Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue acidosis from trauma or ischemia induces cytotoxic brain edema, mainly affecting astrocytes. In vitro, lactacidosis induces a dose-dependent swelling of glial cells. Activation of membrane transporters and channels, also involved in regulation of intracellular pH (pHi), has been identified as underlying mechanism, although details are poorly understood. We have currently studied whether Ca(2+)-ions play a role in acidosis-induced glial swelling and the associated intracellular acidification. The medium pH of a cell suspension (C6 glioma) was lowered from control (7.4) to 6.2 by lactic acid. Cell volume (CV) and pHi were assessed by flow cytometry. During acidosis in normal medium (2.2 mM Ca2+) CV reached a maximum of 125.1%. In a calcium-free medium swelling from acidosis was inhibited by 74%, while additional buffering of intracellular calcium (Ca2+i) by BAPTA-AM had no further effect. Buffering of Ca2+i alone did not affect the CV increase from acidosis at all. pHi which is decreasing during acidosis was not influenced by the above modifications. The present experiments indicate that lactacidosis-induced glial swelling depends on the presence of extracellular Ca(2+)-ions, while alterations of Ca2+i do not seem to be involved.
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PMID:Relevance of calcium homeostasis in glial cell swelling from acidosis. 977 84

The effect of mild to moderate hypothermia (32/27 degrees C) was analyzed on the cell volume of C6 glioma cells and primary cultured astrocytes at normal pH, during lactacidosis (pH6.2) and during exposure to glutamate or arachidonic acid in vitro. The cells were suspended in an incubation chamber under continuous control of pH, pO2 and temperature. Cell swelling was quantified by an advanced Coulter-system. Following a control period at 37 degrees C, the ambient temperature was decreased to 27 and 32 degrees C for 30 min. Hypothermia alone led to an immediate and significant cell volume increase of 107.3 +/- 0.4% (mean +/- SEM) of control after 30 min at 32 degrees C. Yet, hypothermia (27 degrees C) afforded partial protection against the acidosis-induced cell swelling at pH 6.2, attaining 120.4 +/- 0.9% in the normothermic control group after 60 min, while only 111.3 +/- 0.9% at 27 degrees C. Hypothermia, however, was not associated with a reduction of the glutamate- or arachidonic acid-induced cell swelling. The results demonstrate that mild hypothermia per se induces glial cell swelling, but simultaneously inhibits cell swelling from acidosis, while not from glutamate- or arachidonic acid.
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PMID:Glial cell swelling--effect of hypothermia. 1049 43

This study examines the contribution of anion transporters to the swelling and intracellular acidification of glial cells from an extracellular lactacidosis, a condition well-known to accompany cerebral ischemia and traumatic brain injury. Suspended C6 glioma cells were exposed to lactacidosis in physiological or anion-depleted media, and different anion transport inhibitors were applied. Changes in cell volume and intracellular pH (pH(i)) were simultaneously quantified by flow cytometry. Extracellular lactacidosis (pH 6.2) led to an increase in cell volume to 125.1 +/- 2.5% of baseline within 60 min, whereas the pH(i) dropped from the physiological value of 7.13 +/- 0.05 to 6.32 +/- 0.03. Suspension in Cl(-)-free or HCO(3)(-)/CO(2)-free media or application of anion transport inhibitors [0.1 mM bumetanide or 0.5 mM 4, 4'-diisothio-cyanatostilbene-2,2'-disulfonic acid (DIDS)] did not affect cell volume during baseline conditions but significantly reduced cell swelling from lactacidosis. In addition, the Cl(-)-free or HCO(3)(-)/CO(2)-free media and DIDS attenuated intracellular acidosis on extracellular acidification. From these findings it is concluded that besides the known activation of the Na(+)/H(+) exchanger, activation of the Na(+)-independent Cl(-)/HCO(3)(-) exchanger and the Na(+)-K(+)-Cl(-) cotransporter contributes to acidosis-induced glial swelling and the intracellular acidification. Inhibition of these processes may be of interest for future strategies in the treatment of cytotoxic brain edema from cerebral ischemia or traumatic brain injury.
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PMID:Contribution of anion transporters to the acidosis-induced swelling and intracellular acidification of glial cells. 1085 55

