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Jan AlbrechtEDUCATION:June 1966 M. Sc. in Biochemistry at the Department of Biology, University of Warsawedit
Scientometric analysis has become a key tool with which to rank a scientist and/or a scientific institution. The position on the ISI list of a journal publishing the author’s work (that is, the “impact factor”of the journal) and the... more
Scientometric analysis has become a key tool with which to rank a scientist and/or a scientific institution. The position on the ISI list of a journal publishing the author’s work (that is, the “impact factor”of the journal) and the Hirsch index (index h) reflecting the frequency at which the author is being cited by others, are the milestones of the system. The parameters are often employed interchangeably and their validity has become a matter of hot dispute. The author stays away from this controversy. The emphasis of this article is on the need to implement a scientometric bonus that would be distinctly granted to those who contributed the most to a given work. The major contributors could be distinguished on the list of authors as the corresponding author and, perhaps in a lesser degree, the first author. At present most of the research reports in the field of medical biology or related areas, are a result of collaboration of experts representing different specialties and scien...
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Surgery, Medicine, Humans, Portal hypertension, Liver Cirrhosis, and 14 moreFemale, Male, Liver Transplantation, Hepatic Encephalopathy, Middle Aged, Adult, Cirrhosis, Varices, Ascites, Orthotopic Liver Transplantation, Esophageal varices, Esophageal and gastric varices, High risk, and Medical and Health Sciences
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Biochemistry, Metabolism, Biology, Neurochemistry, Cell Biology, and 15 moreMedicine, Energy Metabolism, Glutamate, Humans, Animals, Glutathione, Glial Cell, Enzyme, Eye, Glutamine, Glutamine Synthetase, Glutamic Acid, Glutamate Transporter, Glutamate Receptor, and Medical biochemistry and metabolomics
Brain edema in acute hepatic encephalopathy (HE) is due mainly to swelling of astrocytes. Efflux of potassium is implicated in the prevention of glial swelling under hypoosmotic conditions. We investigated whether pathogenic factors of... more
Brain edema in acute hepatic encephalopathy (HE) is due mainly to swelling of astrocytes. Efflux of potassium is implicated in the prevention of glial swelling under hypoosmotic conditions. We investigated whether pathogenic factors of HE, glutamine (Gln) and/or ammonia, induce alterations in the expression of glial potassium channels (Kir4.1, Kir2.1) and Na+‐K+‐2Cl− cotransporter‐1 (NKCC1) in rat cerebral cortex and cultured rat cortical astrocytes and whether these alterations have consequences for potassium efflux and astrocytic swelling. Thioacetamide‐induced acute liver failure in rats resulted in significant decreases in the Kir4.1 mRNA and protein contents of cerebral cortex, whereas expression of Kir2.1 and NKCC1 remained unaltered. Incubation of primary cortical astrocytes for 72 hr in the presence of Gln (5 mM), but not of ammonia (5 mM or 10 mM), induced a decrease in the levels of Kir4.1 mRNA and protein. Similarly to incubation with Gln, reduction of Kir4.1 mRNA express...
