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Biomedical subjects

Y Sei

Publications and source records attributed to Y Sei.

At least 37 records · Page 2Linked to original sources
PubMed1998

The influence of a targeted deletion of the IFNgamma gene on emotional behaviors.

Evidence suggests that interferon-gamma (IFNgamma) plays an important role in CNS function and development. While the paucity of agents that selectively modify IFNgamma production or interaction with its receptors makes analyses of its potential behavioral relevance difficult, mice with null mutations of the IFNgamma gene have been used to investigate the potential role of IFNgamma in emotional behaviors. C57Bl/6 (B6) mice with null mutations of the IFNgamma gene (IFNgamma (-/-)) showed significantly increased emotionality compared to the wild-type (IFNgamma (+/+)) B6 mice. This was manifested in performance in the elevated plus maze as well as increased defecation scores and decreased locomotor activity both in novel environments and following a sonic stimulus. In contrast, the general level of emotionality of both IFNgamma (+/+) and (-/-) BALB/c (C) mice was substantially greater than that of either of the B6 mouse groups. While C IFNgamma (-/-) showed increased immobility in response to novelty, other indices of emotionality of C IFNgamma (-/-) mice were not significantly different from those of the C IFNgamma (+/+) mice. In summary, the lack of IFNgamma appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALBc) may overshadow the expression of this emotionality. While mice with null mutations of the IFNgamma gene may be useful tools for investigating the role of IFNgamma in brain function and behavior, the influence of the parent strain genome(s) on the behaviors in question must be taken into account.

Adaptation, Psychological↗
PubMed1998

Extracellular glutamate levels are chronically elevated in the brains of LP-BM5-infected mice: a mechanism of retrovirus-induced encephalopathy.

Mice infected with the LP-BM5 leukemia retrovirus mixture develop a progressive immunodeficiency with associated behavioral, histological, and neurochemical alterations consistent with glutamatergic hyperactivation. To gain insight into the contribution of excitatory amino acids to the neurodegeneration observed in these mice, their concentrations were measured in the CSF and striatal microdialysates. Glutamate concentrations were significantly elevated in CSF but not plasma as early as 4 weeks postinoculation. Steady-state glutamate levels in striatal microdialysates were increased threefold and could be reduced 40% by application of L-alpha-aminoadipate, an inhibitor of microglial glutamate transport. Stimulation of infected mice with KCl/L-trans-2,4-pyrrolidine dicarboxylate further increased glutamate levels 170-270% above those evoked in control mice. Tetrodotoxin suppressed the depolarization-evoked increase in glutamate by 88% in control mice, but it had only negligible effects in 40% of infected mice. Analysis of glutamate transport and catabolism suggests that abnormal astrocytic function does not contribute to the increase in basal extracellular glutamate levels. These findings are the first direct evidence that infection with an immunodeficiency-inducing retrovirus leads to a chronic elevation of extracellular free glutamate levels in the brain, which contributes to the neurodegenerative and cognitive deficits observed in these mice.

AIDS-Related Complex↗
PubMed1997

Pentoxifylline decreases brain levels of platelet activating factor in murine AIDS.

Tumor necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) have been implicated in the pathogenesis of human immunodeficiency virus (HIV)-associated encephalopathy. The effects of pentoxifylline on brain PAF levels were examined in mice infected with the LP-BM5 murine leukemia virus (MuLV). Seven weeks after viral inoculation, significant increases in serum TNF-alpha and brain PAF levels were observed. One week of treatment with pentoxifylline initiated 6 weeks postinfection significantly reduced both serum TNF-alpha and brain PAF levels. A significant positive correlation was observed between the levels of these substances (r = 0.62; P < 0.01). This study demonstrates that pentoxifylline treatment was effective in decreasing the levels of TNF-alpha in the serum and PAF levels in the brain of mice infected with the LP-BM5 MuLV.

Animals↗
PubMed1997

Regional changes in constitutive, but not inducible NOS expression in the brains of mice infected with the LP-BM5 leukemia virus.