Cerebral tissue acidosis following ischemia or traumatic brain injury contributes to cytotoxic brain edema formation. In vitro lactacidosis induces swelling of glial cells by intracellular Na+- and Cl--accumulation by the Na+/H+-antiporter, Cl-/HCO3--antiporters and the Na+-K+-2Cl--cotransport. The present study aimed to elucidate whether mechanisms of lactacidosis-induced glial swelling are dependent on intra- or extracellular Ca2+-ions. Therefore, C6 glioma cells were exposed to a lactacidosis of pH 6.2 in standard or calcium-free medium and following intracellular calcium chelation. Cell volume and intracellular pH were assessed by flow cytometry. Lactacidosis of pH 6.2 induced a prompt and sustained swelling of suspended C6 glioma cells reaching a maximum of 128% within 60 min. Omission of Ca2+ from the suspension medium strongly attenuated cell swelling while chelation of intracellular Ca2+ had no effects. Intracellular acidosis was not affected by either treatment. The present data show a strong dependency of lactacidosis-induced glial swelling upon extracellular Ca2+ while intracellular acidosis is not affected by omission of [Ca2+]e. Therefore, our data suggest that the Na+-K+-2Cl--cotransporter, the only so far known transporter involved in cell volume regulation but not in pHi regulation during lactacidosis, is activated in a [Ca2+]e-dependent manner.
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PMID:Lactacidosis-induced glial cell swelling depends on extracellular Ca2+. 1646 48

Recently, many studies seen concerning the expression and distribution of aquaporins and K channels in the central nervous system, and their physiological and pathophysiologic roles in water and ion homeostasis. Whereas most data were collected on aquaporin-4 (AQP4) in astrocytes, only little attention was paid to AQP9 which is a water channel transporting glycerol, mannitol, and urea as well. This is the first study describing AQP9 in human brain and human brain tumors. For comparison, we also investigated the immunohistochemical distribution of AQP9 in the rat glioma RG2. Whereas in the normal rat brain AQP9 is only weakly expressed by astrocytes, the anti-AQP9 immunoreactivity was found to be increased at the tumor border, but not within the tumor. In contrast, in human glioblastoma, most glioma cells throughout the tumor revealed a strong anti-AQP9 immunoreactivity across the whole surface of the cell. In the discussion, the increase of the anti-AQP9 immunoreactivity in glioma cells is suggested to reflect an upregulation and to counteract the glioma-associated lactic acidosis by clearance of glycerol and lactate from the extracellular space. In addition, the increased level of AQP9 immunoreactivity could be involved in the energy metabolism of the glioma and/or surrounding neuronal cells.
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PMID:Expression of the water channel protein aquaporin-9 in malignant brain tumors. 1752 33

A 47-year-old man underwent 5-aminolevulinic acid assisted resection of high grade glioma. Intraoperatively, he developed a compensated lactic acidosis that was managed medically and did not cause long term complications.
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PMID:Intra-operative acidosis during 5-aminolevulinic acid assisted glioma resection. 2591 52

The prognosis of patients with Glioblastoma Multiforme (GBM), the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of GBM warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis (2D-DIGE) followed by spot picking and analysis of proteins/peptides by Mass Spectrometry. We report Glucose Regulated Protein 78 (GRP78) as a differentially expressed protein in the GBM cell line compared to human normal Astrocyte cells. In addition to proteomic studies, we performed microarray analysis which further confirmed up regulation of GRP78 in GBM cells compared to human normal Astrocyte cells. GRP78 has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found in cell plasma membrane, cytoplasm, mitochondria, nucleus and other cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor micro environmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which senses and facilitates the adaptation to the tumor microenvironment. Our findings showed differential expression of this gene in brain cancer GBM and thus confirm similarities in findings in existing transcriptional and translational studies. Thus, these findings could be of further importance for diagnostic, therapeutic and prognostic approaches for dealing with this highly malignant cancer.
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PMID:Identification of the Transmembrane Glucose Regulated Protein 78 as a Biomarker for the Brain Cancer Glioblastoma Multiforme by Gene Expression and Proteomic Studies. 2620 87

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication.
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PMID:Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma. 2748 21


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