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Endocrinology, Neuroscience, Psychology, Biology, Medicine, and 15 moreInternal Medicine, Cerebral Cortex, Animals, Male, Astrocyte, Astrocytes, Hepatic Encephalopathy, Rats, Glutamine, Liver Failure, Thioacetamide, Glutamine Synthetase, Neurosciences, real time polymerase chain reaction, and reverse transcriptase polymerase chain reaction
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Kinetics, Biology, Neurochemistry, Enzyme Inhibitors, Cell Biology, and 15 moreIntelligent Transport System, Medicine, Gene expression, Cerebellum, Cerebral Cortex, Mice, Female, Animals, Astrocyte, Neurons, Astrocytes, Amino Acids, Glutamine, Neurosciences, and Medical biochemistry and metabolomics
One of the aspects of ammonia toxicity to brain cells is increased production of nitric oxide (NO) by NO synthases (NOSs). Previously we showed that ammonia increases arginine (Arg) uptake in cultured rat cortical astrocytes specifically... more
One of the aspects of ammonia toxicity to brain cells is increased production of nitric oxide (NO) by NO synthases (NOSs). Previously we showed that ammonia increases arginine (Arg) uptake in cultured rat cortical astrocytes specifically via y+L amino acid transport system, by activation of its member, a heteromeric y+LAT2 transporter. Here, we tested the hypothesis that up‐regulation of y+LAT2 underlies ammonia‐dependent increase of NO production via inducible NOS (iNOS) induction, and protein nitration. Treatment of rat cortical astrocytes for 48 with 5 mM ammonium chloride (‘ammonia’) (i) increased the y+L‐mediated Arg uptake, (ii) raised the expression of iNOS and endothelial NOS (eNOS), (iii) stimulated NO production, as manifested by increased nitrite+nitrate (Griess) and/or nitrite alone (chemiluminescence), and consequently, (iv) evoked nitration of tyrosine residues of proteins in astrocytes. Except for the increase of eNOS, all the above described effects of ammonia were abrogated by pre‐treatment of astrocytes with either siRNA silencing of the Slc7a6 gene coding for y+LAT2 protein, or antibody to y+LAT2, indicating their strict coupling to y+LAT2 activity. Moreover, induction of y+LAT2 expression by ammonia was sensitive to Nf‐κB inhibitor, BAY 11‐7085, linking y+LAT2 upregulation to the Nf‐κB activation in this experimental setting as reported earlier and here confirmed. Importantly, ammonia did not affect y+LAT2 expression nor y+L‐mediated Arg uptake activity in the cultured cerebellar neurons, suggesting astroglia‐specificity of the above described mechanism. The described coupling of up‐regulation of y+LAT2 transporter with iNOS in ammonia‐exposed astrocytes may be considered as a mechanism to ensure NO supply for protein nitration. image Ammonia (NH4+) increases the expression and activity of the L‐arginine (Arg) transporter (Arg/neutral amino acids [NAA] exchanger) y+LAT2 in cultured rat cortical astrocytes by a mechanism involving activation (nuclear translocation) of the transcription factor nuclear factor‐Nuclear factor‐κB (Nf‐κB‐p65). Up‐regulation of y+LAT2 transporter is coupled with increased inducible nitric oxide synthase (iNOS) expression, which leads to increase nitric oxide (NO) synthesis and protein nitration.
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Objective: Initiation and development of early seizures by chemical stimuli is associated with brain cell swelling resulting in edema of seizure-vulnerable brain regions. We previously reported that pretreatment with a nonconvulsive... more
Objective: Initiation and development of early seizures by chemical stimuli is
associated with brain cell swelling resulting in edema of seizure-vulnerable brain
regions. We previously reported that pretreatment with a nonconvulsive dose of
glutamine (Gln) synthetase inhibitor methionine sulfoximine (MSO) mitigates
the intensity of initial pilocarpine (Pilo)- induced seizures in juvenile rats. We
hypothesized that MSO exerts its protective effect by preventing the seizure-
initiating and seizure-propagating increase of cell volume. Taurine (Tau) is an os-
mosensitive amino acid, whose release reflects increased cell volume. Therefore,
we tested whether the poststimulus rise of amplitude of Pilo-induced electro-
graphic seizures and their attenuation by MSO are correlated with the release of
Tau from seizure-affected hippocampus.
Methods: Lithium- pretreated animals were administered MSO (75 mg/
kg ip) 2.5 h before the induction of convulsions by Pilo (40 mg/kg ip).
Electroencephalographic (EEG) power was analyzed during 60 min post- Pilo, at
5- min intervals. Extracellular accumulation of Tau (eTau) served as a marker of
cell swelling. eTau, extracellular Gln (eGln), and extracellular glutamate (eGlu)
were assayed in the microdialysates of the ventral hippocampal CA1 region col-
lected at 15- min intervals during the whole 3.5-h observation period.
