scholarly journals Increases in Retrograde Injury Signaling Complex-Related Transcripts in Central Axons following Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Gunja K. Pathak ◽  
Hannah Ornstein ◽  
Helim Aranda-Espinoza ◽  
Amy J. Karlsson ◽  
Sameer B. Shah
Keyword(s):  
Nervous System ◽  
De Novo ◽  
Neuronal Response ◽  
Mrna Levels ◽  
Transcript Levels ◽  
Signaling Complex ◽  
Protein Levels ◽  
The Central Nervous System ◽  
Axonal Protein ◽  
Axonal Protein Synthesis

Axons in the peripheral nervous system respond to injury by activating retrograde injury signaling (RIS) pathways, which promote local axonal protein synthesis (LPS) and neuronal regeneration. RIS is also initiated following injury of neurons in the central nervous system (CNS). However, regulation of the localization of axonal mRNA required for LPS is not well understood. We used a hippocampal explant system to probe the regulation of axonal levels of RIS-associated transcripts following axonal injury. Axonal levels of importinβ1 and RanBP1 were elevated biphasically at 1 and 24 hrs after axotomy. Transcript levels forβ-actin, a prototypic axonally synthesized protein, were similarly elevated. Our data suggest differential regulation of axonal transcripts. At 1 hr after injury, deployment of actinomycin revealed that RanBP1, but not importinβ1, requires de novo mRNA synthesis. At 24 hrs after injury, use of importazole revealed that the second wave of increased axonal mRNA levels required importinβ-mediated nuclear import. We also observed increased importinβ1 axonal protein levels at 1 and 6 hrs after injury. RanBP1 levels and vimentin levels fluctuated but were unchanged at 3 and 6 hrs after injury. This study revealed temporally complex regulation of axonal transcript levels, and it has implications for understanding neuronal response to injury in the CNS.

Acute Disseminated Encephalomyelitis

2012 ◽  
Vol 27 (11) ◽  
pp. 1408-1425 ◽  
Author(s):  
Gulay Alper
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Disseminated Encephalomyelitis ◽  
Protein Levels ◽  
Demyelinating Disorder ◽  
Immune Mediated ◽  
Elevated Protein ◽  
Demyelinating Lesions ◽  
Diagnostic Difficulties ◽  
The Central Nervous System

Acute disseminated encephalomyelitis is an immune-mediated inflammatory and demyelinating disorder of the central nervous system, commonly preceded by an infection. It principally involves the white matter tracts of the cerebral hemispheres, brainstem, optic nerves, and spinal cord. Acute disseminated encephalomyelitis mainly affects children. Clinically, patients present with multifocal neurologic abnormalities reflecting the widespread involvement in central nervous system. Cerebrospinal fluid may be normal or may show a mild pleocytosis with or without elevated protein levels. Magnetic resonance image (MRI) shows multiple demyelinating lesions. The diagnosis of acute disseminated encephalomyelitis requires both multifocal involvement and encephalopathy by consensus criteria. Acute disseminated encephalomyelitis typically has a monophasic course with a favorable prognosis. Multiphasic forms have been reported, resulting in diagnostic difficulties in distinguishing these cases from multiple sclerosis. In addition, many inflammatory disorders may have a similar presentation with frequent occurrence of encephalopathy and should be considered in the differential diagnosis of acute disseminated encephalomyelitis.

scholarly journals A case report of rare location of ganglioglioma

2019 ◽  
Vol 34 (1) ◽  
Author(s):  
Vikas Sharma ◽  
S. Bhaskar ◽  
Sumit Ramdas Hire ◽  
Arvind Ahuja
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
De Novo ◽  
Occipital Lobe ◽  
Cystic Mass ◽  
Mass Lesion ◽  
Occipital Region ◽  
Rare Tumors ◽  
Rare Location ◽  
The Central Nervous System

Abstract Background Gangliogliomas are rare tumors of the central nervous system. They can occur anywhere in the central nervous system but are most commonly located in the temporal lobe and are mainly found in children. Anaplastic ganglioglioma can result from either de novo or transformation of a pre-existing lesion. Case presentation We report a case of de novo anaplastic ganglioglioma in the parieto occipital region, which is a rare location. A 34-year-old lady presented with features of raised intracranial pressure (ICP) with right side hemiparesis. Contrast-enhanced magnetic resonance imaging (CEMRI) of the brain showed well-defined intense heterogenously enhancing solid cystic mass lesion 5.3 × 5.2 cm in the left parieto occipital region with mass effect and midline shift. Intraoperatively, a cystic mass lesion with reddish brown nodule was seen in the left occipital lobe. Complete tumor excision was done. Microscopic and IHC examination was suggestive of anaplastic ganglioglioma. The post-operative period was uneventful. The patient received 60-Gy radiotherapy with temozolamide as adjuvant therapy, and repeat imaging showed no tumor recurrence. Conclusion Anaplastic gangliogliomas are rare tumors with parieto occipital as rare location.