Potential neurotoxins such as nitric oxide have been implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS) dementia complex. The LP-BM5 murine leukemia-infected mice, which develop immunological and cognitive deficits reminiscent of human HIV-1 infection, were employed to investigate the changes in brain constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) expression. Cerebellar and striatal cNOS enzymatic activity increased approximately 70% as early as 2 weeks after infection, declining to control levels by 12-16 weeks. In contrast, cNOS protein expression in the striatum and cerebellum was decreased 30% at 4 weeks, declining to 50% of control levels by 16 weeks post-infection. Staining intensity for cNOS, but not neuron number was reduced in the cerebral cortex, striatum, ventromedial hypothalamic nucleus and amygdala. Although iNOS protein expression was elevated in splenic monocytes, neither iNOS activity, mRNA nor protein was detected in the brains of mice 12 weeks after infection. These results indicate that neurons decrease cNOS protein expression to compensate for chronic cNOS activation, probably resulting from glutamatergic stimulation. The cNOS activation is contemporaneous with microglial activation in LP-BM5-infected mice, and precedes the development of cognitive deficits. Moreover, the lack of iNOS induction in either infected macrophages or glial elements suggests that iNOS is not necessary for the development of these cognitive deficits.

Animals↗
PubMed1997

Regional decreases [corrected] in AMPA receptor density in mice infected with the LP-BM5 murine leukemia virus.

The status of alpha-amino-3-hydroxy-5-methyl-4-isoxizole (AMPA) receptors in several brain regions was investigated in a murine model of retrovirus-associated cognitive impairment, the LP-BM5 infected mouse. The Bmax of [3H]AMPA receptors in the cortex, striatum, hippocampus and cerebellum declined by 29-50% as early as 8 weeks post-inoculation. Immunohistochemistry revealed foci of decreased glutamate receptor (GluR)-2/3 protein expression by Purkinje neurons distributed throughout the cerebellum. Immunoblots indicated that cerebellar expression of only GluR-3 protein was reduced. This global decrease in AMPA receptors may constitute a compensatory response to elevated excitotoxin (glutamate) concentrations and are concurrent with the development of spatial learning deficits observed in these mice. Thus, the reduction in AMPA receptor density may contribute to the development of the cognitive abnormalities associated with infection by retroviruses such as HIV-1.

Animals↗
PubMed1997

Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists.

The effects of novel, selective adenosine (ADO) A3 receptor antagonists of diverse structure on cells of the human HL-60 leukemia and U-937 lymphoma cell lines were examined. Both 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3, 5-dicarboxylate (MRS 1191, 0.5 microM) and 6-carboxy-methyl-5, 9-dihydro-9-methyl-2-phenyl-[1,2,4]-triazolo [5,1-a][2,7]naphthyridine (L-249313, 0.5 microM) induced apoptotic cell death and expression of bak protein. Low concentrations of the A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA, 10 nM or 1 microM) protected against antagonist-induced cell death. At concentrations > or = 10 microM, the agonist alone produced apoptosis and bak expression in various cell lines. It is suggested that there exists a tonic low level of A3 receptor activation, possibly induced by release of endogenous adenosine, that results in cell protection.

Adenosine↗
PubMed1996

Gliosis in the LP-BM5 murine leukemia virus-infected mouse: an animal model of retrovirus-induced dementia.