Results: The first EEG signal became apparent at ~10 min post-Pilo. The EEG
amplitude across most frequency bands peaked at ~40 min post-Pilo, and showed
strong (r ~ .72– .96) temporal correlation with eTau, but no correlation with eGln
or eGlu. MSO pretreatment delayed the first EEG signal in Pilo-treated rats by
~10 min, and depressed the EEG amplitude across most frequency bands, to val-
ues that remained strongly correlated with eTau (r > .92) and moderately corre-
lated (r ~ −.59) with eGln, but not with eGlu
associated with brain cell swelling resulting in edema of seizure-vulnerable brain
regions. We previously reported that pretreatment with a nonconvulsive dose of
glutamine (Gln) synthetase inhibitor methionine sulfoximine (MSO) mitigates
the intensity of initial pilocarpine (Pilo)- induced seizures in juvenile rats. We
hypothesized that MSO exerts its protective effect by preventing the seizure-
initiating and seizure-propagating increase of cell volume. Taurine (Tau) is an os-
mosensitive amino acid, whose release reflects increased cell volume. Therefore,
we tested whether the poststimulus rise of amplitude of Pilo-induced electro-
graphic seizures and their attenuation by MSO are correlated with the release of
Tau from seizure-affected hippocampus.
Methods: Lithium- pretreated animals were administered MSO (75 mg/
kg ip) 2.5 h before the induction of convulsions by Pilo (40 mg/kg ip).
Electroencephalographic (EEG) power was analyzed during 60 min post- Pilo, at
5- min intervals. Extracellular accumulation of Tau (eTau) served as a marker of
cell swelling. eTau, extracellular Gln (eGln), and extracellular glutamate (eGlu)
were assayed in the microdialysates of the ventral hippocampal CA1 region col-
lected at 15- min intervals during the whole 3.5-h observation period.
Results: The first EEG signal became apparent at ~10 min post-Pilo. The EEG
amplitude across most frequency bands peaked at ~40 min post-Pilo, and showed
strong (r ~ .72– .96) temporal correlation with eTau, but no correlation with eGln
or eGlu. MSO pretreatment delayed the first EEG signal in Pilo-treated rats by
~10 min, and depressed the EEG amplitude across most frequency bands, to val-
ues that remained strongly correlated with eTau (r > .92) and moderately corre-
lated (r ~ −.59) with eGln, but not with eGlu
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The contribution of glutamatergic transmission to generation of initial convulsive seizures (CS) is debated. We tested whether pretreatment with a glutamine synthetase (GS) inhibitor, methionine sulfoximine (MSO), affects the onset and... more
The contribution of glutamatergic transmission to generation of initial convulsive seizures (CS) is debated. We tested whether pretreatment with a glutamine synthetase (GS) inhibitor, methionine sulfoximine (MSO), affects the onset and progression of initial CS by cholinergic stimulus in juvenile rats. Male rats (24 days old, Sprague Dawley) sequentially received i.p. injections of lithium-carbonate, MSO, methyl-scopolamine, and pilocarpine (Pilo). Pilo was given 150 min after MSO. Animals were continuously monitored using the Racine scale, EEG/EMG and intrahippocampal glutamate (Glu) biosensors. GS activity as measured in hippocampal homogenates, was not altered by MSO at 150 min, showed initial, varied inhibition at 165 (15 min post-Pilo), and dropped down to 11 % of control at 60 min post-Pilo, whereas GS protein expression remained unaltered throughout. Pilo did neither modulate the effect of MSO on GS activity nor affect GS activity itself, at any time point. MSO reduced from 32% to 4% the number of animals showing CS during the first 12 min post-Pilo, delayed by ∼6 min the appearance of electrographic seizures, and tended to decrease EMG power during ∼15 min post-Pilo. The results indicate that MSO impairs an aspect of glutamatergic transmission involved in the transition from the first cholinergic stimulus to the onset of seizures. A continuous rise of extracellular Glu lasting 60 min was insignificantly affected by MSO, leaving the nature of the Glu pool(s) involved in altered glutamatergic transmission undefined.
