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991.
目的 研究胸苷酸合成酶(thymidylate synthase,TS)基因多态性在汉族女性乳腺癌患者中的分布特点及其与临床病理之间的关系.方法收集经病理学确诊的83例初诊乳腺癌患者外周静脉血,术前均未给予任何针对乳腺癌的治疗,应用聚合酶链反应限制性片段长度多态性技术(PCR-RFLP)检测墓因型.基因多态性与临床病理的关系采用卡方分析进行检验.结果 83例乳腺癌患者的基因分布情况为:(1)3R/3R、2R/3R及2R/2R 3种基因型的频率分别为68.7%、27.7%、3.6%;(2)按G→C单核苷酸多态性细分,2R/2R,2R/3C,2R/3G,3G/3G,3C/3C及3G/3C 6种基因型的频率分别为3.6%、19.3%、8.4%、19.3%、37.3%及12.1%;(3)+/+6 bp、+/-6 bp及-/-6 bp3种基因型的频率分别为8.4%、50.6%及41.0%;(4)3种基因多态性均与乳腺癌的组织学分级相关(P<0.05);另外TS 5′-UTR多态性与淋巴结转移(P=0.019)、Ki67(P=0.022)相关,TS 3′-UTR多态性与发病年龄相关(P=0.002),G→C单核苷酸多态性与淋巴结转移相关(P=0.021).结论 汉族女性乳腺癌患者中3R/3R、-/-6 bp基因型频率较高;TS基因多态性与乳腺癌临床病理因素密切相关. 相似文献
992.
Eid T Hammer J Rundén-Pran E Roberg B Thomas MJ Osen K Davanger S Laake P Torgner IA Lee TS Kim JH Spencer DD Ottersen OP de Lanerolle NC 《Acta neuropathologica》2007,113(2):137-152
Patients with mesial temporal lobe epilepsy (MTLE) have increased basal concentrations of extracellular glutamate in the epileptogenic
versus the non-epileptogenic hippocampus. Such elevated glutamate levels have been proposed to underlie the initiation and
maintenance of recurrent seizures, and a key question is what causes the elevation of glutamate in MTLE. Here, we explore
the possibility that neurons in the hippocampal formation contain higher levels of the glutamate synthesizing enzyme phosphate-activated
glutaminase (PAG) in patients with MTLE versus patients with other forms of temporal lobe epilepsy (non-MTLE). Increased PAG
immunoreactivity was recorded in subpopulations of surviving neurons in the MTLE hippocampal formation, particularly in CA1
and CA3 and in the polymorphic layer of the dentate gyrus. Immunogold analysis revealed that PAG was concentrated in mitochondria.
Double-labeling experiments indicated a positive correlation between the mitochondrial contents of PAG protein and glutamate,
as well as between PAG enzyme activity and PAG protein as determined by Western blots. These data suggest that the antibodies
recognize an enzymatically active pool of PAG. Western blots and enzyme activity assays of hippocampal homogenates revealed
no change in PAG between MTLE and non-MTLE, despite a greatly (>50%) reduced number of neurons in the MTLE hippocampal formation
compared to non-MTLE. Thus, the MTLE hippocampal formation contains an increased concentration and activity of PAG per neuron
compared to non-MTLE. This increase suggests an enhanced capacity for glutamate synthesis—a finding that might contribute
to the disrupted glutamate homeostasis in MTLE.
Tore Eid and Janniche Hammer contributed equally to this study. 相似文献
993.
Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders. 相似文献
994.
A key function of fatty acid (FA) transport into the brain is to supply polyunsaturated fatty acids (PUFA) that are not synthesized
in brain cells but are essential signaling molecules and components of the phospholipid membrane. In addition, common dietary
FAs such as palmitic acid are also rapidly taken up by the brain and esterified to phospholipids or oxidized to provide cellular
energy. Most evidence shows that FA crossing the blood brain barrier (BBB) is derived mainly from FA/albumin complexes and,
to a lesser extent, from circulating lipoproteins. Our model proposes that FA diffuse across the lipid bilayer of the BBB
without specific transporters to reach brain cells. They cross the luminal and transluminal leaflets of the endothelial cells
and the plasma membrane of neural cells by reversible flip-flop. Acyl-CoA synthetases trap FA by forming acyl-CoA, which cannot
diffuse out of the cell. Selection of FA is controlled largely by enzymes in the pathways of intracellular metabolism, beginning
with the acyl-CoA synthetase. 相似文献
995.