scholarly journals Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate

2020 ◽  
Vol 17 (3) ◽  
pp. 1142-1152 ◽  
Author(s):  
Karl E. Carlström ◽  
Praveen K. Chinthakindi ◽  
Belén Espinosa ◽  
Faiez Al Nimer ◽  
Elias S. J. Arnér ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
De Novo ◽  
Dimethyl Fumarate ◽  
The Novel ◽  
The Central Nervous System ◽  
Demyelinating Disorders ◽  
Target Effects

Abstract The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1–CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.

scholarly journals Defective carbohydrate metabolism in mice homozygous for the tubby mutation

2006 ◽  
Vol 27 (2) ◽  
pp. 131-140 ◽  
Author(s):  
Yun Wang ◽  
Kevin Seburn ◽  
Lawrence Bechtel ◽  
Bruce Y. Lee ◽  
Jin P. Szatkiewicz ◽  
...  
Keyword(s):  
Carbohydrate Metabolism ◽  
De Novo ◽  
Ketone Bodies ◽  
Late Onset ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Mrna Levels ◽  
Protein Levels ◽  
Energy Needs ◽  
Glucose 6 Phosphate Dehydrogenase

Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late-onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J- Tub tub mice have a lower respiratory quotient than C57BL/6J controls before the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase ( G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-CoA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period, and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism and may contribute to the moderate obesity observed in tubby mice.

The Phenotype High Noxa mRNA/Low NOXA Protein Levels Constitutes a Critical Achilles Heel Of Mantle Cell Lymphoma (MCL) Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 644-644
Author(s):  
Michael A. Dengler ◽  
Andrea Weilbacher ◽  
Matthias Gutekunst ◽  
Annette M. Staiger ◽  
Heike Horn ◽  
...  
Keyword(s):  
Cell Death ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mtor Signaling ◽  
Mrna Levels ◽  
Transcript Levels ◽  
Protein Levels ◽  
Apoptotic Protein ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma with comparatively short response to chemotherapy and frequent relapses. New treatment strategies for this malignancy are urgently needed. The genetic hallmark of MCL is the t(11;14)(q13;q32) translocation. This alteration leads to deregulated expression of the oncogene Cyclin D1 and is considered the primary event in the pathogenesis of MCL. Additionally, deregulations of different oncogenic signaling and cell death pathways have been described in MCL. In this study, we investigated the role of the BH3-only protein NOXA for life/death decision in MCL. We found a stunning discrepancy between constitutive Noxa (PMAIP1) mRNA and NOXA protein levels in MCL cell lines and primary cells. Noxa mRNA was found to be highly expressed whereas NOXA protein levels were low. Remarkably, constitutive high gene expression of this pro-apoptotic Bcl2 family member was dependent on Cyclin D1 overexpression and chronic active B cell receptor (BCR) signaling, two of the major oncogenic alterations in MCL. We identified the PI3K/AKT/mTOR pathway to be crucial in the maintenance of Noxa transcript levels downstream of BCR. Cyclin D1 overexpression contributed to the high Noxa mRNA levels by exerting a positive feedback loop on PI3K/AKT/mTOR signaling. Intriguingly, the high constitutive Noxa transcript levels do not impair cell viability. MCL cells adapt to this constitutive pro-apoptotic signal by keeping NOXA protein low due to extensive ubiquitination and rapid proteasomal degradation of NOXA protein (T½ ∼ 15-30 min). As expected, treatment of the cells with the proteasome inhibitor Bortezomib accumulated NOXA protein and efficiently induced cell death. Additionally, we identified the neddylation inhibitor MNL4924 and the fatty acid synthase (FASN) inhibitor Orlistat as potent inducers of NOXA protein, and thereby apoptosis, in MCL. Cell death upon Bortezomib as well as MLN4924 and Orlistat treatment was dependent on NOXA since RNAi mediated silencing of the pro-apoptotic protein significantly reduced induction of apoptosis. We found that all three inhibitors targeted the rapid NOXA protein turnover by stabilizing the preexisting pool of NOXA. In contrast to Bortezomib, however, MLN4924 and Orlistat inhibited the ubiqutination process of NOXA protein and stabilized the pro-apoptotic protein by a proteasome independent manner. These findings could be of great clinical relevance as Bortezomib resistance is a frequently observed phenomenon. Indeed, both inhibitors were still able to induce NOXA and cell death in Bortezomib resistant clones through targeting ubiquitine-proteasome system-mediated NOXA turnover upstream of the proteasome. Interestingly, active PI3K/AKT/mTOR signaling was needed for effective accumulation of NOXA protein and induction of cell death by all these compounds indicating that the high constitutive Noxa mRNA levels are essential for sensitivity of MCL cells. Together, our data highlight that NOXA regulation may represent an important Achilles heel of MCL cells. Stabilization of NOXA protein by inhibition of the ubiquitin-proteasome system on different levels might be an effective strategy to kill MCL cells and offer novel treatment options. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CXCL13 levels are more increased in cerebrospinal fluid and plasma of patients with acute infectious than in non-infectious diseases of the central nervous system

