tarec Christoffer; Villa, Diego; Michaelsen, Thomas Yssing

2017-01-01

Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknow...

Single Cell Electroporation Method for Mammalian CNS Neurons in Organotypic Slice Cultures

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Uesaka, Naofumi; Hayano, Yasufumi; Yamada, Akito; Yamamoto, Nobuhiko

Axon tracing is an essential technique to study the projection pattern of neurons in the CNS. Horse radish peroxidase and lectins have contributed to revealing many neural connection patterns in the CNS (Itaya and van Hoesen, 1982; Fabian and Coulter, 1985; Yoshihara, 2002). Moreover, a tracing method with fluorescent dye has enabled the observation of growing axons in living conditions, and demon strated a lot of developmental aspects in axon growth and guidance (Harris et al., 1987; O'Rourke and Fraser, 1990; Kaethner and Stuermer, 1992; Halloran and Kalil, 1994; Yamamoto et al., 1997). More recently, genetically encoded fluores cent proteins can be used as a powerful tool to observe various biological events. Several gene transfer techniques such as microinjection, biolistic gene gun, viral infection, lipofection and transgenic technology have been developed (Feng et al., 2000; Ehrengruber et al., 2001; O'Brien et al., 2001; Ma et al., 2002; Sahly et al., 2003). In particular, the electroporation technique was proved as a valuable tool, since it can be applied to a wide range of tissues and cell types with little toxicity and can be performed with relative technical easiness. Most methods, including a stand ard electroporation technique, are suitable for gene transfer to a large number of cells. However, this is not ideal for axonal tracing, because observation of individ ual axons is occasionally required. To overcome this problem, we have developed an electroporation method using glass micropipettes containing plasmid solutions and small current injection. Here we introduce the method in detail and exemplified results with some example applications and discuss its usefulness.

CNS role evolution.

Science.gov (United States)

Payne, J L; Baumgartner, R G

1996-01-01

THE CNS ROLE has been actualized in a variety of ways. Flexibility-inherent in the role-and the revolution in health care consciousness tend to place the CNS at risk for criticism regarding value to the organization. At Vanderbilt University Medical Center, a CNS task force evaluated the current reality of CNS practice and recommended role changes to include the financial analysis of patient care. After incorporating a financial perspective into our present practice, we have embarked on an interesting journey of post-Master's degree study, that of the tertiary care nurse practitioner. This practice option could elevated the clinical and financial aspects of providing cost-effective health care to a more autonomous role form; however, the transition has been challenging. Since 1990, the American Nurses Association has recommended that nursing school curricula change to meet the needs of the health care environment and provide increased career flexibility through creating one advanced degree incorporating both CNS and NP functions. Swiftly moving past differences and toward similarities will bridge the gap for advanced practice nurses in the future.

When the Tail Can't Wag the Dog: The Implications of CNS-Intrinsic Initiation of Neuroinflammation

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Deirdre S Davis

2009-04-01

Full Text Available The CNS (central nervous system is unquestionably the central organ that regulates directly or indirectly all physiological systems in the mammalian body. Yet, when considering the defence of the CNS from pathogens, the CNS has often been considered passive and subservient to the pro-inflammatory responses of the immune system. In this view, neuroinflammatory disorders are examples of when the tail (the immune system wags the dog (the CNS to the detriment of an individual's function and survival.

The retina as a window to the brain-from eye research to CNS disorders.

Science.gov (United States)

London, Anat; Benhar, Inbal; Schwartz, Michal

2013-01-01

Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

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Sayed, Blayne A; Christy, Alison L; Walker, Margaret E; Brown, Melissa A

2010-06-15

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases.

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Sugai, Keiko; Fukuzawa, Ryuji; Shofuda, Tomoko; Fukusumi, Hayato; Kawabata, Soya; Nishiyama, Yuichiro; Higuchi, Yuichiro; Kawai, Kenji; Isoda, Miho; Kanematsu, Daisuke; Hashimoto-Tamaoki, Tomoko; Kohyama, Jun; Iwanami, Akio; Suemizu, Hiroshi; Ikeda, Eiji; Matsumoto, Morio; Kanemura, Yonehiro; Nakamura, Masaya; Okano, Hideyuki

2016-09-19

The risk of tumorigenicity is a hurdle for regenerative medicine using induced pluripotent stem cells (iPSCs). Although teratoma formation is readily distinguishable, the malignant transformation of iPSC derivatives has not been clearly defined due to insufficient analysis of histology and phenotype. In the present study, we evaluated the histology of neural stem/progenitor cells (NSPCs) generated from integration-free human peripheral blood mononuclear cell (PBMC)-derived iPSCs (iPSC-NSPCs) following transplantation into central nervous system (CNS) of immunodeficient mice. We found that transplanted iPSC-NSPCs produced differentiation patterns resembling those in embryonic CNS development, and that the microenvironment of the final site of migration affected their maturational stage. Genomic instability of iPSCs correlated with increased proliferation of transplants, although no carcinogenesis was evident. The histological classifications presented here may provide cues for addressing potential safety issues confronting regenerative medicine involving iPSCs.

Glibenclamide for the Treatment of Acute CNS Injury

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J. Marc Simard

2013-10-01

Full Text Available First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

Mast cell inflammasome activity in the meninges regulates EAE disease severity.

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Russi, Abigail E; Walker-Caulfield, Margaret E; Brown, Melissa A

2018-04-01

Inflammasomes are multiprotein complexes that assemble in response to microbial and other danger signals and regulate the secretion of biologically active IL-1β and IL-18. Although they are important in protective immunity against bacterial, viral and parasitic infections, aberrant inflammasome activity promotes chronic inflammation associated with autoimmune disease. Inflammasomes have been described in many immune cells, but the majority of studies have focused on their activity in macrophages. Here we discuss an important role for mast cell-inflammasome activity in EAE, the rodent model of multiple sclerosis, a CNS demyelinating disease. We review our evidence that mast cells in the meninges, tissues that surround the brain and spinal cord, interact with infiltrating myelin-specific T cells in early disease. This interaction elicits IL-1β expression by mast cells, which in turn, promotes GM-CSF expression by T cells. In view of the essential role that GM-CSF plays in T cell encephalitogenicity, we propose this mast cell-T cell crosstalk in the meninges is critical for EAE disease development. Copyright © 2016 Elsevier Inc. All rights reserved.

An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

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El-Galaly, Tarec Christoffer; Cheah, Chan Yoon; Bendtsen, Mette Dahl

2016-01-01

) determine prognostic factors after SCNS.Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye......Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically lt;6 months. However, data in patients...

Classically and alternatively activated bone marrow derived macrophages differ in cytoskeletal functions and migration towards specific CNS cell types

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Dijkstra Christine D

2011-05-01

Full Text Available Abstract Background Macrophages play an important role in neuroinflammatory diseases such as multiple sclerosis (MS and spinal cord injury (SCI, being involved in both damage and repair. The divergent effects of macrophages might be explained by their different activation status: classically activated (CA/M1, pro-inflammatory, macrophages and alternatively activated (AA/M2, growth promoting, macrophages. Little is known about the effect of macrophages with these phenotypes in the central nervous system (CNS and how they influence pathogenesis. The aim of this study was therefore to determine the characteristics of these phenotypically different macrophages in the context of the CNS in an in vitro setting. Results Here we show that bone marrow derived CA and AA macrophages have a distinct migratory capacity towards medium conditioned by various cell types of the CNS. AA macrophages were preferentially attracted by the low weight ( Conclusion In conclusion, since AA macrophages are more motile and are attracted by NCM, they are prone to migrate towards neurons in the CNS. CA macrophages have a lower motility and a stronger adhesion to ECM. In neuroinflammatory diseases the restricted migration and motility of CA macrophages might limit lesion size due to bystander damage.

Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.

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Higgins, Gerald A; Allyn-Feuer, Ari; Georgoff, Patrick; Nikolian, Vahagn; Alam, Hasan B; Athey, Brian D

2017-07-01

The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS. Copyright © 2017. Published by Elsevier Inc.

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

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Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M.; Daley, George Q.; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D.

2012-01-01

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

Isolated vasculitis of the CNS

International Nuclear Information System (INIS)

Block, F.; Reith, W.

2000-01-01

Vasculitis is a rare cause for disease of the CNS. The isolated vasculitis of the CNS is restricted to the CNS whereas other forms of vasculitis affect various organs including the CNS. Headache, encephalopathy, focal deficits and epileptic seizures are the major symptoms suggestive for vasculitis. One major criterion of the isolated vasculitis of the CNS is the lack of evidence for other vasculitis forms or for pathology of other organs. Angiography displays multifocal segmental stenosis of intracranial vessels. MRI demonstrates multiple lesions which in part show enhancement after gadolinium. A definite diagnosis can only be made on the grounds of biopsy from leptomeninges and parenchyma. Therapy consists of corticosteroids and cyclophosphamid. (orig.) [de

Therapeutic potential of agmatine for CNS disorders.

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Neis, Vivian B; Rosa, Priscila B; Olescowicz, Gislaine; Rodrigues, Ana Lúcia S

2017-09-01

Agmatine is a neuromodulator that regulates multiple neurotransmitters and signaling pathways. Several studies have focused on elucidating the mechanisms underlying the neuroprotective effects of this molecule, which seems to be mediated by a reduction in oxidative damage, neuroinflammation, and proapoptotic signaling. Since these events are implicated in acute and chronic excitotoxicity-related disorders (ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative, and psychiatric disorders) as well as in nociception, agmatine has been proposed as a therapeutic strategy for the treatment of central nervous system (CNS) disorders. Agmatine also stimulates the expression of trophic factors and adult neurogenesis, contributing to its ability to induce endogenous repair mechanisms. Therefore, considering its wide range of biological effects, this review summarizes the current knowledge about its protective and regenerative properties in the CNS. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epigenetic regulation of axon and dendrite growth

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Ephraim F Trakhtenberg

2012-03-01

Full Text Available Neuroregenerative therapies for central nervous system (CNS injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and reinnervate their targets. However, mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases (Yiu and He, 2006. CNS’ regenerative failure may be attributable to the development of an inhibitory CNS environment by glial-associated inhibitory molecules (Yiu and He, 2006, and by various cell-autonomous factors (Sun and He, 2010. Intrinsic axon growth ability also declines developmentally (Li et al., 1995; Goldberg et al., 2002; Bouslama-Oueghlani et al., 2003; Blackmore and Letourneau, 2006 and is dependent on transcription (Moore et al., 2009. Although neurons’ intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors (Moore and Goldberg, 2011, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. Thus a potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. Here we review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study.

Mechanisms of CNS invasion and damage by parasites.

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Kristensson, Krister; Masocha, Willias; Bentivoglio, Marina

2013-01-01

Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection. Copyright © 2013 Elsevier B.V. All rights reserved.

Transcriptome-wide survey of mouse CNS-derived cells reveals monoallelic expression within novel gene families.

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Sierra M Li

Full Text Available Monoallelic expression is an integral component of regulation of a number of essential genes and gene families. To probe for allele-specific expression in cells of CNS origin, we used next-generation sequencing (RNA-seq to analyze four clonal neural stem cell (NSC lines derived from Mus musculus C57BL/6 (B6×Mus musculus molossinus (JF1 adult female mice. We established a JF1 cSNP library, then ascertained transcriptome-wide expression from B6 vs. JF1 alleles in the NSC lines. Validating the assay, we found that 262 of 268 X-linked genes evaluable in at least one cell line showed monoallelic expression (at least 85% expression of the predominant allele, p-value<0.05. For autosomal genes 170 of 7,198 genes (2.4% of the total showed monoallelic expression in at least 2 evaluable cell lines. The group included eight known imprinted genes with the expected pattern of allele-specific expression. Among the other autosomal genes with monoallelic expression were five members of the glutathione transferase gene superfamily, which processes xenobiotic compounds as well as carcinogens and cancer therapeutic agents. Monoallelic expression within this superfamily thus may play a functional role in the response to diverse and potentially lethal exogenous factors, as is the case for the immunoglobulin and olfactory receptor superfamilies. Other genes and gene families showing monoallelic expression include the annexin gene family and the Thy1 gene, both linked to inflammation and cancer, as well as genes linked to alcohol dependence (Gabrg1 and epilepsy (Kcnma1. The annotated set of genes will provide a resource for investigation of mechanisms underlying certain cases of these and other major disorders.

CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.

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Christine M Matullo

2011-12-01

Full Text Available Although viruses have been implicated in central nervous system (CNS diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV and peripherally restricted lymphocytic choriomeningitis virus (LCMV. While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35% of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.

Interneuron progenitor transplantation to treat CNS dysfunction

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Muhammad O Chohan

2016-08-01

Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

Nanomedicines for the Treatment of CNS Diseases.

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Reynolds, Jessica L; Mahato, Ram I

2017-03-01

Targeting and delivering macromolecular therapeutics to the central nervous system (CNS) has been a major challenge. The blood-brain barrier (BBB) is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Therefore, much effort has been channelled into improving transport of therapeutics across the BBB and into the CNS including the use of nanoparticles. In this thematic issue, several reviews and original research are presented that address "Nanomedicines for CNS Diseases." The articles in this issue are concentrated on either CNS-HIV disease or CNS tumors. In regards to CNS-HIV disease, there are two reviews that discuss the role of nanoparticles for improving the delivery of HIV therapeutics to the CNS. In addition, there are two original articles focusing on therapies for CNS-HIV, one of them uses nanoparticles for delivery of siRNA specific to a key protein in autophagy to microglia, and another discusses nanoparticle delivery of a soluble mediator to suppress neuroinflammation. Furthermore, a comprehensive review about gene therapy for CNS neurological diseases is also included. Finally, this issue also includes review articles on enhanced drug targeting to CNS tumors. These articles include a review on the use of nanoparticles for CNS tumors, a review on functionalization (ligands) of nanoparticles for drug targeting to the brain tumor by overcoming BBB, and the final review discusses the use of macrophages as a delivery vehicle to CNS tumors. This thematic issue provides a wealth of knowledge on using nanomedicines for CNS diseases.

Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

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Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

2016-01-01

The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

Cell volume changes regulate slick (Slo2.1), but not slack (Slo2.2) K+ channels.

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Tejada, Maria A; Stople, Kathleen; Hammami Bomholtz, Sofia; Meinild, Anne-Kristine; Poulsen, Asser Nyander; Klaerke, Dan A

2014-01-01

Slick (Slo2.1) and Slack (Slo2.2) channels belong to the family of high-conductance K+ channels and have been found widely distributed in the CNS. Both channels are activated by Na+ and Cl- and, in addition, Slick channels are regulated by ATP. Therefore, the roles of these channels in regulation of cell excitability as well as ion transport processes, like regulation of cell volume, have been hypothesized. It is the aim of this work to evaluate the sensitivity of Slick and Slack channels to small, fast changes in cell volume and to explore mechanisms, which may explain this type of regulation. For this purpose Slick and Slack channels were co-expressed with aquaporin 1 in Xenopus laevis oocytes and cell volume changes of around 5% were induced by exposure to hypotonic or hypertonic media. Whole-cell currents were measured by two electrode voltage clamp. Our results show that Slick channels are dramatically stimulated (196% of control) by cell swelling and inhibited (57% of control) by a decrease in cell volume. In contrast, Slack channels are totally insensitive to similar cell volume changes. The mechanism underlining the strong volume sensitivity of Slick channels needs to be further explored, however we were able to show that it does not depend on an intact actin cytoskeleton, ATP release or vesicle fusion. In conclusion, Slick channels, in contrast to the similar Slack channels, are the only high-conductance K+ channels strongly sensitive to small changes in cell volume.

Creatine kinase BB and beta-2-microglobulin as markers of CNS metastases in patients with small-cell lung cancer

DEFF Research Database (Denmark)

Pedersen, A G; Bach, F W; Nissen, Mogens Holst

1985-01-01

Creatine kinase (CK) and its BB isoenzyme (CK-BB) were measured in CSF in 65 evaluable patients suspected of CNS metastases secondary to small-cell lung cancer (SCLC). In addition, CSF and plasma levels of beta-2-microglobulin (beta-2-m) were measured in a group of 73 evaluable patients. Of the 65...

Comparing the different response of PNS and CNS injured neurons to mesenchymal stem cell treatment.

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Monfrini, Marianna; Ravasi, Maddalena; Maggioni, Daniele; Donzelli, Elisabetta; Tredici, Giovanni; Cavaletti, Guido; Scuteri, Arianna

2018-01-01

Mesenchymal stem cells (MSCs) are adult bone marrow-derived stem cells actually proposed indifferently for the therapy of neurological diseases of both the Central (CNS) and the Peripheral Nervous System (PNS), as a panacea able to treat so many different diseases by their immunomodulatory ability and supportive action on neuronal survival. However, the identification of the exact mechanism of MSC action in the different diseases, although mandatory to define their real and concrete utility, is still lacking. Moreover, CNS and PNS neurons present many different biological properties, and it is still unclear if they respond in the same manner not only to MSC treatment, but also to injuries. For these reasons, in this study we compared the susceptibility of cortical and sensory neurons both to toxic drug exposure and to MSC action, in order to verify if these two neuronal populations can respond differently. Our results demonstrated that Cisplatin (CDDP), Glutamate, and Paclitaxel-treated sensory neurons were protected by the co-culture with MSCs, in different manners: through direct contact able to block apoptosis for CDDP- and Glutamate-treated neurons, and by the release of trophic factors for Paclitaxel-treated ones. A possible key soluble factor for MSC protection was Glutathione, spontaneously released by these cells. On the contrary, cortical neurons resulted more sensitive than sensory ones to the toxic action of the drugs, and overall MSCs failed to protect them. All these data identified for the first time a different susceptibility of cortical and sensory neurons, and demonstrated a protective action of MSCs only against drugs in peripheral neurotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

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Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

2016-01-01

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS).

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Krause, Sarah; Pfeiffer, Christian; Strube, Susanne; Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Loges, Sonja; Waizenegger, Jonas; Ben-Batalla, Isabel; Cario, Gunnar; Möricke, Anja; Stanulla, Martin; Schrappe, Martin; Schewe, Denis M

2015-01-29

Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. © 2015 by The American Society of Hematology.

Meningeal mast cell-T cell crosstalk regulates T cell encephalitogenicity.

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Russi, Abigail E; Walker-Caulfield, Margaret E; Guo, Yong; Lucchinetti, Claudia F; Brown, Melissa A

2016-09-01

GM-CSF is a cytokine produced by T helper (Th) cells that plays an essential role in orchestrating neuroinflammation in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. Yet where and how Th cells acquire GM-CSF expression is unknown. In this study we identify mast cells in the meninges, tripartite tissues surrounding the brain and spinal cord, as important contributors to antigen-specific Th cell accumulation and GM-CSF expression. In the absence of mast cells, Th cells do not accumulate in the meninges nor produce GM-CSF. Mast cell-T cell co-culture experiments and selective mast cell reconstitution of the meninges of mast cell-deficient mice reveal that resident meningeal mast cells are an early source of caspase-1-dependent IL-1β that licenses Th cells to produce GM-CSF and become encephalitogenic. We also provide evidence of mast cell-T cell co-localization in the meninges and CNS of recently diagnosed acute MS patients indicating similar interactions may occur in human demyelinating disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Monocyte Chemoattractant Protein-1 in the choroid plexus: a potential link between vascular pro-inflammatory mediators and the CNS during peripheral tissue inflammation

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Mitchell, K.; Yang, H.-Y. T.; Berk, J. D.; Tran, J. H.; Iadarola, M. J.

2009-01-01

During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of CSF production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the SCYA2 gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCP-1 protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared to other CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the NF-κβ signaling cascade including TNF-α, IL-1β and IκBα in choroid tissue. Given that we also detected increased levels of MCP-1 protein by ELISA, we sought to identify potential downstream targets of MCP-1 and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding E-selectin, a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during

A novel three-dimensional system to study interactions between endothelial cells and neural cells of the developing central nervous system

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Milner Richard

2007-01-01

Full Text Available Abstract Background During angiogenesis in the developing central nervous system (CNS, endothelial cells (EC detach from blood vessels growing on the brain surface, and migrate into the expanding brain parenchyma. Brain angiogenesis is regulated by growth factors and extracellular matrix (ECM proteins secreted by cells of the developing CNS. In addition, recent evidence suggests that EC play an important role in establishing the neural stem cell (NSC niche. Therefore, two-way communication between EC and neural cells is of fundamental importance in the developing CNS. To study the interactions between brain EC and neural cells of the developing CNS, a novel three-dimensional (3-D murine co-culture system was developed. Fluorescent-labelled brain EC were seeded onto neurospheres; floating cellular aggregates that contain NSC/neural precursor cells (NPC and smaller numbers of differentiated cells. Using this system, brain EC attachment, survival and migration into neurospheres was evaluated and the role of integrins in mediating the early adhesive events addressed. Results Brain EC attached, survived and migrated deep into neurospheres over a 5-day period. Neurospheres express the ECM proteins fibronectin and laminin, and brain EC adhesion to neurospheres was inhibited by RGD peptides and antibodies specific for the β1, but not the α6 integrin subunit. Conclusion A novel 3-D co-culture system for analysing the interactions between EC and neural cells of the developing CNS is presented. This system could be used to investigate the reciprocal influence of EC and NSC/NPC; to examine how NSC/NPC influence cerebral angiogenesis, and conversely, to examine how EC regulate the maintenance and differentiation of NSC/NPC. Using this system it is demonstrated that EC attachment to neurospheres is mediated by the fibronectin receptor, α5β1 integrin.

Lentiviral-mediated administration of IL-25 in the CNS induces alternative activation of microglia

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Maiorino, C; Khorooshi, R; Ruffini, F

2013-01-01

Interleukin-25 (IL-25) is the only anti-inflammatory cytokine of the IL-17 family, and it has been shown to be efficacious in inhibiting neuroinflammation. Known for its effects on cells of the adaptive immune system, it has been more recently described to be effective also on cells of the innate...... was partly inhibited and the CNS protected from immune-mediated damage. To our knowledge, this is the first example of M2 shift (alternative activation) induced in vivo on CNS-resident myeloid cells by gene therapy, and may constitute a promising strategy to investigate the potential role of protective...

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence.

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Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

2016-07-02

Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

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Zeka, Bleranda; Hastermann, Maria; Hochmeister, Sonja

2015-01-01

In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since...

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

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Dhong Hyun Lee

2017-05-01

Full Text Available We have established two mouse models of central nervous system (CNS demyelination that differ from most other available models of multiple sclerosis (MS in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2 causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

Non-cell autonomous impairment of oligodendrocyte differentiation precedes CNS degeneration in the Zitter rat: Implications of macrophage/microglial activation in the pathogenesis

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Ookawara Shigeo

2008-04-01

Full Text Available Abstract Background The zitter (zi/zi rat, a loss-of-function mutant of the glycosylated transmembrane protein attractin (atrn, exhibits widespread age-dependent spongiform degeneration, hypomyelination, and abnormal metabolism of reactive oxygen species (ROS in the brain. To date, the mechanisms underlying these phenotypes have remained unclear. Results Here, we show differentiation defects in zi/zi oligodendrocytes, accompanied by aberrant extension of cell-processes and hypomyelination. Axonal bundles were relatively preserved during postnatal development. With increasing in age, the injured oligodendrocytes in zi/zi rats become pathological, as evidenced by the accumulation of iron in their cell bodies. Immunohistochemical analysis revealed that atrn expression was absent from an oligodendrocyte lineage, including A2B5-positive progenitors and CNPase-positive differentiated cells. The number and distribution of Olig2-positive oligodendrocyte progenitors was unchanged in the zi/zi brain. Furthermore, an in vitro differentiation assay of cultured oligodendrocyte progenitors prepared from zi/zi brains revealed their normal competence for proliferation and differentiation into mature oligodendrocytes. Interestingly, we demonstrated the accelerated recruitment of ED1-positive macrophages/microglia to the developing zi/zi brain parenchyma prior to the onset of hypomyelination. Semiquantitative RT-PCR analysis revealed a significant up-regulation of CD26 and IL1-β in the zi/zi brain during this early postnatal stage. Conclusion We demonstrated that the onset of the impairment of oligodendrocyte differentiation occurs in a non-cell autonomous manner in zi/zi rats. Hypomyelination of oligodendrocytes was not due to a failure of the intrinsic program of oligodendrocytes, but rather, was caused by extrinsic factors that interrupt oligodendrocyte development. It is likely that macrophage/microglial activation in the zi/zi CNS leads to disturbances in

CD11c-Expressing Cells Affect Regulatory T Cell Behavior in the Meninges during Central Nervous System Infection.

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O'Brien, Carleigh A; Overall, Christopher; Konradt, Christoph; O'Hara Hall, Aisling C; Hayes, Nikolas W; Wagage, Sagie; John, Beena; Christian, David A; Hunter, Christopher A; Harris, Tajie H

2017-05-15

Regulatory T cells (Tregs) play an important role in the CNS during multiple infections, as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, Tregs in the CNS during T. gondii infection are Th1 polarized, as exemplified by their T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4 + T cells, an MHC class II tetramer reagent specific for T. gondii did not recognize Tregs isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector T cells and Tregs in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Tregs were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4 + T cells within the meninges were highly migratory, whereas Tregs moved more slowly and were found in close association with CD11c + cells. To test whether the behavior of Tregs in the meninges is influenced by interactions with CD11c + cells, mice were treated with anti-LFA-1 Abs to reduce the number of CD11c + cells in this space. The anti-LFA-1 treatment led to fewer contacts between Tregs and the remaining CD11c + cells and increased the speed of Treg migration. These data suggest that Tregs are anatomically restricted within the CNS, and their interaction with CD11c + populations regulates their local behavior during T. gondii infection. Copyright © 2017 by The American Association of Immunologists, Inc.

Cell volume changes regulate slick (Slo2.1, but not slack (Slo2.2 K+ channels.

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Maria A Tejada

Full Text Available Slick (Slo2.1 and Slack (Slo2.2 channels belong to the family of high-conductance K+ channels and have been found widely distributed in the CNS. Both channels are activated by Na+ and Cl- and, in addition, Slick channels are regulated by ATP. Therefore, the roles of these channels in regulation of cell excitability as well as ion transport processes, like regulation of cell volume, have been hypothesized. It is the aim of this work to evaluate the sensitivity of Slick and Slack channels to small, fast changes in cell volume and to explore mechanisms, which may explain this type of regulation. For this purpose Slick and Slack channels were co-expressed with aquaporin 1 in Xenopus laevis oocytes and cell volume changes of around 5% were induced by exposure to hypotonic or hypertonic media. Whole-cell currents were measured by two electrode voltage clamp. Our results show that Slick channels are dramatically stimulated (196% of control by cell swelling and inhibited (57% of control by a decrease in cell volume. In contrast, Slack channels are totally insensitive to similar cell volume changes. The mechanism underlining the strong volume sensitivity of Slick channels needs to be further explored, however we were able to show that it does not depend on an intact actin cytoskeleton, ATP release or vesicle fusion. In conclusion, Slick channels, in contrast to the similar Slack channels, are the only high-conductance K+ channels strongly sensitive to small changes in cell volume.

Application of empowerment theory for CNS practice.

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Carlson-Catalano, J M

1993-11-01

Power is necessary for the clinical nurse specialist (CNS) to successfully conduct objectives of practice in bureaucratic hospital settings. To obtain power, the CNS could use strategies of an empowerment theory to fully operationalize roles in hospitals. This article will discuss how the CNS may be empowered utilizing strategies in four empowering categories. In addition, the many benefits of empowering the CNS are reviewed.

Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

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Vik-Mo Audun O

2006-10-01

Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

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de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

2017-06-01

Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

4th ENRI International Workshop on ATM/CNS

CERN Document Server

2017-01-01

This book is a compilation of selected papers from the 4th ENRI International Workshop on ATM/CNS (EIWAC2015). The work focuses on novel techniques for aviation infrastructure in air traffic management (ATM) and communications, navigation, surveillance, and informatics (CNSI) domains. The contents make valuable contributions to academic researchers, engineers in the industry, and regulators of aviation authorities. As well, readers will encounter new ideas for realizing a more efficient and safer aviation system. .

Malignant lymphoma in central nervous system (CNS)

International Nuclear Information System (INIS)

Fujiyoshi, Kenji; Fukuyama, Hidenao; Akiguchi, Ichiro; Kameyama, Masakuni; Nishimura, Toshio.

1984-01-01

A 71-year-old male was admitted to Kohka Public Hospital on January 4, 1980, because of frequent vomiting and recent memory loss. Two weeks before admission upper G-I series showed no abnormalities. Physical and neurological examinations revealed no abnormalities except for slightly apathetic appearance and recent memory loss. Mild pleocytosis and marked increase of protein in CSF were observed. CT scan on January 17 showed high density areas in both medial sides of temporal lobes with remarkable contrast enhancement. His memory and, consciousness disturbances gradually aggravated, accompanied by abnormal density spreading around the ventricle walls like ventriculitis. He was transfered to Kyoto University Hospital on March 17, and malignant lymphoma was diagnosed on the basis of CSF cytology. Radiation and chemotherapy alleviated the CNS involvement and he regained normal mental function. On June 16, he developed pneumonia followed by status epilepticus. Autopsy findings revealed no lymphoid cell infiltration, but fibrous tissues in both hippocampal gyri and lymphomatous cells in the liver, which could not be suspected on clinical examinations. Apparent malignant lymphoma cells were not found in lymph nodes. This case indicated peculiar evolution of malignant lymphoma from liver to CNS or vice versa. We could not decide which organ was primary. CT findings of this case was very interesting; they resembled ventriculitis, which simulate tumors such as medulloblastoma or ependymoma spreading under ependymal lining. (author)

Central Nervous System (CNS Disease Triggering Takotsubo Syndrome

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Josef Finsterer

2016-01-01

Full Text Available Takotsubo syndrome (TTS is usually triggered by psychological or physical stress. One of the many physical sources of stress are central nervous system (CNS disorders. CNS disorders most frequently triggering TTS include subarachnoid bleeding, epilepsy, ischemic stroke, migraine, and intracerebral bleeding. More rare CNS-triggers of TTS include posterior reversible encephalopathy syndrome (PRES, amyotrophic lateral sclerosis, encephalitis, or traumatic brain or spinal cord injury. TTS triggered by any of the CNS disorders needs to be recognized since adequate treatment of TTS may improve the general outcome from the CNS disorder as well. Neurologists need to be aware of TTS as a complication of specific CNS disorders but TTS may be triggered also by CNS disorders so far not recognised as causes of TTS.