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The binding of a D2 receptor ligand, [3H]spiperone, was measured in striatal membranes derived from rats in which acute hepatic failure induced with thioacetamide (TAA) was associated with symptoms of hepatic encephalopathy (HE), and... more
The binding of a D2 receptor ligand, [3H]spiperone, was measured in striatal membranes derived from rats in which acute hepatic failure induced with thioacetamide (TAA) was associated with symptoms of hepatic encephalopathy (HE), and during recovery from HE. A 28% decrease of Bmax for the binding was measured in a symptomatic stage of HE, 1 day after TAA administration. The B(max) for [3H]spiperone binding was no longer different from control 7 days after TAA administration, when blood and brain biochemical correlates of HE were already absent. At 21 days after TAA administration, the B(max) was increased by 31% above the control level, consistent with other aspects of metabolic activation of the brain characteristic of the late recovery period from acute HE.
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Acute liver failure (ALF) is associated with deregulated nitric oxide (NO) signaling in the brain, which is one of the key molecular abnormalities leading to the neuropsychiatric disorder called hepatic encephalopathy (HE). This study... more
Acute liver failure (ALF) is associated with deregulated nitric oxide (NO) signaling in the brain, which is one of the key molecular abnormalities leading to the neuropsychiatric disorder called hepatic encephalopathy (HE). This study focuses on the effect of ALF on the relatively unexplored endothelial NOS isoform (eNOS). The cerebral prefrontal cortices of rats with thioacetamide (TAA)-induced ALF showed decreased eNOS expression, which resulted in an overall reduction of NOS activity. ALF also decreased the content of the NOS cofactor, tetrahydro-L-biopterin (BH4), and evoked eNOS uncoupling (reduction of the eNOS dimer/monomer ratio). The addition of the NO precursor L-arginine in the absence of BH4 potentiated ROS accumulation, whereas nonspecific NOS inhibitor L-NAME or EDTA attenuated ROS increase. The ALF-induced decrease of eNOS content and its uncoupling concurred with, and was likely causally related to, both increased brain content of reactive oxidative species (ROS) and...
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Pretreatment with non-convulsive dose of methionine sulfoximine (MSO) attenuated lithium-pilocarpine-induced (Li-Pilo) seizures in young rats [1]. We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated... more
Pretreatment with non-convulsive dose of methionine sulfoximine (MSO) attenuated lithium-pilocarpine-induced (Li-Pilo) seizures in young rats [1]. We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition of conversion of Glu/Gln precursors to neurotransmitter Glu, and/or from b) altered synaptic Glu release. Pilo was administered 60 min prior to sacrifice, MSO at 75 mg/kg, i.p., 2.5 h earlier. [1,2-13C]acetate and [U-13C]glucose were i.p.injected either together with Pilo (onset) or 15 min before sacrifice (final phase). Their conversion to Glu and Gln in hippocampus and entorhinal cortex was followed using [13C] gas chromatographymass spectrometry. Release of in vitro loaded [3H]D-Asp from ex vivo brain slices was measured in continuously collected superfusates. Protein and mRNA expression were measured by Western Blot and real-time PCR techniques, respectively. At no time point nor brain region did MSO modify incorporation of [13C] to G...
GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced.... more
GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced. Previously, it was shown that transfection with a sequence encoding GAB, the main GLS2 isoform, decreased the survival, growth, and ability to migrate of human GBM cells T98G and increased their sensitivity towards an alkylating agent temozolomide (TMZ) and oxidative stress compared to the controls, by a not well-defined mechanism. In this study we report that GAB transfection inhibits growth and increases susceptibility towards TMZ and H2O2-mediated oxidative stress of two other GBM cell lines, U87MG and LN229. We also show that in GAB-transfected cells treated with H2O2, the PI3K/AKT pathway is less induced compared to the pcDNA-transfected counterparts and that pretreatment with PDGF-BB, an activator of AKT, protects GAB-transfected cells from death ...
