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151.
Nonheme iron accumulates in CNS tissue after ischemic and hemorrhagic insults and may contribute to cell loss. The source of this iron has not been precisely defined. After blood-brain barrier disruption, CNS cells may be exposed to plasma concentrations of transferrin-bound iron (TBI), which exceed that in the CSF by over 50-fold. In this study, the hypothesis that these concentrations of TBI produce cell iron accumulation and neurotoxicity was tested in primary cortical cultures. Treatment with 0.5-3 mg/ml holotransferrin for 24 h resulted in the loss of 20-40% of neurons, associated with increases in malondialdehyde, ferritin, heme oxygenase-1, and iron; transferrin receptor-1 expression was reduced by about 50%. Deferoxamine, 2,2′-bipyridyl, Trolox, and ascorbate prevented all injury, but apotransferrin was ineffective. Cell TBI accumulation was significantly reduced by deferoxamine, 2,2′-bipyridyl, and apotransferrin, but not by ascorbate or Trolox. After treatment with 55Fe-transferrin, approximately 40% of cell iron was exported within 16 h. Net export was increased by deferoxamine and 2,2′-bipyridyl, but not by apotransferrin. These results suggest that downregulation of transferrin receptor-1 expression is insufficient to prevent iron-mediated death when neurons are exposed to plasma concentrations of TBI. Chelator therapy may be beneficial for acute CNS injuries associated with loss of blood-brain barrier integrity. 相似文献
152.
Lin YW 《Proteins》2011,79(3):679-684
Rational design of functional enzymes is a powerful strategy to gain deep insights into more complex native enzymes, such as nitric oxide reductase (NOR). Recently, we engineered a functional model of NOR by creating a two His and one Glu (2‐His‐1‐Glu) non‐heme iron center in sperm whale myoglobin (swMb L29E, F43H, H64, called FeBMb(‐His)). It was found that FeBMb(‐His) adopts a low‐spin state with bis‐His coordination in the absence of metal ions binding to the designed metal center. However, no structural information was available for the variant in this special spin state. We herein performed molecular modeling of FeBMb(‐His) and compared with the X‐ray structure of its copper bound derivative, Cu(II)‐CN?‐FeBMb(‐His), resolved recently at a high resolution (1.65 Å) (PDB entry 3MN0). The simulated structure shows that mutation of Leu to Glu at position 29 in the hydrophobic heme pocket alters the folding behavior of Mb. The hydrogen bond between Glu29 and His64 further plays a role in stabilizing the bis‐His (His64/His93) coordination structure. This study offers an excellent example of using molecular modeling to gain insights in rational design of both structural and functional proteins. Proteins 2011. © 2010 Wiley‐Liss, Inc. 相似文献
153.
Cytoglobin (Cgb) is a vertebrate heme‐containing globin‐protein expressed in a broad range of mammalian tissues. Unlike myoglobin, Cgb displays a hexa‐coordinated (bis‐hystidyl) heme iron atom, having the heme distal His81(E7) residue as the endogenous sixth ligand. In the present study, we crystallized human Cgb in the presence of a reductant Na2S2O4 under a carbon monoxide (CO) atmosphere, and determined the crystal structure at 2.6 Å resolution. The CO ligand occupies the sixth axial position of the heme ferrous iron. Eventually, the imidazole group of His81(E7) is expelled from the sixth position and swings out of the distal heme pocket. The flipping motion of the His81 imidazole group accompanies structural readjustments of some residues (Gln62, Phe63, Gln72, and Ser75) in both the CD‐corner and D‐helix regions of Cgb. On the other hand, no significant structural changes were observed in other Cgb regions, for example, on the proximal side. These structural alterations that occurred as a result of exogenous ligand (CO) binding are clearly different from those observed in other vertebrate hexa‐coordinated globins (mouse neuroglobin, Drosophila melanogaster hemoglobin) and penta‐coordinated sperm whale myoglobin. The present study provides the structural basis for further discussion of the unique ligand‐binding properties of Cgb. Proteins 2011. © 2011 Wiley‐Liss, Inc. 相似文献
154.