Potential Therapies by Stem Cell-Derived Exosomes in CNS Diseases: Focusing on the Neurogenic Niche

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Alejandro Luarte

2016-01-01

Full Text Available Neurodegenerative disorders are one of the leading causes of death and disability and one of the biggest burdens on health care systems. Novel approaches using various types of stem cells have been proposed to treat common neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, or stroke. Moreover, as the secretome of these cells appears to be of greater benefit compared to the cells themselves, the extracellular components responsible for its therapeutic benefit have been explored. Stem cells, as well as most cells, release extracellular vesicles such as exosomes, which are nanovesicles able to target specific cell types and thus to modify their function by delivering proteins, lipids, and nucleic acids. Exosomes have recently been tested in vivo and in vitro as therapeutic conveyors for the treatment of diseases. As such, they could be engineered to target specific populations of cells within the CNS. Considering the fact that many degenerative brain diseases have an impact on adult neurogenesis, we discuss how the modulation of the adult neurogenic niches may be a therapeutic target of stem cell-derived exosomes. These novel approaches should be examined in cellular and animal models to provide better, more effective, and specific therapeutic tools in the future.

HDAC1 regulates the proliferation of radial glial cells in the developing Xenopus tectum.

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Yi Tao

Full Text Available In the developing central nervous system (CNS, progenitor cells differentiate into progeny to form functional neural circuits. Radial glial cells (RGs are a transient progenitor cell type that is present during neurogenesis. It is thought that a combination of neural trophic factors, neurotransmitters and electrical activity regulates the proliferation and differentiation of RGs. However, it is less clear how epigenetic modulation changes RG proliferation. We sought to explore the effect of histone deacetylase (HDAC activity on the proliferation of RGs in the visual optic tectum of Xenopus laevis. We found that the number of BrdU-labeled precursor cells along the ventricular layer of the tectum decrease developmentally from stage 46 to stage 49. The co-labeling of BrdU-positive cells with brain lipid-binding protein (BLBP, a radial glia marker, showed that the majority of BrdU-labeled cells along the tectal midline are RGs. BLBP-positive cells are also developmentally decreased with the maturation of the brain. Furthermore, HDAC1 expression is developmentally down-regulated in tectal cells, especially in the ventricular layer of the tectum. Pharmacological blockade of HDACs using Trichostatin A (TSA or Valproic acid (VPA decreased the number of BrdU-positive, BLBP-positive and co-labeling cells. Specific knockdown of HDAC1 by a morpholino (HDAC1-MO decreased the number of BrdU- and BLBP-labeled cells and increased the acetylation level of histone H4 at lysine 12 (H4K12. The visual deprivation-induced increase in BrdU- and BLBP-positive cells was blocked by HDAC1 knockdown at stage 49 tadpoles. These data demonstrate that HDAC1 regulates radial glia cell proliferation in the developing optical tectum of Xenopus laevis.

MicroRNA (miRNA Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD-Novel and Unique Pathological Features

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Yuhai Zhao

2015-12-01

Full Text Available Of the approximately ~2.65 × 103 mature microRNAs (miRNAs so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS. This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD and related forms of chronic neurodegeneration; and (ii highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

Science.gov (United States)

Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

2015-01-01

Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

CNS-targets in control of energy and glucose homeostasis.

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Kleinridders, André; Könner, A Christine; Brüning, Jens C

2009-12-01

The exceeding efforts in understanding the signals initiated by nutrients and hormones in the central nervous system (CNS) to regulate glucose and energy homeostasis have largely revolutionized our understanding of the neurocircuitry in control of peripheral metabolism. The ability of neurons to sense nutrients and hormones and to adopt a coordinated response to these signals is of crucial importance in controlling food intake, energy expenditure, glucose and lipid metabolism. Anatomical lesion experiments, pharmacological inhibition of signaling pathways, and, more recently, the analysis of conditional mouse mutants with modifications of hormone and nutrient signaling in defined neuronal populations have broadened our understanding of these complex neurocircuits. This review summarizes recent findings regarding the role of the CNS in sensing and transmitting nutritional and hormonal signals to control energy and glucose homeostasis and aims to define them as potential novel drug targets for the treatment of obesity and type 2 diabetes mellitus.

Analysis of neurocognitive function and CNS endpoints in the PROTEA trial

DEFF Research Database (Denmark)

Clarke, Amanda; Johanssen, Veronika; Gerstoft, Jan

2014-01-01

INTRODUCTION: During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear. METHODS: A total of 273 patients with HIV...... and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse...... events related to the CNS were collected at each visit. RESULTS: Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48...

Volume-regulated anion channel--a frenemy within the brain.

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Mongin, Alexander A

2016-03-01

The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is the contribution of VRAC to the release of the excitatory amino acid neurotransmitters glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field, the molecular nature of VRAC remained unknown until less than 2 years ago. Two pioneer publications identified VRAC as the heterohexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research.

Clearance of an immunosuppressive virus from the CNS coincides with immune reanimation and diversification

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McGavern Dorian B

2007-06-01

Full Text Available Abstract Once a virus infection establishes persistence in the central nervous system (CNS, it is especially difficult to eliminate from this specialized compartment. Therefore, it is of the utmost importance to fully understand scenarios during which a persisting virus is ultimately purged from the CNS by the adaptive immune system. Such a scenario can be found following infection of adult mice with an immunosuppressive variant of lymphocytic choriomeningitis virus (LCMV referred to as clone 13. In this study we demonstrate that following intravenous inoculation, clone 13 rapidly infected peripheral tissues within one week, but more slowly inundated the entire brain parenchyma over the course of a month. During the establishment of persistence, we observed that genetically tagged LCMV-specific cytotoxic T lymphocytes (CTL progressively lost function; however, the severity of this loss in the CNS was never as substantial as that observed in the periphery. One of the most impressive features of this model system is that the peripheral T cell response eventually regains functionality at ~60–80 days post-infection, and this was associated with a rapid decline in virus from the periphery. Coincident with this "reanimation phase" was a massive influx of CD4 T and B cells into the CNS and a dramatic reduction in viral distribution. In fact, olfactory bulb neurons served as the last refuge for the persisting virus, which was ultimately purged from the CNS within 200 days post-infection. These data indicate that a functionally revived immune response can prevail over a virus that establishes widespread presence both in the periphery and brain parenchyma, and that therapeutic enhancement of an existing response could serve as an effective means to thwart long term CNS persistence.

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

Science.gov (United States)

Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

2016-02-25

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

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Hicks Steven D

2012-10-01

Full Text Available Abstract Background Alcohol use disorders (AUDs lead to alterations in central nervous system (CNS architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1 was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5 showed a highly significant correlation with AUD-induced decreases in the volume of the left

Chondroitin sulfate proteoglycans regulate the growth, differentiation and migration of multipotent neural precursor cells through the integrin signaling pathway

Directory of Open Access Journals (Sweden)

Lü He-Zuo

2009-10-01

Full Text Available Abstract Background Neural precursor cells (NPCs are defined by their ability to proliferate, self-renew, and retain the potential to differentiate into neurons and glia. Deciphering the factors that regulate their behaviors will greatly aid in their use as potential therapeutic agents or targets. Chondroitin sulfate proteoglycans (CSPGs are prominent components of the extracellular matrix (ECM in the central nervous system (CNS and are assumed to play important roles in controlling neuronal differentiation and development. Results In the present study, we demonstrated that CSPGs were constitutively expressed on the NPCs isolated from the E16 rat embryonic brain. When chondroitinase ABC was used to abolish the function of endogenous CSPGs on NPCs, it induced a series of biological responses including the proliferation, differentiation and migration of NPCs, indicating that CSPGs may play a critical role in NPC development and differentiation. Finally, we provided evidence suggesting that integrin signaling pathway may be involved in the effects of CSPGs on NPCs. Conclusion The present study investigating the influence and mechanisms of CSPGs on the differentiation and migration of NPCs should help us to understand the basic biology of NPCs during CNS development and provide new insights into developing new strategies for the treatment of the neurological disorders in the CNS.

SINS/CNS Nonlinear Integrated Navigation Algorithm for Hypersonic Vehicle

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Yong-jun Yu

2015-01-01

Full Text Available Celestial Navigation System (CNS has characteristics of accurate orientation and strong autonomy and has been widely used in Hypersonic Vehicle. Since the CNS location and orientation mainly depend upon the inertial reference that contains errors caused by gyro drifts and other error factors, traditional Strap-down Inertial Navigation System (SINS/CNS positioning algorithm setting the position error between SINS and CNS as measurement is not effective. The model of altitude azimuth, platform error angles, and horizontal position is designed, and the SINS/CNS tightly integrated algorithm is designed, in which CNS altitude azimuth is set as measurement information. GPF (Gaussian particle filter is introduced to solve the problem of nonlinear filtering. The results of simulation show that the precision of SINS/CNS algorithm which reaches 130 m using three stars is improved effectively.

Migration, fate and in vivo imaging of stem cells in the CNS

Czech Academy of Sciences Publication Activity Database

Syková, Eva

2009-01-01

Roč. 16, Suppl.3 (2009), s. 4-4 ISSN 1351-5101. [Congress of the European-Federation-of-Neurological-Societies /13./. 12.09.2009-15.09.2009, Florencie] Institutional research plan: CEZ:AV0Z50390703 Keywords : CNS * ESC Subject RIV: FH - Neurology

Genes co-regulated with LBD16 in nematode feeding sites inferred from in silico analysis show similarities to regulatory circuits mediated by the auxin/cytokinin balance in Arabidopsis.

Science.gov (United States)

Cabrera, Javier; Fenoll, Carmen; Escobar, Carolina

2015-01-01

Plant endoparasitic nematodes, root-knot and cyst nematodes (RKNs and CNs) induce within the root vascular cylinder transfer cells used for nourishing, termed giant cells (GCs) and syncytia. Understanding the molecular mechanisms behind this process is essential to develop tools for nematode control. Based on the crucial role in gall development of LBD16, also a key component of the auxin pathway leading to the divisions in the xylem pole pericycle during lateral root (LR) formation, we investigated genes co-regulated with LBD16 in different transcriptomes and analyzed their similarities and differences with those of RKNs and CNs feeding sites (FS). This analysis confirmed LBD16 and its co-regulated genes, integrated in signaling cascades mediated by auxins during LR and callus formation, as a particular feature of RKN-FS distinct to CNs. However, LBD16, and its positively co-regulated genes, were repressed in syncytia, suggesting a selective down- regulation of the LBD16 auxin mediated pathways in CNs-FS. Interestingly, cytokinin-induced genes are enriched in syncytia and we encountered similarities between the transcriptome of shoot regeneration from callus, modulated by cytokinins, and that of syncytia. These findings establish differences in the regulatory networks leading to both FS formation, probably modulated by the auxin/cytokinin balance.

Let7a involves in neural stem cell differentiation relating with TLX level.

Science.gov (United States)

Song, Juhyun; Cho, Kyoung Joo; Oh, Yumi; Lee, Jong Eun

2015-07-10

Neural stem cells (NSCs) have the potential for differentiation into neurons known as a groundbreaking therapeutic solution for central nervous system (CNS) diseases. To resolve the therapeutic efficiency of NSCs, recent researchers have focused on the study on microRNA's role in CNS. Some micro RNAs have been reported significant functions in NSC self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. MicroRNA-Let7a (Let7a) has known as the regulator of diverse cellular mechanisms including cell differentiation and proliferation. In present study, we investigated whether Let7a regulates NSC differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal, proliferation and differentiation. We performed the following experiments: western blot analysis, TaqMan assay, RT-PCR, and immunocytochemistry to confirm the alteration of NSCs. Our data showed that let7a play important roles in controlling NSC fate determination. Thus, manipulating Let-7A and TLX could be a novel strategy to enhance the efficiency of NSC's neuronal differentiation for CNS disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

An invertebrate model for CNS drug discovery

DEFF Research Database (Denmark)

Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

2015-01-01

BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery....

AKAP12 mediates barrier functions of fibrotic scars during CNS repair.

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Jong-Ho Cha

Full Text Available The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process.

Transplanting oligodendrocyte progenitors into the adult CNS

International Nuclear Information System (INIS)

Franklin, R.J.M.; Blakemore, W.F.; Cambridge Univ.

1997-01-01

This review covers a number of aspects of the behaviour of oligodendrocyte progenitors following transplantation into the adult CNS. First, an account is given of the ability of transplanted oligodendrocyte progenitors, grown in tissue culture in the presence of PDGF and bFGF, to extensively remyelinate focal areas of persistent demyelination. Secondly, we describe how transplanted clonal cell lines of oligodendrocyte progenitors will differentiate in to astrocytes as will oligodendrocytes following transplantation into pathological environments in which both oligodendrocytes and astrocytes are absent, thereby manifesting the bipotentially demonstrable in vitro but not during development. Finally, a series of studies examining the migratory behaviour of transplanted oligodendrocyte progenitors (modelled using the oligodendrocyte progenitor cell line CG4) are described. (author)

Regulated internalization of NMDA receptors drives PKD1-mediated suppression of the activity of residual cell-surface NMDA receptors.

Science.gov (United States)

Fang, Xiao-Qian; Qiao, Haifa; Groveman, Bradley R; Feng, Shuang; Pflueger, Melissa; Xin, Wen-Kuan; Ali, Mohammad K; Lin, Shuang-Xiu; Xu, Jindong; Duclot, Florian; Kabbaj, Mohamed; Wang, Wei; Ding, Xin-Sheng; Santiago-Sim, Teresa; Jiang, Xing-Hong; Salter, Michael W; Yu, Xian-Min

2015-11-19

Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization - homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell-surface NMDARs and neuronal functions. In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor

Let7a involves in neural stem cell differentiation relating with TLX level

Energy Technology Data Exchange (ETDEWEB)

Song, Juhyun [Department of Anatomy, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cho, Kyoung Joo; Oh, Yumi [Department of Anatomy, Yonsei University College of Medicine, Seoul (Korea, Republic of); BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lee, Jong Eun, E-mail: jelee@yuhs.ac [Department of Anatomy, Yonsei University College of Medicine, Seoul (Korea, Republic of); BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2015-07-10

Neural stem cells (NSCs) have the potential for differentiation into neurons known as a groundbreaking therapeutic solution for central nervous system (CNS) diseases. To resolve the therapeutic efficiency of NSCs, recent researchers have focused on the study on microRNA's role in CNS. Some micro RNAs have been reported significant functions in NSC self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. MicroRNA-Let7a (Let7a) has known as the regulator of diverse cellular mechanisms including cell differentiation and proliferation. In present study, we investigated whether Let7a regulates NSC differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal, proliferation and differentiation. We performed the following experiments: western blot analysis, TaqMan assay, RT-PCR, and immunocytochemistry to confirm the alteration of NSCs. Our data showed that let7a play important roles in controlling NSC fate determination. Thus, manipulating Let-7A and TLX could be a novel strategy to enhance the efficiency of NSC's neuronal differentiation for CNS disorders. - Highlights: • Let7a influences on NSC differentiation and proliferation. • Let7a involves in mainly NSC differentiation rather than proliferation. • Let7a positively regulates the TLX expression.

Let7a involves in neural stem cell differentiation relating with TLX level

International Nuclear Information System (INIS)

Song, Juhyun; Cho, Kyoung Joo; Oh, Yumi; Lee, Jong Eun

2015-01-01

Neural stem cells (NSCs) have the potential for differentiation into neurons known as a groundbreaking therapeutic solution for central nervous system (CNS) diseases. To resolve the therapeutic efficiency of NSCs, recent researchers have focused on the study on microRNA's role in CNS. Some micro RNAs have been reported significant functions in NSC self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. MicroRNA-Let7a (Let7a) has known as the regulator of diverse cellular mechanisms including cell differentiation and proliferation. In present study, we investigated whether Let7a regulates NSC differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal, proliferation and differentiation. We performed the following experiments: western blot analysis, TaqMan assay, RT-PCR, and immunocytochemistry to confirm the alteration of NSCs. Our data showed that let7a play important roles in controlling NSC fate determination. Thus, manipulating Let-7A and TLX could be a novel strategy to enhance the efficiency of NSC's neuronal differentiation for CNS disorders. - Highlights: • Let7a influences on NSC differentiation and proliferation. • Let7a involves in mainly NSC differentiation rather than proliferation. • Let7a positively regulates the TLX expression

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Science.gov (United States)

Poppensieker, Karola; Otte, David-Marian; Schürmann, Britta; Limmer, Andreas; Dresing, Philipp; Drews, Eva; Schumak, Beatrix; Klotz, Luisa; Raasch, Jennifer; Mildner, Alexander; Waisman, Ari; Scheu, Stefanie; Knolle, Percy; Förster, Irmgard; Prinz, Marco; Maier, Wolfgang; Zimmer, Andreas; Alferink, Judith

2012-01-01

Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4−/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4−/− mice, indicating that CCR4+ DCs are cellular mediators of EAE development. Mechanistically, CCR4−/− DCs were less efficient in GM-CSF and IL-23 production and also TH-17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4−/− mice, whereas intracerebral inoculation using IL-23−/− DCs or GM-CSF−/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type. PMID:22355103

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

DEFF Research Database (Denmark)

Sturm, Dominik; Orr, Brent A; Toprak, Umut H

2016-01-01

with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration...

CNS infections in immunocompetent patients

International Nuclear Information System (INIS)

Hartmann, K.M.; Zimmer, A.; Reith, W.

2008-01-01

This article gives a review of the most frequent infective agents reasonable for CNS infections in immunocompetent patients as well as their localisation and imaging specifications. MRI scanning is the gold standard to detect inflammatory conditions in the CNS. Imaging can be normal or nonspecifically altered although the infection is culturally or bioptically proven. There are no pathognomonic, pathogen-specific imaging criteria. The localization and dimension of the inflammation depends on the infection pathway. (orig.) [de

Dysregulated RNA-Induced Silencing Complex (RISC) Assembly within CNS Corresponds with Abnormal miRNA Expression during Autoimmune Demyelination.

Science.gov (United States)

Lewkowicz, Przemysław; Cwiklińska, Hanna; Mycko, Marcin P; Cichalewska, Maria; Domowicz, Małgorzata; Lewkowicz, Natalia; Jurewicz, Anna; Selmaj, Krzysztof W

2015-05-13

MicroRNAs (miRNAs) associate with Argonaute (Ago), GW182, and FXR1 proteins to form RNA-induced silencing complexes (RISCs). RISCs represent a critical checkpoint in the regulation and bioavailability of miRNAs. Recent studies have revealed dysregulation of miRNAs in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE); however, the function of RISCs in EAE and MS is largely unknown. Here, we examined the expression of Ago, GW182, and FXR1 in CNS tissue, oligodendrocytes (OLs), brain-infiltrating T lymphocytes, and CD3(+)splenocytes (SCs) of EAE mic, and found that global RISC protein levels were significantly dysregulated. Specifically, Ago2 and FXR1 levels were decreased in OLs and brain-infiltrating T cells in EAE mice. Accordingly, assembly of Ago2/GW182/FXR1 complexes in EAE brain tissues was disrupted, as confirmed by immunoprecipitation experiments. In parallel with alterations in RISC complex content in OLs, we found downregulation of miRNAs essential for differentiation and survival of OLs and myelin synthesis. In brain-infiltrating T lymphocytes, aberrant RISC formation contributed to miRNA-dependent proinflammatory helper T-cell polarization. In CD3(+) SCs, we found increased expression of both Ago2 and FXR1 in EAE compared with nonimmunized mice. Therefore, our results demonstrate a gradient in expression of miRNA between primary activated T cells in the periphery and polarized CNS-infiltrating T cells. These results suggest that, in polarized autoreactive effector T cells, miRNA synthesis is inhibited in response to dysregulated RISC assembly, allowing these cells to maintain a highly specific proinflammatory program. Therefore, our findings may provide a mechanism that leads to miRNA dysregulation in EAE/MS. Copyright © 2015 the authors 0270-6474/15/357521-17$15.00/0.

A functional genomics screen in planarians reveals regulators of whole-brain regeneration

Science.gov (United States)

Roberts-Galbraith, Rachel H; Brubacher, John L; Newmark, Phillip A

2016-01-01

Planarians regenerate all body parts after injury, including the central nervous system (CNS). We capitalized on this distinctive trait and completed a gene expression-guided functional screen to identify factors that regulate diverse aspects of neural regeneration in Schmidtea mediterranea. Our screen revealed molecules that influence neural cell fates, support the formation of a major connective hub, and promote reestablishment of chemosensory behavior. We also identified genes that encode signaling molecules with roles in head regeneration, including some that are produced in a previously uncharacterized parenchymal population of cells. Finally, we explored genes downregulated during planarian regeneration and characterized, for the first time, glial cells in the planarian CNS that respond to injury by repressing several transcripts. Collectively, our studies revealed diverse molecules and cell types that underlie an animal’s ability to regenerate its brain. DOI: http://dx.doi.org/10.7554/eLife.17002.001 PMID:27612384

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells.

Science.gov (United States)

Ogasawara, Takashi; Kohashi, Yuko; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hatano, Masahiko; Hirata, Hirokuni; Fukushima, Yasutsugu; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi; Arima, Masafumi

2018-01-01

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate T H 2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4 + T cell-derived memory T H 2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4 + T (MPT) cells and their derived T H 2 (MPT H 2) cells, Bcl6 -manipulated mice , highly conserved intron enhancer (hcIE)-deficient mice , and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated T H 2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPT H 2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPT H 2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPT H 2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPT H 2 cells in T H 2 immune responses related to the pathogenesis of allergies.

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells

Science.gov (United States)

Ogasawara, Takashi; Kohashi, Yuko; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hatano, Masahiko; Hirata, Hirokuni; Fukushima, Yasutsugu; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi; Arima, Masafumi

2018-01-01

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3′ distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies. PMID:29696026

EMA: a developmentally regulated cell-surface glycoprotein of CNS neurons that is concentrated at the leading edge of growth cones.

Science.gov (United States)

Baumrind, N L; Parkinson, D; Wayne, D B; Heuser, J E; Pearlman, A L

1992-08-01

To identify cell-surface molecules that mediate interactions between neurons and their environment during neural development, we used monoclonal antibody techniques to define a developmentally regulated antigen in the central nervous system of the mouse. The antibody we produced (2A1) immunolabels cells throughout the central nervous system; we analyzed its distribution in the developing cerebral cortex, where it is expressed on cells very soon after they complete mitosis and leave the periventricular proliferative zone. Expression continues into adult life. The antibody also labels the epithelium of the choroid plexus and the renal proximal tubules, but does not label neurons of the peripheral nervous system in the dorsal root ganglia. In dissociated cell culture of embryonic cerebral cortex, 2A1 labels the surface of neurons but not glia. Immunolabeling of neurons in tissue culture is particularly prominent on the edge of growth cones, including filopodia and the leading edge of lamellipodia, when observed with either immunofluorescence or freeze-etch immunoelectron microscopy. Immunopurification with 2A1 of a CHAPS-extracted membrane preparation from brains of neonatal mice produces a broad (32-36 kD) electrophoretic band and a less prominent 70 kD band that are sensitive to N-glycosidase but not endoglycosidase H. Thus the 2A1 antibody recognizes a developmentally regulated, neuronal cell surface glycoprotein (or glycoproteins) with complex N-linked oligosaccharide side chains. We have termed the glycoprotein antigen EMA because of its prominence on the edge membrane of growth cones. EMA is similar to the M6 antigen (Lagenaur et al: J. Neurobiol. 23:71-88, 1992) in apparent molecular weight, distribution in tissue sections, and immunoreactivity on Western blots, suggesting that the two antigens are similar or identical. Expression of EMA is a very early manifestation of neuronal differentiation; its distribution on growth cones suggests a role in mediating the

CNS embryonal tumours: WHO 2016 and beyond.

Science.gov (United States)

Pickles, J C; Hawkins, C; Pietsch, T; Jacques, T S

2018-02-01

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. © 2017 British Neuropathological Society.

LATE-BREAKING ABSTRACT: Early relapse of non-small cell lung cancer (NSCLC) found after CNS-symptoms

DEFF Research Database (Denmark)

Hansen, Niels-Chr. G.; Laursen, Christian B.; Jeppesen, Stefan S.

2016-01-01

whether the introduction in 2010 of follow-up by CT of thorax and upper abdomen every three months has reduced the incidence of relapse suspected from CNS-symptoms.Results: All 827 NSCLC patients from Funen completing curative treatment from 2005 to 2013 were included. The total number of relapses found...... or III were found.Conclusion: CT-based follow-up has not reduced the incidence of relapse suspected from CNS-symptoms in stage II-IV, and therefore we suggest routine MR of the brain before curative treatment for this group of patients.Number, fractions(%), and [95%CI]Jan. 2005 - June 2010July 2010 - Dec...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood–brain barrier through paracellular transmigration and ERK activation

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Sagar Divya

2012-10-01

Full Text Available Abstract Background Transmigration of circulating dendritic cells (DCs into the central nervous system (CNS across the blood–brain barrier (BBB has not thus far been investigated. An increase in immune cell infiltration across the BBB, uncontrolled activation and antigen presentation are influenced by chemokines. Chemokine ligand 2 (CCL2 is a potent chemoattractant known to be secreted by the BBB but has not been implicated in the recruitment of DCs specifically at the BBB. Methods Experimental autoimmune encephalomyelitis (EAE was induced in C57BL/6 mice by injection of MOG35–55 peptide and pertussis toxin intraperitoneally. Animals with increasing degree of EAE score were sacrificed and subjected to near-infrared and fluorescence imaging analysis to detect and localize the accumulation of CD11c+-labeled DCs with respect to CCL2 expression. To further characterize the direct effect of CCL2 in DC trafficking at the BBB, we utilized an in vitro BBB model consisting of human brain microvascular endothelial cells to compare migratory patterns of monocyte-derived dendritic cells, CD4+ and CD8+ T cells. Further, this model was used to image transmigration using fluorescence microcopy and to assess specific molecular signaling pathways involved in transmigration. Results Near-infrared imaging of DC transmigration correlated with the severity of inflammation during EAE. Ex vivo histology confirmed the presence of CCL2 in EAE lesions, with DCs emerging from perivascular spaces. DCs exhibited more efficient transmigration than T cells in BBB model studies. These observations correlated with transwell imaging, which indicated a paracellular versus transcellular pattern of migration by DCs and T cells. Moreover, at the molecular level, CCL2 seems to facilitate DC transmigration in an ERK1/2-dependent manner. Conclusion CNS recruitment of DCs correlates with disease severity in EAE via CCL2 chemotaxis and paracellular transmigration across the BBB

Mock-up tests on the combustion of hydrogen-air mixture in the vertical tube simulating the CNS channel of the CARR

International Nuclear Information System (INIS)

Yu Qingfeng; Feng Quanke; Kawai, Takeshi; Xu Jian

2007-01-01

A two-phase thermo-siphon loop for removing nuclear heating and maintaining the stable liquid level in the moderator cell was adopted for the cold neutron source (CNS) of the China advanced research reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon loop consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The main feature of the loop is that the moderator cell is covered by the helium sub-cooling system. The cold helium gas from the helium refrigerator is firstly introduced into the helium sub-cooling system and then flows up through the tube covering the moderator transfer tube into the condenser. The main part of this system is installed in the CNS vertical channel made of aluminum alloy 6061 T6 (Al-6061-T6) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS channel, the combustion tests using a tube compatible with the CNS channel were carried out using the hydrogen-air mixture under which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.14 MPa G. This condition is involved with the maximum design basis accident of the CARR-CNS. The peak pressure due to combustion was 1.09 MPa, and the design pressure of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the maximum design basis accident occurs. The pressure and stress distributions along the axial direction and the displacement of the tube were also measured

Role of galectin-3 in prion infections of the CNS

International Nuclear Information System (INIS)

Mok, Simon W.F.; Riemer, Constanze; Madela, Kazimierz; Hsu, Daniel K.; Liu, Fu-Tong; Gueltner, Sandra; Heise, Ines; Baier, Michael

2007-01-01

Galectin-3 is a multi-functional protein and participates in mediating inflammatory reactions. The pronounced overexpression of galectin-3 in prion-infected brain tissue prompted us to study the role of this protein in a murine prion model. Immunofluorescence double-labelling identified microglia as the major cell type expressing galectin-3. Ablation of galectin-3 did not affect PrP Sc -deposition and development of gliosis. However, galectin-3 -/- -mice showed prolonged survival times upon intracerebral and peripheral scrapie infections. Moreover, protein levels of the lysosomal activation marker LAMP-2 were markedly reduced in prion-infected galectin-3 -/- -mice suggesting a role of galectin-3 in regulation of lysosomal functions. Lower mRNA levels of Beclin-1 and Atg5 in prion-infected wild-type and galectin-3 -/- -mice indicated an impairment of autophagy although autophagosome formation was unchanged. The results point towards a detrimental role of galectin-3 in prion infections of the CNS and suggest that endo-/lysosomal dysfunction in combination with reduced autophagy may contribute to disease development

Regulatory Role of Redox Balance in Determination of Neural Precursor Cell Fate

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Mohamed Ariff Iqbal

2017-01-01

Full Text Available In 1990s, reports of discovery of a small group of cells capable of proliferation and contribution to formation of new neurons in the central nervous system (CNS reversed a century-old concept on lack of neurogenesis in the adult mammalian brain. These cells are found in all stages of human life and contribute to normal cellular turnover of the CNS. Therefore, the identity of regulating factors that affect their proliferation and differentiation is a highly noteworthy issue for basic scientists and their clinician counterparts for therapeutic purposes. The cues for such control are embedded in developmental and environmental signaling through a highly regulated tempo-spatial expression of specific transcription factors. Novel findings indicate the importance of reactive oxygen species (ROS in the regulation of this signaling system. The elusive nature of ROS signaling in many vital processes from cell proliferation to cell death creates a complex literature in this field. Here, we discuss the emerging thoughts on the importance of redox regulation of proliferation and maintenance in mammalian neural stem and progenitor cells under physiological and pathological conditions. The current knowledge on ROS-mediated changes in redox-sensitive proteins that govern the molecular mechanisms in proliferation and differentiation of these cells is reviewed.