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Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system... more
Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons for the replenishment of both neurotransmitters. Here, we tested the hypothesis that activation of Nrf2 is the process that links ammonia-induced OS formation in astrocytes to downregulation and inactivation of SN1 and that it may involve the formation of a complex between Nrf2 and Sp1. Treatment of cultured cortical mouse astrocytes with ammonia (5 mM NH4Cl for 24 h) evoked Nrf2 nuclear translocation, increased its activity in a p38 MAPK pathway-dependent manner, and enhanced Nrf2 binding to Slc38a3 promoter. Nrf2 silencing increased SN1 mRNA and protein level without influencing astrocytic [3H]glutamine transport. Ammonia decreased SN1 expression in Nrf2 siRNA treated astrocyt...
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GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced.... more
GLS-encoded glutaminase promotes tumorigenesis, while GLS2-encoded glutaminase displays tumor-suppressive properties. In glioblastoma (GBM), the most aggressive brain tumor, GLS is highly expressed and in most cases GLS2 is silenced. Previously, it was shown that transfection with a sequence encoding GAB, the main GLS2 isoform, decreased the survival, growth, and ability to migrate of human GBM cells T98G and increased their sensitivity towards an alkylating agent temozolomide (TMZ) and oxidative stress compared to the controls, by a not well-defined mechanism. In this study we report that GAB transfection inhibits growth and increases susceptibility towards TMZ and H2O2-mediated oxidative stress of two other GBM cell lines, U87MG and LN229. We also show that in GAB-transfected cells treated with H2O2, the PI3K/AKT pathway is less induced compared to the pcDNA-transfected counterparts and that pretreatment with PDGF-BB, an activator of AKT, protects GAB-transfected cells from death ...
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Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more... more
Studies of the last two decades have demonstrated the presence in astrocytic cell membranes of N-methyl-d-aspartate (NMDA) receptors (NMDARs), albeit their apparently low abundance makes demonstration of their presence and function more difficult than of other glutamate (Glu) receptor classes residing in astrocytes. Activation of astrocytic NMDARs directly in brain slices and in acutely isolated or cultured astrocytes evokes intracellular calcium increase, by mutually unexclusive ionotropic and metabotropic mechanisms. However, other than one report on the contribution of astrocyte-located NMDARs to astrocyte-dependent modulation of presynaptic strength in the hippocampus, there is no sound evidence for the significant role of astrocytic NMDARs in astrocytic-neuronal interaction in neurotransmission, as yet. Durable exposure of astrocytic and neuronal co-cultures to NMDA has been reported to upregulate astrocytic synthesis of glutathione, and in this way to increase the antioxidativ...
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Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y⁺LAT2. Ammonia also increases the... more
Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y⁺LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y⁺LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cort...
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Genetics, Biology, Medicine, Cell line, Nitric oxide, and 7 moreAnimals, Astrocytes, Ammonia, Molecular sciences, Rats, Arginine, and Wistar Rats
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Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect... more
Initial seizures observed in young rats during the 60 min after administration of pilocarpine (Pilo) were delayed and attenuated by pretreatment with a non-convulsive dose of methionine sulfoximine (MSO). We hypothesized that the effect of MSO results from a) glutamine synthetase block-mediated inhibition of conversion of Glu/Gln precursors to neurotransmitter Glu, and/or from b) altered synaptic Glu release. Pilo was administered 60 min prior to sacrifice, MSO at 75 mg/kg, i.p., 2.5 h earlier. [1,2-13C]acetate and [U-13C]glucose were i.p.-injected either together with Pilo (short period) or 15 min before sacrifice (long period). Their conversion to Glu and Gln in the hippocampus and entorhinal cortex was followed using [13C] gas chromatography-mass spectrometry. Release of in vitro loaded Glu surrogate, [3H]d-Asp from ex vivo brain slices was monitored in continuously collected superfusates. [3H]d-Asp uptake was tested in freshly isolated brain slices. At no time point nor brain re...
