| 1. |
- Oltean, Mihai, 1976, et al.
(author)
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Donor pretreatment with FK506 reduces reperfusion injury and accelerates intestinal graft recovery in rats
- 2007
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In: Surgery. - : Elsevier BV. - 0039-6060. ; 141:5, s. 667-77
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Journal article (peer-reviewed)abstract
- BACKGROUND: FK506 alleviates warm ischemia-reperfusion injury, but it remains unknown if such protection is manifest after cold storage and transplantation. We studied the early outcome after transplantation of intestines from donors pretreated with FK506 compared to grafts from controls treated with saline (154 mM NaCl). METHODS: Sprague-Dawley rats received 0.3 mg/kg FK506 or saline intravenously 6 hours before graft retrieval. The small bowel was harvested, stored for 3 hours, and then transplanted heterotopically. Samples were taken after preservation and at 20 minutes, 6 hours, 12 hours, and 24 hours after reperfusion. Heat shock protein 72 (Hsp72) and iintercellular adhesion molecule (ICAM)-1 expression and nuclear factor kappaB (NF-kappaB) activation were assessed via Western blots and eelectrophoretic mobility shift assay (EMSA), respectively. Dissacharidase activity and enterocyte proliferation rate were also studied. RESULTS: Preservation injury was similar between groups, but pretreated grafts had better morphology already 20 minutes after reperfusion. Control grafts always had thinner mucosa and more PMN infiltration. Hsp72 expression was greater in pretreated grafts. ICAM-1 was absent after harvesting, preservation, and immediately after reperfusion but increased in control grafts at the later time points. Control grafts showed a biphasic NF-kappaB activation pattern, whereas NF-kappaB activation was inhibited effectively in pretreated grafts. Dissacharidase activity decreased during the first 6 hours after reperfusion but recovered within 24 hours in pretreated grafts but not in control grafts. Earlier enterocyte proliferation was observed in pretreated grafts. CONCLUSIONS: FK506 donor pretreatment reduced graft proinflammatory activation and neutrophil inflammation. Pretreated groups revealed a milder reperfusion injury and accelerated morphologic and functional recovery. The mechanisms involved appear to involve Hsp72 upregulation and NF-kappaB inhibition.
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| 2. |
- Payton, K. S., et al.
(author)
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Antioxidant status alters levels of Fas-associated death domain-like IL-1B-converting enzyme inhibitory protein following neonatal hypoxia-ischemia
- 2007
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In: Dev Neurosci. - 1421-9859. ; 29:4-5, s. 403-11
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Journal article (peer-reviewed)abstract
- Activation of Fas death receptor (Fas DR) signaling cascade is seen after neonatal hypoxia-ischemia (HI). Cell survival is favored when signaling through the death-inducing signaling complex and cleavage of caspase 8 to its active form is blocked by FLIP, a dominant negative of caspase 8. H2O2 quickly downregulates expression of FLIP. Neonatal mice overexpressing glutathione peroxidase (GPx) have less injury and less H2O2 accumulation compared with neonatal mice overexpressing superoxide dismutase (SOD) or wild-type (WT) littermates. Expression of both FLIP(L) and FLIP(S) is increased in GPx-oxerexpressing mice relative to WT mice at 24 h and relative to SOD-overexpressing mice at 2 and 24 h following neonatal HI (ANOVA, p < 0.05). There is an increase in Fas DR expression at 24 h in both WT and GPx-overexpressing mice and significant differences between WT and SOD-overexpressing mice (ANOVA, p < 0.01). There is no difference in FADD expression among the 3 groups 24 h after HI. At 24 h following HI, the ratio of FLIP to Fas DR expression supports a significant negative correlation with injury score (r2 = 0.99, slope = -4.01), and expression of both the active fragment of caspase 8 and caspase 8 activity is increased in SOD overexpressors compared to GPx overexpressors at 24 h after HI (ANOVA, p < 0.05). The overall degree of injury previously seen in these 3 strains correlates well with changes in expression of Fas DR signaling proteins favoring neuroprotection in the GPx-overexpressing mice, i.e. increased FLIP expression and decreased caspase 8 activity compared to SODtg mice. The mechanism by which antioxidant status alters FLIP levels following neonatal HI may be related to the ability to detoxify H2O2 produced following neonatal HI.