Laminin-411 Is a Vascular Ligand for MCAM and Facilitates TH17 Cell Entry into the CNS

Science.gov (United States)

Flanagan, Ken; Fitzgerald, Kent; Baker, Jeanne; Regnstrom, Karin; Gardai, Shyra; Bard, Frederique; Mocci, Simonetta; Seto, Pui; You, Monica; Larochelle, Catherine; Prat, Alexandre; Chow, Samuel; Li, Lauri; Vandevert, Chris; Zago, Wagner; Lorenzana, Carlos; Nishioka, Christopher; Hoffman, Jennifer; Botelho, Raquel; Willits, Christopher; Tanaka, Kevin; Johnston, Jennifer; Yednock, Ted

2012-01-01

TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation. PMID:22792325

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

DEFF Research Database (Denmark)

Reinert, Line S; Lopušná, Katarína; Winther, Henriette

2016-01-01

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced t......Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV......-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication...... is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway...

Air pollution: mechanisms of neuroinflammation and CNS disease.

Science.gov (United States)

Block, Michelle L; Calderón-Garcidueñas, Lilian

2009-09-01

Air pollution has been implicated as a chronic source of neuroinflammation and reactive oxygen species (ROS) that produce neuropathology and central nervous system (CNS) disease. Stroke incidence and Alzheimer's and Parkinson's disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain; systemic effects that impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that microglial activation and changes in the blood-brain barrier are key components. Here we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS, culminating in CNS disease.

Immune and inflammatory responses in the CNS : Modulation by astrocytes

DEFF Research Database (Denmark)

Penkowa, Milena; aschner, michael; hidalgo, juan

2008-01-01

Beyond their long-recognized support functions, astrocytes are active partners of neurons in processing information, synaptic integration, and production of trophic factors, just to name a few. Both microglia and astrocytes produce and secrete a number of cytokines, modulating and integrating...... the communication between hematogenous cells and resident cells of the central nervous system (CNS). This review will address (1) the functions of astrocytes in the normal brain and (2) their role in surveying noxious stimuli within the brain, with particular emphasis on astrocytic responses to damage or disease...

P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.

Science.gov (United States)

Davis, Thomas P; Sanchez-Covarubias, Lucy; Tome, Margaret E

2014-01-01

The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. © 2014 Elsevier Inc. All rights reserved.

Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

Science.gov (United States)

Bernhart, Eva; Kollroser, Manfred; Rechberger, Gerald; Reicher, Helga; Heinemann, Akos; Schratl, Petra; Hallström, Seth; Wintersperger, Andrea; Nusshold, Christoph; DeVaney, Trevor; Zorn-Pauly, Klaus; Malli, Roland; Graier, Wolfgang; Malle, Ernst; Sattler, Wolfgang

2014-01-01

Microglia, the immunocompetent cells of the CNS, are rapidly activated in response to injury and microglia migration towards and homing at damaged tissue plays a key role in CNS regeneration. Lysophosphatidic acid (LPA) is involved in signaling events evoking microglia responses through cognate G protein-coupled receptors. Here we show that human immortalized C13NJ microglia express LPA receptor subtypes LPA1, LPA2, and LPA3 on mRNA and protein level. LPA activation of C13NJ cells induced Rho and extracellular signal-regulated kinase activation and enhanced cellular ATP production. In addition, LPA induced process retraction, cell spreading, led to pronounced changes of the actin cytoskeleton and reduced cell motility, which could be reversed by inhibition of Rho activity. To get an indication about LPA-induced global alterations in protein expression patterns a 2-D DIGE/LC-ESI-MS proteomic approach was applied. On the proteome level the most prominent changes in response to LPA were observed for glycolytic enzymes and proteins regulating cell motility and/or cytoskeletal dynamics. The present findings suggest that naturally occurring LPA is a potent regulator of microglia biology. This might be of particular relevance in the pathophysiological context of neurodegenerative disorders where LPA concentrations can be significantly elevated in the CNS. PMID:19899077

Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.

Science.gov (United States)

Noda, Mami

2018-01-01

The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.

CNS adverse events associated with antimalarial agents. Fact or fiction?

NARCIS (Netherlands)

Phillips-Howard, P. A.; ter Kuile, F. O.

1995-01-01

CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

Targeting α4β2 nAChRs in CNS disorders: Perspectives on positive allosteric modulation as a therapeutic approach

DEFF Research Database (Denmark)

Grupe, Morten; Grunnet, Morten; Bastlund, Jesper F.

2015-01-01

The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional character......The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional...... characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric α4β2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders...... and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the α4β2 nAChR. The potential...

The glymphatic system in CNS health and disease: past, present and future

Science.gov (United States)

Plog, Benjamin A.; Nedergaard, Maiken

2018-01-01

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here we review the role of the glymphatic pathway in CNS physiology, factors known to regulate glymphatic flow, and pathologic processes where a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, will also be discussed. PMID:29195051

3rd ENRI International Workshop on ATM/CNS

CERN Document Server

2014-01-01

The Electronic Navigation Research Institute (ENRI) held its third　International Workshop on ATM / CNS in 2013 with the theme of "Drafting　the future sky". There is worldwide activity taking place in the research and development　of modern air traffic management (ATM) and its enabling technologies in　Communication, Navigation and Surveillance (CNS). Pioneering work is necessary to contribute to the global harmonization　of air traffic management and control. At this workshop, leading experts　in  research, industry and academia from around the world met to share　their ideas and approaches on ATM/CNS related topics.

CNS penetration of ART in HIV-infected children

NARCIS (Netherlands)

van den Hof, Malon; Blokhuis, Charlotte; Cohen, Sophie; Scherpbier, Henriette J.; Wit, Ferdinand W. N. M.; Pistorius, M. C. M.; Kootstra, Neeltje A.; Teunissen, Charlotte E.; Mathot, Ron A. A.; Pajkrt, Dasja

2018-01-01

Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce. Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function. Patients and methods: Antiretroviral drug levels were measured in paired

Effects of x rays on the morphology and physiology of the CNS blood vessels of mice

Energy Technology Data Exchange (ETDEWEB)

Gladysz, J [Akademia Medyczna, Poznan (Poland)

1974-01-01

Irradiation of the CNS of mice with 4000 to 7600 R produces transitional disorder of the permeability of vascular walls, followed by a permanent (irreversible) degenerative lesion of blood capillaries and the surrounding astrogial cells. Intensity of this alterations may however not be the same in different terminal blood vessels. It is very likely that the above described lesion appearing in the acute phase can be the main cause of further alterations in the CNS which are observed in late phase of postradiation disease.

Regulation of beta cell replication

DEFF Research Database (Denmark)

Lee, Ying C; Nielsen, Jens Høiriis

2008-01-01

Beta cell mass, at any given time, is governed by cell differentiation, neogenesis, increased or decreased cell size (cell hypertrophy or atrophy), cell death (apoptosis), and beta cell proliferation. Nutrients, hormones and growth factors coupled with their signalling intermediates have been...... suggested to play a role in beta cell mass regulation. In addition, genetic mouse model studies have indicated that cyclins and cyclin-dependent kinases that determine cell cycle progression are involved in beta cell replication, and more recently, menin in association with cyclin-dependent kinase...... inhibitors has been demonstrated to be important in beta cell growth. In this review, we consider and highlight some aspects of cell cycle regulation in relation to beta cell replication. The role of cell cycle regulation in beta cell replication is mostly from studies in rodent models, but whether...

Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.

Science.gov (United States)

Berger, Philipp; Sirkowski, Erich E; Scherer, Steven S; Suter, Ueli

2004-11-01

Mutations in the gene encoding N-myc downstream-regulated gene-1 (NDRG1) lead to truncations of the encoded protein and are associated with an autosomal recessive demyelinating neuropathy--hereditary motor and sensory neuropathy-Lom. NDRG1 protein is highly expressed in peripheral nerve and is localized in the cytoplasm of myelinating Schwann cells, including the paranodes and Schmidt-Lanterman incisures. In contrast, sensory and motor neurons as well as their axons lack NDRG1. NDRG1 mRNA levels in developing and injured adult sciatic nerves parallel those of myelin-related genes, indicating that the expression of NDRG1 in myelinating Schwann cells is regulated by axonal interactions. Oligodendrocytes also express NDRG1, and the subtle CNS deficits of affected patients may result from a lack of NDRG1 in these cells. Our data predict that the loss of NDRG1 leads to a Schwann cell autonomous phenotype resulting in demyelination, with secondary axonal loss.

The Choroid Plexus Functions as a Niche for T-Cell Stimulation Within the Central Nervous System

Directory of Open Access Journals (Sweden)

Itai Strominger

2018-05-01

Full Text Available The choroid plexus (CP compartment in the ventricles of the brain comprises fenestrated vasculature and, therefore, it is permeable to blood-borne mediators of inflammation. Here, we explored whether T-cell activation in the CP plays a role in regulating central nervous system (CNS inflammation. We show that CD4 T cells injected into the lateral ventricles adhere to the CP, transmigrate across its epithelium, and undergo antigen-specific activation and proliferation. This process is enhanced following peripheral immune stimulation and significantly impacts the immune signaling induced by the CP. Ex vivo studies demonstrate that T-cell harboring the CP through its apical surface is a chemokine- and adhesion molecule-dependent process. We suggest that, within the CNS, the CP serves an immunological niche, which rapidly responds to peripheral inflammation and, thereby, promotes two-way T-cell trafficking that impact adaptive immunity in the CNS.

Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

Energy Technology Data Exchange (ETDEWEB)

Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com [BioMarin Pharmaceutical Inc., Novato, CA (United States); Kennedy, Derek [BioMarin Pharmaceutical Inc., Novato, CA (United States); Reed, Randall P.; Boyd, Robert B. [Northern Biomedical Research, Inc., Muskegon, MI (United States); Butt, Mark T. [Tox Path Specialists, LLC, Hagerstown, MD (United States); Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O' Neill, Charles A. [BioMarin Pharmaceutical Inc., Novato, CA (United States)

2014-05-15

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

International Nuclear Information System (INIS)

Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

2014-01-01

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

Cell Cycle Regulation of Stem Cells by MicroRNAs.

Science.gov (United States)

Mens, Michelle M J; Ghanbari, Mohsen

2018-06-01

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury

Directory of Open Access Journals (Sweden)

Emma V. Jones

2018-02-01

Full Text Available The proper formation and maintenance of functional synapses in the central nervous system (CNS requires communication between neurons and astrocytes and the ability of astrocytes to release neuromodulatory molecules. Previously, we described a novel role for the astrocyte-secreted matricellular protein SPARC (Secreted Protein, Acidic and Rich in Cysteine in regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs and plasticity at developing synapses. SPARC is highly expressed by astrocytes and microglia during CNS development but its level is reduced in adulthood. Interestingly, SPARC has been shown to be upregulated in CNS injury and disease. However, the role of SPARC upregulation in these contexts is not fully understood. In this study, we investigated the effect of chronic SPARC administration on glutamate receptors on mature hippocampal neuron cultures and following CNS injury. We found that SPARC treatment increased the number of GluA1-containing AMPARs at synapses and enhanced synaptic function. Furthermore, we determined that the increase in synaptic strength induced by SPARC could be inhibited by Philanthotoxin-433, a blocker of homomeric GluA1-containing AMPARs. We then investigated the effect of SPARC treatment on neuronal health in an injury context where SPARC expression is upregulated. We found that SPARC levels are increased in astrocytes and microglia following middle cerebral artery occlusion (MCAO in vivo and oxygen-glucose deprivation (OGD in vitro. Remarkably, chronic pre-treatment with SPARC prevented OGD-induced loss of synaptic GluA1. Furthermore, SPARC treatment reduced neuronal death through Philanthotoxin-433 sensitive GluA1 receptors. Taken together, this study suggests a novel role for SPARC and GluA1 in promoting neuronal health and recovery following CNS damage.

Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis

Science.gov (United States)

Chen, Jing; Zhang, Xiaolu; Kusumo, Handojo; Costa, Lucio G.; Guizzetti, Marina

2012-01-01

Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS. PMID:23010475

Thermodynamic considerations on self-regulating characteristics of a cold neutron source with a closed thermosiphon

International Nuclear Information System (INIS)

Kawai, Takeshi; Utsuro, Masahiko; Ogino, Fumimaru.

1991-01-01

The present report describes that a cold neutron source (CNS) having a closed-thermosiphon cooling loop shows a self-regulating characteristic under thermal disturbances if the effect of the moderator transfer tube is negligible. Due to this property, the liquid level in the moderator cell is kept almost constant under thermal disturbances. The thermodynamic meaning of the self-regulating property in the idealized closed-thermosiphon and the effect of the moderator transfer tube to the self-regulation are described. (author)

TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

DEFF Research Database (Denmark)

Reinert, Line; Harder, Louis Andreas; Holm, Christian

2012-01-01

Herpes simplex viruses (HSVs) are highly prevalent neurotropic viruses. While they can replicate lytically in cells of the epithelial lineage, causing lesions on mucocutaneous surfaces, HSVs also establish latent infections in neurons, which act as reservoirs of virus for subsequent reactivation......, it is not known what cell type mediates the role of TLR3 in the immunological control of HSV, and it is not known whether TLR3 sensing occurs prior to or after CNS entry. Here, we show that in mice TLR3 provides early control of HSV-2 infection immediately after entry into the CNS by mediating type I IFN...... responses in astrocytes. Tlr3-/- mice were hypersusceptible to HSV-2 infection in the CNS after vaginal inoculation. HSV-2 exhibited broader neurotropism in Tlr3-/- mice than it did in WT mice, with astrocytes being most abundantly infected. Tlr3-/- mice did not exhibit a global defect in innate immune...

Gene therapy for CNS diseases – Krabbe disease

Directory of Open Access Journals (Sweden)

Mohammad A. Rafi

2016-06-01

Full Text Available This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases.

Immediate and persistent transcriptional correlates of long-term sensitization training at different CNS loci in Aplysia californica.

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Samantha Herdegen

Full Text Available Repeated noxious stimulation produces long-term sensitization of defensive withdrawal reflexes in Aplysia californica, a form of long-term memory that requires changes in both transcription and translation. Previous work has identified 10 transcripts which are rapidly up-regulated after long-term sensitization training in the pleural ganglia. Here we use quantitative PCR to begin examining how these transcriptional changes are expressed in different CNS loci related to defensive withdrawal reflexes at 1 and 24 hours after long-term sensitization training. Specifically, we sample from a the sensory wedge of the pleural ganglia, which exclusively contains the VC nociceptor cell bodies that help mediate input to defensive withdrawal circuits, b the remaining pleural ganglia, which contain withdrawal interneurons, and c the pedal ganglia, which contain many motor neurons. Results from the VC cluster show different temporal patterns of regulation: 1 rapid but transient up-regulation of Aplysia homologs of C/EBP, C/EBPγ, and CREB1, 2 delayed but sustained up-regulation of BiP, Tolloid/BMP-1, and sensorin, 3 rapid and sustained up-regulation of Egr, GlyT2, VPS36, and an uncharacterized protein (LOC101862095, and 4 an unexpected lack of regulation of Aplysia homologs of calmodulin (CaM and reductase-related protein (RRP. Changes in the remaining pleural ganglia mirror those found in the VC cluster at 1 hour but with an attenuated level of regulation. Because these samples had almost no expression of the VC-specific transcript sensorin, our data suggests that sensitization training likely induces transcriptional changes in either defensive withdrawal interneurons or neurons unrelated to defensive withdrawal. In the pedal ganglia, we observed only a rapid but transient increase in Egr expression, indicating that long-term sensitization training is likely to induce transcriptional changes in motor neurons but raising the possibility of different

Prophylactic CNS therapy in childhood leukemia

International Nuclear Information System (INIS)

Yokoyama, Takashi; Hiyoshi, Yasuhiko; Fujimoto, Takeo

1982-01-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm 3 ) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm 3 ) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m 2 ) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m 2 , the CSF concentration of MTX rose to 2.3 +- 2.4 x 10 -6 M after initiation of infusion and remained in 10 -7 M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% i n Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC. (author)

Durable treatment response of relapsing CNS plasmacytoma using intrathecal chemotherapy, radiotherapy, and Daratumumab.

Science.gov (United States)

Elhassadi, Ezzat; Murphy, Maurice; Hacking, Dayle; Farrell, Michael

2018-04-01

CNS myelomatous involvement is a rare complication of multiple myeloma with dismal outcome. This disease's optimal treatment is unclear. Combined approach of systemic therapy, radiotherapy, and intrathecal injections chemotherapy should be considered and autologous stem cell transplant consolidation is offered to eligible patients. The role of Daratumumab in this disease deserves further evaluation.

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis.

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Ramakrishna, Chandran; Cantin, Edouard M

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection.

Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.

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Stephanie M C Smith

Full Text Available Intermittent hypoxia (IH during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2 for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells. We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.

Dual DNA methylation patterns in the CNS reveal developmentally poised chromatin and monoallelic expression of critical genes.

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Jinhui Wang

Full Text Available As a first step towards discovery of genes expressed from only one allele in the CNS, we used a tiling array assay for DNA sequences that are both methylated and unmethylated (the MAUD assay. We analyzed regulatory regions of the entire mouse brain transcriptome, and found that approximately 10% of the genes assayed showed dual DNA methylation patterns. They include a large subset of genes that display marks of both active and silent, i.e., poised, chromatin during development, consistent with a link between differential DNA methylation and lineage-specific differentiation within the CNS. Sixty-five of the MAUD hits and 57 other genes whose function is of relevance to CNS development and/or disorders were tested for allele-specific expression in F(1 hybrid clonal neural stem cell (NSC lines. Eight MAUD hits and one additional gene showed such expression. They include Lgi1, which causes a subtype of inherited epilepsy that displays autosomal dominance with incomplete penetrance; Gfra2, a receptor for glial cell line-derived neurotrophic factor GDNF that has been linked to kindling epilepsy; Unc5a, a netrin-1 receptor important in neurodevelopment; and Cspg4, a membrane chondroitin sulfate proteoglycan associated with malignant melanoma and astrocytoma in human. Three of the genes, Camk2a, Kcnc4, and Unc5a, show preferential expression of the same allele in all clonal NSC lines tested. The other six genes show a stochastic pattern of monoallelic expression in some NSC lines and bi-allelic expression in others. These results support the estimate that 1-2% of genes expressed in the CNS may be subject to allelic exclusion, and demonstrate that the group includes genes implicated in major disorders of the CNS as well as neurodevelopment.

Autoimmune process in CNS under Cs-137 inner irradiation

International Nuclear Information System (INIS)

Lisyany, N.I.; Liubich, L.D.

1996-01-01

Autoimmune hypothesis as to the development of radiation-induced brain injuries stands high among the concepts of the CNS post-radiation damage pathogenesis. To study the changes occurring in a living organism affected by a small-dose radiation due to incorporated radionuclides as well as to create adequate models are of critical importance in the post-Chernobyl period. The effects of chronic small-dose inner radiation on the development of autoimmune responses were evaluated by determining the level of the CNS proteins and protein-induced antibodies to the CNS components. (author)

Redox regulation of cell proliferation: Bioinformatics and redox proteomics approaches to identify redox-sensitive cell cycle regulators.

Science.gov (United States)

Foyer, Christine H; Wilson, Michael H; Wright, Megan H

2018-03-29

Plant stem cells are the foundation of plant growth and development. The balance of quiescence and division is highly regulated, while ensuring that proliferating cells are protected from the adverse effects of environment fluctuations that may damage the genome. Redox regulation is important in both the activation of proliferation and arrest of the cell cycle upon perception of environmental stress. Within this context, reactive oxygen species serve as 'pro-life' signals with positive roles in the regulation of the cell cycle and survival. However, very little is known about the metabolic mechanisms and redox-sensitive proteins that influence cell cycle progression. We have identified cysteine residues on known cell cycle regulators in Arabidopsis that are potentially accessible, and could play a role in redox regulation, based on secondary structure and solvent accessibility likelihoods for each protein. We propose that redox regulation may function alongside other known posttranslational modifications to control the functions of core cell cycle regulators such as the retinoblastoma protein. Since our current understanding of how redox regulation is involved in cell cycle control is hindered by a lack of knowledge regarding both which residues are important and how modification of those residues alters protein function, we discuss how critical redox modifications can be mapped at the molecular level. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Role of T cell – glial cell interactions in creating and amplifying Central Nervous System inflammation and Multiple Sclerosis disease symptoms

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Eric S. Huseby

2015-08-01

Full Text Available Multiple Sclerosis (MS is an inflammatory disease of the Central Nervous System (CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process. We have recently found that T cells targeting astrocyte-specific antigens can drive unique aspects of inflammatory CNS autoimmunity, including the targeting of gray matter and white matter of the brain and inducing heterogeneous clinical disease courses. In addition to being a target of T cells, astrocytes play a critical role in propagating the inflammatory response within the CNS through cytokine induced NF-ΚB signaling. Here, we will discuss the pathophysiology of CNS inflammation mediated by T cell – glial cell interactions and its contributions to CNS autoimmunity.

Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells

OpenAIRE

Cheng, Xiaoxin; Wang, Yaping; He, Qian; Qiu, Mengsheng; Whittemore, Scott R.; Cao, Qilin

2007-01-01

Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understandin...

MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases

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Dan-Dan Cao

2016-05-01

Full Text Available MicroRNAs (miRNAs are a class of small, well-conserved noncoding RNAs that regulate gene expression post-transcriptionally. They have been demonstrated to regulate a lot of biological pathways and cellular functions. Many miRNAs are dynamically regulated during central nervous system (CNS development and are spatially expressed in adult brain indicating their essential roles in neural development and function. In addition, accumulating evidence strongly suggests that dysfunction of miRNAs contributes to neurological diseases. These observations, together with their gene regulation property, implicated miRNAs to be the key regulators in the complex genetic network of the CNS. In this review, we first focus on the ways through which miRNAs exert the regulatory function and how miRNAs are regulated in the CNS. We then summarize recent findings that highlight the versatile roles of miRNAs in normal CNS physiology and their association with several types of neurological diseases. Subsequently we discuss the limitations of miRNAs research based on current studies as well as the potential therapeutic applications and challenges of miRNAs in neurological disorders. We endeavor to provide an updated description of the regulatory roles of miRNAs in normal CNS functions and pathogenesis of neurological diseases.

Peroxisome Proliferator-Activated Receptors (PPARs as Potential Inducers of Antineoplastic Effects in CNS Tumors

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Lars Tatenhorst

2008-01-01

Full Text Available The peroxisome proliferator-activated receptors (PPARs are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS. The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.

Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS

DEFF Research Database (Denmark)

Babcock, Alicia A; Kuziel, William A; Rivest, Serge

2003-01-01

Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by e...

Engineering progress of CNS concept in Hanaro

International Nuclear Information System (INIS)

Choi, C.O.; Park, K.N.; Park, S.H.

1997-01-01

The Korea Atomic Energy research Institute (KAERI) strives to provide utilizing facilities on and around the Hanaro reactor in order to activate advanced researches by neutron application. As one of the facilities to be installed, the conceptual design work of CNS was started in 1996 with a project schedule of 5 years so that its installation work can be finished by the year 2000. And the major engineering targets of this CNS facility are established for a minimum physical interference with the present facilities of the Hanaro, a reach-out of very-high-gain factors in the cold neutron flux, a simplicity of the maintenance of the facility, and a safety in the operation of the facility as well as the reactor. For the conceptual design of Hanaro CNS, the experience of utilization and production of cold neutron at WWR-M reactor Gatchina, Russia has been used with that of elaborations for PIK reactor in design for neutron guide systems and instruments. (author)

Sleep disorders in children after treatment for a CNS tumour.

Science.gov (United States)

Verberne, Lisa M; Maurice-Stam, Heleen; Grootenhuis, Martha A; Van Santen, Hanneke M; Schouten-Van Meeteren, Antoinette Y N

2012-08-01

The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with clinical characteristics and daily performance (fatigue and psychosocial functioning). In a cross-sectional study at the outpatient clinic of the Emma Children's Hospital AMC (February-June 2010), sleep, fatigue and psychosocial functioning were analysed in 31 CNS tumour patients (mean age: 11.8years; 20 boys) and compared with 78 patients treated for a non-CNS malignancy (mean age: 9.7years; 41 boys) and norm data. Questionnaires applied were the Sleep Disorder Scale for Children, the Epworth Sleepiness Scale, the Pediatric Quality of Life Inventory, and the Strengths and Difficulties Questionnaire. Sleeping habits and endocrine deficiencies were assessed with a self-developed questionnaire. Increased somnolence was found in CNS tumour patients compared with those with a non-CNS malignancy (8.8±2.8 versus 7.5±2.7; Psleep. No specific risk factors were identified for a sleep disorder in CNS tumour patients, but their excessive somnolence was correlated with lower fatigue related quality of life (QoL) (r=-0.78, Psleep quality and diminish fatigue. © 2011 European Sleep Research Society.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

NARCIS (Netherlands)

Yamamoto, Yumi; Valitalo, Pyry A.; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; Kokki, Hannu; Kokki, Merja; Danhof, Meindert; van Hasselt, Johan G. C.; de Lange, Elizabeth C. M.

2018-01-01

Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human,

Applications of Genomic Sequencing in Pediatric CNS Tumors.

Science.gov (United States)

Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

2016-05-01

Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

Therapy of CNS leukemia with intraventricular chemotherapy and low-dose neuraxis radiotherapy

International Nuclear Information System (INIS)

Steinherz, P.; Jereb, B.; Galicich, J.

1985-01-01

Successful treatment of CNS leukemic relapse has been frustrated by frequent local recurrence and eventual marrow relapse. The authors describe the treatment of meningeal leukemia in 39 children with intrathecal remission induction followed by the placement of an Ommaya reservoir to facilitate the administration and distribution of chemotherapeutic agents into the CSF. Six hundred or 900 rad of craniospinal radiation and maintenance intraventricular and intrathecal chemotherapy was then administered. Systemic reinduction therapy was added in the later cases. Sixteen children (41%) experienced no further events, with 17+ months to 13+ years (median, 25 months) follow-up . Eleven patients (28%) had CNS recurrence, nine (23%) bone marrow (BM) relapse, and two (5%) testicular relapse as the next adverse event. The course of patients with first isolated CNS relapse differed from that of the others. Eleven (69%) of 16 patients treated for first isolated CNS relapse are alive and 9 are event free, while only 35% of patients whose CNS relapse occurred simultaneously or after recurrent disease at other sites are alive (P = .04). Seven of 23 in the later group are event free. The difference is due to the increased incidence of BM relapse in the later group (30% v 6%; P = .04). For patients with first isolated CNS relapse, the life-table median CNS remission duration is 42 months. The projected CNS relapse-free survival and event-free survival 8 to 10 years after CNS relapse are 40% and 32%, respectively. Headache, nausea, and emesis of short duration were frequent during therapy. In three patients, the reservoir had to be removed for infection. No patient suffered neurologic deficit related to the reservoir. The therapy described can reduce the CNS relapse rate with manageable toxicity

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Science.gov (United States)

Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

2017-07-01

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

Invasive ability of human renal cell carcinoma cell line Caki-2 is accelerated by gamma-aminobutyric acid, via sustained activation of ERK1/2 inducible matrix metalloproteinases.

Science.gov (United States)

Inamoto, Teruo; Azuma, Haruhito; Sakamoto, Takeshi; Kiyama, Satoshi; Ubai, Takanobu; Kotake, Yatsugu; Watanabe, Masahito; Katsuoka, Yoji

2007-10-01

Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.

Cell cycle regulation of hematopoietic stem or progenitor cells.

Science.gov (United States)

Hao, Sha; Chen, Chen; Cheng, Tao

2016-05-01

The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

Palmitoylethanolamide in CNS health and disease.

Science.gov (United States)

Mattace Raso, Giuseppina; Russo, Roberto; Calignano, Antonio; Meli, Rosaria

2014-08-01

The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases. Copyright © 2014. Published by Elsevier Ltd.

Ion Channels Involved in Cell Volume Regulation

DEFF Research Database (Denmark)

Hoffmann, Else Kay

2011-01-01

regulatory ion channels involved, and the mechanisms (cellular signalling pathways) that regulate these channels. Finally, I shall also briefly review current investigations in these two cell lines that focuses on how changes in cell volume can regulate cell functions such as cell migration, proliferation......This mini review outlines studies of cell volume regulation in two closely related mammalian cell lines: nonadherent Ehrlich ascites tumour cells (EATC) and adherent Ehrlich Lettre ascites (ELA) cells. Focus is on the regulatory volume decrease (RVD) that occurs after cell swelling, the volume...

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

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Downey, Luke A.; Loftis, Jennifer M.

2014-01-01

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

Essentials and Perspectives of Computational Modelling Assistance for CNS-oriented Nanoparticle-based Drug Delivery Systems.