996.
Huang Y Feld JJ Sapp RK Nanda S Lin JH Blatt LM Fried MW Murthy K Liang TJ 《Gastroenterology》2007,132(2):733-744
BACKGROUND & AIMS: Approximately half of hepatitis C virus (HCV)-infected patients do not respond to current interferon (IFN)-alpha combination therapy. To understand IFN-alpha resistance in vivo, we examined the dynamic responses to both type I and type II IFNs, human IFN (hIFN)-alpha, -gamma, and consensus IFN, in the chimpanzee model. METHODS: Naive and HCV-infected chimpanzees were treated with 3 forms of hIFNs in vivo. Quantitative real-time polymerase chain reaction was performed to evaluate the expression of IFN-stimulated genes (ISGs) in both peripheral blood mononuclear cells and liver to compare the responses to hIFN between naive and infected chimpanzees. The hepatic expression of IFN signaling components and inhibitory regulators including suppressor of cytokine signaling 3 (SOCS3) were assessed. SOCS3 expression was also evaluated in the liver of HCV-infected patients undergoing IFN treatment. RESULTS: The in vivo responses to all 3 hIFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. This defect was particularly evident in the liver because induction of hepatic ISGs was barely detectable in the infected animals. Following IFN administration, the expression of SOCS3 was significantly up-regulated, possibly through induction of interleukin-6, in the liver of HCV-infected chimpanzees. HCV-infected humans also showed a differential pattern of hepatic SOCS3 expression in response to IFN that is associated with treatment response. CONCLUSIONS: Our data indicate a predominantly defective hepatic response to IFN in HCV-infected chimpanzees, which is probably mediated through the activation of SOCS3 and may explain the nonresponse of many HCV patients to IFN-based therapy. 相似文献
997.
Perlov E Philipsen A Hesslinger B Buechert M Ahrendts J Feige B Bubl E Hennig J Ebert D Tebartz van Elst L 《Journal of psychiatric research》2007,41(11):934-941
BACKGROUND: The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD. In the present study, we wanted to test the hypothesis that prefrontal glutamate signals indirectly indicate dopaminergic dysfunction in adult patients with ADHD. METHODS: Twenty-eight adult patients with ADHD and 28 group-matched healthy volunteers were studied clinically and using chemical-shift MR spectroscopy (MRS) of the prefrontal cortex covering the anterior cingulate gyrus. RESULTS: A significant reduction of the combined glutamate/glutamine to creatine ratio in the right anterior cingulate cortex in patients with ADHD was found. DISCUSSION: Glutamatergic alterations as measured with MRS might play a role in the pathogenesis of adult patients with ADHD. 相似文献
998.
It has been shown that glutamine protects the heart from ischemia/reperfusion (I/R) injury; however, the mechanisms underlying this protection have not been identified. Glutamine:fructose-6-phosphate amidotransferase (GFAT) regulates the entry of glucose into the hexosamine biosynthesis pathway (HBP), and activation of this pathway has been shown to be cardioprotective. Glutamine is required for metabolism of glucose via GFAT; therefore, the goal of this study was to determine whether glutamine cardioprotection could be attributed to increased flux through the HBP and elevated levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins. Hearts from male rats were isolated and perfused with Krebs-Henseliet buffer containing 5 mM glucose, and global, no-flow ischemia was induced for 20 min followed by 60 min of reperfusion. Thirty-minute pre-treatment with 2.5 mM glutamine significantly improved functional recovery (RPP: 15.6+/-5.7% vs. 59.4+/-6.1%; p<0.05) and decreased cardiac troponin I release (25.4+/-3.0 vs. 4.7+/-1.9 ng/ml; p<0.05) during reperfusion. This protection was associated with a significant increase in the levels of protein O-GlcNAc and ATP. Pre-treatment with 80 muM azaserine, an inhibitor of GFAT, completely reversed the protection seen with glutamine and prevented the increase in protein O-GlcNAc. O-GlcNAc transferase (OGT) catalyzes the formation of O-GlcNAc, and inhibition of OGT with 5 mM alloxan also reversed the protection associated with glutamine. These data support the hypothesis that in the ex vivo perfused heart glutamine cardioprotection is due, at least in part, to enhanced flux through the HBP and increased protein O-GlcNAc levels. 相似文献
999.
