ADEM ADEM - Academia.edu (original) (raw)

Papers by ADEM ADEM

Research paper thumbnail of Loss of neurones after long-term adrenalectomy in the adult rat hippocampal formation

NeuroReport, 1994

The effects of long-term adrenalectomy (ADX) on hippocampal neurones were investigated 5 months a... more The effects of long-term adrenalectomy (ADX) on hippocampal neurones were investigated 5 months after surgery in male Sprague-Dawley rats. Cells in Nissl-stained sections from ADX rats were counted and compared with those in sections from sham-operated rats. The ADX rats had a significantly reduced number of dentate granule cells. A novel finding was a significant reduction in the number of pyramidal cells in CA1, CA2, CA3 and CA4 regions of the hippocampus. Thus long-term adrenalectomy causes loss of dentate granule cells and pyramidal neurones of the hippocampus.

Research paper thumbnail of Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations

PLoS ONE, 2009

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the devel... more The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in a-cells or an insulin promoter in b-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated a-cells or bcells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.

Research paper thumbnail of Somatogenic and lactogenic binding sites in rat brain and liver: quantitative autoradiographic localization

Neuroscience Research, 1994

The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well... more The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well as in liver was studied by quantitative receptor autoradiography using 125I-human growth hormone (t25I-hGH) as a iigand. Quantitative measurement of binding sites for 125I-hGH showed differences in the levels of these sites in the female and male brain and liver. Moreover, regional differences in the brain were also observed in each sex. In the female brain high levels of J25I-hGH binding sites were found in the choroid plexus. Intermediate levels were observed in the striatum, the hypothalamus and the hippocampus, whereas low levels of these sites were found in the central gray, the temporal, the piriform and the entorhinal cortices. In the male brain high levels of 1251-hGH binding sites were detected in the choroid plexus. Intermediate levels were observed in the parietal cortex, the hypothalamus and the hippocampus, whereas low levels were found in the tegmentum, the temporal cortex and the striatum. Quantification of 125I-hGH binding sites in the liver revealed higher levels in the female than in the male liver. In general, higher levels of binding sites (16%-77%) were observed in the female than in the male tissues. The quantification of rat growth hormone (rGH) by radioimmunoassay was also performed in this study. Varying amounts of rGH immunoreactivity were detected in the different brain regions, with the highest levels of rGH-like material being found in the midbrain and cortex of both sexes. Moreover, higher levels of rGH-like material were observed in the female than in the male brain. Thus, sex differences in the levels of both J251-hGH binding sites and rGH-like material were observed between the female and male rat brain.

Research paper thumbnail of Prolactin binding sites in rat brain and liver: effects of long-term ovariectomy and ovarian steroids

Neuroscience Letters, 1995

The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as... more The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as well as plasma and liver prolactin (PRL) have been investigated in sham-operated and ovariectomized rats receiving either 17fl estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX-V). The levels of lactogenic binding sites in the parietal and piriform cortices, amygdala, thalamus, hypothalamus, as well as in the liver were significantly decreased after long-term ovariectomy. Moreover, the levels of plasma and liver PRL were also significantly decreased. Exogenous estradiol and progesterone replacement restored the levels of lactogenic binding sites in the parietal cortex and hypothalamus as well as in the liver. However, plasma and liver PRL levels were significantly increased by estradiol but only restored by progesterone. These results suggest that ovarian steroids influence the levels of lactogenic binding sites and prolactin.

Research paper thumbnail of Change in nicotinic receptor subtypes in temporal cortex of Alzheimer brains