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Kisała, Joanna; Heclik, Kinga I; Pogocki, Krzysztof; Pogocki, Dariusz

2018-05-16

The blood-brain barrier (BBB) is a complex system controlling two-way substances traffic between circulatory (cardiovascular) system and central nervous system (CNS). It is almost perfectly crafted to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. For potential drug candidates, the CNS-oriented neuropharmaceuticals as well as for those of primary targets in the periphery, the extent to which a substance in the circulation gains access to the CNS seems crucial. With the advent of nanopharmacology the problem of the BBB permeability for drug nano-carriers gains new significance. Compare to some other fields of medicinal chemistry, the computational science of nanodelivery is still prematured to offer the black-box type solutions, especially for the BBB-case. However, even its enormous complexity can be spell out the physical principles, and as such subjected to computation. Basic understanding of various physico-chemical parameters describing the brain uptake is required to take advantage of their usage for the BBB-nanodelivery. This mini-review provides a sketchy introduction into essential concepts allowing application of computational simulation to the BBB-nanodelivery design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.

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Prajeeth, Chittappen K; Kronisch, Julius; Khorooshi, Reza; Knier, Benjamin; Toft-Hansen, Henrik; Gudi, Viktoria; Floess, Stefan; Huehn, Jochen; Owens, Trevor; Korn, Thomas; Stangel, Martin

2017-10-16

Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS. To understand the effects driven by Th17 cells in the CNS, we induced experimental autoimmune encephalomyelitis in wild-type mice and CD4 + T cell-specific integrin α4-deficient mice where trafficking of Th1 cells into the CNS was affected. We compared microglial and astrocyte response in the brain and spinal cord of these mice. We further treated astrocytes with supernatants from highly pure Th1 and Th17 cultures and assessed the messenger RNA expression of neurotrophic factors, cytokines and chemokines, using real-time PCR. Data obtained was analyzed using the Kruskal-Wallis test. We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates, suggesting that Th17 cells target astrocytes and not microglia. In vitro, in response to supernatants from Th1 and Th17 cultures, astrocytes showed altered expression of neurotrophic factors, pro-inflammatory cytokines and chemokines. Furthermore, increased expression of chemokines in Th1- and Th17-treated astrocytes enhanced recruitment of microglia and transendothelial migration of Th17 cells in vitro. Our results demonstrate the delicate interaction between T cell subsets and glial cells and how they communicate to mediate their effects. Effectors of Th1 act on both microglia and astrocytes whereas Th17 effectors preferentially target astrocytes to promote neuroinflammation.

Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

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Jacinta Nwamaka Nwogu

2016-01-01

Full Text Available Neurological complications associated with the human immunodeficiency virus (HIV are a matter of great concern. While antiretroviral (ARV drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

P13.10 Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

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Yust-Katz, S.; Dudnik, E.; Perlov, E.; Zer, A.; Flex, D.; Peled, N.; Siegal, T.

2016-01-01

Abstract Background: Central nervous system (CNS) metastases occur in about 30% of patients (pts) with advanced non-small cell lung cancer (NSCLC). Local treatment strategies (e.g., radiotherapy or surgery) result in delays in systemic therapy administration and are frequently associated with neurocognitive impairment. Nivolumab is an anti-PD1 immune check-point inhibitor which has been recently approved by the FDA as a second line treatment of NSCLC. Data regarding its intracranial activity is lacking. Methods: We retrospectively reviewed efficacy and safety of nivolumab administered intravenously at a dose of 3mg/kg q2 weeks in five pts with advanced NSCLC and new or progressing intracranial metastases which were diagnosed before or within 1 month after starting the treatment. Results: Pt baseline characteristics were as follows: median age 78y (range, 52–84); 2 males; 4 smokers; ECOG PS 0/1/2 - 2 pts/1 pt/2 pts; histological subtype: adenocarcinoma/ squamous-cell carcinoma/NSCLC NOS 3 pts /1 pt/1 pt; EGFR WT/ALK neg/KRAS M all/all/2 pts. Four pts had parenchymal brain metastases, three pts had leptomeningeal disease. All pts were asymptomatic and did not require corticosteroids or immediate brain irradiation. Dramatic response in the brain was observed in two pts (including 1 pt with leptomeningeal spread demonstrating a complete response in the CNS); time-to-response comprised 5 weeks and 9 weeks; all responses are still ongoing at the time of the report (18+ weeks, 19+ weeks). In one pt stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved. Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS-metastases related grade ≥ 3 adverse events were observed. Conclusions: Nivolumab has a promising intracranial activity and favorable safety profile in pts with NSCLC and untreated/progressing CNS metastases. Nivolumab CNS activity warrants further evaluation.

Neuroimmune regulation of neurophysiology in the cerebellum.

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Gruol, Donna L

2013-06-01

Recent studies have established the existence of an innate immune system in the central nervous system (CNS) and implicated a critical role for this system in both normal and pathological processes. Astrocytes and microglia, normal components of the CNS, are the primary cell types that comprise the innate immune system of the CNS. Basic to their role during normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate downstream cellular actions. During adverse conditions, cytokines and chemokines function in defensive and repair. However, if expression of these factors becomes dysregulated, abnormal CNS function can result. Both neurons and glial cells of the CNS express receptors for cytokines and chemokines, but the biological consequence of receptor activation has yet to be fully resolved. Our studies show that neuroadaptive changes are produced in primary cultures of rat cerebellar cells chronically treated with the cytokine interleukin-6 (IL-6) and in the cerebellum of transgenic mice that chronically express elevated levels of IL-6 in the CNS. In the cerebellum in culture and in vivo, the neuroadaptive changes included alterations in the level of expression of proteins involved in gene expression, signal transduction, and synaptic transmission. Associated with these changes were alterations in neuronal function. A comparison of results from the cultured cerebellar cells and cerebellum of the transgenic mice indicated that the effects of IL-6 can vary across neuronal types. However, alterations in mechanisms involved in Ca(2+) homeostasis were observed in all cell types studied. These results indicate that modifications in cerebellar function are likely to occur in disorders associated with elevated levels of IL-6 in the cerebellum.

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures

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Studzinski Diane

2009-01-01

Full Text Available Abstract Background Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS in multiple sclerosis (MS. Methods We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M. Results In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE, related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1 seen at 6 hours with microarray. Conclusion Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter

Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

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Fabio Cavaliere

2016-01-01

Full Text Available Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson’s disease, and cerebral ischemia.

CNS-directed gene therapy for lysosomal storage diseases

OpenAIRE

Sands, Mark S; Haskins, Mark E

2008-01-01

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders usually caused by deficient activity of a single lysosomal enzyme. As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems, including the central nervous system (CNS). At least 75% of all LSDs have a significant CNS component. Approaches such as bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) can effectively treat the systemic dis...

The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity

International Nuclear Information System (INIS)

Zhou Naiming; Zhang Xiaoling; Fan Xuejun; Argyris, Elias; Fang Jianhua; Acheampong, Edward; DuBois, Garrett C.; Pomerantz, Roger J.

2003-01-01

The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS

The crosstalk between the kidney and the central nervous system: the role of renal nerves in blood pressure regulation.

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Nishi, Erika E; Bergamaschi, Cássia T; Campos, Ruy R

2015-04-20

What is the topic of this review? This review describes the role of renal nerves as the key carrier of signals from the kidneys to the CNS and vice versa; the brain and kidneys communicate through this carrier to maintain homeostasis in the body. What advances does it highlight? Whether renal or autonomic dysfunction is the predominant contributor to systemic hypertension is still debated. In this review, we focus on the role of the renal nerves in a model of renovascular hypertension. The sympathetic nervous system influences the renal regulation of arterial pressure and body fluid composition. Anatomical and physiological evidence has shown that sympathetic nerves mediate changes in urinary sodium and water excretion by regulating the renal tubular water and sodium reabsorption throughout the nephron, changes in the renal blood flow and the glomerular filtration rate by regulating the constriction of renal vasculature, and changes in the activity of the renin-angiotensin system by regulating the renin release from juxtaglomerular cells. Additionally, renal sensory afferent fibres project to the autonomic central nuclei that regulate blood pressure. Hence, renal nerves play a key role in the crosstalk between the kidneys and the CNS to maintain homeostasis in the body. Therefore, the increased sympathetic nerve activity to the kidney and the renal afferent nerve activity to the CNS may contribute to the outcome of diseases, such as hypertension. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

Genetic models for CNS inflammation

DEFF Research Database (Denmark)

Owens, T; Wekerle, H; Antel, J

2001-01-01

The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on ...

Molecular stress response in the CNS of mice after systemic exposureto interferon-alpha, ionizing radiation and ketamine

Energy Technology Data Exchange (ETDEWEB)

Lowe, Xiu R.; Marchetti, Francesco; Lu, Xiaochen; Wyrobek, Andrew J.

2009-03-03

We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adultmice 30 min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4 h after systemic exposure to interferon-a (IFN-a) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-a (a single i.p. injection at 1 x 105 IU/kg) or whole body gamma-radiation (10 cGy or 2 Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-a, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10 cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-a treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex andhippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

Regulation of cell wall biosynthesis.

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Zhong, Ruiqin; Ye, Zheng-Hua

2007-12-01

Plant cell walls differ in their amount and composition among various cell types and even in different microdomains of the wall of a given cell. Plants must have evolved regulatory mechanisms controlling biosynthesis, targeted secretion, and assembly of wall components to achieve the heterogeneity in cell walls. A number of factors, including hormones, the cytoskeleton, glycosylphosphatidylinositol-anchored proteins, phosphoinositides, and sugar nucleotide supply, have been implicated in the regulation of cell wall biosynthesis or deposition. In the past two years, there have been important discoveries in transcriptional regulation of secondary wall biosynthesis. Several transcription factors in the NAC and MYB families have been shown to be the key switches for activation of secondary wall biosynthesis. These studies suggest a transcriptional network comprised of a hierarchy of transcription factors is involved in regulating secondary wall biosynthesis. Further investigation and integration of the regulatory players participating in the making of cell walls will certainly lead to our understanding of how wall amounts and composition are controlled in a given cell type. This may eventually allow custom design of plant cell walls on the basis of our needs.

Signalling from the periphery to the brain that regulates energy homeostasis.

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Kim, Ki-Suk; Seeley, Randy J; Sandoval, Darleen A

2018-04-01

The CNS regulates body weight; however, we still lack a clear understanding of what drives decisions about when, how much and what to eat. A vast array of peripheral signals provides information to the CNS regarding fluctuations in energy status. The CNS then integrates this information to influence acute feeding behaviour and long-term energy homeostasis. Previous paradigms have delegated the control of long-term energy homeostasis to the hypothalamus and short-term changes in feeding behaviour to the hindbrain. However, recent studies have identified target hindbrain neurocircuitry that integrates the orchestration of individual bouts of ingestion with the long-term regulation of energy balance.

Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation

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Wang, Guang; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China); Han, Zhe [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Chuai, Manli [College of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH (United Kingdom); Wang, Li-jing [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Ho Lee, Kenneth Ka [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Geng, Jian-guo, E-mail: jgeng@umich.edu [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 (United States); Yang, Xuesong, E-mail: yang_xuesong@126.com [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China)

2013-05-01

Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over-expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1{sup +} migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug{sup +} pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1{sup +} migrating NCCs but reduced Pax7 expression and fewer Slug{sup +} pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube

Resveratrol Neuroprotection in Stroke and Traumatic CNS injury

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Lopez, Mary; Dempsey, Robert J; Vemuganti, Raghu

2015-01-01

Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection. PMID:26277384

Numerical simulation on self-regulating characteristics of a cold neutron source with a closed-thermosiphon

International Nuclear Information System (INIS)

Kawai, Takeshi; Utsuro, Masahiko; Okamoto, Sunao

1989-01-01

A cold neutron source (CNS) having a closed-thermosiphon cooling loop shows a characteristic of self-regulation to the heat load fluctuations if the moderator transfer tube fulfills certain conditions. A dynamical equation of the closed-thermosiphon type CNS having such a property has been presented on the basis of the non-equilibrium thermodynamics. Kyoto University Reactor (KUR) CNS is investigated by numerical simulation of this equation. The numerical predictions for the self-regulating characteristics are in agreement with available experimental data. (author)

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Science.gov (United States)

Timper, Katharina; Brüning, Jens C.

2017-01-01

ABSTRACT The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. PMID:28592656

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity.

Science.gov (United States)

Timper, Katharina; Brüning, Jens C

2017-06-01

The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. © 2017. Published by The Company of Biologists Ltd.

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Directory of Open Access Journals (Sweden)

Katharina Timper

2017-06-01

Full Text Available The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.

Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

International Nuclear Information System (INIS)

Trigg, M.E.; Makuch, R.; Glaubiger, D.

1985-01-01

Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolate CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving DNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to CNS

Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties

DEFF Research Database (Denmark)

Prajeeth, Chittappen K; Kronisch, Julius; Khorooshi, Reza M. H.

2017-01-01

Background: Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously we have shown that only Th1...... mice where trafficking of Th1 cells into the CNS was affected. We compared microglia and astrocyte response in the brain and spinal cord of these mice. We further treated astrocytes with supernatants from highly pure Th1 and Th17 cultures and assessed the mRNA expression of neurotrophic factors......, cytokines and chemokines using real-time PCR. Data obtained was analysed using Kruskal- Wallis test. Results: We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates suggesting that Th17...

Can injured adult CNS axons regenerate by recapitulating development?

Science.gov (United States)

Hilton, Brett J; Bradke, Frank

2017-10-01

In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

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Stefania Varani

2015-11-01

Full Text Available Toscana virus (TOSV is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs and cytokine levels in plasma and cerebrospinal fluid (CSF from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.

Blood-CNS Barrier Impairment in ALS Patients versus an Animal Model

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Svitlana eGarbuzova-Davis

2014-02-01

Full Text Available Amyotrophic lateral sclerosis (ALS is a severe neurodegenerative disease with a compli-cated and poorly understood pathogenesis. Recently, alterations in the blood-Central Nervous System barrier (B-CNS-B have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been deter-mined in mutant SOD1 rodent models, identifying barrier damage during disease develop-ment which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS has been limited. We recently showed structural and functional impairment in postmortem gray and white mat-ter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degenera-tion, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages are indicated in both mutant SOD1 animal models of ALS and SALS pa-tients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnor-malities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood-CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.

Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

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Andrea R. Yung

2018-02-01

Full Text Available During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR, and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.

CNS complications of rotavirus gastroenteritis

International Nuclear Information System (INIS)

Volosinova, D.

2010-01-01

Rotavirus infection may be accompanied by serious complications, e.g. disabilities central nervous system (CNS). Theory rotavirus penetration across the blood-brain barrier and subsequent rota-associated convulsions by the 2-year case-history of the patient. Rotavirosis minor gastrointestinal symptoms may lead to erroneous diagnosis. (author)

Circadian Regulation of Glutamate Transporters

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Donají Chi-Castañeda

2018-06-01

Full Text Available L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS. This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases. Increasing evidence indicates glutamate transporters are controlled by the circadian system in direct and indirect manners, so in this contribution we focus on the mechanisms of circadian regulation (transcriptional, translational, post-translational and post-transcriptional regulation of glutamate transport in neuronal and glial cells, and their consequence in brain function.

Regulators of Tfh cell differentiation

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Gajendra Motiram Jogdand

2016-11-01

Full Text Available The follicular helper T (Tfh cells help is critical for activation of B cells, antibody class switching and germinal center formation. The Tfh cells are characterized by the expression of CXCR5, ICOS, PD-1, Bcl-6, and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. Tfh cells are generated from naïve CD4 T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A, migration and positioning in the germinal center by CXCR5, surface receptors (ICOS/ICOSL, SAP/SLAM as well as transcription factor (Bcl-6, c-Maf, STAT3 signaling and repressor miR155. On the other hand Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7, surface receptor (PD-1, CTLA-4, transcription factors Blimp-1, STAT5, T-bet, KLF-2 signaling and repressor miR 146a. Interestingly, miR 17-92 and FOXO1 acts as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin Ligase and miRNA as positive and negative regulators for Tfh differentiation.

CNS Involvement in AML Patient Treated with 5-Azacytidine

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Diamantina Vasilatou

2014-01-01

Full Text Available Central nervous system (CNS involvement in acute myeloid leukemia (AML is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status.

Interleukin-6 Regulates Adult Neural Stem Cell Numbers during Normal and Abnormal Post-natal Development

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Mekayla A. Storer

2018-05-01

Full Text Available Summary: Circulating systemic factors can regulate adult neural stem cell (NSC biology, but the identity of these circulating cues is still being defined. Here, we have focused on the cytokine interleukin-6 (IL-6, since increased circulating levels of IL-6 are associated with neural pathologies such as autism and bipolar disorder. We show that IL-6 promotes proliferation of post-natal murine forebrain NSCs and that, when the IL-6 receptor is inducibly knocked out in post-natal or adult neural precursors, this causes a long-term decrease in forebrain NSCs. Moreover, a transient circulating surge of IL-6 in perinatal or adult mice causes an acute increase in neural precursor proliferation followed by long-term depletion of adult NSC pools. Thus, IL-6 signaling is both necessary and sufficient for adult NSC self-renewal, and acute perturbations in circulating IL-6, as observed in many pathological situations, have long-lasting effects on the size of adult NSC pools. : In this report, Storer and colleagues demonstrate that the circulating cytokine IL-6, which is elevated in humans in different pathological situations, can perturb neural stem cell biology after birth. They show that IL-6 signaling is essential for self-renewal and maintenance of post-natal and adult NSCs in the murine forebrain under normal homeostatic conditions. Keywords: interleukin-6, neural stem cell, adult neurogenesis, CNS cytokines, postnatal brain development, stem cell depletion, neural stem cell niche, circulating stem cell factors, olfactory bulb

miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice

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Fang Gao

2017-04-01

Full Text Available Summary: Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl, was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs into intermediate neural progenitors (INPs in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. : In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP. Keywords: neural stem cells, intermediate neural progenitors, Notch, RBP-J, neuron, glia, miR-342-5p

Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination.

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Vidal, Marie; Maniglier, Madlyne; Deboux, Cyrille; Bachelin, Corinne; Zujovic, Violetta; Baron-Van Evercooren, Anne

2015-06-01

It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system. We compared them in vitro and in vivo to the well-characterized adult spinal cord-NPCs derived from the same donors. Using micro-dissection and neurosphere cultures, we demonstrate that adult DRG-NPCs have quasi unlimited self-expansion capacities without compromising their tissue specific molecular signature. Moreover, they differentiate into multiple peripheral lineages in vitro. After transplantation, adult DRG-NPCs generate pericytes in the developing forebrain but remyelinating Schwann cells in response to spinal cord demyelination. In addition, we show that axonal and endothelial/astrocytic factors as well astrocytes regulate the fate of adult DRG-NPCs in culture. Although the adult DRG-NPC multipotency is restricted to the neural crest lineage, their dual responsiveness to developmental and lesion cues highlights their impressive adaptive and repair potentials making them valuable targets for regenerative medicine. © 2015 AlphaMed Press.

Adverse CNS-effects of beta-adrenoceptor blockers.

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Gleiter, C H; Deckert, J

1996-11-01

In 1962 propranolol, the first beta adrenoceptor antagonist (beta blocker), was brought on to the market. There is now a host of different beta blockers available, and these compounds are among the most commonly prescribed groups of drugs. The efficacy of beta blockers has been proven predominantly for the treatment of cardiovascular diseases. Beta blockers are also used for certain types of CNS disorders, such as anxiety disorders, essential tremor and migraine. While low toxicity means that they have a favorable risk-benefit ratio, given the high intensity of use, it is essential to have a comprehensive knowledge of adverse events. Adverse events of beta blockers that can be related to the CNS are quite often neglected, even in textbooks of clinical pharmacology or review articles, and thus often misdiagnosed. The following article, therefore, after summarizing the use of beta blockers for CNS indications, critically reviews the literature on centrally mediated adverse events. General pharmacological features of beta blockers and their molecular basis of action will briefly be addressed to the extent that they are or may become relevant for central nervous pharmacotherapy and side-effects.

Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

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Espejo, C; Carrasco, J; Hidalgo, J

2001-01-01

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein......-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression...

Beta1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance

DEFF Research Database (Denmark)

Campos, Lia S; Leone, Dino P; Relvas, Joao B

2004-01-01

, signalling is required for neural stem cell maintenance, as assessed by neurosphere formation, and inhibition or genetic ablation of beta1 integrin using cre/lox technology reduces the level of MAPK activity. We conclude that integrins are therefore an important part of the signalling mechanisms that control......The emerging evidence that stem cells develop in specialised niches highlights the potential role of environmental factors in their regulation. Here we examine the role of beta1 integrin/extracellular matrix interactions in neural stem cells. We find high levels of beta1 integrin expression...... in the stem-cell containing regions of the embryonic CNS, with associated expression of the laminin alpha2 chain. Expression levels of laminin alpha2 are reduced in the postnatal CNS, but a population of cells expressing high levels of beta1 remains. Using neurospheres - aggregate cultures, derived from...

Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphé neurones and cranial motoneurones.

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Norton, Will H; Mangoli, Maryam; Lele, Zsolt; Pogoda, Hans-Martin; Diamond, Brianne; Mercurio, Sara; Russell, Claire; Teraoka, Hiroki; Stickney, Heather L; Rauch, Gerd-Jörg; Heisenberg, Carl-Philipp; Houart, Corinne; Schilling, Thomas F; Frohnhoefer, Hans-Georg; Rastegar, Sepand; Neumann, Carl J; Gardiner, R Mark; Strähle, Uwe; Geisler, Robert; Rees, Michelle; Talbot, William S; Wilson, Stephen W

2005-02-01

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol-/- embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol-/- mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphenucleus and the trochlear motor nucleus are absent in mol-/- embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins.

TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

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Tansey Malú G

2008-10-01

Full Text Available Abstract The role of tumor necrosis factor (TNF as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1 is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF or transmembrane TNF (tmTNF, with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD, Parkinson's (PD, amyotrophic lateral sclerosis (ALS, and multiple sclerosis (MS. The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. | Center for Cancer Research

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The process by which self-reactive CD4+ T cells infiltrate the central nervous system (CNS) and trigger neuroinflammation is not fully understood. Lazarevic and colleagues show that NKp46+innate lymphoid cells dependent on the transcription factor T-bet are critical mediators in facilitating the entry of autoreactive CD4+ cells of the TH17 subset of helper T cells into the

CXCL10 is the key ligand for CXCR3 on CD8+ effector T cells involved in immune surveillance of the lymphocytic choriomeningitis virus-infected central nervous system

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Christensen, Jeanette Erbo; de Lemos, Carina; Moos, Torben

2006-01-01

/ligand pair is thought to play a central role in regulating T cell-mediated inflammation in this organ site. In this report, we investigated the role of CXCL10 in regulating CD8(+) T cell-mediated inflammation in the virus-infected brain. This was done through analysis of CXCL10-deficient mice infected...... indicate a central role for CXCL10 in regulating the accumulation of effector T cells at sites of CNS inflammation, with no apparent compensatory effect of other CXCR3 ligands....

Potential Role of Oxidative Stress in mediating the Effect of Hypergravity on the Developing CNS.

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Sajdel-Sulkowska, E. M.; Nguon, K.; Sulkowski, Z. L.; Lipinski, B.

The present studies will explore the mechanisms through which altered gravity affects the developing CNS We have previously shown that exposure to hypergravity during the perinatal period adversely impacts cerebellar structure and function Pregnant rat dams were exposed to 1 65 G on a 24-ft centrifuge at NASA-ARC from gestational day G 5 through giving birth Both dams and their offspring remained at 1 65 G until pups reached postnatal day P 21 Control rats were raised under identical conditions in stationary cages On P21 motor behavior as determined by performance on a rotorod was more negatively impacted in hypergravity-exposed HG male 39 5 than in HG female pups 29 1 The total number of Purkinje cells determined stereologically in cerebella isolated from a subset of P21 rats was decreased in both HG males and HG female pups but the correlation between Purkinje cell number and rotorod performance was more consistent in male pups The level of 3-nitrosotyrosine 3-NT an index of oxidative damage to proteins was determined by ELISA in cerebellar tissue derived from a separate subset of P21 rats The level of 3-NT was increased by 127 in HG males but only 42 in HG females These results suggest that the effect of altered gravity on the developing brain may be mediated by oxidative stress These results also suggest that the developing male CNS may be more sensitive to hypergravity-induced oxidative stress than the developing female CNS Supported by NIEHS grant ES11946-01

Regulation of cell cycle progression by cell-cell and cell-matrix forces

NARCIS (Netherlands)

Uroz, Marina; Wistorf, Sabrina; Serra-Picamal, Xavier; Conte, Vito; Sales-Pardo, Marta; Roca-Cusachs, Pere; Guimerà, Roger; Trepat, Xavier

2018-01-01

It has long been proposed that the cell cycle is regulated by physical forces at the cell-cell and cell-extracellular matrix (ECM) interfaces 1-12 . However, the evolution of these forces during the cycle has never been measured in a tissue, and whether this evolution affects cell cycle progression

Dose-dense chemoimmunotherapy and CNS prophylaxis in patients with high-risk DLBCL: a comparison of Nordic CRY-04 and CHIC studies

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Leppä, Sirpa; Jørgensen, Judit Meszaros; Brown, Peter De Nully

Background: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two completed Nordic trials...... including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these studies to compare clinical outcome and prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) vs at the end (CRY-04) of therapy. Patients and methods: Inclusion...... proliferation index (Ki67 expression available PET data, Deauville score 5 at the end of treatment was associated with increased rate of progression and death in both trials (p=0.012). Only one out of 17 biopsies from PET positive...

Causes of CNS inflammation and potential targets for anticonvulsants.

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Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

2013-08-01

Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

Cell cycle regulation in human embryonic stem cells: links to adaptation to cell culture.

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Barta, Tomas; Dolezalova, Dasa; Holubcova, Zuzana; Hampl, Ales

2013-03-01

Cell cycle represents not only a tightly orchestrated mechanism of cell replication and cell division but it also plays an important role in regulation of cell fate decision. Particularly in the context of pluripotent stem cells or multipotent progenitor cells, regulation of cell fate decision is of paramount importance. It has been shown that human embryonic stem cells (hESCs) show unique cell cycle characteristics, such as short doubling time due to abbreviated G1 phase; these properties change with the onset of differentiation. This review summarizes the current understanding of cell cycle regulation in hESCs. We discuss cell cycle properties as well as regulatory machinery governing cell cycle progression of undifferentiated hESCs. Additionally, we provide evidence that long-term culture of hESCs is accompanied by changes in cell cycle properties as well as configuration of several cell cycle regulatory molecules.

Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

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Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

2009-05-06

We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients.

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Roth, Patrick; Keller, Andreas; Hoheisel, Jörg D; Codo, Paula; Bauer, Andrea S; Backes, Christina; Leidinger, Petra; Meese, Eckart; Thiel, Eckhard; Korfel, Agnieszka; Weller, Michael

2015-02-01

Despite improved therapeutic regimens, primary CNS lymphoma (PCNSL) remains a therapeutic challenge. A prognostic classification of PCNSL patients may represent an important step towards optimised patient-adapted therapy. However, only higher age and low Karnofsky Performance Status (KPS) have repeatedly been reported to be associated with shorter overall survival (OS). Here we characterised microRNA (miRNA) fingerprints in the blood of PCNSL patients with short-term survival (STS) versus long-term survival (LTS) to assess their potential as novel prognostic biomarkers. Blood was collected from patients enrolled in the G-PCNSL-SG1 trial, a phase III study for patients with newly diagnosed PCNSL. miRNAs were extracted from the blood and analysed by next generation sequencing. The STS group comprised 20 patients with a median OS of 3 months and was compared to 20 LTS patients with a median OS of 55 months. The cohorts were balanced for age and KPS. Twelve annotated miRNAs were significantly deregulated between the two groups. Among them, miR-151a-5p and miR-151b exhibited the most prominent differences. Importantly, the combination of several miRNA allowed for a good separation between short- and long-term survivors with maximal Area Under Curve (AUC) above 0.75. Besides the known miRNAs we identified putative novel miRNA candidates with potential regulatory influence of PCNSL. Finally, the differential regulation of the most promising candidate miRNAs was confirmed by real-time polymerase chain reaction (PCR) in a validation cohort consisting of 20 STS and LTS patients. In conclusion, peripheral blood miRNA expression patterns hold promise as a prognostic tool in PCNSL patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

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Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P; Voskuhl, Rhonda R

2014-02-18

Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

Cerebral blood flow variations in CNS lupus

International Nuclear Information System (INIS)

Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M.

1990-01-01

We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery

Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells.

Science.gov (United States)

Cheng, Xiaoxin; Wang, Yaping; He, Qian; Qiu, Mengsheng; Whittemore, Scott R; Cao, Qilin

2007-12-01

Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders. Disclosure of potential conflicts of interest is found at the end of this article.

Substrate Curvature Regulates Cell Migration -A Computational Study

Science.gov (United States)

He, Xiuxiu; Jiang, Yi

Cell migration in host microenvironment is essential to cancer etiology, progression and metastasis. Cellular processes of adhesion, cytoskeletal polymerization, contraction, and matrix remodeling act in concert to regulate cell migration, while local extracellular matrix architecture modulate these processes. In this work we study how stromal microenvironment with native and cell-derived curvature at micron-meter scale regulate cell motility pattern. We developed a 3D model of single cell migration on a curved substrate. Mathematical analysis of cell morphological adaption to the cell-substrate interface shows that cell migration on convex surfaces deforms more than on concave surfaces. Both analytical and simulation results show that curved surfaces regulate the cell motile force for cell's protruding front through force balance with focal adhesion and cell contraction. We also found that cell migration on concave substrates is more persistent. These results offer a novel biomechanical explanation to substrate curvature regulation of cell migration. NIH 1U01CA143069.

Basic Concepts of CNS Development.

Science.gov (United States)

Nowakowski, R. S.

1987-01-01

The goals of this review are to: (1) provide a set of concepts to aid in the understanding of complex processes which occur during central nervous system (CNS) development; (2) illustrate how they contribute to our knowlege of adult brain anatomy; and (3) delineate how modifications of normal developmental processes may affect the structure and…

Microglia Induce Neurotoxic IL-17+ γδ T Cells Dependent on TLR2, TLR4, and TLR9 Activation.