Mice infected with the LP-BM5 murine leukemia virus (MuLV) mixture develop severe immunosuppression, neurotransmitter abnormalities and cognitive impairments in the absence of significant viral or macrophage invasion of the CNS. The time-course of the changes in glial activation have been characterized in an effort to understand the cellular basis of the neurobehavioral abnormalities observed in these mice. Glial activation was determined by measuring the relative changes in F4/80 protein and GFAP immunoreactivity using immunoblots. Augmented F4/80 expression preceded that of GFAP, with global elevations of 4-6-fold at 3 weeks, sustained for up to 12 weeks after inoculation. GFAP immunoreactivity increased 2-fold only in the cerebral cortex and striatum 5 weeks postinfection, declining to control levels by 12 weeks. Immunohistochemistry revealed significant increases in microglial size and staining intensity in the cortex, corpus callosum and striatum, with the development of a unique population of highly ramified, intensely stained microglia and microglial nodules in the corpus callosum and striatum. No evidence of ameboid microglia was found. Astrocyte size and degree of ramification was increased in the hippocampus, cortex, striatum and corpus callosum. Thus, microgliosis is an early event in LP-BM5 infection, preceding astrocytosis, neurotransmitter loss, and development of cognitive deficits. Activated microglia may secrete neurotoxins leading to the neurochemical alterations and cognitive deficits observed in these mice. Because gliosis and microglial nodule formation are hallmarks of HIV-1 encephalopathy, LP-BM5 MuLV-infected C57/B16 mice may afford insights into the mechanisms contributing to the early stages of this syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Early increases in TNF-alpha, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain.

The effects of transient global ischemia using bilateral carotid artery occlusion on regional cytokine levels in gerbil brain were investigated using enzyme-linked immunoassay techniques. Brain concentrations of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) were increased during the early recirculation period ( < 6 h) after 10 min of ischemia, with lesser degrees of elevation following only 5 min of ischemia. TNF-alpha levels in the hippocampus and striatum were significantly increased as early as 1 h after recirculation, declining sharply to control levels by 12 h, then transiently increasing at 24 h. Elevated levels of IL-1 beta and IL-6 were not seen until 3-6 h post-occlusion. No significant increases in cytokine concentrations were observed in the cerebellum or thalamus. These results suggest that regionally selective increases in cytokines may be involved in the pathophysiological changes in hippocampus and striatum following transient cerebral ischemia.

Analysis of Variance↗
PubMed1996

Induction of apoptosis in HL-60 human promyelocytic leukemia cells by adenosine A(3) receptor agonists.

The effects of adenosine (ADO) analogs on cells of the human promyelocytic HL-60 line were examined. ADO A(3) receptor agonists, N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA, 30-60 microM) and 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (CI-IB-MECA, 10-30 microM) induced apoptotic cell death. In contrast, neither an A(1)/A(2) antagonist (XAC) nor other selective ADO receptor agonists (CPA, NECA and CGS21680) induced apoptosis at concentrations of <30 microM. Both IB-MECA and CI-IB-MECA significantly induced Ca(2+) release from intracellular Ca(2+) pools followed by Ca(2+) influx, suggesting the presence of phospholipase C-coupled ADO A(3) receptors on HL-60 cells. This was further supported by the presence of mRNA of ADO A3 receptor in the cells. These results suggest that activation of ADO A(3) receptors is responsible for the ADO-induced apoptosis in HL-60 cells and could be of potential therapeutic value in the treatment of leukemia.

Adenosine↗
PubMed1996

The defective secretion of a naturally occurring alpha-1-antichymotrypsin variant with a frameshift mutation.

A newly found variant alpha-1-antichymotrypsin (ACT), ACT Isehara-2, has a deletion of two bases (AA) at codon 391 near the carboxyl terminus. This frameshift mutation caused a change in the amino acid sequence and generated 10 extra amino acids (408 amino acids total) [Tsuda, M., Sei, Y., Matsumoto, M., Kamiguchi, H., Yamamoto, Y., Shinohara, Y., Igarashi, T. & Yamamura, M. (1992) Hum. Genet. 91. 467-468]. The serum ACT levels in three unrelated heterozygotes with this mutant ACT gene were 37% 49% and 54% that of the normal individuals. To examine the reduced serum levels, the normal ACT and the mutant ACT created by site-directed mutagenesis were transfected into COS-7 cells for comparison. The value for the retention rate (intracellular ACT/total ACT) was apparently higher in the cells expressing mutant ACT Isehara-2 than those bearing the normal gene. In the pulse-chase experiments, the secretion of the synthesized mutant ACT into the medium was not observed, whereas the normal ACT was mostly secreted as a 64-kDa form. The endoglycosidase H digestion and an electron microscopic analysis indicated that the retained mutant ACT was present in the endoplasmic reticulum. These results provide the biochemical basis for the decreased serum ACT level of individuals with ACT Isehara-2, and suggest the importance of the carboxyl-terminal region for its secretion.