Neuroscience Letters, 1988

Competition experiments using (-)-[3H]nicotine and unlabelled nicotine revealed both high and low... more Competition experiments using (-)-[3H]nicotine and unlabelled nicotine revealed both high and low affinity nicotinic binding sites in temporal cortex of control and Alzheimer (AD/SDAT) brains. A significant reduction in the proportion of high affinity nicotinic binding sites (-20%) and a parallel increase in the proportion of low affinity nicotinic binding sites was obtained in AD/SDAT brain cortex compared to control brain. Moreover, a marked decrease was observed in the affinity of the low affinity nicotinic binding sites in AD,'SDAT. Recently the involvement of cholinergic nicotinic receptors in neurological and psychiatric disorders such as Alzheimer's disease and senile dementia of Alzheimer type (AD/SDAT) has been investigated. A reduced number of high affinity nicotinic binding sites in cortex of Alzheimer brains (AD/SDAT) was recently reported [6, 12, 18]. In AD/SDAT cortices a parallel reduction was also observed in choline acetyltransferase (CHAT) activity I! 2, 18] and in vitro acetylcholine (ACh) release [10, 14], but not in muscarinic receptors [12]. These observations together with findings obtained in animal lesion studies [5, 8, 16] suggested that the high affinity nicotinic binding sites might preferentially be presynaptically located. Available data today indicate heterogeneous nicotinic binding sites in human brain [1 3, 9, 15, 17]. In this study a further analysis of changes in nicotinic subtypes (high affinity and low affinity) in cortex of AD/SDAT brains has been performed using [3H]nicotine competition studies. The findings indicate in AD/SDAT a change in the proportion of high affinity nicotinic binding sites to low affinity nicotinic binding sites in cortical tissue and a decrease in receptor affinity especially for the low affinity binding sites.

Research paper thumbnail of Expression of MHC class II, CD4+ and ED1 molecules in association with selective hippocampal neuronal degeneration after long-term adrenalectomy

Research paper thumbnail of Long-term adrenalectomy decreases NMDA receptors in rat hippocampus

NeuroReport, 1998

THE effect of long-term adrenalectomy on NMDA receptors in the rat hippocampus was studied. Hippo... more THE effect of long-term adrenalectomy on NMDA receptors in the rat hippocampus was studied. Hippocampal sections of control and adrenalectomized rats were incubated with [ 3 H]MK-801, a radiolabeled non-competitive inhibitor of the NMDA receptor. Analysis by in vitro autoradiography showed a significant decrease in [ 3 H]MK-801 binding in the dentate gyrus, CA1 and CA4 areas, as well as the temporal cortex. Results of this study suggest that glucocorticoids are vital for the regulation of the NMDA receptors.

Research paper thumbnail of Growth factor receptors in amyotrophic lateral sclerosis

Molecular Neurobiology, 1994

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) r... more The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Research paper thumbnail of Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis

Journal of Neural Transmission, 1994

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous sys... more Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-l receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Research paper thumbnail of Euler characteristics and cohomology of p-local discrete groups

Journal of Algebra, 1992

Let r be a discrete group of finite virtual cohomological dimension. Calculating the cohomology o... more Let r be a discrete group of finite virtual cohomological dimension. Calculating the cohomology of such a group is in general a very difficult task. Indeed, there are very few general theorems about the cohomological structure of such groups. This is in contrast to the situation for a linite group G, where it is well known that a local approach is required, i.e., Syf,(G) must be considered for each prime p dividing jG/. In this paper we formulate a local approach for the cohomological analysis of the groups K An essential aspect of this is the use of Farrell Cohomology. Briefly, it can be described as follows. Fix an extension l+r'+r+G-+l, (0.1) where PC r is torsion-free. Now let P= Syl,(G), for some prime p dividing IG/. Then clearly the extension I+rf+r*-+P-+1 (0.2) defines a subgroup of index [G: Syl,(G)] in r, and it is easy to see that res;, defines an embedding fi(r, H),,, 4 k*(P, Z), whose image consists of stable elements defined in a manner analogous to the finite setting.

Research paper thumbnail of Field Theory and the Cohomology of Some Galois Groups

Journal of Algebra, 2001

We prove that two arithmetically significant extensions of a field F coincide if and only if the ... more We prove that two arithmetically significant extensions of a field F coincide if and only if the Witt ring W F is a group ring Z/n[G]. Furthermore, working modulo squares with Galois groups which are 2-groups, we establish a theorem analogous to Hilbert's theorem 90 and show that an identity linking the cohomological dimension of the Galois group of the quadratic closure of F , the length of a filtration on a certain module over a Galois group, and the dimension over F 2 of the square class group of the field holds for a number of interesting families of fields. Finally, we discuss the cohomology of a particular Galois group in a topological context.