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Katja Derkow

Full Text Available Interleukin-17 (IL-17 acts as a key regulator in central nervous system (CNS inflammation. γδ T cells are an important innate source of IL-17. Both IL-17+ γδ T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.In this study, we investigated the crosstalk between γδ T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ γδ T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.We report here that IL-17+ γδ T cells but not naïve γδ T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of γδ T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of γδ T cells through IL-1β and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88 expressed by both γδ T cells and microglia, but did not require the expression of TLRs by γδ T cells. Similarly to cytokine-primed IL-17+ γδ T cells, IL-17+ γδ T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ γδ T cells required a direct cell-cell contact between T

Modelling the endothelial blood-CNS barriers: a method for the production of robust in vitro models of the rat blood-brain barrier and blood-spinal cord barrier.

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Watson, P Marc D; Paterson, Judy C; Thom, George; Ginman, Ulrika; Lundquist, Stefan; Webster, Carl I

2013-06-18

Modelling the blood-CNS barriers of the brain and spinal cord in vitro continues to provide a considerable challenge for research studying the passage of large and small molecules in and out of the central nervous system, both within the context of basic biology and for pharmaceutical drug discovery. Although there has been considerable success over the previous two decades in establishing useful in vitro primary endothelial cell cultures from the blood-CNS barriers, no model fully mimics the high electrical resistance, low paracellular permeability and selective influx/efflux characteristics of the in vivo situation. Furthermore, such primary-derived cultures are typically labour-intensive and generate low yields of cells, limiting scope for experimental work. We thus aimed to establish protocols for the high yield isolation and culture of endothelial cells from both rat brain and spinal cord. Our aim was to optimise in vitro conditions for inducing phenotypic characteristics in these cells that were reminiscent of the in vivo situation, such that they developed into tight endothelial barriers suitable for performing investigative biology and permeability studies. Brain and spinal cord tissue was taken from the same rats and used to specifically isolate endothelial cells to reconstitute as in vitro blood-CNS barrier models. Isolated endothelial cells were cultured to expand the cellular yield and then passaged onto cell culture inserts for further investigation. Cell culture conditions were optimised using commercially available reagents and the resulting barrier-forming endothelial monolayers were characterised by functional permeability experiments and in vitro phenotyping by immunocytochemistry and western blotting. Using a combination of modified handling techniques and cell culture conditions, we have established and optimised a protocol for the in vitro culture of brain and, for the first time in rat, spinal cord endothelial cells. High yields of both CNS

Zika (PRVABC59 Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice.

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Mohanraj Manangeeswaran

2016-11-01

Full Text Available The recent spread of Zika virus (ZIKV and its association with increased rates of Guillain Barre and other neurological disorders as well as congenital defects that include microcephaly has created an urgent need to develop animal models to examine the pathogenesis of the disease and explore the efficacy of potential therapeutics and vaccines. Recently developed infection models for ZIKV utilize mice defective in interferon responses. In this study we establish and characterize a new model of peripheral ZIKV infection using immunocompetent neonatal C57BL/6 mice and compare its clinical progression, virus distribution, immune response, and neuropathology with that of C57BL/6-IFNAR KO mice. We show that while ZIKV infected IFNAR KO mice develop bilateral hind limb paralysis and die 5-6 days post-infection (dpi, immunocompetent B6 WT mice develop signs of neurological disease including unsteady gait, kinetic tremors, severe ataxia and seizures by 13 dpi that subside gradually over 2 weeks. Immunohistochemistry show viral antigen predominantly in cerebellum at the peak of the disease in both models. However, whereas IFNAR KO mice showed infiltration by neutrophils and macrophages and higher expression of IL-1, IL-6 and Cox2, B6 WT mice show a cellular infiltration in the CNS composed predominantly of T cells, particularly CD8+ T cells, and increased mRNA expression levels of IFNg, GzmB and Prf1 at peak of disease. Lastly, the CNS of B6 WT mice shows evidence of neurodegeneration predominantly in the cerebellum that are less prominent in mice lacking the IFN response possibly due to the difference in cellular infiltrates and rapid progression of the disease in that model. The development of the B6 WT model of ZIKV infection will provide insight into the immunopathology of the virus and facilitate assessments of possible therapeutics and vaccines.

TGF-β Signaling Regulates Pancreatic β-Cell Proliferation through Control of Cell Cycle Regulator p27 Expression

International Nuclear Information System (INIS)

Suzuki, Tomoyuki; Dai, Ping; Hatakeyama, Tomoya; Harada, Yoshinori; Tanaka, Hideo; Yoshimura, Norio; Takamatsu, Tetsuro

2013-01-01

Proliferation of pancreatic β-cells is an important mechanism underlying β-cell mass adaptation to metabolic demands. Increasing β-cell mass by regeneration may ameliorate or correct both type 1 and type 2 diabetes, which both result from inadequate production of insulin by β-cells of the pancreatic islet. Transforming growth factor β (TGF-β) signaling is essential for fetal development and growth of pancreatic islets. In this study, we exposed HIT-T15, a clonal pancreatic β-cell line, to TGF-β signaling. We found that inhibition of TGF-β signaling promotes proliferation of the cells significantly, while TGF-β signaling stimulation inhibits proliferation of the cells remarkably. We confirmed that this proliferative regulation by TGF-β signaling is due to the changed expression of the cell cycle regulator p27. Furthermore, we demonstrated that there is no observed effect on transcriptional activity of p27 by TGF-β signaling. Our data show that TGF-β signaling mediates the cell-cycle progression of pancreatic β-cells by regulating the nuclear localization of CDK inhibitor, p27. Inhibition of TGF-β signaling reduces the nuclear accumulation of p27, and as a result this inhibition promotes proliferation of β-cells

Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

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Morioka, Norimitsu, E-mail: mnori@hiroshima-u.ac.jp; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

2016-01-08

Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

International Nuclear Information System (INIS)

Morioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

2016-01-01

Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

Problems of prophylactic CNS radiotherapy in acute children's leukemia

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Bek, V.; Pribylova, O.; Abrahamova, J.; Hynieova, H.; Hrodek, O.

1980-01-01

The prophylactic treatment of the CNS was conducted by cobalt teletherapy of the cranium and by intrathecal application of MTX after the induction of primary remission in 70 children with acute leukemia throughout 5 years up to the end of 1978. The method of the combined radio- and chemoprophylaxis of the CNS was being changed during the years, especially as far as the radiation dose for the cranium was concerned. A detailed analysis made in a group of 59 children with the minimum interval of 18 months from the beginning of the treatment showed the best results after the application of a dose of 24 Gy/3 weeks. Following this procedure the relapse of leukemia in the CNS occurred in 9% only, whereas on the application of doses of 20 Gy and lower it occurred in 35 to 40%. On the whole 24 out of 59 children, i.e. 41%, are surviving, 35 children, i.e. 59%, died. Mostly complete, but only temporary, epilation was an invariable consequence of the irradiation of the cranium. The somnolence syndrome was only sporadically observed. It cannot be excluded, however, that some of its forms in patients discharged from hospital escaped attention. No case was recorded of serious impairment of the CNS of the leukoencephalopathic type. Up to now the psychomotor, intellectual and emotional development of the surviving children has been normal. (author)

VIIP: Central Nervous System (CNS) Modeling

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Vera, Jerry; Mulugeta, Lealem; Nelson, Emily; Raykin, Julia; Feola, Andrew; Gleason, Rudy; Samuels, Brian; Ethier, C. Ross; Myers, Jerry

2015-01-01

Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al.

Cross-talk between KLF4 and STAT3 regulates axon regeneration

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Qin, Song; Zou, Yuhua; Zhang, Chun-Li

2013-10-01

Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.

CNS metastasis from malignant uveal melanoma: a clinical and histopathological characterisation

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Holfort, S K; Lindegaard, J; Isager, P

2008-01-01

was observed in two cases (14%). The amount of tumour infiltrating lymphocytes was pronounced in three cases (23%). CONCLUSION: The proportion of uveal melanoma patients having CNS metastasis was 0.7%. Eleven patients had multiple organ metastases, and the average time from the initial CNS symptoms to death...

Deletion of a coordinate regulator of type 2 cytokine expression in mice

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Mohrs, Markus; Blankespoor, Catherine M.; Wang, Zhi-En; Loots, Gaby G.; Hadeiba, Husein; Shinkai, Kanade; Rubin, Edward M.; Locksley, Richard M.

2001-07-30

Mechanisms underlying the differentiation of stable T helper subsets will be important in understanding how discrete types of immunity develop in response to different pathogens. An evolutionarily conserved {approx}400 base pair non-coding sequence in the IL-4/IL-13 intergenic region, designated CNS-1, was deleted in mice. The capacity to develop Th2 cells was compromised in vitro and in vivo in the absence of CNS-1. Despite the profound effect in T cells, mast cells from CNS-1-deleted mice maintained their capacity to produce IL-4. A T cell-specific element critical for optimal expression of type 2 cytokines may represent evolution of a regulatory sequence exploited by adaptive immunity.

Regulation of Constitutive GPR3 Signaling and Surface Localization by GRK2 and β-arrestin-2 Overexpression in HEK293 Cells.

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Katie M Lowther

Full Text Available G protein-coupled receptor 3 (GPR3 is a constitutively active receptor that maintains high 3'-5'-cyclic adenosine monophosphate (cAMP levels required for meiotic arrest in oocytes and CNS function. Ligand-activated G protein-coupled receptors (GPCRs signal at the cell surface and are silenced by phosphorylation and β-arrestin recruitment upon endocytosis. Some GPCRs can also signal from endosomes following internalization. Little is known about the localization, signaling, and regulation of constitutively active GPCRs. We demonstrate herein that exogenously-expressed GPR3 localizes to the cell membrane and undergoes internalization in HEK293 cells. Inhibition of endocytosis increased cell surface-localized GPR3 and cAMP levels while overexpression of GPCR-Kinase 2 (GRK2 and β-arrestin-2 decreased cell surface-localized GPR3 and cAMP levels. GRK2 by itself is sufficient to decrease cAMP production but both GRK2 and β-arrestin-2 are required to decrease cell surface GPR3. GRK2 regulates GPR3 independently of its kinase activity since a kinase inactive GRK2-K220R mutant significantly decreased cAMP levels. However, GRK2-K220R and β-arrestin-2 do not diminish cell surface GPR3, suggesting that phosphorylation is required to induce GPR3 internalization. To understand which residues are targeted for desensitization, we mutated potential phosphorylation sites in the third intracellular loop and C-terminus and examined the effect on cAMP and receptor surface localization. Mutation of residues in the third intracellular loop dramatically increased cAMP levels whereas mutation of residues in the C-terminus produced cAMP levels comparable to GPR3 wild type. Interestingly, both mutations significantly reduced cell surface expression of GPR3. These results demonstrate that GPR3 signals at the plasma membrane and can be silenced by GRK2/β-arrestin overexpression. These results also strongly implicate the serine and/or threonine residues in the third

Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells

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Takahashi Takashi

2007-04-01

Full Text Available Abstract Background TGF-beta is one of the key cytokines implicated in various disease processes including cancer. TGF-beta inhibits growth and promotes apoptosis in normal epithelial cells and in contrast, acts as a pro-tumour cytokine by promoting tumour angiogenesis, immune-escape and metastasis. It is not clear if various actions of TGF-beta on normal and tumour cells are due to differential gene regulations. Hence we studied the regulation of gene expression by TGF-beta in normal and cancer cells. Results Using human 19 K cDNA microarrays, we show that 1757 genes are exclusively regulated by TGF-beta in A549 cells in contrast to 733 genes exclusively regulated in HPL1D cells. In addition, 267 genes are commonly regulated in both the cell-lines. Semi-quantitative and real-time qRT-PCR analysis of some genes agrees with the microarray data. In order to identify the signalling pathways that influence TGF-beta mediated gene regulation, we used specific inhibitors of p38 MAP kinase, ERK kinase, JNK kinase and integrin signalling pathways. The data suggest that regulation of majority of the selected genes is dependent on at least one of these pathways and this dependence is cell-type specific. Interestingly, an integrin pathway inhibitor, RGD peptide, significantly affected TGF-beta regulation of Thrombospondin 1 in A549 cells. Conclusion These data suggest major differences with respect to TGF-beta mediated gene regulation in normal and transformed cells and significant role of non-canonical TGF-beta pathways in the regulation of many genes by TGF-beta.

Biophysical regulation of stem cell differentiation.

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Govey, Peter M; Loiselle, Alayna E; Donahue, Henry J

2013-06-01

Bone adaptation to its mechanical environment, from embryonic through adult life, is thought to be the product of increased osteoblastic differentiation from mesenchymal stem cells. In parallel with tissue-scale loading, these heterogeneous populations of multipotent stem cells are subject to a variety of biophysical cues within their native microenvironments. Bone marrow-derived mesenchymal stem cells-the most broadly studied source of osteoblastic progenitors-undergo osteoblastic differentiation in vitro in response to biophysical signals, including hydrostatic pressure, fluid flow and accompanying shear stress, substrate strain and stiffness, substrate topography, and electromagnetic fields. Furthermore, stem cells may be subject to indirect regulation by mechano-sensing osteocytes positioned to more readily detect these same loading-induced signals within the bone matrix. Such paracrine and juxtacrine regulation of differentiation by osteocytes occurs in vitro. Further studies are needed to confirm both direct and indirect mechanisms of biophysical regulation within the in vivo stem cell niche.

Neuroprotective effects of estrogen in CNS injuries: insights from animal models

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Raghava N

2017-07-01

Full Text Available Narayan Raghava,1 Bhaskar C Das,2 Swapan K Ray1 1Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Among the estrogens that are biosynthesized in the human body, 17β-estradiol (estradiol or E2 is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS injuries such as spinal cord injury (SCI, traumatic brain injury (TBI, and ischemic brain injury (IBI. These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for

Visualization of Carbon Nanoparticles Within Cells and Implications for Toxicity

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Porter, Alexandra; Gass, Mhairi

Carbon nanostructures (CNS), such as C60, single-walled nanotubes (SWNTs) exhibit extraordinary properties and are one of the most commercially relevant class of NS. CNS have already found uses in high-performance sports equipment (nanotubes) and face cream (C60), whilst potential applications include optical and electronic materials and superconductors. Following the huge growth in these nanotechnology-related industries, significant concerns have arisen about their potential toxicity and impact on the environment. A lack in understanding of the interaction of such small structures with cellular material has resulted in concerns over their impact on human health. The potential toxicity of CNS and safety to human health requires an understanding of their interaction with cells and this in turn relies on the measurement of the pathways by which they enter the cell, their spatial distribution within and whether the CNS are transformed by the action of the cell; visualization of intracellular CNS is therefore imperative. However visualizing unlabelled CNS within cells is demanding because it is difficult to distinguish CNS from carbon-rich organelles given their similarity in composition and dimensions. In particular, the challenge lies in translating analytical imaging tools developed for inorganic systems to organic systems. This chapter describes how the state-of-the-art transmission electron microscopy (TEM) techniques, such as low-loss energy-filtered TEM (EFTEM) can be employed to differentiate between unlabelled C60, SWNTs and the cell. Further, we demonstrate how these techniques can be used to trace the uptake of CNS into the cell and to assess their localized effects on cell structure.

Targeted CNS delivery using human MiniPromoters and demonstrated compatibility with adeno-associated viral vectors

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Charles N de Leeuw

2014-01-01

Full Text Available Critical for human gene therapy is the availability of small promoters tools to drive gene expression in a highly specific and reproducible manner. We tackled this challenge by developing human DNA MiniPromoters (MiniPs using computational biology and phylogenetic conservation. MiniPs were tested in mouse as single-copy knock-ins at the Hprt locus on the X chromosome and evaluated for lacZ reporter expression in central nervous system (CNS and non–CNS tissue. Eighteen novel MiniPs driving expression in mouse brain were identified, 2 MiniPs for driving pan-neuronal expression and 17 MiniPs for the mouse eye. Key areas of therapeutic interest were represented in this set: the cerebral cortex, embryonic hypothalamus, spinal cord, bipolar and ganglion cells of the retina, and skeletal muscle. We also demonstrated that three retinal ganglion cell MiniPs exhibit similar cell type specificity when delivered via adeno-associated virus vectors intravitreally. We conclude that our methodology and characterization has resulted in desirable expression characteristics that are intrinsic to the MiniPromoter, not dictated by copy-number effects or genomic location, and results in constructs predisposed to success in adeno-associated virus. These MiniPs are immediately applicable for preclinical studies toward gene therapy in humans and are publicly available to facilitate basic and clinical research, and human gene therapy.

Loss rather than downregulation of CD4+ T cells as a mechanism for remission from experimental allergic encephalomyelitis

DEFF Research Database (Denmark)

Zeine, R; Owens, T

1993-01-01

reduction in the number of CNS CD4+ T cells in remitted mice 10 days following the initial attack. More than 60% of CNS CD4+ cells were of a CD44high, CD45RBlow memory/effector phenotype both in active EAE, peak EAE and in remission, in contrast to lymph nodes where this phenotype never constituted more...... than 17%. The proportion of CD8+ T cells was not increased in remitted mice, and we detected no TCR gamma delta+ cells within the CNS. Our findings demonstrate an overt loss of CD4+ T cells from the CNS and the maintenance of an activated state by T cells within the CNS and during remission from EAE...... infiltrating the central nervous system (CNS) in symptomatic and remitted mice. We isolated mononuclear cells from the CNS at various time points during the course of EAE and used flow cytometry to describe the kinetics of CNS infiltration by CD45+, CD2+, CD3+, TCR alpha beta+, CD4+ cells. There was a 30-fold...

Management of CNS tumors

International Nuclear Information System (INIS)

Griem, M.L.

1987-01-01

The treatment of tumors of the CNS has undergone a number of changes based on the impact of CT. The use of intraoperative US for the establishment of tumor location and tumor histology is demonstrated. MR imaging also is beginning to make an impact on the diagnosis and treatment of tumors of the CNS. Examples of MR images are shown. The authors then discuss the important aspects of tumor histology as it affects management and newer concepts in surgery, radiation, and chemotherapy on tumor treatment. The role of intraoperative placement of radioactive sources, the utilization of heavy particle radiation therapy, and the potential role of other experimental radiation therapy techniques are discussed. The role of hyperfractionated radiation and of neutrons and x-ray in a mixed-beam treatment are discussed in perspective with standard radiation therapy. Current chemotherapy techniques, including intraarterial chemotherapy, are discussed. The complications of radiation therapy alone and in combination with chemotherapy in the management of primary brain tumors, brain metastases, and leukemia are reviewed. A summary of the current management of pituitary tumors, including secreting pituitary adenomas and chromophobe adenomas, are discussed. The treatment with heavy particle radiation, transsphenoidal microsurgical removal, and combined radiotherapeutic and surgical management are considered. Tumor metastasis management of lesions of the brain and spinal cord are considered

Regulation of the cell cycle by irradiation

International Nuclear Information System (INIS)

Akashi, Makoto

1995-01-01

The molecular mechanism of cell proliferation is extremely complex; deregulation results in neoplastic transformation. In eukaryotes, proliferation of cells is finely regulated through the cell cycle. Studies have shown that the cell cycle is regulated by s series of enzymes known as cyclin-dependent kinases (CDKs). The activities of CDKs are controlled by their association with regulatory subunits, cyclins; the expression of cyclins and the activation of the different cyclin-CDK complexes are required for the cell to cycle. Thus, the cell cycle is regulated by activating and inhibiting phosphorylation of the CDK subunits and this program has internal check points at different stages of the cell cycle. When cells are exposed to external insults such as DNA damaging agents, negative regulation of the cell cycle occurs; arrest in either G1 or G2 stage is induced to prevent the cells from prematurely entering into the next stage before DNA is repaired. Recently, a potent inhibitor of CDKs, which inhibits the phosphorylation of retinoblastoma susceptibility (Rb) gene product by cyclin A-CDK2, cyclin E-CDK2, cyclin D1-CDK4, and cyclin D2-CDK4 complexes has been identified. This protein named WAF1, Sdi1, Cip1, or p21 (a protein of Mr 21,000) contains a p53-binding site in its promoter and studies have reported that the expression of WAF1 was directly regulated by p53; cells with loss of p53 activity due to mutational alteration were unable to induce WAF1. This chapter will be focused on the mechanisms of the cell cycle including inhibitors of CDKs, and the induction of WAF1 by irradiation through a pathway independent of p53 will be also described. (author)

Novel agents in CNS myeloma treatment.

Science.gov (United States)

Gozzetti, Alessandro; Cerase, Alfonso

2014-01-01

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM.Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease.

Regulation of lipid metabolism by energy availability: a role for the central nervous system.

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Nogueiras, R; López, M; Diéguez, C

2010-03-01

The central nervous system (CNS) is crucial in the regulation of energy homeostasis. Many neuroanatomical studies have shown that the white adipose tissue (WAT) is innervated by the sympathetic nervous system, which plays a critical role in adipocyte lipid metabolism. Therefore, there are currently numerous reports indicating that signals from the CNS control the amount of fat by modulating the storage or oxidation of fatty acids. Importantly, some CNS pathways regulate adipocyte metabolism independently of food intake, suggesting that some signals possess alternative mechanisms to regulate energy homeostasis. In this review, we mainly focus on how neuronal circuits within the hypothalamus, such as leptin- ghrelin-and resistin-responsive neurons, as well as melanocortins, neuropeptide Y, and the cannabinoid system exert their actions on lipid metabolism in peripheral tissues such as WAT, liver or muscle. Dissecting the complicated interactions between peripheral signals and neuronal circuits regulating lipid metabolism might open new avenues for the development of new therapies preventing and treating obesity and its associated cardiometabolic sequelae.

Impact of cycling cells and cell cycle regulation on Hydra regeneration.

Science.gov (United States)

Buzgariu, Wanda; Wenger, Yvan; Tcaciuc, Nina; Catunda-Lemos, Ana-Paula; Galliot, Brigitte

2018-01-15

Hydra tissues are made from three distinct populations of stem cells that continuously cycle and pause in G2 instead of G1. To characterize the role of cell proliferation after mid-gastric bisection, we have (i) used flow cytometry and classical markers to monitor cell cycle modulations, (ii) quantified the transcriptomic regulations of 202 genes associated with cell proliferation during head and foot regeneration, and (iii) compared the impact of anti-proliferative treatments on regeneration efficiency. We confirm two previously reported events: an early mitotic wave in head-regenerating tips, when few cell cycle genes are up-regulated, and an early-late wave of proliferation on the second day, preceded by the up-regulation of 17 cell cycle genes. These regulations appear more intense after mid-gastric bisection than after decapitation, suggesting a position-dependent regulation of cell proliferation during head regeneration. Hydroxyurea, which blocks S-phase progression, delays head regeneration when applied before but not after bisection. This result is consistent with the fact that the Hydra central region is enriched in G2-paused adult stem cells, poised to divide upon injury, thus forming a necessary constitutive pro-blastema. However a prolonged exposure to hydroxyurea does not block regeneration as cells can differentiate apical structures without traversing S-phase, and also escape in few days the hydroxyurea-induced S-phase blockade. Thus Hydra head regeneration, which is a fast event, is highly plastic, relying on large stocks of adult stem cells paused in G2 at amputation time, which immediately divide to proliferate and/or differentiate apical structures even when S-phase is blocked. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis

OpenAIRE

Kocalis, Heidi E.; Hagan, Scott L.; George, Leena; Turney, Maxine K.; Siuta, Michael A.; Laryea, Gloria N.; Morris, Lindsey C.; Muglia, Louis J.; Printz, Richard L.; Stanwood, Gregg D.; Niswender, Kevin D.

2014-01-01

Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing...

LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo

NARCIS (Netherlands)

Zuurman, MW; Heeroma, J; Brouwer, N; Boddeke, HWGM; Biber, K

There is increasing evidence that chemokines, specialized regulators of the peripheral immune system, are also involved in the physiology and pathology of the CNS. It is known that glial cells (astrocytes and microglia) express various chemokine receptors like CCR1, -3, -5, and CXCR4. We have

The epigenetic regulation of stem cell factors in hepatic stellate cells.

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Reister, Sven; Kordes, Claus; Sawitza, Iris; Häussinger, Dieter

2011-10-01

The epigenetic regulation by DNA methylation is an important mechanism to control the expression of stem cell factors as demonstrated in tumor cells. It was recently shown that hepatic stellate cells (HSC) express stem/progenitor cell factors and have a differentiation potential. The aim of this work was to investigate if the expression of stem cell markers is regulated by DNA methylation during activation of rat HSC. It was found that CD133, Notch1, and Notch3 are regulated via DNA methylation in HSC, whereas Nestin shows no DNA methylation in HSC and other undifferentiated cells such as embryonic stem cells and umbilical cord blood stem cells from rats. In contrast to this, DNA methylation controls Nestin expression in differentiated cells like hepatocytes and the hepatoma cell line H4IIE. Demethylation by 5-Aza-2-deoxycytidine was sufficient to induce Nestin in H4IIE cells. In quiescent stellate cells and embryonic stem cells, the Nestin expression was suppressed by histone H3 methylation at lysine 9, which is another epigenetic mechanism. Apart from the known induction of Nestin in cultured HSC, this intermediate filament protein was also induced after partial hepatectomy, indicating activation of HSC during liver regeneration. Taken together, this study demonstrates for the first time that the expression of stem cell-associated factors such as CD133, Notch1, and Notch3 is controlled by DNA methylation in HSC. The regulation of Nestin by DNA methylation seems to be restricted to differentiated cells, whereas undifferentiated cells use different epigenetic mechanisms such as histone H3 methylation to control Nestin expression.

T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases.

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Newman, T A; Woolley, S T; Hughes, P M; Sibson, N R; Anthony, D C; Perry, V H

2001-11-01

Recent evidence has highlighted the fact that axon injury is an important component of multiple sclerosis pathology. The issue of whether a CNS antigen-specific immune response is required to produce axon injury remains unresolved. We investigated the extent and time course of axon injury in a rodent model of a delayed-type hypersensitivity (DTH) reaction directed against the mycobacterium bacille Calmette-Guérin (BCG). Using MRI, we determined whether the ongoing axon injury is restricted to the period during which the blood-brain barrier is compromised. DTH lesions were initiated in adult rats by intracerebral injection of heat-killed BCG followed by a peripheral challenge with BCG. Our findings demonstrate that a DTH reaction to a non-CNS antigen within a CNS white matter tract leads to axon injury. Ongoing axon injury persisted throughout the 3-month period studied and was not restricted to the period of blood-brain barrier breakdown, as detected by MRI enhancing lesions. We have previously demonstrated that matrix metalloproteinases (MMPs) are upregulated in multiple sclerosis plaques and DTH lesions. In this study we demonstrated that microinjection of activated MMPs into the cortical white matter results in axon injury. Our results show that axon injury, possibly mediated by MMPs, is immunologically non-specific and may continue behind an intact blood-brain barrier.

Thermo-siphon Mock-up Test for the HANARO-CNS

Energy Technology Data Exchange (ETDEWEB)

Choi, Jungwoon; Lee, Kye Hong; Kim, Hark Rho; Kim, Youngki; Kim, Myong Seop; Wu, Sang Ik; Kim, Bong Su

2006-04-15

In order to moderate thermal neutrons into cold neutrons, the liquid hydrogen is selected as a moderator for the HANARO CNS. By the non-nuclear heat load and nuclear heat load induced from collision of gamma-ray, beta-ray, and thermal neutrons, the liquid hydrogen in the moderator cell evaporates and flows into the heat exchanger. This evaporated hydrogen gas is liquefied by the cryogenic helium supplied from the helium refrigeration system,, then flows back to the moderator cell. This is so-called two-phase thermo-siphon. The most important point in the stable thermo-siphon is to have the good balance between the cooling capacity of the HRS and the heat load on the moderator cell so as to maintain the stable two-phase liquid level in the moderator cell. Accordingly, for not only the experience of the cryogenic two-phase thermo-siphon but also setup of the operation procedure, the full-scaled mock-up test has been performed using the liquid hydrogen. Through the test, the stable thermo-siphon establishment is confirmed at the cold normal operation; furthermore, the detail design parameter is validated. On top of the normal operation procedure setup, the abnormal operation procedure is settled based on the understanding the abnormal pressure and temperature transient dynamics in the hydrogen system.

Understanding cell cycle and cell death regulation provides novel weapons against human diseases.

Science.gov (United States)

Wiman, K G; Zhivotovsky, B

2017-05-01

Cell division, cell differentiation and cell death are the three principal physiological processes that regulate tissue homoeostasis in multicellular organisms. The growth and survival of cells as well as the integrity of the genome are regulated by a complex network of pathways, in which cell cycle checkpoints, DNA repair and programmed cell death have critical roles. Disruption of genomic integrity and impaired regulation of cell death may both lead to uncontrolled cell growth. Compromised cell death can also favour genomic instability. It is becoming increasingly clear that dysregulation of cell cycle and cell death processes plays an important role in the development of major disorders such as cancer, cardiovascular disease, infection, inflammation and neurodegenerative diseases. Research achievements in these fields have led to the development of novel approaches for treatment of various conditions associated with abnormalities in the regulation of cell cycle progression or cell death. A better understanding of how cellular life-and-death processes are regulated is essential for this development. To highlight these important advances, the Third Nobel Conference entitled 'The Cell Cycle and Cell Death in Disease' was organized at Karolinska Institutet in 2016. In this review we will summarize current understanding of cell cycle progression and cell death and discuss some of the recent advances in therapeutic applications in pathological conditions such as cancer, neurological disorders and inflammation. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Post-transcriptional trafficking and regulation of neuronal gene expression.