Amino Acid Sequence↗
PubMed1996

Quinolinic acid levels in a murine retrovirus-induced immunodeficiency syndrome.

Mice infected with the retrovirus mixture designated LP-BM5 murine leukemia virus (MuLV) develop an immunosuppressive disease. Quinolinic acid (QUIN) is an endogenous neurotoxic N-methyl-D-aspartate agonist that may contribute to the pathogenesis of HIV-associated neurologic disease. In the present study, the levels of QUIN in brain and blood were measured in mice infected with LP-BM5 MuLV and compared with those in uninfected mice and mice infected with the nonpathogenic strain of ecotropic MuLV (helper component of LP-BM5 MuLV). Infection with LP-BM5 MuLV resulted in progressive increases in blood QUIN levels beginning 2 weeks after inoculation that peaked by 16 weeks postinfection. QUIN levels were also increased in cerebral cortex, hippocampus, and striatum. In systemic tissues, QUIN levels were increased in lung, liver, and spleen. In contrast, infection with the ecotropic viral component of the LP-BM5 MuLV mixture was not associated with any changes in brain, blood, or systemic tissue QUIN levels, even though helper virus burdens were comparable to those in mice infected with LP-BM5 MuLV. Treatment of LP-BM5 MuLV-infected mice with the antiretroviral agent zidovudine (azidothymidine) significantly reduced blood and brain QUIN levels in association with reductions in viral load in brain and spleen. These observations suggest that elevated QUIN production is not attributable to productive infection with retrovirus per se but occurs in response to an agent or agents, such as cytokines, that are produced by the host in response to virus infection.

AIDS Dementia Complex↗
PubMed1996

Increased brain levels of platelet-activating factor in a murine acquired immune deficiency syndrome are NMDA receptor-mediated.

Mice infected with the LP-BM5 murine leukemia virus (MuLV) develop an immunodeficiency syndrome (murine AIDS) and an encephalopathy characterized by impaired spatial learning and memory. Because platelet-activating factor (PAF) has been implicated in the pathogenesis of HIV-associated dementia complex, brain PAF levels were measured in LP-BM5 MuLV-infected mice. PAF levels in cerebral cortex and hippocampus were significantly increased at 6 and 12 weeks after LP-BM5 MuLV inoculation, whereas significant increases in striatal and cerebellar PAF levels were observed only at 12 weeks after inoculation. Administration of the NMDA antagonist MK-801 significantly reduced the increased PAF levels in the cerebral cortex and hippocampus of LP-BM5 MuLV-infected mice. These results indicate that the LP-BM5 MuLV-induced increases in brain PAF levels are the results of NMDA receptor activation and are consistent with the hypothesis that elevated CNS PAF levels contribute to the behavioral deficits observed in LP-BM5 MuLV-infected mice.

AIDS Dementia Complex↗
PubMed1996

Altered brain fyn kinase in a murine acquired immunodeficiency syndrome.

Mice infected with the replication-defective virus (BM5def) in the LP-BM5 murine leukemia virus (MuLV) mixture develop an immune deficiency syndrome and encephalopathy characterized by impaired spatial learning and memory as demonstrated in the Morris water maze. However, the molecular mechanism (or mechanisms) underlying this cognitive deficit remains unknown. Here we report that brain fyn kinase, which has been proposed to be involved in spatial learning and memory, was unresponsive to glutamatergic stimulation in mice with MAIDS. Thus, whereas application of glutamate to hippocampal slices from control mice increased fyn protein tyrosine kinase (PTK) activity more than 2.5-fold, these changes were significantly impaired in LP-BM5 MuLV-infected mice. Moreover, mice with MAIDS exhibited an abnormal histological distribution of fyn PTK in the hippocampus. These findings suggest that virus-associated disruption of fyn kinase-mediated signaling contributes to the cognitive deficits observed in mice with MAIDS and other retrovirus-induced encephalopathies.