Research paper thumbnail of International Neuroscience Conference on Research Strategies and Clinical Challenges in Neuroscience, Al Ain, United Arab Emirates, November 2005

Experimental Brain Research, 2006

Research paper thumbnail of Muscarinic receptors in human SH-SY5Y neuroblastoma cell line: regulation by phorbol ester and retinoic acid-induced differentiation

Developmental Brain Research, 1987

The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate ([3H]QNB) to cell me... more The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate ([3H]QNB) to cell membranes of human SH-SY5Y neuroblastoma cells was studied. Saturation isotherms yielded a K d = 0.28 + t),06 nM and a Bin, ~ of 337 + 47 pmol/g protein. Pircnzepme inhibited [3HIQNB binding; inhibition data showed best fit to a 2-site binding model revealing both it high affinity pirenzepine site (34'V~, K u = 10 nM) and a low affinity site (66%, K k = 1 uM). These results indicate that muscarinie receptors on SH-SY5Y cells may be subclassified as M1/M 2 subtypes. Morphological and biochemical differentiation of these cells after treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA) resulted in a decrease and an increase in the number of muscarinic binding sites, respectively. Furthermore. TPA-and RA-treated cells showed a significant increase in acetylcholinesterase activity compared with non-treated cells. However, only RA-treated cells showed significant increase in choline acetyltransferasc activity compared to nontreated cells. These findings demonstrate that TPA and RA can regulate both the number of muscarinic receptors and the acetvlcholinesterase activity in human SH-SY5Y neuroblastoma cells.

Research paper thumbnail of Functional Characterization of Filamin A Interacting Protein 1–Like, a Novel Candidate for Antivascular Cancer Therapy

Cancer Research, 2008

Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify... more Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify common intracellular mediators, we previously analyzed gene expression profiles of endothelial cells after treatment with angiogenesis inhibitors. Filamin A interacting protein 1-like (FILIP1L; previously known as down-regulated in ovarian cancer 1) was identified as one of the genes up-regulated in endothelial cells in response to these inhibitors. However, the expression and function of FILIP1L protein is uncharacterized. Here, we provide the first description of the expression and specific subcellular localization of FILIP1L protein in human tissue. Overexpression of FILIP1L resulted in inhibition of cell proliferation and migration and increased apoptosis. In addition, overexpression of FILIP1L truncation mutants showed differential antiproliferative activity. A COOH terminal truncation mutant (FILIP1LΔC103) was more potent than wild-type FILIP1L in mediating this activity. Targeted...

Research paper thumbnail of Commuting elements, simplicial spaces and filtrations of classifying spaces

Mathematical Proceedings of the Cambridge Philosophical Society, 2011

Let G denote a topological group. In this paper the descending central series of free groups are ... more Let G denote a topological group. In this paper the descending central series of free groups are used to construct simplicial spaces of homomorphisms with geometric realizations B(q, G) that provide a filtration of the classifying space BG. In particular this setting gives rise to a single space constructed out of all the spaces of ordered commuting n–tuples of elements in G. Basic properties of these constructions are discussed, including the homotopy type and cohomology when the group G is either a finite group or a compact connected Lie group. For a finite group the construction gives rise to a covering space with monodromy related to a delicate result in group theory equivalent to the odd-order theorem of Feit–Thompson. The techniques here also yield a counting formula for the cardinality of Hom(π, G) where π is any descending central series quotient of a finitely generated free group. Another application is the determination of the structure of the spaces B(2, G) obtained from ...

Research paper thumbnail of Inhibition of acetylcholine muscarinic M1 receptor function by the M1 -selective ligand muscarinic toxin 7 (MT-7)