Science.gov (United States)

Goldie, Belinda J; Cairns, Murray J

2012-02-01

Intracellular messenger RNA (mRNA) traffic and translation must be highly regulated, both temporally and spatially, within eukaryotic cells to support the complex functional partitioning. This capacity is essential in neurons because it provides a mechanism for rapid input-restricted activity-dependent protein synthesis in individual dendritic spines. While this feature is thought to be important for synaptic plasticity, the structures and mechanisms that support this capability are largely unknown. Certainly specialized RNA binding proteins and binding elements in the 3' untranslated region (UTR) of translationally regulated mRNA are important, but the subtlety and complexity of this system suggests that an intermediate "specificity" component is also involved. Small non-coding microRNA (miRNA) are essential for CNS development and may fulfill this role by acting as the guide strand for mediating complex patterns of post-transcriptional regulation. In this review we examine post-synaptic gene regulation, mRNA trafficking and the emerging role of post-transcriptional gene silencing in synaptic plasticity.

Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI)

International Nuclear Information System (INIS)

Wenz, Frederik; Steinvorth, Sarah; Lohr, Frank; Fruehauf, Stefan; Wildermuth, Susanne; Kampen, Michael van; Wannenmacher, Michael

2000-01-01

Purpose: Prospective evaluation of chronic radiation effects on the healthy adult brain using neuropsychological testing of intelligence, attention, and memory. Methods and Materials: 58 patients (43 ± 10 yr) undergoing hyperfractionated total body irradiation (TBI) (TBI, 14.4 Gy, 12 x 1.2 Gy in 4 days) before bone marrow or peripheral blood stem cell transplantation were prospectively included. Twenty-one recurrence-free long-term survivors were re-examined 6-36 months (median 27 months) after completion of TBI. Neuropsychological testing included assessment of general intelligence, attention, and memory using normative, standardized psychometric tests. Mood status was controlled, as well. Test results are given as IQ scores (population mean 100) or percentiles for attention and memory (population mean 50). Results: The 21 patients showed normal baseline test results of IQ (101 ± 13) and attention (53 ± 28), with memory test scores below average (35 ± 21). Test results of IQ (98 ± 17), attention (58 ± 27), and memory (43 ± 28) showed no signs of clinically measurable radiation damage to higher CNS (central nervous system) functions during the follow-up. The mood status was improved. Conclusion: The investigation of CNS toxicity after hyperfractionated TBI showed no deterioration of test results in adult recurrence-free patients with tumor-free CNS. The median follow-up of 27 months will be extended.

New evidence for the origin of intracranial germ cell tumours from primordial germ cells

DEFF Research Database (Denmark)

Hoei-Hansen, C E; Sehested, A; Juhler, M

2006-01-01

that it is not required for the initiation of malignant germ cell transformation. The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumours strongly suggests that these tumours are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which...... germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children...... and young adults with intracranial germinomas and non-germinomas, contributing to a careful description of these unusual tumours and adding to the understanding of pathogenesis. Stem cell related proteins were highly expressed in intracranial germ cell tumours, and many similarities were detected...

Integrating physiological regulation with stem cell and tissue homeostasis

Science.gov (United States)

Nakada, Daisuke; Levi, Boaz P.; Morrison, Sean J.

2015-01-01

Summary Stem cells are uniquely able to self-renew, to undergo multilineage differentiation, and to persist throughout life in a number of tissues. Stem cells are regulated by a combination of shared and tissue-specific mechanisms and are distinguished from restricted progenitors by differences in transcriptional and epigenetic regulation. Emerging evidence suggests that other aspects of cellular physiology, including mitosis, signal transduction, and metabolic regulation also differ between stem cells and their progeny. These differences may allow stem cells to be regulated independently of differentiated cells in response to circadian rhythms, changes in metabolism, diet, exercise, mating, aging, infection, and disease. This allows stem cells to sustain homeostasis or to remodel relevant tissues in response to physiological change. Stem cells are therefore not only regulated by short-range signals that maintain homeostasis within their tissue of origin, but also by long-range signals that integrate stem cell function with systemic physiology. PMID:21609826

Neuroinflammation, Bone Marrow Stem Cells, and Chronic Pain

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Yul Huh

2017-08-01

Full Text Available Current treatments for chronic pain, such as inflammatory pain, neuropathic pain, and cancer pain are insufficient and cause severe side effects. Mounting evidence suggests that neuroinflammation in the peripheral and central nervous system (PNS and CNS plays a pivotal role in the genesis and maintenance of chronic pain. Characteristic features of neuroinflammation in chronic pain conditions include infiltration of immune cells into the PNS [e.g., the sciatic nerve and dorsal root ganglion (DRG], activation of glial cells such as microglia and astrocytes in the CNS (spinal cord and brain, and production and secretion of pro-inflammatory cytokines and chemokines [TNF, interleukin (IL-1β, IL-6, CCL2, and CXCL1]. Recent studies suggest that bone marrow stem cells or bone marrow stromal cells (BMSCs produce powerful analgesic effects in animal models of inflammatory pain, neuropathic pain, and cancer pain. We recently demonstrated that intrathecal injection of BMSCs resulted in a long-term relief of neuropathic pain for several weeks after peripheral nerve injury. Strikingly, this analgesic effect is mediated by the anti-inflammatory cytokine transforming growth factor beta secreted from BMSCs. Additionally, BMSCs exhibit potent modulation of neuroinflammation, by inhibiting monocyte infiltration, glial activation, and cytokine/chemokine production in the DRG and spinal cord. Thus, BMSCs control chronic pain by regulation of neuroinflammation in the PNS and CNS via paracrine signaling. In this review, we discuss the similar results from different laboratories of remarkable anti-nociceptive efficacy of BMSCs in animal and clinical studies. We also discuss the mechanisms by which BMSCs control neuroinflammation and chronic pain and how these cells specifically migrate to damaged tissues.

Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease.

Science.gov (United States)

Hur, Eun-Mi; Lee, Byoung Dae

2014-12-01

Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.

Microtubule-Targeting Agents Enter the Central Nervous System (CNS: Double-edged Swords for Treating CNS Injury and Disease

Directory of Open Access Journals (Sweden)

Eun-Mi Hur

2014-12-01

Full Text Available Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.

Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury

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Katja M. Piltti

2015-09-01

Full Text Available The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury.

Sex-specific effects of dehydroepiandrosterone (DHEA) on glucose metabolism in the CNS.

Science.gov (United States)

Vieira-Marques, Claudia; Arbo, Bruno Dutra; Cozer, Aline Gonçalves; Hoefel, Ana Lúcia; Cecconello, Ana Lúcia; Zanini, Priscila; Niches, Gabriela; Kucharski, Luiz Carlos; Ribeiro, Maria Flávia M

2017-07-01

DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases. Copyright © 2016. Published by Elsevier Ltd.

CNS effects following the treatment of malignancy

International Nuclear Information System (INIS)

Rane, N.; Quaghebeur, G.

2012-01-01

Corporeal and central nervous system (CNS) axis chemotherapy and radiotherapy have long been used for the effective treatment and prophylaxis of CNS, body malignancies, and leukaemias. However, they are not without their problems. Following the proliferation of magnetic resonance neuroimaging in recent years it has become clear that the spectrum of toxicity that these therapies produce ranges from subclinical white matter changes to overt brain necrosis. The effects are both direct and indirect and via different pathological mechanisms. Chronic and progressive changes can be detected many years after the initial intervention. In addition to leucoencephalopathic changes, grey matter changes are now well described. Changes may be difficult to distinguish from tumour recurrence, though may be reversible and remediable, and are thus very important to differentiate. In this review toxic effects are classified and their imaging appearances discussed, with reference to specific syndromes.

Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia

DEFF Research Database (Denmark)

Rohde, Christopher; Polcwiartek, Christoffer; Asztalos, Marton

2018-01-01

were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model. RESULTS: CNS...

Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

DEFF Research Database (Denmark)

Wlodarczyk, Agnieszka; Løbner, Morten; Cédile, Oriane

2014-01-01

BACKGROUND: Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells...... (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. METHODS: In this work we compared the antigen presenting capacity of CD11c+ and CD11c- microglia subsets with infiltrating CD11c......+ APC, which include DC. The microglial subpopulations (CD11c- CD45dim CD11b+ and CD11c+ CD45dim CD11b+) as well as infiltrating CD11c+ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR...

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

Science.gov (United States)

Schulte, Simone Laura; Waha, Andreas; Steiger, Barbara; Denkhaus, Dorota; Dörner, Evelyn; Calaminus, Gabriele; Leuschner, Ivo; Pietsch, Torsten

2016-01-01

CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy. PMID:27391150

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor.

Science.gov (United States)

Hinson, Shannon R; Clift, Ian C; Luo, Ningling; Kryzer, Thomas J; Lennon, Vanda A

2017-05-23

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

Immune Players in the CNS : The Astrocyte

NARCIS (Netherlands)

Jensen, Cathy J.; Massie, Ann; De Keyser, Jacques

In the finely balanced environment of the central nervous system astrocytes, the most numerous cell type, play a role in regulating almost every physiological system. First found to regulate extracellular ions and pH, they have since been shown to regulate neurotransmitter levels, cerebral blood

Nicotine induces cell proliferation in association with cyclin D1 up-regulation and inhibits cell differentiation in association with p53 regulation in a murine pre-osteoblastic cell line

International Nuclear Information System (INIS)

Sato, Tsuyoshi; Abe, Takahiro; Nakamoto, Norimichi; Tomaru, Yasuhisa; Koshikiya, Noboru; Nojima, Junya; Kokabu, Shoichiro; Sakata, Yasuaki; Kobayashi, Akio; Yoda, Tetsuya

2008-01-01

Recent studies have suggested that nicotine critically affects bone metabolism. Many studies have examined the effects of nicotine on proliferation and differentiation, but the underlying molecular mechanisms remain unclear. We examined cell cycle regulators involved in the proliferation and differentiation of MC3T3-E1 cells. Nicotine induced cell proliferation in association with p53 down-regulation and cyclin D1 up-regulation. In differentiated cells, nicotine reduced alkaline phosphatase activity and mineralized nodule formation in dose-dependent manners. Furthermore, p53 expression was sustained in nicotine-treated cells during differentiation. These findings indicate that nicotine promotes the cell cycle and inhibits differentiation in association with p53 regulation in pre-osteoblastic cells

Current approaches to enhance CNS delivery of drugs across the brain barriers

Directory of Open Access Journals (Sweden)

Lu CT

2014-05-01

Full Text Available Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB, central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF

The CNS connectome of a tadpole larva of Ciona intestinalis (L.) highlights sidedness in the brain of a chordate sibling.

Science.gov (United States)

Ryan, Kerrianne; Lu, Zhiyuan; Meinertzhagen, Ian A

2016-12-06

Left-right asymmetries in brains are usually minor or cryptic. We report brain asymmetries in the tiny, dorsal tubular nervous system of the ascidian tadpole larva, Ciona intestinalis . Chordate in body plan and development, the larva provides an outstanding example of brain asymmetry. Although early neural development is well studied, detailed cellular organization of the swimming larva's CNS remains unreported. Using serial-section EM we document the synaptic connectome of the larva's 177 CNS neurons. These formed 6618 synapses including 1772 neuromuscular junctions, augmented by 1206 gap junctions. Neurons are unipolar with at most a single dendrite, and few synapses. Some synapses are unpolarised, others form reciprocal or serial motifs; 922 were polyadic. Axo-axonal synapses predominate. Most neurons have ciliary organelles, and many features lack structural specialization. Despite equal cell numbers on both sides, neuron identities and pathways differ left/right. Brain vesicle asymmetries include a right ocellus and left coronet cells.

Protein kinase C signaling and cell cycle regulation

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Adrian R Black

2013-01-01

Full Text Available A link between T cell proliferation and the protein kinase C (PKC family of serine/threonine kinases has been recognized for about thirty years. However, despite the wealth of information on PKC-mediated control of T cell activation, understanding of the effects of PKCs on the cell cycle machinery in this cell type remains limited. Studies in other systems have revealed important cell cycle-specific effects of PKC signaling that can either positively or negatively impact proliferation. The outcome of PKC activation is highly context-dependent, with the precise cell cycle target(s and overall effects determined by the specific isozyme involved, the timing of PKC activation, the cell type, and the signaling environment. Although PKCs can regulate all stages of the cell cycle, they appear to predominantly affect G0/G1 and G2. PKCs can modulate multiple cell cycle regulatory molecules, including cyclins, cyclin-dependent kinases (cdks, cdk inhibitors and cdc25 phosphatases; however, evidence points to Cip/Kip cdk inhibitors and D-type cyclins as key mediators of PKC-regulated cell cycle-specific effects. Several PKC isozymes can target Cip/Kip proteins to control G0/G1→S and/or G2→M transit, while effects on D-type cyclins regulate entry into and progression through G1. Analysis of PKC signaling in T cells has largely focused on its roles in T cell activation; thus, observed cell cycle effects are mainly positive. A prominent role is emerging for PKCθ, with non-redundant functions of other isozymes also described. Additional evidence points to PKCδ as a negative regulator of the cell cycle in these cells. As in other cell types, context-dependent effects of individual isozymes have been noted in T cells, and Cip/Kip cdk inhibitors and D-type cyclins appear to be major PKC targets. Future studies are anticipated to take advantage of the similarities between these various systems to enhance understanding of PKC-mediated cell cycle regulation in

Adult neural stem cells: The promise of the future

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Philippe Taupin

2007-01-01

Full Text Available Philippe TaupinNational Neuroscience Institute, National University of SingaporeAbstract: Stem cells are self-renewing undifferentiated cells that give rise to multiple types of specialized cells of the body. In the adult, stem cells are multipotents and contribute to homeostasis of the tissues and regeneration after injury. Until recently, it was believed that the adult brain was devoid of stem cells, hence unable to make new neurons and regenerate. With the recent evidences that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS, the adult brain has the potential to regenerate and may be amenable to repair. The function(s of NSCs in the adult CNS remains the source of intense research and debates. The promise of the future of adult NSCs is to redefine the functioning and physiopathology of the CNS, as well as to treat a broad range of CNS diseases and injuries.Keywords: neurogenesis, transdifferentiation, plasticity, cellular therapy

NCAM regulates cell motility

DEFF Research Database (Denmark)

Prag, Søren; Lepekhin, Eugene A; Kolkova, Kateryna

2002-01-01

Cell migration is required during development of the nervous system. The regulatory mechanisms for this process, however, are poorly elucidated. We show here that expression of or exposure to the neural cell adhesion molecule (NCAM) strongly affected the motile behaviour of glioma cells...... independently of homophilic NCAM interactions. Expression of the transmembrane 140 kDa isoform of NCAM (NCAM-140) caused a significant reduction in cellular motility, probably through interference with factors regulating cellular attachment, as NCAM-140-expressing cells exhibited a decreased attachment...... to a fibronectin substratum compared with NCAM-negative cells. Ectopic expression of the cytoplasmic part of NCAM-140 also inhibited cell motility, presumably via the non-receptor tyrosine kinase p59(fyn) with which NCAM-140 interacts. Furthermore, we showed that the extracellular part of NCAM acted as a paracrine...

Aberrant over-expression of a forkhead family member, FOXO1A, in a brain tumor cell line

International Nuclear Information System (INIS)

Dallas, Peter B; Egli, Simone; Terry, Philippa A; Kees, Ursula R

2007-01-01

The mammalian FOXO (forkhead box, O subclass) proteins are a family of pleiotropic transcription factors involved in the regulation of a broad range of cellular processes critical for survival. Despite the essential and diverse roles of the FOXO family members in human cells and their involvement in tumor pathogenesis, the regulation of FOXO expression remains poorly understood. We have addressed the mechanisms underlying the high level of expression of the FOXO1A gene in a cell line, PER-453, derived from a primitive neuroectodermal tumor of the central nervous system (CNS-PNET). The status of the FOXO1A locus in the PER-453 CNS-PNET cell line was investigated by Southern blotting and DNA sequence analysis of the proximal promoter, 5'-UTR, open reading frame and 3'-UTR. FOXO1A expression was assessed by conventional and quantitative RT-PCR, Northern and Western blotting. Quantitative real-time RT-PCR (qRT-PCR) data indicated that after normalization to ACTB mRNA levels, canonical FOXO1A mRNA expression in the PER-453 cell line was 124-fold higher than the average level of five other CNS-PNET cell lines tested, 24-fold higher than the level in whole fetal brain, and 3.5-fold higher than the level in fetal brain germinal matrix cells. No mutations within the FOXO1A open reading frame or gross rearrangements of the FOXO1A locus were detected. However, a single nucleotide change within the proximal promoter and several nucleotide changes within the 3'-UTR were identified. In addition, two novel FOXO1A transcripts were isolated that differ from the canonical transcript by alternative splicing within the 3'-UTR. The CNS-PNET cell line, PER-453, expresses FOXO1A at very high levels relative to most normal and cancer cells from a broad range of tissues. The FOXO1A open reading frame is wild type in the PER-453 cell line and the abnormally high FOXO1A mRNA expression is not due to mutations affecting the 5'-UTR or proximal promoter. Over expression

European regulation for therapeutic use of stem cells.

Science.gov (United States)

Ferry, Nicolas

2017-01-01

The regulation for the use of stem cells has evolved during the past decade with the aim of ensuring a high standard of quality and safety for human derived products throughout Europe to comply with the provision of the Lisbon treaty. To this end, new regulations have been issued and the regulatory status of stem cells has been revised. Indeed, stem cells used for therapeutic purposes can now be classified as a cell preparation, or as advanced therapy medicinal products depending on the clinical indication and on the procedure of cell preparation. Furthermore, exemptions to the European regulation are applicable for stem cells prepared and used within the hospital. The aim of this review is to give the non-specialized reader a broad overview of this particular regulatory landscape.

Astrocyte physiopathology: At the crossroads of intercellular networking, inflammation and cell death.

Science.gov (United States)

Rossi, Daniela

2015-07-01

Recent breakthroughs in neuroscience have led to the awareness that we should revise our traditional mode of thinking and studying the CNS, i.e. by isolating the privileged network of "intelligent" synaptic contacts. We may instead need to contemplate all the variegate communications occurring between the different neural cell types, and centrally involving the astrocytes. Basically, it appears that a single astrocyte should be considered as a core that receives and integrates information from thousands of synapses, other glial cells and the blood vessels. In turn, it generates complex outputs that control the neural circuitry and coordinate it with the local microcirculation. Astrocytes thus emerge as the possible fulcrum of the functional homeostasis of the healthy CNS. Yet, evidence indicates that the bridging properties of the astrocytes can change in parallel with, or as a result of, the morphological, biochemical and functional alterations these cells undergo upon injury or disease. As a consequence, they have the potential to transform from supportive friends and interactive partners for neurons into noxious foes. In this review, we summarize the currently available knowledge on the contribution of astrocytes to the functioning of the CNS and what goes wrong in various pathological conditions, with a particular focus on Amyotrophic Lateral Sclerosis, Alzheimer's Disease and ischemia. The observations described convincingly demonstrate that the development and progression of several neurological disorders involve the de-regulation of a finely tuned interplay between multiple cell populations. Thus, it seems that a better understanding of the mechanisms governing the integrated communication and detrimental responses of the astrocytes as well as their impact towards the homeostasis and performance of the CNS is fundamental to open novel therapeutic perspectives. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

Science.gov (United States)

Malik, Jai; Karan, Maninder; Vasisht, Karan

2011-12-01

Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

The shifting landscape of metastatic breast cancer to the CNS.

Science.gov (United States)

Quigley, Matthew R; Fukui, Olivia; Chew, Brandon; Bhatia, Sanjay; Karlovits, Steven

2013-07-01

The improved survival following the diagnosis of breast cancer has potentially altered the characteristics and course of patients presenting with CNS involvement. We therefore sought to define our current cohort of breast cancer patients with metastatic disease to the CNS in regard to modern biomarkers and clinical outcome. Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases. There were 88 women analyzed who were treated over the period of January 2003 to February 2010, average age 56.9 years. At the time of initial presentation of CNS disease, 68 % of patients had multiple brain metastases, 17 % had a solitary metastasis, and 15 % had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor-positive pathology (57.6 v. 38.2 months, p = .02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p = .004, HR = 3.1, Cox regression) and triple-negative hormonal/HER2 status (p = .02, HR = 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26 %) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33). The recently described Graded Prognostic Assessment (GPA) tumor index stratified median survival at 2.5, 5.9, 13.1, and 21.7 months, respectively, for indices of 1-4 (p = .004, log-rank), which

Malignant lymphoma in central nervous system (CNS). Report of a case with characteristic CT finding and amnesia

Energy Technology Data Exchange (ETDEWEB)

Fujiyoshi, Kenji; Fukuyama, Hidenao; Akiguchi, Ichiro; Kameyama, Masakuni [Kyoto Univ. (Japan). Faculty of Medicine; Nishimura, Toshio

1984-07-01

A 71-year-old male was admitted to Kohka Public Hospital on January 4, 1980, because of frequent vomiting and recent memory loss. Two weeks before admission upper G-I series showed no abnormalities. Physical and neurological examinations revealed no abnormalities except for slightly apathetic appearance and recent memory loss. Mild pleocytosis and marked increase of protein in CSF were observed. CT scan on January 17 showed high density areas in both medial sides of temporal lobes with remarkable contrast enhancement. His memory and, consciousness disturbances gradually aggravated, accompanied by abnormal density spreading around the ventricle walls like ventriculitis. He was transfered to Kyoto University Hospital on March 17, and malignant lymphoma was diagnosed on the basis of CSF cytology. Radiation and chemotherapy alleviated the CNS involvement and he regained normal mental function. On June 16, he developed pneumonia followed by status epilepticus. Autopsy findings revealed no lymphoid cell infiltration, but fibrous tissues in both hippocampal gyri and lymphomatous cells in the liver, which could not be suspected on clinical examinations. Apparent malignant lymphoma cells were not found in lymph nodes. This case indicated peculiar evolution of malignant lymphoma from liver to CNS or vice versa. We could not decide which organ was primary. CT findings of this case was very interesting; they resembled ventriculitis, which simulate tumors such as medulloblastoma or ependymoma spreading under ependymal lining.

Physiology of cell volume regulation in vertebrates

DEFF Research Database (Denmark)

Hoffmann, Else K; Lambert, Ian H; Pedersen, Stine F

2009-01-01

and their regulation by, e.g., membrane deformation, ionic strength, Ca(2+), protein kinases and phosphatases, cytoskeletal elements, GTP binding proteins, lipid mediators, and reactive oxygen species, upon changes in cell volume. We also discuss the nature of the upstream elements in volume sensing in vertebrate...... organisms. Importantly, cell volume impacts on a wide array of physiological processes, including transepithelial transport; cell migration, proliferation, and death; and changes in cell volume function as specific signals regulating these processes. A discussion of this issue concludes the review.......The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most...

Extrinsic and intrinsic regulation of axon regeneration at a crossroads.

Science.gov (United States)

Kaplan, Andrew; Ong Tone, Stephan; Fournier, Alyson E

2015-01-01

Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

Directory of Open Access Journals (Sweden)

Sarah E. Lutz

2017-11-01

Full Text Available Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs or caveolae to induce tissue inflammation. In the CNS, Th17 lymphocytes cross the blood-brain barrier (BBB before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE model for multiple sclerosis. We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.

Proximity-based differential single cell analysis of the niche to identify stem/progenitor cell regulators

Science.gov (United States)

Silberstein, Lev; Goncalves, Kevin A; Kharchenko, Peter V; Turcotte, Raphael; Kfoury, Youmna; Mercier, Francois; Baryawno, Ninib; Severe, Nicolas; Bachand, Jacqueline; Spencer, Joel; Papazian, Ani; Lee, Dongjun; Chitteti, Brahmananda Reddy; Srour, Edward F; Hoggatt, Jonathan; Tate, Tiffany; Celso, Cristina Lo; Ono, Noriaki; Nutt, Stephen; Heino, Jyrki; Sipilä, Kalle; Shioda, Toshihiro; Osawa, Masatake; Lin, Charles P; Hu, Guo-fu; Scadden, David T

2016-01-01

SUMMARY Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on differential single-cell gene expression analysis of mesenchymal osteolineage cells close to and further removed from hematopoietic stem/progenitor cells to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. Amongst the genes which were preferentially expressed in proximal cells, we functionally examined three secreted or cell surface molecules not previously connected to HSPC biology: the secreted RNase Angiogenin, the cytokine IL18 and the adhesion molecule Embigin and discovered that all of these factors are HSPC quiescence regulators. Our proximity-based differential single cell approach therefore reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance understanding of microenvironmental regulation of stem cell function. PMID:27524439

GABA not only a neurotransmitter: osmotic regulation by GABAAR signalling

Directory of Open Access Journals (Sweden)

Tiziana eCesetti

2012-01-01

Full Text Available In neurons the anionic channel γ-aminobutyric (GABA A receptor (GABAAR plays a central role in mediating both the neurotrophic and neurotransmitter role of GABA. Activation of this receptor by GABA also affects the function of non-neuronal cells in the central nervous system (CNS, as GABAARs are expressed in mature macroglia and in almost all progenitor types, including neural stem cells. The relevance of GABA signalling in non-neuronal cells has been comparatively less investigated than in neurons. However, it is becoming increasingly evident that these cells are direct targets of GABA regulation. In non-neuronal cells GABAAR activation leads to influx or efflux of chloride (Cl- depending on the electrochemical gradient. Ion transport is indissolubly associated to water fluxes across the plasma membrane and plays a key role in brain physiology. Therefore, GABAAR could affect osmotic tension in the brain by modulating ion gradients. In addition, since water movements also occur through specialized water channels and transporters, GABAAR signalling could affect the movement of water also by regulating the function of the channels and transporters involved, thereby affecting not only the direction of the water fluxes but also their dynamics. This regulation has consequences at the cellular level as it modulates cell volume and activates multiple intracellular signalling mechanisms important for cell proliferation, maturation and survival. It may also have consequences at the systemic level. For example, it may indirectly control neuronal excitability, by regulating the extracellular space and interstitial concentration of Cl-, and contribute to brain water homeostasis. Therefore, GABAergic osmotic regulation should be taken into account during the treatment of pathologies requiring the administration of GABAAR modulators and for the development of therapies for diseases causing water unbalance in the brain.

Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo

International Nuclear Information System (INIS)

Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.

2006-01-01

[ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

OpenAIRE

Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R. Douglas

2004-01-01

Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility...

Lipids in the cell: organisation regulates function.

Science.gov (United States)

Santos, Ana L; Preta, Giulio

2018-06-01

Lipids are fundamental building blocks of all cells and play important roles in the pathogenesis of different diseases, including inflammation, autoimmune disease, cancer, and neurodegeneration. The lipid composition of different organelles can vary substantially from cell to cell, but increasing evidence demonstrates that lipids become organised specifically in each compartment, and this organisation is essential for regulating cell function. For example, lipid microdomains in the plasma membrane, known as lipid rafts, are platforms for concentrating protein receptors and can influence intra-cellular signalling. Lipid organisation is tightly regulated and can be observed across different model organisms, including bacteria, yeast, Drosophila, and Caenorhabditis elegans, suggesting that lipid organisation is evolutionarily conserved. In this review, we summarise the importance and function of specific lipid domains in main cellular organelles and discuss recent advances that investigate how these specific and highly regulated structures contribute to diverse biological processes.

Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells.

Science.gov (United States)

Benkhoucha, Mahdia; Molnarfi, Nicolas; Dunand-Sauthier, Isabelle; Merkler, Doron; Schneiter, Gregory; Bruscoli, Stefano; Riccardi, Carlo; Tabata, Yasuhiko; Funakoshi, Hiroshi; Nakamura, Toshikazu; Reith, Walter; Santiago-Raber, Marie-Laure; Lalive, Patrice H

2014-09-15

Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions. Copyright © 2014 by The American Association of Immunologists, Inc.

VMP1 related autophagy and apoptosis in colorectal cancer cells: VMP1 regulates cell death

Energy Technology Data Exchange (ETDEWEB)

Qian, Qinyi [Department of Ultrasonograph, Changshu No. 2 People’s Hospital, Changshu (China); Zhou, Hao; Chen, Yan [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China); Shen, Chenglong [Department of General Surgery, Changshu No. 2 People’s Hospital, Changshu (China); He, Songbing; Zhao, Hua; Wang, Liang [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China); Wan, Daiwei, E-mail: 372710369@qq.com [Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou (China); Gu, Wen, E-mail: 505339704@qq.com [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China)

2014-01-17

Highlights: •This research confirmed VMP1 as a regulator of autophagy in colorectal cancer cell lines. •We proved the pro-survival role of VMP1-mediated autophagy in colorectal cancer cell lines. •We found the interaction between VMP1 and BECLIN1 also existing in colorectal cancer cell lines. -- Abstract: Vacuole membrane protein 1 (VMP1) is an autophagy-related protein and identified as a key regulator of autophagy in recent years. In pancreatic cell lines, VMP1-dependent autophagy has been linked to positive regulation of apoptosis. However, there are no published reports on the role of VMP1 in autophagy and apoptosis in colorectal cancers. Therefore, to address this gap of knowledge, we decided to interrogate regulation of autophagy and apoptosis by VMP1. We have studied the induction of autophagy by starvation and rapamycin treatment in colorectal cell lines using electron microscopy, immunofluorescence, and immunoblotting. We found that starvation-induced autophagy correlated with an increase in VMP1 expression, that VMP1 interacted with BECLIN1, and that siRNA mediated down-regulation of VMP1-reduced autophagy. Next, we examined the relationship between VMP1-dependent autophagy and apoptosis and found that VMP1 down-regulation sensitizes cells to apoptosis and that agents that induce apoptosis down-regulate VMP1. In conclusion, similar to its reported role in other cell types, VMP1 is an important regulator of autophagy in colorectal cell lines. However, in contrast to its role in pancreatic cell lines, in colorectal cancer cells, VMP1-dependent autophagy appears to be pro-survival rather than pro-cell death.

[11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

DEFF Research Database (Denmark)

Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø

2014-01-01

-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [11C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [11C]methanolate...... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...... on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET....