2017 ◽  
Vol 25 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Brîndușa Țilea ◽  
Septimiu Voidăzan ◽  
Rodica Bălașa ◽  
Adina Huțanu ◽  
Andrea Fodor
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Infectious Diseases ◽  
Cell Count ◽  
Plasma Levels ◽  
Neurological Diseases ◽  
Protein Levels ◽  
Median Plasma ◽  
The Central Nervous System ◽  
Elisa Technique

Abstract Background: During the acute inflammatory process, the CXCL13 chemokine plays an important role in B cell recruitment within the central nervous system (CNS). Objective: The objective of the study consisted of the evaluation of CXCL13 chemokine cerebral spinal fluid (CSF) and plasma levels in patients with acute infectious and non-infectious neurological diseases correlated with pleocytosis and CSF protein levels. Material and method: This retrospective study was conducted over one year and included 72 patients. Thirty-eight patients (52.8%) suffering from infectious neurological disease, acute viral and bacterial meningitis, meningoencephalitis, and 34 patients (44.2%) diagnosed with non-infectious neurological diseases. CXCL13 chemokine CSF and plasma levels were determined through the ELISA technique with the Human CXCL13/BLC/BCA-1 kit. CSF cell count, glucose and protein levels, along with anti-Borrelia burgdorferi antibodies were monitored using the ELISA technique. Results: CXCL13 chemokine levels in the CSF of patients with acute infectious neurological diseases showed a median value of 23.07 pg/mL, which was significantly higher in comparison with the median value of 11.5 pg/mL of patients with noninfectious neurological diseases (p-0.03). CXCL13 median plasma concentration in patients with infectious neurological diseases was 108.1 pg/mL, in comparison with the second patient category, 50.7 pg/ml (p-0.001). We observed a statistically significant association between CXCL13 concentrations, CSF cell count and proteins. The higher the CXCL13 chemokine level, the more increased the cell count was. Conclusions: CXCL13 levels in the CSF was significantly increased in patients with acute infectious neurological diseases compared with patients with non-infectious diseases. Moreover, CXCL13 chemokine concentration was significantly correlated with the number of cells and proteins in the CSF of patients suffering from neuroinfections.

The 2016 revision of the WHO classification of tumours of the central nervous system

2017 ◽  
Author(s):  
Paul Kleihues ◽  
Elisabeth Rushing ◽  
Hiroko Ohgaki
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Who Classification ◽  
De Novo ◽  
Genetic Profiling ◽  
Primary Glioblastoma ◽  
System P ◽  
Significant Step ◽  
The Central Nervous System

The revised fourth edition of the WHO classification of Tumours of the Central Nervous System, published in 2016, comprises several newly recognized tumour entities, and a significant restructuring of the classification, mainly based on genetic profiling. Glioblastomas are now classified into two major types. Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (primary glioblastoma IDH-wildtype) develops rapidly de novo without a recognizable precursor lesion. IDH-mutant glioblastoma (secondary glioblastoma IDH-mutant) develops more slowly through malignant progression from diffuse or anaplastic astrocytoma. Medulloblastomas are now defined by combining histological patterns (classic, desmoplastic/nodular, extensive nodularity, anaplastic) and genetic hallmarks (WNT-activated; SHH-activated, TP53-mutant; SHH-activated, TP53-wildtype; non-WNT/non-SHH). Other newly recognized tumour entities include diffuse midline glioma, H3 K27M-mutant; ependymoma, RELA fusion-positive; and embryonal tumour with multilayered rosettes. The new classification is a significant step forward and will facilitate the development of novel targeted therapies of brain tumours.

Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats

1999 ◽  
Vol 96 (3) ◽  
pp. 307-312 ◽  
Author(s):  
Simon DRYDEN ◽  
Peter KING ◽  
Lucy PICKAVANCE ◽  
Patrick DOYLE ◽  
Gareth WILLIAMS
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Zucker Rats ◽  
Mrna Levels ◽  
Zucker Rat ◽  
Direct Effects ◽  
The Central Nervous System

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P< 0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 μg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P< 0.01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P< 0.01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P< 0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.

scholarly journals Central nervous system: cholesterol turnover, brain development and neurodegeneration

2009 ◽  
Vol 390 (4) ◽  
Author(s):  
John M. Dietschy
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Brain Development ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Brain Size ◽  
Average Amount ◽  
Early Brain Development ◽  
The Central Nervous System

Abstract The average amount of cholesterol in the whole animal equals approximately 2100 mg/kg body weight, and 15% and 23% of this sterol in the mouse and human, respectively, is found in the central nervous system. There is no detectable uptake across the blood-brain barrier of cholesterol carried in lipoproteins in the plasma, even in the newborn. However, high rates of de novo cholesterol synthesis in the glia and neurons provide the sterol necessary for early brain development. Once a stable brain size is achieved in the adult, cholesterol synthesis continues, albeit at a much lower rate, and this synthesis is just balanced by the excretion of an equal amount of sterol, either as 24(S)-hydroxycholesterol or, presumably, as cholesterol itself.

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