Animals↗
PubMed1995

Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3.

The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.

Antineoplastic Agents↗
PubMed1995

Distinct mechanisms for Ca2+ entry induced by OKT3 and Ca2+ depletion in Jurkat T cells.

Ca2+ influx triggered by antigen binding to T cell receptors (TCR) is an early event in T cell activation. An additional Ca2+ influx induced by depletion of intracellular Ca2+ (CDCI) has been characterized in human Jurkat T cells that is both temporally and mechanistically distinct from TCR-mediated Ca2+ influx (TCRCI). Both TCRCI and CDCI were insensitive to voltage-gated Ca2+ channel antagonists (e.g., nifedipine, verapamil, and omega-conotoxin G) and pertussis toxin, yet were voltage-sensitive and inhibited by SKF 96365 (a receptor-gated Ca2+ channel blocker) and cholera toxin. However, TCRCI but not CDCI was associated with a significant increase in inositol phosphate (IP chi) levels and inhibited by phorbol ester, while CDCI but not TCRCI was inhibited by Sr2+, forskolin (FSK), and 1,9-dideoxy FSK in a cAMP-independent fashion. Moreover, TCR stimulation did not deplete thapsigargin-sensitive Ca2+ stores, suggesting that TCRCI is not merely a consequence of Ca2+ depletion. These results indicate that Ca2+ entry following the depletion of intracellular Ca2+ stores or TCR stimulation occur through distinct cellular mechanisms coexisting in Jurkat T cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Thapsigargin induces IL-2 receptor alpha-chain in human peripheral and Jurkat T cells via a protein kinase C-independent mechanism.

Thapsigargin (TG), an inhibitor of Ca(2+)-ATPase, depletes intracellular Ca2+ stores and induces a sustained Ca2+ influx without altering phosphatidyl inositol levels. TG plus phorbol myristate acetate (PMA) but not TG alone induced IL-2 in Jurkat T cells, suggesting that TG had no effect on protein kinase C (PKC). However, TG induced increases in IL-2R alpha protein as well as IL-2R alpha mRNA in Jurkat T cells in a dose-dependent manner. A similar increase in IL-2R alpha by TG was also observed in human peripheral T cells. Further, like PMA, TG markedly induced NF kappa B in Jurkat T cells. However, TG and PMA exhibited a synergistic action on IL-2R alpha expression, suggesting that TG and PMA induce IL-2R alpha through distinct pathways. PMA- but not TG-induced IL-2R alpha is inhibited by the PKC inhibitor H7, whereas TG- but not PMA-induced IL-2R alpha was inhibited by cholera toxin, forskolin and 1,9-dideoxy forskolin. In toto, these results suggest that TG induces IL-2R alpha in human T cells through a PKC-independent pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Effects of immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase) inhibitors, cyclosporin A, FK506, ascomycin and rapamycin, on hair growth initiation in mouse: immunosuppression is not required for new hair growth.

The effects of immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase) inhibitors, cyclosporin A, FK506, ascomycin and rapamycin, on hair growth initiation (anagen hair induction) in mouse were studied by topical application on the dorsal skin surface during the telogen phase of the hair cycle. Single applications of cyclosporin A and FK506 (10 to 100 nmol in 5 microliters of ethanol) induced new hair growth in 12 days within the restricted area where the compounds were applied. On the other hand, ascomycin and rapamycin did not initiate new anagen hairs even at higher doses (1 mumol in 5 to 10 microliters of ethanol). The effects of simultaneous application of the immunosuppressants were also tested by a single topical application. Ascomycin did not inhibit the anagen hair induction by cyclosporin A, but inhibited hair induction by FK506. Rapamycin inhibited new hair growth induced by cyclosporin A and FK506. These results suggest that the inhibition of PPIase is not required for the initiation of a new hair cycle in mice, and that anagen hair induction caused by cyclosporin A and FK506 is not a result of immunosuppression. The present results also indicate that a single application of an adequate quantity of cyclosporin A and FK506 is sufficient to initiate new hair growth.

Administration, Topical↗