Hox gene regulation in the central nervous system of Drosophila

Directory of Open Access Journals (Sweden)

Maheshwar eGummalla

2014-04-01

Full Text Available Hox genes specify the structures that form along the anteroposterior (AP axis of bilateria. Within the genome, they often form clusters where, remarkably enough, their position within the clusters reflects the relative positions of the structures they specify along the AP axis. This correspondence between genomic organization and gene expression pattern has been conserved through evolution and provides a unique opportunity to study how chromosomal context affects gene regulation. In Drosophila, a general rule, often called posterior dominance, states that Hox genes specifying more posterior structures repress the expression of more anterior Hox genes. This rule explains the apparent spatial complementarity of Hox gene expression patterns in Drosophila. Here we review a noticeable exception to this rule where the more-posteriorly expressed Abd-B hox gene fails to repress the more-anterior abd-A gene in cells of the central nervous system (CNS. While Abd-B is required to repress ectopic expression of abd-A in the posterior epidermis, abd-A repression in the posterior CNS is accomplished by a different mechanism that involves a large 92kb long non-coding RNA (lncRNA encoded by the intergenic region separating abd-A and Abd-B (the iab8ncRNA. Dissection of this lncRNA revealed that abd-A is repressed by the lncRNA using two redundant mechanisms. The 1st mechanism is mediated by a microRNA (mir-iab-8 encoded by intronic sequence within the large iab8-ncRNA. Meanwhile, the second mechanism seems to involve transcriptional interference by the long iab-8 ncRNA on the abd-A promoter. Recent work demonstrating CNS-specific regulation of genes by ncRNAs in Drosophila, seem to highlight a potential role for the iab-8-ncRNA in the evolution of the Drosophila hox complexes

Primary CNS Nonamyloidogenic Light Chain Deposition Disease: Case Report and Brief Review.

Science.gov (United States)

Mercado, Juan Jose; Markert, James M; Meador, William; Chapman, Philip; Perry, Arie; Hackney, James R

2017-12-01

The true incidence of light chain deposition disease (LCDD) restricted to the central nervous system (CNS) is unknown. To our knowledge only 7 cases of LCDD restricted to the brain have been previously reported. We herein describe an unusual example. A 44-year-old man presented with a history of ischemic retinopathy in 2004 and left lower extremity hypoesthesia in 2007 that progressed gradually to left-sided weakness and numbness in the 2 years prior to his hospitalization in 2015. A stereotactic brain biopsy was performed, displaying nonspecific hyaline deposits of amorphous "amyloid-like" material involving deep brain white matter and vessels. These were Congo red negative and were accompanied by a sparse lymphoplasmacytic infiltrate. Plasma cells demonstrated kappa light chain class restriction by chromogenic in situ hybridization (CISH). There was patchy reactivity with kappa immunohistochemistry in the amorphous deposits. A diagnosis of light chain deposition disease was made. Subsequent systemic myeloma and lymphoma workups were negative. Previously reported cases have included men and women, spanning the ages of 19 and 72 years, often presenting with hemiparesis, hypoesthesia, or seizures. Deposits have been reported in the cerebrum and cerebellum. T2/FLAIR (fluid attenuation inversion recovery) changes are usual, but lesions may or may not produce contrast enhancement. The light chain deposition may be of kappa or lambda class. Most lesions have been accompanied by local lymphoid and/or plasma cell infiltrates exhibiting light chain restriction of the same class as the deposits. In summary, LCDD limited to the CNS is a rare lesion consisting of deposition of amyloid-like, but Congo red-negative monotypic light chain usually produced by local lymphoplasmacytic infiltrates.

Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE)

DEFF Research Database (Denmark)

Penkowa, M; Hidalgo, J

2001-01-01

cytokines and apoptosis during EAE could contribute to the reported diminution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expression of proinflammatory cytokines and the number of apoptotic neurons during EAE......, which is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant protein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clinical symptoms, mortality, and leukocyte infiltration of the CNS during EAE....... However, it is not known how EAE progression is regulated nor how cytokine production and cell death can be reduced. We herewith demonstrate that treatment with Zn-MT-II significantly decreased the CNS expression of IL-6 and TNF-alpha during EAE. Zn-MT-II treatment could also significantly reduce...

Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors.

Science.gov (United States)

Heppner, Kristy M; Piechowski, Carolin L; Müller, Anne; Ottaway, Nickki; Sisley, Stephanie; Smiley, David L; Habegger, Kirk M; Pfluger, Paul T; Dimarchi, Richard; Biebermann, Heike; Tschöp, Matthias H; Sandoval, Darleen A; Perez-Tilve, Diego

2014-01-01

Growth hormone secretagogue receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-AG (dAG) has biological activity through GHSR-independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100 nmol/L) and dAG (100 nmol/L) significantly increased inositol triphosphate formation in human embryonic kidney-293 cells transfected with human GHSR. As expected, intracerebroventricular infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Intracerebroventricular dAG also increased FM at the highest dose tested (5 nmol/day). Chronic intracerebroventricular infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison with saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered intracerebroventricularly. Furthermore, intracerebroventricular dAG failed to regulate FM and induce hyperinsulinemia in GHSR-deficient (Ghsr(-/-)) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that intracerebroventricular dAG impairs glucose clearance without affecting endogenous glucose production. Together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism.

Mockup tests of void fraction in moderator cell and two-phase thermosiphon loop of cold neutron source in China Advanced Research Reactor

International Nuclear Information System (INIS)

Du Shejiao; Bi Qincheng; Chen Tingkuan; Feng Quanke; Li Xiaoming

2004-01-01

Full-scale mockup tests were carried out using freon-113 as a working fluid to verify the design of China Advanced Research Reactor (CARR) Cold neutron Source (CNS), which is a two-phase hydrogen thermosiphon loop consisting of an annular cylindrical moderator cell, two separated hydrogen transfer tubes and a condenser. The circulation characteristics, liquid level and void fraction in the moderator cell against the variation of the heat load were studied. The density ratio and the volumetric evaporating rate of the mockup test are kept the same as those of CARR CNS. The test results show that the mockup loop can establish stable circulation and has a self-regulating characteristic. Within the moderator cell, the inner shell contains only vapor and the outer shell contains the mixture of vapor-liquid with void fraction in a certain range. (authors)

Matrix regulators in neural stem cell functions.

Science.gov (United States)

Wade, Anna; McKinney, Andrew; Phillips, Joanna J

2014-08-01

Neural stem/progenitor cells (NSPCs) reside within a complex and dynamic extracellular microenvironment, or niche. This niche regulates fundamental aspects of their behavior during normal neural development and repair. Precise yet dynamic regulation of NSPC self-renewal, migration, and differentiation is critical and must persist over the life of an organism. In this review, we summarize some of the major components of the NSPC niche and provide examples of how cues from the extracellular matrix regulate NSPC behaviors. We use proteoglycans to illustrate the many diverse roles of the niche in providing temporal and spatial regulation of cellular behavior. The NSPC niche is comprised of multiple components that include; soluble ligands, such as growth factors, morphogens, chemokines, and neurotransmitters, the extracellular matrix, and cellular components. As illustrated by proteoglycans, a major component of the extracellular matrix, the NSPC, niche provides temporal and spatial regulation of NSPC behaviors. The factors that control NSPC behavior are vital to understand as we attempt to modulate normal neural development and repair. Furthermore, an improved understanding of how these factors regulate cell proliferation, migration, and differentiation, crucial for malignancy, may reveal novel anti-tumor strategies. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. Copyright © 2014 Elsevier B.V. All rights reserved.

Morphological evaluation of fetus CNS and its related anomalies

International Nuclear Information System (INIS)

Oi, Shizuo; Tamaki, Norihiko; Matsumoto, Satoshi; Katayama, Kazuaki; Mochizuki, Matsuto

1989-01-01

The fetus central nervous system was evaluated morphologically by ultrasonography (US), magnetic resonance imaging (MRI), and CT scan to analyze the prenatal diagnostic value for CNS anomalies. A total of 31 patients with 42 lesions had been diagnosed during the preceding 7 years. The patients included 24 with hydrocephalus, three with anencephaly, three with myeloschisis, three with holoprosencephaly, three with an encephalocele, two with a Dandy-Walker cyst, one with hydroencephalodysplasia, one with an intracranial neoplasm, one with sacrococcygeal teratoma, and one with sacral agenesis. Compared with US and MRI, CT proved to be more accurate in the detection of spine and cranium-bone morphology. This finding seems to be valuable in the diagnosis of spina bifida, cranium bifidum and some cases of hypertensive hydrocephalus, especially in the axial view. MRI was definitely superior in the anatomico-pathological diagnosis of cerebral dysgenesis, ventriculomegaly, intracranial tumors, and other brain parenchymal changes in view of multi-dimensional analysis. The most considerable disadvantage of MRI in the diagnosis of a fetus CNS anomaly is the poor information about spine and cranium morphology. A super-conducting MRI system is still insufficient to demonstrate the spinal cord of a fetus. US was routinely used, and the multidimensional slices were useful for screening the CNS abnormalies. Some of the fetus brain lesions, such as intracranial hematomas, had a specific echogenecity on US. However, US sometimes failed to demarcate the cerebral parenchymal or subdural morphological changes because its artifacts had hyperchoic shadows. While US, MRI, and CT were valuable diagnostic tools in the morphological evaluation of fetus CNS and its related anomalies, each modality has different diagnostic advantages and disadvantages. Improvement can be expected when these diagnostic imaging modalities are complementary, depending upon the nature of the anatomy. (J.P.N.)

Tip cells: master regulators of tubulogenesis?

Science.gov (United States)

Weavers, Helen; Skaer, Helen

2014-07-01

The normal development of an organ depends on the coordinated regulation of multiple cell activities. Focusing on tubulogenesis, we review the role of specialised cells or groups of cells that are selected from within tissue primordia and differentiate at the outgrowing tips or leading edge of developing tubules. Tip or leading cells develop distinctive patterns of gene expression that enable them to act both as sensors and transmitters of intercellular signalling. This enables them to explore the environment, respond to both tissue intrinsic signals and extrinsic cues from surrounding tissues and to regulate the behaviour of their neighbours, including the setting of cell fate, patterning cell division, inducing polarity and promoting cell movement and cell rearrangements by neighbour exchange. Tip cells are also able to transmit mechanical tension to promote tissue remodelling and, by interacting with the extracellular matrix, they can dictate migratory pathways and organ shape. Where separate tubular structures fuse to form networks, as in the airways of insects or the vascular system of vertebrates, specialised fusion tip cells act to interconnect disparate elements of the developing network. Finally, we consider their importance in the maturation of mature physiological function and in the development of disease. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Regulation of Autophagy by Glucose in Mammalian Cells

OpenAIRE

Moruno, Félix; Pérez-Jiménez, Eva; Knecht, Erwin

2012-01-01

Autophagy is an evolutionarily conserved process that contributes to maintain cell homeostasis. Although it is strongly regulated by many extracellular factors, induction of autophagy is mainly produced by starvation of nutrients. In mammalian cells, the regulation of autophagy by amino acids, and also by the hormone insulin, has been extensively investigated, but knowledge about the effects of other autophagy regulators, including another nutrient, glucose, is more limited. Here we will focu...

Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.

Science.gov (United States)

Elmeliegy, Mohamed A; Carcaboso, Angel M; Tagen, Michael; Bai, Feng; Stewart, Clinton F

2011-01-01

To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420. After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers. P(Brain) in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P(Brain) in Abcg2(-/-) and Mdr1a/b(-/-)Abcg2(-/-) mice were significantly higher than in wild-type mice. Mdr1a/b(-/-) mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells. Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms. ©2010 AACR.

Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

International Nuclear Information System (INIS)

2015-01-01

The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

Metallothionein expression and roles in the CNS

DEFF Research Database (Denmark)

Penkowa, Milena

2002-01-01

  Metallothioneins (MTs) are low-molecular-weight (6-7 kDa) nonenzymatic proteins (60-68 amino acid residues, 25-30% being cysteine) expressed ubiquitous in the animal kingdom. In the central nervous system (CNS), three MT isoforms are known, namely MT-I to MT-III. MT-I and MT-II (MT...

CNS Involvement in Hemophagocytic Lymphohistiocytosis: CT and MR Findings

International Nuclear Information System (INIS)

Chung, Tae Woong

2007-01-01

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by proliferation of benign histiocytes, and this commonly involves the liver, spleen, lymph nodes, bone marrow and central nervous system (CNS). We report here on the CT and MR imaging findings in a case of CNS HLH that showed multiple ring enhancing masses mimicking abscess or another mass on the CT and MR imaging. emophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by nonmalignant diffuse infiltration of multiple organs, including the central nervous system (CNS), by lymphocytes and histiocytes (1). Many radiologic reports describing diffuse white matter infiltrations, parenchymal atrophy and calcification have been published, but the characteristics of these findings remain non-specific, especially in immunocompromised patients. We present here a case of HLH in a 3-year-old boy who presented with multiple ring enhancing lesions involving the brain. In conclusion, although the CT and MRI findings of HLH with ring enhancing parenchymal lesions are nonspecific and mimic abscess, and especially in the immunosuppressed patients, increased diffusion at the center on DWI may be a finding of HLH to differentiate it from abscess, which has restricted diffusion at the center. However, the pathologic correlation with DWI according to the lesion stage certainly needs further study with a larger number of patients

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial

DEFF Research Database (Denmark)

Pestalozzi, B.C.; Francis, P.; Quinaux, E.

2008-01-01

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG...

Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators.

Science.gov (United States)

Silberstein, Lev; Goncalves, Kevin A; Kharchenko, Peter V; Turcotte, Raphael; Kfoury, Youmna; Mercier, Francois; Baryawno, Ninib; Severe, Nicolas; Bachand, Jacqueline; Spencer, Joel A; Papazian, Ani; Lee, Dongjun; Chitteti, Brahmananda Reddy; Srour, Edward F; Hoggatt, Jonathan; Tate, Tiffany; Lo Celso, Cristina; Ono, Noriaki; Nutt, Stephen; Heino, Jyrki; Sipilä, Kalle; Shioda, Toshihiro; Osawa, Masatake; Lin, Charles P; Hu, Guo-Fu; Scadden, David T

2016-10-06

Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function. Copyright © 2016 Elsevier Inc. All rights reserved.

Neural Crossroads in the Hematopoietic Stem Cell Niche.

Science.gov (United States)

Agarwala, Sobhika; Tamplin, Owen J

2018-05-29

The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Stem cell biology and cell transplantation therapy in the retina.

Science.gov (United States)

Osakada, Fumitaka; Hirami, Yasuhiko; Takahashi, Masayo

2010-01-01

Embryonic stem (ES) cells, which are derived from the inner cell mass of mammalian blastocyst stage embryos, have the ability to differentiate into any cell type in the body and to grow indefinitely while maintaining pluripotency. During development, cells undergo progressive and irreversible differentiation into specialized adult cell types. Remarkably, in spite of this restriction in potential, adult somatic cells can be reprogrammed and returned to the naive state of pluripotency found in the early embryo simply by forcing expression of a defined set of transcription factors. These induced pluripotent stem (iPS) cells are molecularly and functionally equivalent to ES cells and provide powerful in vitro models for development, disease, and drug screening, as well as material for cell replacement therapy. Since functional impairment results from cell loss in most central nervous system (CNS) diseases, recovery of lost cells is an important treatment strategy. Although adult neurogenesis occurs in restricted regions, the CNS has poor potential for regeneration to compensate for cell loss. Thus, cell transplantation into damaged or diseased CNS tissues is a promising approach to treating various neurodegenerative disorders. Transplantation of photoreceptors or retinal pigment epithelium cells derived from human ES cells can restore some visual function. Patient-specific iPS cells may lead to customized cell therapy. However, regeneration of retinal function will require a detailed understanding of eye development, visual system circuitry, and retinal degeneration pathology. Here, we review the current progress in retinal regeneration, focusing on the therapeutic potential of pluripotent stem cells.

Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system.

Science.gov (United States)

Buckman, Laura B; Hasty, Alyssa H; Flaherty, David K; Buckman, Christopher T; Thompson, Misty M; Matlock, Brittany K; Weller, Kevin; Ellacott, Kate L J

2014-01-01

Obesity is associated with chronic low-grade inflammation in peripheral tissues caused, in part, by the recruitment of inflammatory monocytes into adipose tissue. Studies in rodent models have also shown increased inflammation in the central nervous system (CNS) during obesity. The goal of this study was to determine whether obesity is associated with recruitment of peripheral immune cells into the CNS. To do this we used a bone marrow chimerism model to track the entry of green-fluorescent protein (GFP) labeled peripheral immune cells into the CNS. Flow cytometry was used to quantify the number of GFP(+) immune cells recruited into the CNS of mice fed a high-fat diet compared to standard chow fed controls. High-fat feeding resulted in obesity associated with a 30% increase in the number of GFP(+) cells in the CNS compared to control mice. Greater than 80% of the GFP(+) cells recruited to the CNS were also CD45(+) CD11b(+) indicating that the GFP(+) cells displayed characteristics of microglia/macrophages. Immunohistochemistry further confirmed the increase in GFP(+) cells in the CNS of the high-fat fed group and also indicated that 93% of the recruited cells were found in the parenchyma and had a stellate morphology. These findings indicate that peripheral immune cells can be recruited to the CNS in obesity and may contribute to the inflammatory response. Copyright © 2013 Elsevier Inc. All rights reserved.

The regulation of apoptotic cell death

Directory of Open Access Journals (Sweden)

Amarante-Mendes G.P.

1999-01-01

Full Text Available Apoptosis is a fundamental biological phenomenon in which the death of a cell is genetically and biochemically regulated. Different molecules are involved in the regulation of the apoptotic process. Death receptors, coupled to distinct members of the caspases as well as other adapter molecules, are involved in the initiation of the stress signals (The Indictment. Members of the Bcl-2 family control at the mitochondrial level the decision between life and death (The Judgement. The effector caspases are responsible for all morphological and biochemical changes related to apoptosis including the "eat-me" signals perceived by phagocytes and neighboring cells (The Execution. Finally, apoptosis would have little biological significance without the recognition and removal of the dying cells (The Burial.

Regulation of Autophagy by Glucose in Mammalian Cells

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Erwin Knecht

2012-07-01

Full Text Available Autophagy is an evolutionarily conserved process that contributes to maintain cell homeostasis. Although it is strongly regulated by many extracellular factors, induction of autophagy is mainly produced by starvation of nutrients. In mammalian cells, the regulation of autophagy by amino acids, and also by the hormone insulin, has been extensively investigated, but knowledge about the effects of other autophagy regulators, including another nutrient, glucose, is more limited. Here we will focus on the signalling pathways by which environmental glucose directly, i.e., independently of insulin and glucagon, regulates autophagy in mammalian cells, but we will also briefly mention some data in yeast. Although glucose deprivation mainly induces autophagy via AMPK activation and the subsequent inhibition of mTORC1, we will also comment other signalling pathways, as well as evidences indicating that, under certain conditions, autophagy can be activated by glucose. A better understanding on how glucose regulates autophagy not only will expand our basic knowledge of this important cell process, but it will be also relevant to understand common human disorders, such as cancer and diabetes, in which glucose levels play an important role.

Intraoperative squash smear cytology in CNS lesions: A study of 150 pediatric cases

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Arpita Jindal

2017-01-01

Full Text Available Background: Tumors of the central nervous system in the pediatric age group occur relatively frequently during the early years of life. Brain tumors are the most common solid malignancies of childhood and only second to acute childhood leukemia. Squash cytology is an indispensable diagnostic aid to central nervous system (CNS lesions. The definitive diagnosis of brain lesions is confirmed by histological examination. Aim: To study the cytology of CNS lesions in pediatric population and correlate it with histopathology. Materials and Methods: One hundred and fifty cases of CNS lesions in pediatric patients were studied over a period of 2 years. Intraoperative squash smears were prepared, stained with hematoxylin and eosin, and examined. Remaining sample was subjected to histopathological examination. Results: Medulloblastoma (24.0% was the most frequently encountered tumor followed by pilocyctic astrocytoma (21.33% and ependymoma (13.33%. Diagnostic accuracy of squash smear technique was 94.67% when compared with histological diagnosis. Conclusion: Smear cytology is a fairly accurate tool for intraoperative CNS consultations.

Distinct spatial distribution of microglia and macrophages following mesenchymal stem cell implantation in mouse brain.

Science.gov (United States)

Le Blon, Debbie; Hoornaert, Chloé; Daans, Jasmijn; Santermans, Eva; Hens, Niel; Goossens, Herman; Berneman, Zwi; Ponsaerts, Peter

2014-09-01

Although implantation of cellular material in the central nervous system (CNS) is a key direction in CNS regenerative medicine, this approach is currently limited by the occurrence of strong endogenous immune cell responses. In a model of mesenchymal stem cell (MSC) grafting in the CNS of immune-competent mice, we previously described that MSC grafts become highly surrounded and invaded by Iba1(+) myeloid cells (microglia and/or macrophages). Here, following grafting of blue fluorescent protein (BFP)-expressing MSC in the CNS of CX3CR1(+/-) and CX3CR1(-/-) mice, our results indicate: (1) that the observed inflammatory response is independent of the fractalkine signalling axis, and (2) that a significant spatial distribution of Iba1(+) inflammatory cells occurs, in which Iba1(+) CX3CR1(+) myeloid cells mainly surround the MSC graft and Iba1(+) CX3CR1(-) myeloid cells mainly invade the graft at 10 days post transplantation. Although Iba1(+) CX3CR1(+) myeloid cells are considered to be of resident microglial origin, Iba1(+) CX3CR1(-) myeloid cells are most likely of peripheral monocyte/macrophage origin. In order to confirm the latter, we performed MSC-BFP grafting experiments in the CNS of eGFP(+) bone marrow chimeric C57BL/6 mice. Analysis of MSC-BFP grafts in the CNS of these mice confirmed our observation that peripheral monocytes/macrophages invade the MSC graft and that resident microglia surround the MSC graft site. Furthermore, analysis of major histocompatibility complex class II (MHCII) expression revealed that mainly macrophages, but not microglia, express this M1 pro-inflammatory marker in the context of MSC grafting in the CNS. These results again highlight the complexity of cell implantation immunology in the CNS.

CXCL1 can be regulated by IL-6 and promotes granulocyte adhesion to brain capillaries during bacterial toxin exposure and encephalomyelitis

Directory of Open Access Journals (Sweden)

Roy Monica

2012-01-01

Full Text Available Abstract Background Granulocytes generally exert protective roles in the central nervous system (CNS, but recent studies suggest that they can be detrimental in experimental autoimmune encephalomyelitis (EAE, the most common model of multiple sclerosis. While the cytokines and adhesion molecules involved in granulocyte adhesion to the brain vasculature have started to be elucidated, the required chemokines remain undetermined. Methods CXCR2 ligand expression was examined in the CNS of mice suffering from EAE or exposed to bacterial toxins by quantitative RT-PCR and in situ hybridization. CXCL1 expression was analyzed in IL-6-treated endothelial cell cultures by quantitative RT-PCR and ELISA. Granulocytes were counted in the brain vasculature after treatment with a neutralizing anti-CXCL1 antibody using stereological techniques. Results CXCL1 was the most highly expressed ligand of the granulocyte receptor CXCR2 in the CNS of mice subjected to EAE or infused with lipopolysaccharide (LPS or pertussis toxin (PTX, the latter being commonly used to induce EAE. IL-6 upregulated CXCL1 expression in brain endothelial cells by acting transcriptionally and mediated the stimulatory effect of PTX on CXCL1 expression. The anti-CXCL1 antibody reduced granulocyte adhesion to brain capillaries in the three conditions under study. Importantly, it attenuated EAE severity when given daily for a week during the effector phase of the disease. Conclusions This study identifies CXCL1 not only as a key regulator of granulocyte recruitment into the CNS, but also as a new potential target for the treatment of neuroinflammatory diseases such as multiple sclerosis.

Intellectual abilities among survivors of childhood leukaemia as a function of CNS irradiation

International Nuclear Information System (INIS)

Eiser, C.

1978-01-01

Twenty-eight children in remission at least 2 years after completing chemotherapy for acute lymphoblastic leukaemia were assessed on standardised psychological tests. It was found that 7 who never had central nervous system (CNS) irradiation and 9 having prophylactic CNS irradiation at least 6 months after diagnosis tended to perform at average or above levels, while those 10 each having prophylactic CNS irradiation (within 2 months of diagnosis) were generally at lower ability. Within the latter group 3 children showed serious intellectual impairments, while the group as a whole functioned especially poorly on quantitative tasks and those involving speeded performance with abstract material. General language ability was not affected. Practical and theoretical implications are discussed. (author)

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

Science.gov (United States)

Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

NSA2, a novel nucleolus protein regulates cell proliferation and cell cycle

International Nuclear Information System (INIS)

Zhang, Heyu; Ma, Xi; Shi, Taiping; Song, Quansheng; Zhao, Hongshan; Ma, Dalong

2010-01-01

NSA2 (Nop seven-associated 2) was previously identified in a high throughput screen of novel human genes associated with cell proliferation, and the NSA2 protein is evolutionarily conserved across different species. In this study, we revealed that NSA2 is broadly expressed in human tissues and cultured cell lines, and located in the nucleolus of the cell. Both of the putative nuclear localization signals (NLSs) of NSA2, also overlapped with nucleolar localization signals (NoLSs), are capable of directing nucleolar accumulation. Moreover, over-expression of the NSA2 protein promoted cell growth in different cell lines and regulated the G1/S transition in the cell cycle. SiRNA silencing of the NSA2 transcript attenuated the cell growth and dramatically blocked the cell cycle in G1/S transition. Our results demonstrated that NSA2 is a nucleolar protein involved in cell proliferation and cell cycle regulation.

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells.

Science.gov (United States)

Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R Douglas

2004-02-01

Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2(A) adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators

International Nuclear Information System (INIS)

Claveria, Cristina; Torres, Miguel

2003-01-01

Multicellular organisms eliminate unwanted or damaged cells by cell death, a process essential to the maintenance of tissue homeostasis. Cell death is a tightly regulated event, whose alteration by excess or defect is involved in the pathogenesis of many diseases such as cancer, autoimmune syndromes, and neurodegenerative processes. Studies in model organisms, especially in the nematode Caenorhabditis elegans, have been crucial in identifying the key molecules implicated in the regulation and execution of programmed cell death. In contrast, the study of cell death in Drosophila melanogaster, often an excellent model organism, has identified regulators and mechanisms not obviously conserved in other metazoans. Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway

Activation of ion transport systems during cell volume regulation

International Nuclear Information System (INIS)

Eveloff, J.L.; Warnock, D.G.

1987-01-01

This review discusses the activation of transport pathways during volume regulation, including their characteristics, the possible biochemical pathways that may mediate the activation of transport pathways, and the relations between volume regulation and transepithelial transport in renal cells. Many cells regulate their volume when exposed to an anisotonic medium. The changes in cell volume are caused by activation of ion transport pathways, plus the accompanying osmotically driven water movement such that cell volume returns toward normal levels. The swelling of hypertonically shrunken cells is termed regulatory volume increase (RVI) and involves an influx of NaCl into the cell via either activation of Na-Cl, Na-K-2Cl cotransport systems, or Na + -H + and Cl - -HCO 3 - exchangers. The reshrinking of hypotonically swollen cells is termed regulatory volume decrease (RVD) and involves an efflux of KCl and water from the cell by activation of either separate K + and Cl - conductances, a K-Cl cotransport system, or parallel K + -H + and Cl - -HCO 3 - exchangers. The biochemical mechanisms involved in the activation of transport systems are largely unknown, however, the phosphoinositide pathway may be implicated in RVI; phorbol esters, cGMP, and Ca 2+ affect the process of volume regulation. Renal tubular cells, as well as the blood cells that transverse the medulla, are subjected to increasing osmotic gradients from the corticomedullary junction to the papillary tip, as well as changing interstitial and tubule fluid osmolarity, depending on the diuretic state of the animal. Medullary cells from the loop of Henle and the papilla can volume regulate by activating Na-K-2Cl cotransport or Na + -H + and Cl - -HCO 3 - exchange systems

Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets.

Science.gov (United States)

Drees, Christoph; Vahl, J Christoph; Bortoluzzi, Sabrina; Heger, Klaus D; Fischer, Julius C; Wunderlich, F Thomas; Peschel, Christian; Schmidt-Supprian, Marc

2017-04-01

NKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA-binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell-specific ablation of the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2-deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog-deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and periphery. Copyright © 2017 by The American Association of Immunologists, Inc.

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

OpenAIRE

DeSalvo, Michael K.; Hindle, Samantha J.; Rusan, Zeid M.; Orng, Souvinh; Eddison, Mark; Halliwill, Kyle; Bainton, Roland J.

2014-01-01

Central nervous system (CNS) function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB) structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; ...

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.

Science.gov (United States)

Kuerten, Stefanie; Pommerschein, Giovanna; Barth, Stefanie K; Hohmann, Christopher; Milles, Bianca; Sammer, Fabian W; Duffy, Cathrina E; Wunsch, Marie; Rovituso, Damiano M; Schroeter, Michael; Addicks, Klaus; Kaiser, Claudia C; Lehmann, Paul V

2014-01-01

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease. Copyright © 2014. Published by Elsevier Inc.

Electric Signals Regulate the Directional Migration of Oligodendrocyte Progenitor Cells (OPCs via β1 Integrin

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Bangfu Zhu

2016-11-01

Full Text Available The guided migration of neural cells is essential for repair in the central nervous system (CNS. Oligodendrocyte progenitor cells (OPCs will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric fields (EFs are known to influence cell migration in vivo, and have been utilised in this study to direct the migration of OPCs isolated from neonatal Sprague-Dawley rats. The OPCs were exposed to physiological levels of electrical stimulation, and displayed a marked electrotactic response that was dependent on β1 integrin, one of the key subunits of integrin receptors. We also observed that F-actin, an important component of the cytoskeleton, was re-distributed towards the leading edge of the migrating cells, and that this asymmetric rearrangement was associated with β1 integrin function.