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| 3. |
- Qiu, L., et al.
(author)
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Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia
- 2007
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In: J Cereb Blood Flow Metab. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 27:4, s. 785-94
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Journal article (peer-reviewed)abstract
- The effects of hypoxia-ischemia (HI) on proliferation and differentiation in the immature (postnatal day 9) and juvenile (postnatal day 21) mouse hippocampus were investigated by injecting bromodeoxyuridine (50 mg/kg) daily for 7 days after the insult and evaluating the labeling 5 weeks after HI. Phenotypic differentiation was evaluated using NeuN, Iba1, APC, and S100beta as markers of neurons, microglia, oligodendrocytes, and astrocytes, respectively. The basal proliferation, in particular neurogenesis, was higher in the immature than in the juvenile hippocampus. Hypoxia-ischemia did not increase neurogenesis significantly in the immature dentate gyrus (DG), but it increased several-fold in the juvenile brain, reaching the same level as in the normal, noninjured immature brain. This suggests that the immature hippocampus is already working at the top of its proliferative capacity and that even though basal neurogenesis decreased with age, the injury-induced generation of new neurons in the juvenile hippocampus could not increase beyond the basal level of the immature brain. Generation of glial cells of all three types after HI was significantly more pronounced in the cornu ammonis of the hippocampus region of the juvenile hippocampus. In the DG, only microglia production was greater in the juvenile brain. Increased microglia proliferation correlated with increased levels of the proinflammatory cytokines MCP-1 and IL-18 3 days after HI, indicating that the inflammatory response is stronger in the juvenile hippocampus. In summary, contrary to what has been generally assumed, our results indicate that the juvenile brain has a greater capacity for neurogenesis after injury than the immature brain.
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| 4. |
- Romanko, M. J., et al.
(author)
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Death effector activation in the subventricular zone subsequent to perinatal hypoxia/ischemia
- 2007
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In: J Neurochem. - : Wiley. - 0022-3042. ; 103:3, s. 1121-31
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Journal article (peer-reviewed)abstract
- Perinatal hypoxia/ischemia (H/I) is the leading cause of neurological injury resulting from birth complications and pre-maturity. Our studies have demonstrated that this injury depletes the subventricular zone (SVZ) of progenitors. In this study, we sought to reveal which cell death pathways are activated within these progenitors after H/I. We found that calpain activity is detected as early as 4 h of reperfusion and is sustained for 48 h, while caspase 3 activation does not occur until 8 h and peaks at 24 h post-insult. Activated calpains and caspase 3 co-localized within precursors situated in the lateral aspects of the SVZ (which coincides with progenitor cell death), whereas neither enzyme was activated in the medial SVZ (which harbors the neural stem cells that are resilient to this insult). These studies reveal targets for neuroprotective agents to protect precursors from cell death towards the goal of restoring normal brain development after H/I.
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| 5. |
- Shao, Linus Ruijin, 1964, et al.
(author)
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Ciliated epithelial-specific and regional-specific expression and regulation of the estrogen receptor-beta2 in the fallopian tubes of immature rats: a possible mechanism for estrogen-mediated transport process in vivo
- 2007
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In: American journal of physiology. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 293:1
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Journal article (peer-reviewed)abstract
- Several ERbeta isoforms have been identified in human and rodent tissues, but it is unclear whether each isoform has distinctly different cellular targeting characteristics and physiological functions. We have investigated the intracellular localization and regulatory patterns for ERbeta isoforms in rat fallopian tubes. Western blot analysis reveals that two ERbeta isoforms corresponding to ERbeta1 and ERbeta2 are expressed in rat fallopian tubes. However, ERbeta2 is the predominant form of ERbeta in this tissue. High-resolution confocal imaging and immunohistochemical analysis provide ample evidence that ERbeta expression is limited almost exclusively to the ciliated epithelial cells, in contrast to ERalpha, which is widely distributed. Furthermore, within the ciliated epithelial cells, ERbeta is colocalized with beta-tubulin IV at stem portion of the cilia. We show that ERbeta2 protein expression is tightly regulated by E(2) or DPN in a time-dependent manner without changes in ERbeta1 expression. These estrogenic effects are inhibited by an ER antagonist, ICI 182,780. In addition, significant alteration of ERbeta immunoreactivity is detected only histologically in the ampullary region. Since the cilia are considered an essential determinant of tubal transport, we further demonstrate that E(2)- or DPN-induced ERbeta2 activation is associated with alterations in tubal protein expression crucial for the regulation of calcium-dependent ciliary beating. Given the coordinated regulation and interaction of ER and progesterone receptor in the cilia, we hypothesize that tubal ERbeta2 may facilitate the estrogen-mediated transport process by processing protein-protein interaction under physiological and/or pathological conditions. We show for the first time that a previously unrecognized localization of ERbeta isoform in rat fallopian tubes can combine with estrogen to individually control the expression of ER beta-isoforms in normal target tissues.