British Journal of Pharmacology, 2000

MT-7 (1 ± 30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angustic... more MT-7 (1 ± 30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angusticeps and previously found to bind selectively to the muscarinic M 1 receptor, inhibited the acetylcholine (ACh)-stimulated [ 35 S]-guanosine-5'-O-(3-thio)triphosphate ([ 35 S]-GTPgS) binding to membranes of Chinese hamster ovary (CHO) cells stably expressing the cloned human muscarinic M 1 receptor subtype. 2 MT-7 failed to aect the ACh-stimulated [ 35 S]-GTPgS binding in membranes of CHO cells expressing either the M 2 , M 3 or M 4 receptor subtype. 3 In N1E-115 neuroblastoma cells endogenously expressing the M 1 and M 4 receptor subtypes, MT-7 (0.3 ± 3.0 nM) inhibited the carbachol (CCh)-stimulated inositol phosphates accumulation, but failed to aect the CCh-induced inhibition of pituitary adenylate cyclase activating polypeptide (PACAP) 38-stimulated cyclic AMP accumulation. 4 In both CHO/M 1 and N1E-115 cells the MT-7 inhibition consisted in a decrease of the maximal agonist eect with minimal changes in the agonist EC 50 value. 5 In CHO/M 1 cell membranes, MT-7 (0.05 ± 25 nM) reduced the speci®c binding of 0.05, 1.0 and 15 nM [ 3 H]-N-methylscopolamine ([ 3 H]-NMS) in a concentration-dependent manner, but failed to cause a complete displacement of the radioligand. Moreover, MT-7 (3 nM) decreased the dissociation rate of [ 3 H]-NMS by about 5 fold. 6 CHO/M 1 cell membranes preincubated with MT-7 (10 nM) and washed by centrifugation and resuspension did not recover control [ 3 H]-NMS binding for at least 8 h at 308C. 7 It is concluded that MT-7 acts as a selective noncompetitive antagonist of the muscarinic M 1 receptors by binding stably to an allosteric site.

Research paper thumbnail of Ultrastructural analysis of the hippocampus of adult rats after long-term adrenalectomy

Brain Research, 1999

Removal of adrenal steroids modulates various functions in the brain. However, adrenalectomy (ADX... more Removal of adrenal steroids modulates various functions in the brain. However, adrenalectomy (ADX) induced cell death in the hippocampal formation of the adult rat is a recently described phenomenon. We undertook this ultrastructural study on long-term adrenalectomized (5 months) rats to investigate the mode of cell death in the hippocampus. Our results showed apoptotic changes in the hippocampus. In addition we have observed other types of degeneration in the hippocampal neurons. The novel finding in this study is that different morphological patterns of cell death were evident both in the dentate gyrus and in the pyramidal areas, which may reflect different stages of the same death process.

Research paper thumbnail of Enhanced localization of amyloid β precursor protein in the rat hippocampus following long-term adrenalectomy

Brain Research, 1998

... Brain Res., 593 (1992), pp. 128–135. Corresponding Author Contact Information Corresponding a... more ... Brain Res., 593 (1992), pp. 128–135. Corresponding Author Contact Information Corresponding author. CBV Path Group, MRC Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. Fax: +44-191-272-5291; E-mail: rnkalaria@ncl.ac.uk. ...

Research paper thumbnail of Changes in IGF-1 receptors in the hippocampus of adult rats after long-term adrenalectomy: receptor autoradiography and in situ hybridization histochemistry

Brain Research, 1998

Alteration of insulin-like growth factor-1 (IGF-1) receptor and its mRNA after long-term adrenale... more Alteration of insulin-like growth factor-1 (IGF-1) receptor and its mRNA after long-term adrenalectomy (ADX) was studied in the hippocampus by in vitro receptor autoradiography and in situ hybridization histochemistry, respectively. Significantly, decreased levels of IGF-1 receptor and its mRNA was noted in the dentate and CA1-CA4 regions of the hippocampus of the ADX animals, suggesting that the level and expression of IGF-1 receptors in the hippocampus is influenced by adrenal hormones.

Research paper thumbnail of Toxins from the venom of the green mamba Dendroaspis angusticeps that inhibit the binding of quinuclidinyl benzilate to muscarinic acetylcholine receptors

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1988

Two protein toxins that displace the muscarinic antagonist quinuclidinyl benzilate from rat corte... more Two protein toxins that displace the muscarinic antagonist quinuclidinyl benzilate from rat cortex synaptosomai membranes have been isolated from the green mamba (Dendroaspis angusticeps) venom by gel filtration on sephadex G-50, chromatography on the ion-exchangers Bio-Rex 70 and SulphopropyI-Sephadex C-25 and reversed-phase HPLC. Toxin 1 has 64 amino acids and four disulfides and a formula weight of 7200 and the corresponding values for toxin 2 are 63, 4 and 6840, respectively. UItracentrifugation gave a molecular weight of 6900 for toxin 1 and 6700 for toxin 2, Quinuclidinyl benzilate that binds to all types of muscarinic cholinergic receptor was displaced to about 50% by both toxins. This partial displacement indicates that the toxins might be specific for one subtype of receptor.