Yang YC Lii CK Lin AH Yeh YW Yao HT Li CC Liu KL Chen HW 《Free radical biology & medicine》2011,51(11):2073-2081
Butein and phloretin are chalcones that are members of the flavonoid family of polyphenols. Flavonoids have well-known antioxidant and anti-inflammatory activities. In rat primary hepatocytes, we examined whether butein and phloretin affect tert-butylhydroperoxide (tBHP)-induced oxidative damage and the possible mechanism(s) involved. Treatment with butein and phloretin markedly attenuated tBHP-induced peroxide formation, and this amelioration was reversed by l-buthionine-S-sulfoximine [a glutamate cysteine ligase (GCL) inhibitor] and zinc protoporphyrin [a heme oxygenase 1 (HO-1) inhibitor]. Butein and phloretin induced both HO-1 and GCL protein and mRNA expression and increased intracellular glutathione (GSH) and total GSH content. Butein treatment activated the ERK1/2 signaling pathway and increased Nrf2 nuclear translocation, Nrf2 nuclear protein-DNA binding activity, and ARE-luciferase reporter activity. The roles of the ERK signaling pathway and Nrf2 in butein-induced HO-1 and GCL catalytic subunit (GCLC) expression were determined by using RNA interference directed against ERK2 and Nrf2. Both siERK2 and siNrf2 abolished butein-induced HO-1 and GCLC protein expression. These results suggest the involvement of ERK2 and Nrf2 in the induction of HO-1 and GCLC by butein. In an animal study, phloretin was shown to increase GSH content and HO-1 expression in rat liver and decrease carbon tetrachloride-induced hepatotoxicity. In conclusion, we demonstrate that butein and phloretin up-regulate HO-1 and GCL expression through the ERK2/Nrf2 pathway and protect hepatocytes against oxidative stress. 相似文献
155.
Singh RK Mandal T Balsubramanian N Viaene T Leedahl T Sule N Cook G Srivastava DK 《Bioorganic & medicinal chemistry letters》2011,21(19):5920-5923
We report, for the first time, that certain N-acetylthiourea derivatives serve as highly potent and isozyme selective activators for the recombinant form of human histone deacetylase-8 in the assay system containing Fluor-de-Lys as a fluorescent substrate. The experimental data reveals that such activating feature is manifested via decrease in the K(m) value of the enzyme's substrate and increase in the catalytic turnover rate of the enzyme. 相似文献
156.
Nagarapu L Mateti J Gaikwad HK Bantu R Sheeba Rani M Prameela Subhashini NJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4138-4140
A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents. 相似文献
157.
Bello C Dal Bello G Cea M Nahimana A Aubry D Garuti A Motta G Moran E Fruscione F Pronzato P Grossi F Patrone F Ballestrero A Dupuis M Sordat B Zimmermann K Loretan J Wartmann M Duchosal MA Nencioni A Vogel P 《Bioorganic & medicinal chemistry》2011,19(24):7720-7727
New derivatives of 1,4-dideoxy-1,4-imino-d-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-d-ribitol (13, IC50 ∼2 μM) and its C18-analogues (IC50 <10 μM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC50 ∼8 μM) growth of JURKAT cells. 相似文献
158.
159.
Ferdinand Bohlmann Thomas Gerke Jasmin Jakupovic Robert M. King Harold Robinson 《Phytochemistry》1984,23(5):1183-1184
Viguiera oblongifolia afforded two known furanoheliangolides and a new cadinane derivative whose structure was established by spectroscopic methods. From V. lanceolata 17,18-dihydrobudlein A was isolated. 相似文献
160.
Astroglial cytoprotection by erythropoietin pre-conditioning: implications for ischemic and degenerative CNS disorders 总被引:4,自引:0,他引:4
Erythropoietin (Epo) is a glycoprotein secreted by the kidney in response to hypoxia that stimulates erythropoiesis through interaction with cell surface Epo receptors. Pre-treatment with Epo has been shown to protect neurons in models of ischemic injury. The mechanism responsible for this neuroprotection and the effects of Epo on astroglial and other non-neuronal cell populations remain unknown. In the present study, we determined whether Epo pre-treatment protects neonatal rat astrocytes from apoptotic cell death resulting from treatment with nitric oxide, staurosporine (STS) and arsenic trioxide and possible mechanisms mediating Epo-related cytoprotection. Epo (5-20 U/mL) significantly attenuated multiple hallmarks of apoptotic cell death in astroglia exposed to nitric oxide and STS but not arsenic trioxide. Epo (20 U/mL) induced mild oxidative stress as shown by increases in heme oxygenase (HO)-1 mRNA and protein expression that could be suppressed by antioxidant coadministration. Moreover, coincubation with tin-mesoporphyrin, a competitive inhibitor of HO activity, abrogated the cytoprotective effects of Epo (20 U/mL) in the face of STS treatment. Thus, induction of the ho-1 gene may contribute to the glioprotection accruing from high-dose Epo exposure. Epo may augment astroglial resistance to certain chemical stressors by oxidative stress-dependent and -independent mechanisms. 相似文献