Nora Sandow Robert K. Zahn Siegrun Gabriel Uwe Heinemann †Thomas-Nicolas Lehmann 《Epilepsia》2009,50(4):849-858
Purpose: Glutamine (GLN) is a precursor for synthesis of glutamate and γ-aminobutyric acid (GABA) and has been found in the cerebrospinal fluid (CSF) at mean concentrations of 0.6 mM. Experiments on slices are usually performed in artificial CSF (aCSF) kept free of amino acids. Therefore, the role of glutamine, particularly in tissue of epileptic animals, remains elusive.
Methods: Using extracellular recordings we studied effects of GLN on field potentials and stimulus-evoked field responses in the medial entorhinal cortex (MEC) of combined entorhinal cortex hippocampal slices from pilocarpine-treated chronic epileptic rats and age-matched saline-injected control rats.
Results: In presence of GLN (0.5 and 2 mM) recurrent epileptiform discharges (REDs) were observed in slices from epileptic rats (64% and 80%, respectively), but not in slices from control rats. REDs were restricted to the superficial MEC, suppressed by the α-Amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (30 μM), attenuated by the inhibitor of neuronal glutamine transporters methylamino-isobutyric acid (10 mM), and apparently augmented and prolonged by the GABAA receptor antagonist bicuculline-methiodide (5 μM). In contrast, amplitudes of stimulus evoked nonsynaptic and synaptic field responses increased in slices from control rats (+23% and +12% of the reference values) and insignificantly less or not in those of epileptic rats (+6.5% and −0.25%, respectively). Notably, stimulus-evoked slow negative transients confined to slices of epileptic animals were reduced in amplitude (−18%).
Discussion: In combined entorhinal hippocampal slices from chronic epileptic animals, GLN induces glutamatergic REDs via neuronal uptake in superficial layers of the MEC where inhibitory function seemed to be partially preserved. 相似文献
Methods: Using extracellular recordings we studied effects of GLN on field potentials and stimulus-evoked field responses in the medial entorhinal cortex (MEC) of combined entorhinal cortex hippocampal slices from pilocarpine-treated chronic epileptic rats and age-matched saline-injected control rats.
Results: In presence of GLN (0.5 and 2 mM) recurrent epileptiform discharges (REDs) were observed in slices from epileptic rats (64% and 80%, respectively), but not in slices from control rats. REDs were restricted to the superficial MEC, suppressed by the α-Amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (30 μM), attenuated by the inhibitor of neuronal glutamine transporters methylamino-isobutyric acid (10 mM), and apparently augmented and prolonged by the GABA
Discussion: In combined entorhinal hippocampal slices from chronic epileptic animals, GLN induces glutamatergic REDs via neuronal uptake in superficial layers of the MEC where inhibitory function seemed to be partially preserved. 相似文献
1000.
Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide 总被引:3,自引:0,他引:3
This review describes the laboratory evidence and microvascularmechanisms responsible for the beneficial effects of statinsin sepsis. During sepsis, changes occur within the microcirculationincluding alterations in arteriolar tone influencing blood pressure,adaptations to endothelial cell integrity causing leakage ofproteins and macromolecules, and adhesion and migration of leucocytesthrough the vascular endothelium. Statins are widely used ascholesterol-lowering agents, but appear to have anti-inflammatoryactions during sepsis. We have discussed the effects of statinson specific pathological processed within the microcirculationand focused on the role of nitric oxide (NO). The main mechanism by which statins appear to be an effectivetreatment for sepsis is increased expression of endothelialnitric oxide synthase (eNOS), in conjunction with down-regulationof inducible nitric oxide synthase. Combined, this results inan increase in physiological concentrations of NO, thus restoringendothelial function. Laboratory studies have therefore suggestedthat enhancement of eNOS activity during sepsis may lead torestoration of microvascular tone, maintenance of microvascularintegrity, and inhibition of cell adhesion molecules. However,other mechanisms independent of lipid-lowering effects, includingantioxidant activity and alterations in the development of vascularatherosclerosis, may also contribute to the beneficial effectsof statins. We have also addressed the influence on the effectsof statins of lipid solubility and pre- and pro-phylactic administration. 相似文献