Research paper thumbnail of Loss of neurones after long-term adrenalectomy in the adult rat hippocampal formation

NeuroReport, 1994

The effects of long-term adrenalectomy (ADX) on hippocampal neurones were investigated 5 months a... more The effects of long-term adrenalectomy (ADX) on hippocampal neurones were investigated 5 months after surgery in male Sprague-Dawley rats. Cells in Nissl-stained sections from ADX rats were counted and compared with those in sections from sham-operated rats. The ADX rats had a significantly reduced number of dentate granule cells. A novel finding was a significant reduction in the number of pyramidal cells in CA1, CA2, CA3 and CA4 regions of the hippocampus. Thus long-term adrenalectomy causes loss of dentate granule cells and pyramidal neurones of the hippocampus.

Research paper thumbnail of Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations

PLoS ONE, 2009

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the devel... more The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in a-cells or an insulin promoter in b-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated a-cells or bcells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.

Research paper thumbnail of Somatogenic and lactogenic binding sites in rat brain and liver: quantitative autoradiographic localization

Neuroscience Research, 1994

The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well... more The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well as in liver was studied by quantitative receptor autoradiography using 125I-human growth hormone (t25I-hGH) as a iigand. Quantitative measurement of binding sites for 125I-hGH showed differences in the levels of these sites in the female and male brain and liver. Moreover, regional differences in the brain were also observed in each sex. In the female brain high levels of J25I-hGH binding sites were found in the choroid plexus. Intermediate levels were observed in the striatum, the hypothalamus and the hippocampus, whereas low levels of these sites were found in the central gray, the temporal, the piriform and the entorhinal cortices. In the male brain high levels of 1251-hGH binding sites were detected in the choroid plexus. Intermediate levels were observed in the parietal cortex, the hypothalamus and the hippocampus, whereas low levels were found in the tegmentum, the temporal cortex and the striatum. Quantification of 125I-hGH binding sites in the liver revealed higher levels in the female than in the male liver. In general, higher levels of binding sites (16%-77%) were observed in the female than in the male tissues. The quantification of rat growth hormone (rGH) by radioimmunoassay was also performed in this study. Varying amounts of rGH immunoreactivity were detected in the different brain regions, with the highest levels of rGH-like material being found in the midbrain and cortex of both sexes. Moreover, higher levels of rGH-like material were observed in the female than in the male brain. Thus, sex differences in the levels of both J251-hGH binding sites and rGH-like material were observed between the female and male rat brain.

Research paper thumbnail of Prolactin binding sites in rat brain and liver: effects of long-term ovariectomy and ovarian steroids

Neuroscience Letters, 1995

The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as... more The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as well as plasma and liver prolactin (PRL) have been investigated in sham-operated and ovariectomized rats receiving either 17fl estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX-V). The levels of lactogenic binding sites in the parietal and piriform cortices, amygdala, thalamus, hypothalamus, as well as in the liver were significantly decreased after long-term ovariectomy. Moreover, the levels of plasma and liver PRL were also significantly decreased. Exogenous estradiol and progesterone replacement restored the levels of lactogenic binding sites in the parietal cortex and hypothalamus as well as in the liver. However, plasma and liver PRL levels were significantly increased by estradiol but only restored by progesterone. These results suggest that ovarian steroids influence the levels of lactogenic binding sites and prolactin.

Research paper thumbnail of Change in nicotinic receptor subtypes in temporal cortex of Alzheimer brains