Extracellular Matrix as a Regulator of Epidermal Stem Cell Fate.

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Chermnykh, Elina; Kalabusheva, Ekaterina; Vorotelyak, Ekaterina

2018-03-27

Epidermal stem cells reside within the specific anatomic location, called niche, which is a microenvironment that interacts with stem cells to regulate their fate. Regulation of many important processes, including maintenance of stem cell quiescence, self-renewal, and homeostasis, as well as the regulation of division and differentiation, are common functions of the stem cell niche. As it was shown in multiple studies, extracellular matrix (ECM) contributes a lot to stem cell niches in various tissues, including that of skin. In epidermis, ECM is represented, primarily, by a highly specialized ECM structure, basement membrane (BM), which separates the epidermal and dermal compartments. Epidermal stem cells contact with BM, but when they lose the contact and migrate to the overlying layers, they undergo terminal differentiation. When considering all of these factors, ECM is of fundamental importance in regulating epidermal stem cells maintenance, proper mobilization, and differentiation. Here, we summarize the remarkable progress that has recently been made in the research of ECM role in regulating epidermal stem cell fate, paying special attention to the hair follicle stem cell niche. We show that the destruction of ECM components impairs epidermal stem cell morphogenesis and homeostasis. A deep understanding of ECM molecular structure as well as the development of in vitro system for stem cell maintaining by ECM proteins may bring us to developing new approaches for regenerative medicine.

Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia.

Science.gov (United States)

Zheng, Changcheng; Liu, Xin; Zhu, Weibo; Cai, Xiaoyan; Wu, Jingsheng; Sun, Zimin

2014-06-01

The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P adult AML, but further studies are needed to improve the long-term survival.

Differentiation, distribution and gammadelta T cell-driven regulation of IL-22-producing T cells in tuberculosis.

Directory of Open Access Journals (Sweden)

Shuyu Yao

2010-02-01

Full Text Available Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vgamma2Vdelta2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNgamma-producing Vgamma2Vdelta2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNgamma neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vgamma2Vdelta2 T-cell-driven IFNgamma-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vgamma2Vdelta2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB.

Chemokine receptor expression by inflammatory T cells in EAE

DEFF Research Database (Denmark)

Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

2014-01-01

Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20...... receptor CCR6 has been reported to be selectively expressed by CD4(+) T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed...... whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4(+) T cells produced IFNγ in flow cytometric cytokine assays...

Treatment options for Primary CNS Lymphoma.

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Laghari, Altaf Ali; Ahmed, Syed Ijlal; Jabbar, Adnan; Shamim, Muhammad Shahzad

2018-03-01

Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumour that is uniformly fatal. The rarity of the disease and the poor response to treatment makes it difficult to reach a consensus with regards to treatment options. In this review, the authors have discussed different treatment modalities used in the management of PCNSL including chemotherapy, surgery and radiation, as well as the results of recent clinical trials on treatment options for PCNSL.

Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo

Energy Technology Data Exchange (ETDEWEB)

Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)

2006-02-15

[{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.

Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-07-01

The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6-aminonicotinamide

DEFF Research Database (Denmark)

Penkowa, Milena; Giralt, Mercedes; Camats, Jordi

2002-01-01

6-Aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes. Metallothionein 1+2 (MT-1+2) are neuroprotective factors in the central nervous system (CNS), and to determine the roles for MT after 6-AN, we have examined transgenic mice overexpressing MT-1...... (NITT), and the number of terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine triphosphate [dUTP]-digoxigenin nick end labeling-positive (TUNEL+), caspase-3+ apoptotic cells were significantly increased in the brainstem of normal mice after 6-AN. In the TgMTI* mice, the 6-AN-induced tissue...... damage was decreased in comparison to control mice, and they showed significantly reduced numbers of recruited macrophages and T lymphocytes, and a drastic reduction of oxidative stress and apoptotic cell death. In addition, the accompanying reactive astrogliosis was increased in the transgenic mice...

Ion channels involved in cell volume regulation: effects on migration, proliferation, and programmed cell death in non adherent EAT cells and adherent ELA cells.

Science.gov (United States)

Hoffmann, Else Kay

2011-01-01

This mini review outlines studies of cell volume regulation in two closely related mammalian cell lines: nonadherent Ehrlich ascites tumour cells (EATC) and adherent Ehrlich Lettre ascites (ELA) cells. Focus is on the regulatory volume decrease (RVD) that occurs after cell swelling, the volume regulatory ion channels involved, and the mechanisms (cellular signalling pathways) that regulate these channels. Finally, I shall also briefly review current investigations in these two cell lines that focuses on how changes in cell volume can regulate cell functions such as cell migration, proliferation, and programmed cell death. Copyright © 2011 S. Karger AG, Basel.

Heteromeric Slick/Slack K+ channels show graded sensitivity to cell volume changes

DEFF Research Database (Denmark)

Tejada, Maria A; Hashem, Nadia; Callø, Kirstine

2017-01-01

Slick and Slack high-conductance K+ channels are found in the CNS, kidneys, pancreas, among other organs, where they play an important role in cell excitability as well as in ion transport processes. They are both activated by Na+ and Cl- but show a differential regulation by cell volume changes....... Slick has been shown to be regulated by cell volume changes, whereas Slack is insensitive. α-subunits of these channels form homomeric as well as heteromeric channels. It is the aim of this work to explore whether the subunit composition of the Slick/Slack heteromeric channel affects the response...... to osmotic challenges. In order to provide with the adequate water permeability to the cell membrane of Xenopus laevis oocytes, mRNA of aquaporin 1 was co-expressed with homomeric or heteromeric Slick and Slack α-subunits. Oocytes were superfused with hypotonic or hypertonic buffers and changes in currents...

Redox regulation of plant stem cell fate.

Science.gov (United States)

Zeng, Jian; Dong, Zhicheng; Wu, Haijun; Tian, Zhaoxia; Zhao, Zhong

2017-10-02

Despite the importance of stem cells in plant and animal development, the common mechanisms of stem cell maintenance in both systems have remained elusive. Recently, the importance of hydrogen peroxide (H 2 O 2 ) signaling in priming stem cell differentiation has been extensively studied in animals. Here, we show that different forms of reactive oxygen species (ROS) have antagonistic roles in plant stem cell regulation, which were established by distinct spatiotemporal patterns of ROS-metabolizing enzymes. The superoxide anion (O2·-) is markedly enriched in stem cells to activate WUSCHEL and maintain stemness, whereas H 2 O 2 is more abundant in the differentiating peripheral zone to promote stem cell differentiation. Moreover, H 2 O 2 negatively regulates O2·- biosynthesis in stem cells, and increasing H 2 O 2 levels or scavenging O2·- leads to the termination of stem cells. Our results provide a mechanistic framework for ROS-mediated control of plant stem cell fate and demonstrate that the balance between O2·- and H 2 O 2 is key to stem cell maintenance and differentiation. © 2017 The Authors.

Neural stem cells in the adult ciliary epithelium express GFAP and are regulated by Wnt signaling

International Nuclear Information System (INIS)

Das, Ani V.; Zhao Xing; James, Jackson; Kim, Min; Cowan, Kenneth H.; Ahmad, Iqbal

2006-01-01

The identification of neural stem cells with retinal potential in the ciliary epithelium (CE) of the adult mammals is of considerable interest because of their potential for replacing or rescuing degenerating retinal neurons in disease or injury. The evaluation of such a potential requires characterization of these cells with regard to their phenotypic properties, potential, and regulatory mechanisms. Here, we demonstrate that rat CE stem cells/progenitors in neurosphere culture display astrocytic nature in terms of expressing glial intermediate neurofilament protein, GFAP. The GFAP-expressing CE stem cells/progenitors form neurospheres in proliferating conditions and generate neurons when shifted to differentiating conditions. These cells express components of the canonical Wnt pathway and its activation promotes their proliferation. Furthermore, we demonstrate that the activation of the canonical Wnt pathway influences neuronal differentiation of CE stem cells/progenitors in a context dependent manner. Our observations suggest that CE stem cells/progenitors share phenotypic properties and regulatory mechanism(s) with neural stem cells elsewhere in the adult CNS

Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis

KAUST Repository

Merzaban, Jasmeen; Imitola, Jaime; Starossom, Sarah C.; Zhu, Bing; Wang, Yue; Lee, Jack; Ali, Amal J.; Olah, Marta; AbuElela, Ayman; Khoury, Samia J.; Sackstein, Robert

2015-01-01

Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs

Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells.

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Wenmeng Wang

Full Text Available High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC and human aortic endothelial cells (HAEC down-regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP-induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down-regulation. The over-expression of nucleolin by gene transfer partly reversed ADP-induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down-regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin.

Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells

International Nuclear Information System (INIS)

Teng, Ying; Wang, Xiuwen; Wang, Yawei; Ma, Daoxin

2010-01-01

Wnt/β-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that β-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of β-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of β-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/β-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.

Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells.

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Fan, Hong; Paiboonrungruan, Chorlada; Zhang, Xinyan; Prigge, Justin R; Schmidt, Edward E; Sun, Zheng; Chen, Xiaoxin

2017-11-04

Oxidative stress is known to play a pivotal role in the development of oral squamous cell carcinoma (OSCC). We have demonstrated that activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has chemopreventive effects against oxidative stress-associated OSCC. However, Nrf2 have dual roles in cancer development; while it prevents carcinogenesis of normal cells, hyperactive Nrf2 also promotes the survival of cancer cells. This study is aimed to understand the function of Nrf2 in regulating cellular behaviors of OSCC cells, and the potential mechanisms through which Nrf2 facilitates OSCC. We established the Nrf2-overexpressing and Nrf2-knockdown OSCC cell lines, and examined the function of Nrf2 in regulating cell proliferation, migration, invasion, cell cycle and colony formation. Our data showed that Nrf2 overexpression promoted cancer phenotypes in OSCC cells, whereas Nrf2 silencing inhibited these phenotypes. In addition, Nrf2 positively regulated Notch signaling pathway in OSCC cells in vitro. Consistent with this observation, Nrf2 activation in Keap1 -/- mice resulted in not only hyperproliferation of squamous epithelial cells in mouse tongue as evidenced by increased expression of PCNA, but also activation of Notch signaling in these cells as evidenced by increased expression of NICD1 and Hes1. In conclusion, Nrf2 regulates cancer behaviors and Notch signaling in OSCC cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant?

Science.gov (United States)

Glaser, Kirsten; Speer, Christian P

2015-02-01

Colonization with Ureaplasma species has been associated with adverse pregnancy outcome, and perinatal transmission has been implicated in the development of bronchopulmonary dysplasia in preterm neonates. Little is known about Ureaplasma-mediated infection and inflammation of the CNS in neonates. Controversy remains concerning its incidence and implication in the pathogenesis of neonatal brain injury. In vivo and in vitro data are limited. Despite improving care options for extremely immature preterm infants, relevant complications remain. Systematic knowledge of ureaplasmal infection may be of great benefit. This review aims to summarize pathogenic mechanisms, clinical data and diagnostic pitfalls. Studies in preterm and term neonates are critically discussed with regard to their limitations. Clinical questions concerning therapy or prophylaxis are posed. We conclude that ureaplasmas may be true pathogens, especially in preterm neonates, and may cause CNS inflammation in a complex interplay of host susceptibility, serovar pathogenicity and gestational age-dependent CNS vulnerability.

Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.

Science.gov (United States)

JavanMoghadam, Sonia; Weihua, Zhang; Hunt, Kelly K; Keyomarsi, Khandan

2016-06-17

Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P cycle duration were observed in the S and G2/M phases, whereas the G1 phase was indistinguishable under liganded and unliganded conditions. In addition, ERα knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ERα-negative MDA-MB-231 cells with exogenous ERα significantly shortened the S and G2/M phases (by 9.1 hours, P cycle progression through the S and G2/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ERα protein. Together, these results show that ERα modulates breast cancer cell proliferation by regulating events during the S and G2/M phases of the cell cycle in a ligand-dependent fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.

Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

International Nuclear Information System (INIS)

Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

2016-01-01

The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

2016-02-12

The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

Regulation of Floral Stem Cell Termination in Arabidopsis

Directory of Open Access Journals (Sweden)

Toshiro eIto

2015-02-01

Full Text Available In Arabidopsis, floral stem cells are maintained only at the initial stages of flower development, and they are terminated at a specific time to ensure proper development of the reproductive organs. Floral stem cell termination is a dynamic and multi-step process involving many transcription factors, chromatin remodeling factors and signaling pathways. In this review, we discuss the mechanisms involved in floral stem cell maintenance and termination, highlighting the interplay between transcriptional regulation and epigenetic machinery in the control of specific floral developmental genes. In addition, we discuss additional factors involved in floral stem cell regulation, with the goal of untangling the complexity of the floral stem cell regulatory network.

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity.

Science.gov (United States)

Omori, Yoshihiro; Kubo, Shun; Kon, Tetsuo; Furuhashi, Mayu; Narita, Hirotaka; Kominami, Taro; Ueno, Akiko; Tsutsumi, Ryotaro; Chaya, Taro; Yamamoto, Haruka; Suetake, Isao; Ueno, Shinji; Koseki, Haruhiko; Nakagawa, Atsushi; Furukawa, Takahisa

2017-09-26

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7- null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7 -deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam

Science.gov (United States)

Song, Yuanquan; Ori-McKenney, Kassandra M.; Zheng, Yi; Han, Chun; Jan, Lily Yeh; Jan, Yuh Nung

2012-01-01

Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. Here we report that, like the axons of mammalian sensory neurons, the axons of certain Drosophila dendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNA bantam but is facilitated by cell-autonomous activation of the Akt pathway. Our study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN–Akt pathway that is also important for axon regeneration. We thus established an important new model system—the fly da neuron regeneration model that resembles the mammalian injury model—with which to study and gain novel insights into the regeneration machinery. PMID:22759636

Glial cell biology in the Great Lakes region.

Science.gov (United States)

Feinstein, Douglas L; Skoff, Robert P

2016-03-31

We report on the tenth bi-annual Great Lakes Glial meeting, held in Traverse City, Michigan, USA, September 27-29 2015. The GLG meeting is a small conference that focuses on current research in glial cell biology. The array of functions that glial cells (astrocytes, microglia, oligodendrocytes, Schwann cells) play in health and disease is constantly increasing. Despite this diversity, GLG meetings bring together scientists with common interests, leading to a better understanding of these cells. This year's meeting included two keynote speakers who presented talks on the regulation of CNS myelination and the consequences of stress on Schwann cell biology. Twenty-two other talks were presented along with two poster sessions. Sessions covered recent findings in the areas of microglial and astrocyte activation; age-dependent changes to glial cells, Schwann cell development and pathology, and the role of stem cells in glioma and neural regeneration.

The Arabidopsis synaptotagmin SYTA regulates the cell-to-cell movement of diverse plant viruses

Directory of Open Access Journals (Sweden)

Asako eUchiyama

2014-11-01

Full Text Available Synaptotagmins are a large gene family in animals that have been extensively characterized due to their role as calcium sensors to regulate synaptic vesicle exocytosis and endocytosis in neurons, and dense core vesicle exocytosis for hormone secretion from neuroendocrine cells. Thought to be exclusive to animals, synaptotagmins have recently been characterized in Arabidopsis thaliana, in which they comprise a five gene family. Using infectivity and leaf-based functional assays, we have shown that Arabidopsis SYTA regulates endocytosis and marks an endosomal vesicle recycling pathway to regulate movement protein-mediated trafficking of the Begomovirus Cabbage leaf curl virus (CaLCuV and the Tobamovirus Tobacco mosaic virus (TMV through plasmodesmata (Lewis and Lazarowitz, 2010. To determine whether SYTA has a central role in regulating the cell-to-cell trafficking of a wider range of diverse plant viruses, we extended our studies here to examine the role of SYTA in the cell-to-cell movement of additional plant viruses that employ different modes of movement, namely the Potyvirus Turnip mosaic virus (TuMV, the Caulimovirus Cauliflower mosaic virus (CaMV and the Tobamovirus Turnip vein clearing virus (TVCV, which in contrast to TMV does efficiently infect Arabidopsis. We found that both TuMV and TVCV systemic infection, and the cell-to-cell trafficking of the their movement proteins, were delayed in the Arabidopsis Col-0 syta-1 knockdown mutant. In contrast, CaMV systemic infection was not inhibited in syta-1. Our studies show that SYTA is a key regulator of plant virus intercellular movement, being necessary for the ability of diverse cell-to-cell movement proteins encoded by Begomoviruses (CaLCuV MP, Tobamoviruses (TVCV and TMV 30K protein and Potyviruses (TuMV P3N-PIPO to alter PD and thereby mediate virus cell-to-cell spread.

EZH2: a pivotal regulator in controlling cell differentiation.

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Chen, Ya-Huey; Hung, Mien-Chie; Li, Long-Yuan

2012-01-01

Epigenetic regulation plays an important role in stem cell self-renewal, maintenance and lineage differentiation. The epigenetic profiles of stem cells are related to their transcriptional signature. Enhancer of Zeste homlog 2 (EZH2), a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), has been shown to be a key regulator in controlling cellular differentiation. EZH2 is a histone methyltransferase that not only methylates histone H3 on Lys 27 (H3K27me3) but also interacts with and recruits DNA methyltransferases to methylate CpG at certain EZH2 target genes to establish firm repressive chromatin structures, contributing to tumor progression and the regulation of development and lineage commitment both in embryonic stem cells (ESCs) and adult stem cells. In addition to its well-recognized epigenetic gene silencing function, EZH2 also directly methylates nonhistone targets such as the cardiac transcription factor, GATA4, resulting in attenuated GATA4 transcriptional activity and gene repression. This review addresses recent progress toward the understanding of the biological functions and regulatory mechanisms of EZH2 and its targets as well as their roles in stem cell maintenance and cell differentiation.

A Glio-Protective Role of mir-263a by Tuning Sensitivity to Glutamate

DEFF Research Database (Denmark)

Aw, Sherry Shiying; Lim, Isaac Kok Hwee; Tang, Melissa Xue Mei

2017-01-01

of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte-like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation...... of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment....

A 3-D Thermal Analysis of the HANARO Cold Neutron Moderator Cell

International Nuclear Information System (INIS)

Han, Gee Y.; Kim, Heo Nil

2007-01-01

Fundamental studies on a thermal analysis of a cryogenic system such as a cold neutron source (CNS) have increased significantly for a successful CNS design in cold neutron research during recent years. A three-dimensional (3-D) thermal analysis model for the HANARO CNS was developed and used to accurately predict a temperature distribution between the hydrogen inside and the entire inner and outer surfaces of a moderator cell, whose moderator and cell walls are heated differently, under a steady-state operating condition by using the HEATING 7 code. The objective of this study is primarily to predict a temperature distribution through a heat flow in a cold neutron moderator cell heated from a nuclear heating and cooled by a cryogenic coolant. This paper presents satisfactory results of a steady-state temperature distribution in a cryogenic moderator cell. They are used to support the thermal stress analysis of the moderator cell walls and to provide a safe operation for the HANARO CNS facility

Dynamic ubiquitin signaling in cell cycle regulation.

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Gilberto, Samuel; Peter, Matthias

2017-08-07

The cell division cycle is driven by a collection of enzymes that coordinate DNA duplication and separation, ensuring that genomic information is faithfully and perpetually maintained. The activity of the effector proteins that perform and coordinate these biological processes oscillates by regulated expression and/or posttranslational modifications. Ubiquitylation is a cardinal cellular modification and is long known for driving cell cycle transitions. In this review, we emphasize emerging concepts of how ubiquitylation brings the necessary dynamicity and plasticity that underlie the processes of DNA replication and mitosis. New studies, often focusing on the regulation of chromosomal proteins like DNA polymerases or kinetochore kinases, are demonstrating that ubiquitylation is a versatile modification that can be used to fine-tune these cell cycle events, frequently through processes that do not involve proteasomal degradation. Understanding how the increasing variety of identified ubiquitin signals are transduced will allow us to develop a deeper mechanistic perception of how the multiple factors come together to faithfully propagate genomic information. Here, we discuss these and additional conceptual challenges that are currently under study toward understanding how ubiquitin governs cell cycle regulation. © 2017 Gilberto and Peter.

Imaging aspects of neurologic emergencies in children treated for non-CNS malignancies

International Nuclear Information System (INIS)

Kaste, S.C.; Langston, J.; Rodriguez-Galindo, C.; Furman, W.L.; Thompson, S.J.

2000-01-01

There is a paucity of radiologic literature addressing neurologic emergencies in children receiving therapy for non-CNS primary malignancies. In the acute setting, many of these children present to local community hospitals. This pictorial is from a single institutional experience describing the spectrum of neurologic emergencies seen in children with non-CNS cancers. We hope to familiarize pediatric radiologists with these entities in order to expedite diagnosis, facilitate treatment, and minimize morbity and mortality that may be associated with these complications. (orig.)

Analysis of cell-cycle regulation following exposure of lung-derived cells to γ-rays

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Trani, D.; Lucchetti, C.; Cassone, M.; D'Agostino, L.; Caputi, M.; Giordano, A.

Acute exposure of mammalian cells to ionizing radiation results in a delay of cell-cycle progression and/or augmentation of apoptosis. Following ionizing radiation-induced DNA damage, cell-cycle arrest in the G1- or G2-phase of the cell-cycle prevents or delays DNA replication or mitosis, providing time for the DNA repair machinery to exert its function. Deregulation or failing of cell-cycle checkpoints and/or DNA repair mechanisms may lead normal cells bearing chromosome mutations to acquire neoplastic autonomy, which in turn can trigger the onset of cancer. Existing studies have focused on the impact of p53 status on the radiation response of lung cancer (LC) cell lines in terms of both cell-cycle regulation and apoptosis, while no comparative studies have been performed on the radiation response of lung derived normal and cancerous epithelial cells. To investigate the radiation response in normal and cancerous phenotypes, along with the role and impact of p53 status, and possible correlations with pRb/p105 or other proteins involved in carcinogenesis and cell-cycle regulation, we selected two lung-derived epithelial cell lines, one normal (NL20, p53 wild-type) and one non-small cell lung cancer (NSCLC), H358 (known to be p53-deficient). We compared the levels of γ-induced cell proliferation ability, cell-cycle arrest, apoptotic index, and expression levels of cell-cycle regulating and regulated proteins. The different cell sensitivity, apoptotic response and protein expression profiles resulting from our study for NL20 and H358 cells suggest that still unknown mechanisms involving p53, pRb/p105 and their target molecules might play a pivotal role in determining cell sensitivity and resistance upon exposure to ionizing radiation.

Metallothionein-1+2 protect the CNS after a focal brain injury

DEFF Research Database (Denmark)

Giralt, Mercedes; Penkowa, Milena; Lago, Natalia

2002-01-01

We have evaluated the physiological relevance of metallothionein-1+2 (MT-1+2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number...... dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1+2 knock-out mice. These results fully support the notion that MT-1+2 are essential in the CNS for coping...

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

OpenAIRE

de Lange, Elizabeth CM

2013-01-01

Despite enormous advances in CNS research, CNS disorders remain the world?s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood?brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. ...

Cancers of the Brain and CNS: Global Patterns and Trends in Incidence.

Science.gov (United States)

Mortazavi, S M J; Mortazavi, S A R; Paknahad, M

2018-03-01

Miranda-Filho et al. in their recently published paper entitled "Cancers of the brain and CNS: global patterns and trends in incidence" provided a global status report of the geographic and temporal variations in the incidence of brain and CNS cancers in different countries across continents worldwide. While the authors confirm the role of genetic risk factors and ionizing radiation exposures, they claimed that no firm conclusion could be drawn about the role of exposure to non-ionizing radiation. The paper authored by Miranda-Filho et al. not only addresses a challenging issue, it can be considered as a good contribution in the field of brain and CNS cancers. However, our correspondence addresses a basic shortcoming of this paper about the role of electromagnetic fields and cancers and provides evidence showing that exposure to radiofrequency electromagnetic fields (RF-EMFs), at least at high levels and long durations, can increases the risk of cancer.

[Regularities of fixation of brain serum antibodies from patients with lateral amyotrophic sclerosis in rabbit CNS].

Science.gov (United States)

Musaeva, L S; Gannyshkina, I V; Zavalishin, I A; Markova, E D; Ivanova-Smolenskaia, I A

2002-01-01

Kuhns' indirect immunofluorescent test was used to study fixation of serum brain antibodies (Ab) of patients with bulbar, cervicothoracic, lumbosacral lateral amyotropic sclerosis (LAS) on brain sections of rabbits. The disease is characterized by formation of brain Ab complementary to various structures of nervous and glial cells, myelin of fibers from different conducting systems, vessels which exhibit both common and individual antigenic properties. It was found that fixation of antineuronal, antimyelin brain Ab of patients with bulbar, cervicothoracic and lumbosacral LAS in different CNS structures varies.

Rat bone marrow progenitor cells transduced in situ by rSV40 vectors differentiate into multiple central nervous system cell lineages.

Science.gov (United States)

Louboutin, Jean-Pierre; Liu, Bianling; Reyes, Beverly A S; Van Bockstaele, Elisabeth J; Strayer, David S

2006-12-01

Using bone marrow-directed gene transfer, we tested whether bone marrow-derived cells may function as progenitors of central nervous system (CNS) cells in adult animals. SV40-derived gene delivery vectors were injected directly into femoral bone marrow, and we examined transgene expression in blood and brain for 0-16 months thereafter by immunostaining for FLAG epitope marker. An average of 5% of peripheral blood cells and 25% of femoral marrow cells were FLAG(+) throughout the study. CNS FLAG-expressing cells were mainly detected in the dentate gyrus (DG) and periventricular subependymal zone (PSZ). Although absent before 1 month and rare at 4 months, DG and PSZ FLAG(+) cells were abundant 16 months after bone marrow injection. Approximately 5% of DG cells expressed FLAG, including neurons (48.6%) and microglia (49.7%), and occasional astrocytes (1.6%), as determined by double immunostaining for FLAG and lineage markers. These data suggest that one or more populations of cells resident within adult bone marrow can migrate to the brain and differentiate into CNS-specific cells.

Quantitative regulation of B cell division destiny by signal strength.

Science.gov (United States)

Turner, Marian L; Hawkins, Edwin D; Hodgkin, Philip D

2008-07-01

Differentiation to Ab secreting and isotype-switched effector cells is tightly linked to cell division and therefore the degree of proliferation strongly influences the nature of the immune response. The maximum number of divisions reached, termed the population division destiny, is stochastically distributed in the population and is an important parameter in the quantitative outcome of lymphocyte responses. In this study, we further assessed the variables that regulate B cell division destiny in vitro in response to T cell- and TLR-dependent stimuli. Both the concentration and duration of stimulation were able to regulate the average maximum number of divisions undergone for each stimulus. Notably, a maximum division destiny was reached during provision of repeated saturating stimulation, revealing that an intrinsic limit to proliferation exists even under these conditions. This limit was linked directly to division number rather than time of exposure to stimulation and operated independently of the survival regulation of the cells. These results demonstrate that a B cell population's division destiny is regulable by the stimulatory conditions up to an inherent maximum value. Division destiny is a crucial parameter in regulating the extent of B cell responses and thereby also the nature of the immune response mounted.

Daughter-specific transcription factors regulate cell size control in budding yeast.

Science.gov (United States)

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M; Rosebrock, Adam P; Futcher, Bruce; Cross, Frederick R

2009-10-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

Science.gov (United States)

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M.; Rosebrock, Adam P.; Futcher, Bruce; Cross, Frederick R.

2009-01-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. PMID:19841732

Daughter-specific transcription factors regulate cell size control in budding yeast.

Directory of Open Access Journals (Sweden)

Stefano Di Talia

2009-10-01

Full Text Available In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells.

Science.gov (United States)

Alghanem, Ahmad F; Wilkinson, Emma L; Emmett, Maxine S; Aljasir, Mohammad A; Holmes, Katherine; Rothermel, Beverley A; Simms, Victoria A; Heath, Victoria L; Cross, Michael J

2017-08-01

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.

Central nervous system prophylaxis in diffuse large B-cell lymphoma.

Science.gov (United States)

Zahid, Mohammad Faizan; Khan, Nadia; Hashmi, Shahrukh K; Kizilbash, Sani Haider; Barta, Stefan K

2016-08-01

Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cystatin F as a regulator of immune cell cytotoxicity.

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Kos, Janko; Nanut, Milica Perišić; Prunk, Mateja; Sabotič, Jerica; Dautović, Esmeralda; Jewett, Anahid

2018-05-10

Cysteine cathepsins are lysosomal peptidases involved in the regulation of innate and adaptive immune responses. Among the diverse processes, regulation of granule-dependent cytotoxicity of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells during cancer progression has recently gained significant attention. The function of cysteine cathepsins is regulated by endogenous cysteine protease inhibitors-cystatins. Whereas other cystatins are generally cytosolic or extracellular proteins, cystatin F is present in endosomes and lysosomes and is thus able to regulate the activity of its target directly. It is delivered to endosomal/lysosomal vesicles as an inactive, disulphide-linked dimer. Proteolytic cleavage of its N-terminal part leads to the monomer, the only form that is a potent inhibitor of cathepsins C, H and L, involved in the activation of granzymes and perforin. In NK cells and CTLs the levels of active cathepsin C and of granzyme B are dependent on the concentration of monomeric, active cystatin F. In tumour microenvironment, inactive dimeric cystatin F can be secreted from tumour cells or immune cells and further taken up by the cytotoxic cells. Subsequent monomerization and inhibition of cysteine cathepsins within the endosomal/lysosomal vesicles impairs granzyme and perforin activation, and provokes cell anergy. Further, the glycosylation pattern has been shown to be important in controlling secretion of cystatin F from target cells, as well as internalization by cytotoxic cells and trafficking to endosomal/lysosomal vesicles. Cystatin F is therefore an important mediator used by bystander cells to reduce NK and T-cell cytotoxicity.

IFN-beta inhibits T cell activation capacity of central nervous system APCs