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Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the... more
Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the functional astroglia-specific proteins, glutamine synthetase (GS), and the water channel protein aquaporin-4 (AQP4) and also reduces GS activity. Similar to rat astrocytes (Obara-Michlewska et al. Neurochem Int 88:20-25, 2015), the exposure of mouse astrocytes to NMDA also decreased the expression of the inward rectifying potassium channel Kir4.1. NMDA failed to elicit the effects in those cells incubated in the absence of Ca and in those in which the GluN1 subunit of the NMDAR was silenced with GluN1 siRNA. The downregulation of GS, AQP4, and Kir4.1 observed in vitro may reflect NMDAR-mediated alterations of astrocytic functions noted in central nervous system pathologies associated with increased glutamate (Glu) release and excitotoxic tissue damage.
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By histological, morphological criteria, and malignancy, brain tumors are classified by WHO into grades I (most benign) to IV (highly malignant), and gliomas are the most frequently occurring class throughout the grades. Similar to... more
By histological, morphological criteria, and malignancy, brain tumors are classified by WHO into grades I (most benign) to IV (highly malignant), and gliomas are the most frequently occurring class throughout the grades. Similar to peripheral tumors, the growth of glia-derived tumor cells largely depends on glutamine (Gln), which is vividly taken up by the cells, using mostly ASCT2 and SN1 as Gln carriers. Tumor growth-promoting effects of Gln are associated with its phosphate-activated glutaminase (GA) (specifically KGA)-mediated degradation to glutamate (Glu) and/or with its entry to the energy- and intermediate metabolite-generating pathways related to the tricarboxylic acid cycle. However, a subclass of liver-type GA are absent in glioma cells, a circumstance which allows phenotype manipulations upon their transfection to the cells. Gln-derived Glu plays a major role in promoting tumor proliferation and invasion. Glu is relatively inefficiently recycled to Gln and readily leaves the cells by exchange with the extracellular pool of the glutathione (GSH) precursor Cys mediated by xc- transporter. This results in (a) cell invasion-fostering interaction of Glu with ionotropic Glu receptors in the surrounding tissue, (b) intracellular accumulation of GSH which increases tumor resistance to radio- and chemotherapy.
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Glutamine (Gln) is a crucial metabolite in cancer cells of different origin, and the expression and activity of different isoforms of the Gln-degrading enzyme, glutaminase (GA), have variable implications for tumor growth and metabolism.... more
Glutamine (Gln) is a crucial metabolite in cancer cells of different origin, and the expression and activity of different isoforms of the Gln-degrading enzyme, glutaminase (GA), have variable implications for tumor growth and metabolism. Human glutaminases are encoded by two genes: the GLS gene encodes the kidney-type glutaminases, KGA and GAC, while the GLS2 gene encodes the liver-type glutaminases, GAB and LGA. Recent studies suggest that the GAC isoform and thus high GAC/KGA ratio, are characteristic of highly proliferating tumors, while GLS2 proteins have an inhibitory effect on tumor growth. Here we analyzed the expression levels of distinct GA transcripts in 7 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with low proliferation index and 7 non-neoplastic tissues. GEP-NETs overexpressed KGA, while GAC, which was the most abundant isoform, was not different from control. The expression of the GLS2 gene showed tendency towards elevation in GEP-NETs compared to control. Collectively, the expression pattern of GA isoforms conforms to the low proliferative capacity of GEP-NETs encompassed in this study.