Neuroscience Letters, 1988

Competition experiments using (-)-[3H]nicotine and unlabelled nicotine revealed both high and low... more Competition experiments using (-)-[3H]nicotine and unlabelled nicotine revealed both high and low affinity nicotinic binding sites in temporal cortex of control and Alzheimer (AD/SDAT) brains. A significant reduction in the proportion of high affinity nicotinic binding sites (-20%) and a parallel increase in the proportion of low affinity nicotinic binding sites was obtained in AD/SDAT brain cortex compared to control brain. Moreover, a marked decrease was observed in the affinity of the low affinity nicotinic binding sites in AD,'SDAT. Recently the involvement of cholinergic nicotinic receptors in neurological and psychiatric disorders such as Alzheimer's disease and senile dementia of Alzheimer type (AD/SDAT) has been investigated. A reduced number of high affinity nicotinic binding sites in cortex of Alzheimer brains (AD/SDAT) was recently reported [6, 12, 18]. In AD/SDAT cortices a parallel reduction was also observed in choline acetyltransferase (CHAT) activity I! 2, 18] and in vitro acetylcholine (ACh) release [10, 14], but not in muscarinic receptors [12]. These observations together with findings obtained in animal lesion studies [5, 8, 16] suggested that the high affinity nicotinic binding sites might preferentially be presynaptically located. Available data today indicate heterogeneous nicotinic binding sites in human brain [1 3, 9, 15, 17]. In this study a further analysis of changes in nicotinic subtypes (high affinity and low affinity) in cortex of AD/SDAT brains has been performed using [3H]nicotine competition studies. The findings indicate in AD/SDAT a change in the proportion of high affinity nicotinic binding sites to low affinity nicotinic binding sites in cortical tissue and a decrease in receptor affinity especially for the low affinity binding sites.

Research paper thumbnail of Expression of MHC class II, CD4+ and ED1 molecules in association with selective hippocampal neuronal degeneration after long-term adrenalectomy

Research paper thumbnail of Long-term adrenalectomy decreases NMDA receptors in rat hippocampus

NeuroReport, 1998

THE effect of long-term adrenalectomy on NMDA receptors in the rat hippocampus was studied. Hippo... more THE effect of long-term adrenalectomy on NMDA receptors in the rat hippocampus was studied. Hippocampal sections of control and adrenalectomized rats were incubated with [ 3 H]MK-801, a radiolabeled non-competitive inhibitor of the NMDA receptor. Analysis by in vitro autoradiography showed a significant decrease in [ 3 H]MK-801 binding in the dentate gyrus, CA1 and CA4 areas, as well as the temporal cortex. Results of this study suggest that glucocorticoids are vital for the regulation of the NMDA receptors.

Research paper thumbnail of Growth factor receptors in amyotrophic lateral sclerosis

Molecular Neurobiology, 1994

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) r... more The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Research paper thumbnail of Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis

Journal of Neural Transmission, 1994

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous sys... more Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-l receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Research paper thumbnail of Euler characteristics and cohomology of p-local discrete groups

Journal of Algebra, 1992

Let r be a discrete group of finite virtual cohomological dimension. Calculating the cohomology o... more Let r be a discrete group of finite virtual cohomological dimension. Calculating the cohomology of such a group is in general a very difficult task. Indeed, there are very few general theorems about the cohomological structure of such groups. This is in contrast to the situation for a linite group G, where it is well known that a local approach is required, i.e., Syf,(G) must be considered for each prime p dividing jG/. In this paper we formulate a local approach for the cohomological analysis of the groups K An essential aspect of this is the use of Farrell Cohomology. Briefly, it can be described as follows. Fix an extension l+r'+r+G-+l, (0.1) where PC r is torsion-free. Now let P= Syl,(G), for some prime p dividing IG/. Then clearly the extension I+rf+r*-+P-+1 (0.2) defines a subgroup of index [G: Syl,(G)] in r, and it is easy to see that res;, defines an embedding fi(r, H),,, 4 k*(P, Z), whose image consists of stable elements defined in a manner analogous to the finite setting.

Research paper thumbnail of Field Theory and the Cohomology of Some Galois Groups

Journal of Algebra, 2001

We prove that two arithmetically significant extensions of a field F coincide if and only if the ... more We prove that two arithmetically significant extensions of a field F coincide if and only if the Witt ring W F is a group ring Z/n[G]. Furthermore, working modulo squares with Galois groups which are 2-groups, we establish a theorem analogous to Hilbert's theorem 90 and show that an identity linking the cohomological dimension of the Galois group of the quadratic closure of F , the length of a filtration on a certain module over a Galois group, and the dimension over F 2 of the square class group of the field holds for a number of interesting families of fields. Finally, we discuss the cohomology of a particular Galois group in a topological context.