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| 6. |
- Svedin, Pernilla, 1979, et al.
(author)
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Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia
- 2007
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In: J Neurosci. ; 27:7, s. 1511-8
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Journal article (peer-reviewed)abstract
- Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.
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| 7. |
- Wang, Xiaoyang, 1965, et al.
(author)
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Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia
- 2007
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In: J Neuropathol Exp Neurol. ; 66:6, s. 552-61
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Journal article (peer-reviewed)abstract
- Epidemiologic evidence has underlined the impact of prenatal inflammation on the development of postnatal hypoxia-ischemia (HI) brain injury. To study to what extent prenatal inflammation affects CNS vulnerability later during development, C57BL/6 mice were subjected to intrauterine injection of lipopolysaccharide (LPS) at gestational day 15. At postnatal day (PND) 5, 9, and 70, the offspring were subjected to HI. It was found that, in neonatal mice, LPS-exposed brains showed markedly enhanced brain injury after HI, whereas in adult mice, LPS exposure resulted in a significant reduction in tissue loss after HI. Reduced myelin in subcortical white matter was noticed after HI in the LPS-exposed brains at PND14 and PND75. Increased activities of nuclear factor-kappaB and caspase-3 were obtained in fetal/neonatal brain after LPS administration. Conclusions were that 1) a prenatal low dose of LPS sensitized to HI-induced brain injury in neonates but confers protection in adulthood, 2) reduced myelination is seen after prenatal LPS exposure and HI in both neonatal and adult mice despite the fact that LPS reduced total tissue loss in adult mice; and 3) nuclear factor-kappaB and caspase-3 activation early after LPS exposure may play a role in the sensitization/protection (preconditioning) effects.
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| 8. |
- Wang, Xiaoyang, 1965, et al.
(author)
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Effects of intrauterine inflammation on the developing mouse brain
- 2007
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In: Brain Res. ; 1144, s. 180-5
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Journal article (peer-reviewed)abstract
- Clinical and experimental evidence indicate that the presence of intrauterine inflammation in pregnancy is not only a cause of preterm birth but is also associated with perinatal brain damage and long-term neurological handicap. In the present study, the neuropathological outcome was investigated in surviving pups in a model of inflammation-induced preterm delivery. C57BL/6 mice were subjected to intrauterine injection of lipopolysaccharide (LPS) or saline, at a time corresponding to 79% of average gestation (gestational day 15). Fetuses that survived after LPS administration were sacrificed on postnatal day 14 (PND 14). At PND 14, the brain weight of LPS-exposed pups was significantly lower than that of saline-exposed. A high proportion of LPS-exposed brains were found affected and exhibited hypomyelination, enlarged ventricles, and in some cortical gray matter lesions were evident. None of these pathologies were detected in sham-treated animals. Conclusions: Intrauterine inflammation impaired brain development and various brain lesions were produced in both the white and gray matter after intrauterine LPS administration in mice.
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| 9. |
- Wang, Xiaoyang, 1965, et al.
(author)
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N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury.
- 2007
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In: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 61:3, s. 263-71
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model. METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.
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| 10. |
- Zhu, Changlian, 1964, et al.
(author)
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Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia
- 2007
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In: Cell Death Differ. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 14:4, s. 775-84
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Journal article (peer-reviewed)abstract
- Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)(Hq) mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX(Hq)) and female (X(Hq)X(Hq)) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH(2)-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.
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