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Inorganic mercury salts administered systemically at low mg/ml doses produce neurotoxic effects without penetrating the cerebral microvascular endothelial cells which form the blood-brain barrier (BBB). This phenomenon promoted... more
Inorganic mercury salts administered systemically at low mg/ml doses produce neurotoxic effects without penetrating the cerebral microvascular endothelial cells which form the blood-brain barrier (BBB). This phenomenon promoted investigations testing a hypothesis relating inorganic mercury-induced brain dysfunction to its interference with the BBB transport. In the present study, we tested the effect of a single i.p. administration of mercuric chloride (MC) (6 mg/kg body weight) on the activity and ultrastructural localization of cerebral alkaline phosphatase (AP), a cerebromicrovascular marker enzyme primarily located on luminal plasmalemma of endothelial cells. At 1h after MC administration, light microscopy revealed a virtual absence of AP in cerebral cortical layers II and III, and its dramatic reduction in the remaining layers. Electron microscopy confirmed the disappearance of the AP reaction product from luminal endothelial cell membranes, and luminal phasmalemma revealed pinocytic vesicles and invaginations likely to manifest changes in BBB transport. At 18h post-treatment, a moderate enzyme activity appeared on abluminal endothelial plasmalemma and on basement membrane, but remained absent from luminal plasmalemma. A similar picture persisted through day 5 post-treatment. The inhibition and subsequent translocation of AP activity from luminal to abluminal site and the accompanying ultrastructural changes are typical of the formation of "leaky" microvessels, previously reported for a variety of neuropathological conditions associated with BBB damage.
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The GABA level, and the glutamic acid decarboxylase (GAD) and GABA-aminotransferase (GABA-T) activities were measured in the cortex and striatum of rats in which the early stages of hepatogenic encephalopathy (HE) had been induced by few... more
The GABA level, and the glutamic acid decarboxylase (GAD) and GABA-aminotransferase (GABA-T) activities were measured in the cortex and striatum of rats in which the early stages of hepatogenic encephalopathy (HE) had been induced by few intraperitoneal administrations of thioacetamide (TAA). Besides, the GABA binding to synaptic plasma membranes (SPM) isolated from whole brain hemispheres was examined. The first part of the study revealed significant changes both in the neurotransmitter level and in the enzyme activities; no correlation was observed, however, between the accumulation of GABA and the progression of the disease. In contrast, subsequent stages of HE in the TAA model were found to be characterized by a gradual decrease of both Bmax and KD values for GABA binding, which may reflect a gradual decrease in the number of binding sites, accompanied by sensitization of the remaining receptors. The results are discussed in view of the possible involvement of this inhibitory neurotransmitter in the pathogenesis of HE.
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Exposure of rat cerebral mitochondria to 2-10 mM glutamine (Gln) for 20 min, produced a concentration-dependent, gradual decrease of light scattering reflecting mitochondrial swelling. The light scattering decreasing effect of 5 mM Gln... more
Exposure of rat cerebral mitochondria to 2-10 mM glutamine (Gln) for 20 min, produced a concentration-dependent, gradual decrease of light scattering reflecting mitochondrial swelling. The light scattering decreasing effect of 5 mM Gln was attenuated by 0.5 microM cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition (mPT) induction. Histidine (His), which is a potent inhibitor of high affinity Gln uptake to mitochondria, attenuated Gln-induced decrease of mitochondrial light scattering when added at equimolar concentration, and abolished the decrease when added at 15 mM concentration shortly before addition of Gln. His inhibited the uptake of 5 mM [14C]Gln in a concentration-dependent manner as measured during 3 min incubation. CsA did neither affect [14C]Gln uptake nor modified its inhibition by His. The effects of 5 mM His and 0.5 microM CsA on mitochondrial light scattering were additive, indicating that mitochondrial swelling represents a cumulative effect of Gln -driven entry of osmotically obligated water and induction of mPT. Addition of ammonium ions at neurotoxic concentrations neither influenced the decrease of light scattering induced by Gln, nor produced any change in light scattering when added alone. The results point to mitochondrial swelling and subsequent activation of mPT, as one of the potential mechanisms by which Gln induces metabolic disturbances in the brain in hyperammonemic conditions.