Research paper thumbnail of International Neuroscience Conference on Research Strategies and Clinical Challenges in Neuroscience, Al Ain, United Arab Emirates, November 2005

Experimental Brain Research, 2006

Research paper thumbnail of Muscarinic receptors in human SH-SY5Y neuroblastoma cell line: regulation by phorbol ester and retinoic acid-induced differentiation

Developmental Brain Research, 1987

The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate ([3H]QNB) to cell me... more The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate ([3H]QNB) to cell membranes of human SH-SY5Y neuroblastoma cells was studied. Saturation isotherms yielded a K d = 0.28 + t),06 nM and a Bin, ~ of 337 + 47 pmol/g protein. Pircnzepme inhibited [3HIQNB binding; inhibition data showed best fit to a 2-site binding model revealing both it high affinity pirenzepine site (34'V~, K u = 10 nM) and a low affinity site (66%, K k = 1 uM). These results indicate that muscarinie receptors on SH-SY5Y cells may be subclassified as M1/M 2 subtypes. Morphological and biochemical differentiation of these cells after treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA) resulted in a decrease and an increase in the number of muscarinic binding sites, respectively. Furthermore. TPA-and RA-treated cells showed a significant increase in acetylcholinesterase activity compared with non-treated cells. However, only RA-treated cells showed significant increase in choline acetyltransferasc activity compared to nontreated cells. These findings demonstrate that TPA and RA can regulate both the number of muscarinic receptors and the acetvlcholinesterase activity in human SH-SY5Y neuroblastoma cells.

Research paper thumbnail of Functional Characterization of Filamin A Interacting Protein 1–Like, a Novel Candidate for Antivascular Cancer Therapy

Cancer Research, 2008

Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify... more Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify common intracellular mediators, we previously analyzed gene expression profiles of endothelial cells after treatment with angiogenesis inhibitors. Filamin A interacting protein 1-like (FILIP1L; previously known as down-regulated in ovarian cancer 1) was identified as one of the genes up-regulated in endothelial cells in response to these inhibitors. However, the expression and function of FILIP1L protein is uncharacterized. Here, we provide the first description of the expression and specific subcellular localization of FILIP1L protein in human tissue. Overexpression of FILIP1L resulted in inhibition of cell proliferation and migration and increased apoptosis. In addition, overexpression of FILIP1L truncation mutants showed differential antiproliferative activity. A COOH terminal truncation mutant (FILIP1LΔC103) was more potent than wild-type FILIP1L in mediating this activity. Targeted...

Research paper thumbnail of Commuting elements, simplicial spaces and filtrations of classifying spaces

Mathematical Proceedings of the Cambridge Philosophical Society, 2011

Let G denote a topological group. In this paper the descending central series of free groups are ... more Let G denote a topological group. In this paper the descending central series of free groups are used to construct simplicial spaces of homomorphisms with geometric realizations B(q, G) that provide a filtration of the classifying space BG. In particular this setting gives rise to a single space constructed out of all the spaces of ordered commuting n–tuples of elements in G. Basic properties of these constructions are discussed, including the homotopy type and cohomology when the group G is either a finite group or a compact connected Lie group. For a finite group the construction gives rise to a covering space with monodromy related to a delicate result in group theory equivalent to the odd-order theorem of Feit–Thompson. The techniques here also yield a counting formula for the cardinality of Hom(π, G) where π is any descending central series quotient of a finitely generated free group. Another application is the determination of the structure of the spaces B(2, G) obtained from ...

Research paper thumbnail of Inhibition of acetylcholine muscarinic M1 receptor function by the M1 -selective ligand muscarinic toxin 7 (MT-7)

