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11.
PARP cleavage, DNA fragmentation, and pyknosis during excitotoxin-induced neuronal death 总被引:6,自引:0,他引:6
Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme activated by DNA breaks and serves a role in DNA repair through the formation of polymers (poly(ADP)ribosylation) at sites of DNA damage. PARP-1 is activated by DNA damage in neurons of the hippocampus and cerebral cortex following excessive exposure to glutamate receptor agonists such as NMDA or kainic acid. In addition, recent studies suggest that degradation of PARP-1 occurs in cells that undergo apoptotic versus nonapoptotic forms of cell death. To investigate this process further, we examined the spatiotemporal aspects of excitotoxic injury in the rodent visual cortex by making focal intracerebral injections of kainic acid. These injections resulted in DNA damage, PARP-1 activation, and neuronal cell death over a 5-day period. Rapid neuronal cell injury assessed by Fluoro-Jade staining appeared within hours, but increased TUNEL staining occurred only after 24 h. A dramatic increase in caspase-3 activity, as well as an increase in the number of neurons containing active caspase-3, peaked 2 days after injury. Last, increased PARP-1 immunoreactivity and PARP-1 cleavage reached peak levels 2 to 3 days after delivering the excitotoxin. These findings suggest that increased caspase-3 activity may regulate the degradation of PARP-1 in subsets of cortical neurons during excitotoxic cell death. 相似文献
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We isolated cancer cell-specific phages by subtracting and selecting complex peptide display phage libraries on cultured human cancer cells. The best candidate was selected by performing three rounds of subtraction before each of five selections on the human colorectal WiDr cell line. The phage showed more than 1000-fold higher binding efficiency for WiDr cells when compared to five other human cancer cell lines, including two of colorectal origin, and when compared to wild-type M13 phage. Fifty-fold higher binding efficiency was also seen for a human breast cancer cell line. We show that the WiDr cell binding of the selected phage was efficiently competed by the synthetic peptide HEWSYLAPYPWF, predicted from the phage sequence. This confirms that the specificity of the peptide is independent of the display by the phage coat proteins. The identified peptide may target biomarkers linked to colorectal cancer, and thus be useful for designing gene transfer vectors as well as diagnostic and prognostic tools for this disease. 相似文献
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Ohne Zusammenfassung 相似文献
14.
MR imaging and (1)H spectroscopy of brain metabolites in hepatic encephalopathy: time-course of renormalization after liver transplantation 总被引:5,自引:0,他引:5
Naegele T Grodd W Viebahn R Seeger U Klose U Seitz D Kaiser S Mader I Mayer J Lauchart W Gregor M Voigt K 《Radiology》2000,216(3):683-691
PURPOSE: To evaluate changes in hydrogen 1 magnetic resonance (MR) spectroscopic findings in overt or subclinical hepatic encephalopathy (HE) after liver transplantation and to compare these changes with clinical outcomes and basal ganglia high signal intensity (BGH). MATERIALS AND METHODS: Twenty-two patients scheduled for liver transplantation and 17 healthy control subjects were examined with (1)H MR spectroscopy and standard nonenhanced MR imaging. Eight patients underwent complete MR imaging and (1)H spectroscopic examinations before liver transplantation and at 3-4-week, 12-28-week, and 10-12-month follow-up after liver transplantation. RESULTS: Before liver transplantation, typical (1)H spectroscopic changes-decreased myo-inositol (mI)/creatine (Cr) and choline (Cho)/Cr ratios and an elevated glutamine and glutamate (Glx)/Cr ratio-were found in 21 patients. Eighteen patients had BGH at T1-weighted imaging. Three to 7 months after liver transplantation, the mI/Cr and Glx/Cr ratios were within the normal range in five of eight and eight of eight patients, respectively, without any residual signs of subclinical or overt HE; however, at MR imaging, seven patients still had BGH. CONCLUSION: After successful liver transplantation, renormalization of HE-specific brain metabolite changes is detected at (1)H spectroscopy and precedes the disappearance of BGH. The neuropsychologic signs of subclinical or overt HE follow the changes seen at (1)H spectroscopy rather than those seen at MR imaging. 相似文献
15.
Narasimhaiah R Tuchman A Lin SL Naegele JR 《Cerebral cortex (New York, N.Y. : 1991)》2005,15(6):696-707
DNA repair plays a critical, but imprecisely defined role in neuronal survival during cortical neurogenesis. We examined cortical development in mice deficient for the DNA end-joining protein, Ku70. At gestational day 14.5, corresponding to the peak of neurogenesis, the Ku70(-/-) embryonic cerebral cortex displayed 25- to 30-fold more cell death than heterozygous littermates, as judged by DNA breaks, pyknosis and active caspase-3. In Ku70(-/-) embryos only, large clusters of dying neurons were found in the intermediate zone. Cell death declined until P4, when the number of dying cells became comparable to that in heterozygous mice. Two groups of dying cells were evident: a GLAST(+) neural progenitor population in the subventricular and ventricular zones, and a doublecortin(+) immature neuron population in the intermediate zone, the latter exhibiting strong staining for oxidative DNA damage. Antioxidants and lower oxygen tension reduced the high levels of neuronal death in primary cortical cultures derived from Ku70(-/-) mice, but not the low levels of cell death in wildtype cortical cultures. Results indicate migrating cortical neurons undergo oxidative DNA damage, which is normally repaired by non-homologous end joining. Failure to repair oxidative damage triggers a form of apoptosis involving caspase-3 activation. 相似文献
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Antibody responses to Epstein-Barr virus-specific DNase in relation to the prognosis of juvenile patients with nasopharyngeal carcinoma 总被引:1,自引:0,他引:1
R S Tan Y C Cheng R F Naegele W Henle R Glaser J Champion 《International journal of cancer. Journal international du cancer》1982,30(5):561-565
We have examined serial sera from 17 juvenile patients with nasopharyngeal carcinoma (NPC) for their capacity to neutralize the activity of Epstein-Barr virus (EBV)-specific DNase. The results revealed that NPC patients who became long-term survivors (LTS) without evidence of the disease either never possessed significant levels of antibodies to the enzyme or showed a gradual decline in the number of EBV DNase units neutralized from an elevated level at diagnosis to an insignificant figure several years later. All the 10 LTS neutralized less than 4, and some neutralized less than 2 units of the enzyme 3 or more years after the initial diagnosis. In contrast, serial sera from juvenile patients who died of NPC neutralized over 10 and as many as 25 units of EBV DNase either persistently until death occurred or with transient declines during unmaintained remissions. Rises and declines in the neutralizing activity were, with few exceptions, accompanied by corresponding changes in the titers of IgA and IgG antibodies to EB viral capsid antigen and to the diffuse component of the early antigens. Although the number of juvenile NPC cases available for study was small, the observations suggest that the EBV DNase neutralization test may serve to provide information on the prognosis of the patients. 相似文献
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