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ABSTRACT This special issue of Neurochemical Research is devoted to Dr. Michael D. Norenberg, a pathologist whose thorough analytical attitude to the microscopy of brain tissue, combined with intuitive feeling for the biology of the... more
ABSTRACT This special issue of Neurochemical Research is devoted to Dr. Michael D. Norenberg, a pathologist whose thorough analytical attitude to the microscopy of brain tissue, combined with intuitive feeling for the biology of the central nervous system, have led to breakthrough observations regarding the role of astrocytes in the normal and pathological brain. We believe the keys to his fruitful research career will emerge in all clarity from a brief account of his curriculum vitae.Mike’s parents were Polish Jews who immigrated to Cuba before his birth: he was born in 1938 in Havana. Few years later the family resettled in the USA, where Mike received his education. He obtained his B.S. from Trinity College, Hartford, Connecticut, and his M.D. from University of Rochester School of Medicine and Dentistry, Rochester, NY. From the beginning he disclosed interests in neuroanatomy and neuropathology. He became associated with the Strong Memorial Hospital in Rochester, NY, which was the place of ...
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Rats were subjected to repeated intraperitoneal administrations of thioacetamide (TAA) in order to produce the following stages of hepatogenic encephalopathy (HE): the early stage, characterized by activation of brain metabolism (Group... more
Rats were subjected to repeated intraperitoneal administrations of thioacetamide (TAA) in order to produce the following stages of hepatogenic encephalopathy (HE): the early stage, characterized by activation of brain metabolism (Group 1), the precomatose stage with impairment of brain metabolism (Group 2) and the stage of recovery (Group 3). A decrease of cerebral blood flow (CBF) of 50%, related to a drop of systemic arterial pressure and to increased hematocrit, were observed in groups 1 and 2 but not in group 3. However, the cerebral oxygen consumption (CMRO2), calculated from arterial venous difference in oxygen content and taking into account CBF, was markedly decreased in group 2, but remained unchanged in group 1. This reflects the state of cerebral metabolism at these stages. The results underscore the necessity of simultaneous monitoring of CBF and blood gases for distinguishing between the particular stages of HE revealed by biochemical tests.
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Rat synaptosomes and astroglia cell-enriched fraction were tested for the uptake of histamine (HA) and its precursor histidine, and the activities of the HA-synthesizing enzyme, histidine decarboxylase (HD) and HA-metabolizing enzyme,... more
Rat synaptosomes and astroglia cell-enriched fraction were tested for the uptake of histamine (HA) and its precursor histidine, and the activities of the HA-synthesizing enzyme, histidine decarboxylase (HD) and HA-metabolizing enzyme, histamine methyltransferase (HMT). While histidine uptake was more active into synaptosomes than into astrocytes, only astrocytes were capable of a significant HA uptake. Kinetic analysis of the astrocytic HA uptake revealed a high affinity-low capacity system (Km = 5 X 10(-7) M, Vmax = 1.6 X 10(-12) mol.min-1 X mg-1) similar to the astroglial transport systems for other neurotransmitters. HMT was 70% more active in astrocytes than in synaptosomes, whereas HD activity was not different in these two preparations. The results indicate that astrocytes could be the major site of neurotransmitter HA inactivation.
Research Interests:
Psychology, Cognitive Science, Histamine, Animals, Male, and 7 moreAstrocyte, Astrocytes, Rats, Rat, SYNAPTOSOMES, Neurosciences, and Histidine
The release of preloaded radiolabeled taurine (TAU) and ?-aminobutyric acid (GABA) from cultured rat cortical astrocytes was monitored 15 min before and 30 min after pulse treatment with aluminum chloride, at 5 min intervals. AlCl(3) at... more
The release of preloaded radiolabeled taurine (TAU) and ?-aminobutyric acid (GABA) from cultured rat cortical astrocytes was monitored 15 min before and 30 min after pulse treatment with aluminum chloride, at 5 min intervals. AlCl(3) at concentrations ranging from 0.125 to 1 mM stimulated TAU release to 252 and 519%, respectively, in a relatively dose-dependent manner. Release of GABA was not affected by 0.5 mM but was almost doubled by 1 mM AlCl(3). The effects of AlCl(3) were greatly diminished or abolished when isotonic sucrose was substituted for NaCl in the superfusion media. Interaction of Al(3+) ions with membrane transporters of amino acids is suggested to account for their increased release. Possible neurophysiological consequences of the acute effects of aluminum on the neuroactive amino acid transport in astrocytes are discussed.