British Journal of Pharmacology, 2000

MT-7 (1 ± 30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angustic... more MT-7 (1 ± 30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angusticeps and previously found to bind selectively to the muscarinic M 1 receptor, inhibited the acetylcholine (ACh)-stimulated [ 35 S]-guanosine-5'-O-(3-thio)triphosphate ([ 35 S]-GTPgS) binding to membranes of Chinese hamster ovary (CHO) cells stably expressing the cloned human muscarinic M 1 receptor subtype. 2 MT-7 failed to aect the ACh-stimulated [ 35 S]-GTPgS binding in membranes of CHO cells expressing either the M 2 , M 3 or M 4 receptor subtype. 3 In N1E-115 neuroblastoma cells endogenously expressing the M 1 and M 4 receptor subtypes, MT-7 (0.3 ± 3.0 nM) inhibited the carbachol (CCh)-stimulated inositol phosphates accumulation, but failed to aect the CCh-induced inhibition of pituitary adenylate cyclase activating polypeptide (PACAP) 38-stimulated cyclic AMP accumulation. 4 In both CHO/M 1 and N1E-115 cells the MT-7 inhibition consisted in a decrease of the maximal agonist eect with minimal changes in the agonist EC 50 value. 5 In CHO/M 1 cell membranes, MT-7 (0.05 ± 25 nM) reduced the speci®c binding of 0.05, 1.0 and 15 nM [ 3 H]-N-methylscopolamine ([ 3 H]-NMS) in a concentration-dependent manner, but failed to cause a complete displacement of the radioligand. Moreover, MT-7 (3 nM) decreased the dissociation rate of [ 3 H]-NMS by about 5 fold. 6 CHO/M 1 cell membranes preincubated with MT-7 (10 nM) and washed by centrifugation and resuspension did not recover control [ 3 H]-NMS binding for at least 8 h at 308C. 7 It is concluded that MT-7 acts as a selective noncompetitive antagonist of the muscarinic M 1 receptors by binding stably to an allosteric site.

Research paper thumbnail of Ultrastructural analysis of the hippocampus of adult rats after long-term adrenalectomy

Brain Research, 1999

Removal of adrenal steroids modulates various functions in the brain. However, adrenalectomy (ADX... more Removal of adrenal steroids modulates various functions in the brain. However, adrenalectomy (ADX) induced cell death in the hippocampal formation of the adult rat is a recently described phenomenon. We undertook this ultrastructural study on long-term adrenalectomized (5 months) rats to investigate the mode of cell death in the hippocampus. Our results showed apoptotic changes in the hippocampus. In addition we have observed other types of degeneration in the hippocampal neurons. The novel finding in this study is that different morphological patterns of cell death were evident both in the dentate gyrus and in the pyramidal areas, which may reflect different stages of the same death process.

Research paper thumbnail of Enhanced localization of amyloid β precursor protein in the rat hippocampus following long-term adrenalectomy

Brain Research, 1998

... Brain Res., 593 (1992), pp. 128–135. Corresponding Author Contact Information Corresponding a... more ... Brain Res., 593 (1992), pp. 128–135. Corresponding Author Contact Information Corresponding author. CBV Path Group, MRC Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. Fax: +44-191-272-5291; E-mail: rnkalaria@ncl.ac.uk. ...

Research paper thumbnail of Changes in IGF-1 receptors in the hippocampus of adult rats after long-term adrenalectomy: receptor autoradiography and in situ hybridization histochemistry

Brain Research, 1998

Alteration of insulin-like growth factor-1 (IGF-1) receptor and its mRNA after long-term adrenale... more Alteration of insulin-like growth factor-1 (IGF-1) receptor and its mRNA after long-term adrenalectomy (ADX) was studied in the hippocampus by in vitro receptor autoradiography and in situ hybridization histochemistry, respectively. Significantly, decreased levels of IGF-1 receptor and its mRNA was noted in the dentate and CA1-CA4 regions of the hippocampus of the ADX animals, suggesting that the level and expression of IGF-1 receptors in the hippocampus is influenced by adrenal hormones.

Research paper thumbnail of Toxins from the venom of the green mamba Dendroaspis angusticeps that inhibit the binding of quinuclidinyl benzilate to muscarinic acetylcholine receptors

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1988

Two protein toxins that displace the muscarinic antagonist quinuclidinyl benzilate from rat corte... more Two protein toxins that displace the muscarinic antagonist quinuclidinyl benzilate from rat cortex synaptosomai membranes have been isolated from the green mamba (Dendroaspis angusticeps) venom by gel filtration on sephadex G-50, chromatography on the ion-exchangers Bio-Rex 70 and SulphopropyI-Sephadex C-25 and reversed-phase HPLC. Toxin 1 has 64 amino acids and four disulfides and a formula weight of 7200 and the corresponding values for toxin 2 are 63, 4 and 6840, respectively. UItracentrifugation gave a molecular weight of 6900 for toxin 1 and 6700 for toxin 2, Quinuclidinyl benzilate that binds to all types of muscarinic cholinergic receptor was displaced to about 50% by both toxins. This partial displacement indicates that the toxins might be specific for one subtype of receptor.