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91.
92.
The mechanism of increasing effect of CuCl2 on specific [3H]cimetidine binding was examined in brain membranes of rats. CuCl2-Induced elevation of [3H]cimetidine binding was high in Krebs-Ringer solution (pH 7.4) compared to those in 50 mM Na, K-phosphate buffer (pH 7.4) and in 50 mM Tris-HCl buffer (pH 7.4). CaCl2 (5–50 mM) inhibited effect of CuCl2, but NaCl (25–200 mM), KCl (5–100 mM) or MgCl2 (5–50 mM) did not. CuCl2 (50 μM) elevated 9.3- and 2.5-fold the binding in phosphate- and Tris—HCl buffer, respectively. EDTA-2Na decreased the binding elevated by 50 μM CuCl2 in phosphate buffer to the similar level in Tris-HCl buffer, whereas it did not affect those in Tris-HCl buffer. The absorption spectra of cimetidine and CuCl2 mixture showed a peak at 317 nm in phosphate buffer that was not observed in Tris-HCl buffer. It is suggested that cimetidine-Cu2+ chelate complex could be formed in phosphate buffer, resulting in higher amount of binding in phosphate buffer than in Tris-HCl buffer. PdCl2 also caused a marked elevation in [3H]cimetidine binding, seeming to be due to formation of cimetidine-Pd2+ chelate complex. There were two types of [3H]cimetidine binding in the presence of 20 nM PdCl2: high affinity binding with Kd = 0.7 ± 0.1 nM and low affinity binding with Kd = 44.3 ± 3.0 nM. It is suggested that cimetidine-Cu2+ complex binds to cimetidine binding sites in brain with higher affinity than cimetidine alone. 相似文献
93.
A novel mutated acetolactate synthase gene conferring specific resistance to pyrimidinyl carboxy herbicides in rice 总被引:3,自引:0,他引:3
Acetolactate synthase (ALS) is the first common enzyme in the biosynthetic pathway of branched-chain amino acids. Mutations
of specific amino acids in ALS have been known to confer resistance to ALS-inhibiting herbicides such as sulfonylureas and
pyrimidinyl carboxy (PC) herbicides. However, mutations conferring exclusive resistance to PC have not yet been reported to
date. We selected PC resistant rice calli, which were derived from anther culture, using one of the PCs, bispyribac-sodium
(BS), as a selection agent. Two lines of BS-resistant plants carrying a novel mutation, the 95th Glycine to Alanine (G95A),
in ALS were obtained. In vitro ALS activity assay indicated that the recombinant protein of G95A-mutated ALS (ALS-G95A) conferred
highly specific resistance to PC herbicides. In order to determine if the ALS-G95A gene could be used as a selection marker
for rice transformation, the ALS-G95A gene was connected to ubiquitin promoter and introduced into rice. PC resistant plants
containing integrated ALS-G95A gene were obtained after selection with BS as a selection agent. In conclusion, novel G95A
mutated ALS gene confers highly specific resistant to PC-herbicides and can be used as a selection marker. 相似文献
94.
Sugiura H Liu X Togo S Kobayashi T Shen L Kawasaki S Kamio K Wang XQ Mao LJ Rennard SI 《Journal of cellular physiology》2007,210(1):99-110
Prostaglandin E(2) (PGE(2)) has been shown to have a strong cytoprotective effect, inhibiting apoptosis. In the present study, we evaluated whether PGE(2) has a protective effect on cigarette smoke extract (CSE)-induced apoptosis in human lung fibroblasts. Apoptosis was assessed by various methods, including DNA content analysis. CSE (15%-20%) led to apoptosis and induced imbalance in favor of pro- over anti-apoptotic protein expression and activated caspases. PGE(2) blocked CSE-induced apoptosis and modulated the balance of pro- and anti-apoptotic proteins and decreased the activation of caspases. This anti-apoptotic effect was mediated via EP(2) receptor activation as the EP(2) agonist butaprost mimicked PGE(2) activity and siRNA for the EP(2) receptor blocked it. An adenylyl cyclase inhibitor was found to abolish the PGE(2)-mediated cytoprotective effect. Correspondingly, c-AMP analogs blocked CSE-induced apoptosis. Consistently, the protein kinase A (PKA) inhibitor KT-5720 abolished PGE(2)-mediated protection. PGE(2) and butaprost phosphorylated Bad and KT-5720 blocked phosphorylation. These results suggest that PGE(2) inhibits CSE-induced apoptosis via EP(2) receptor activation and activation of PKA, which leads to an alteration in the balance between pro- and anti-apoptotic factors. Through such a mechanism, PGE(2) may alter survival of cells in the smoke-exposed lungs, thus affecting the pathogenesis of cigarette smoke-induced disease. 相似文献
95.
Molecular basis of guanine nucleotide dissociation inhibitor activity of human neuroglobin by chemical cross-linking and mass spectrometry 总被引:1,自引:0,他引:1
Kitatsuji C Kurogochi M Nishimura S Ishimori K Wakasugi K 《Journal of molecular biology》2007,368(1):150-160
Oxidized human neuroglobin (Ngb), a heme protein expressed in the brain, has been proposed to act as a guanine nucleotide dissociation inhibitor (GDI) for the GDP-bound form of the heterotrimeric G protein alpha-subunit (Galpha(i)). Here, to elucidate the molecular mechanism underlying the GDI activity of Ngb, we used an glutathione-S-transferase pull-down assay to confirm that Ngb competes with G-protein betagamma-subunits (Gbetagamma) for binding to Galpha(i), and identified the Galpha(i)-binding site in Ngb by chemical cross-linking with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and sulfo-N-hydroxysuccinimide, coupled with mass spectrometry (MS). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS analysis for tryptic peptides derived from the cross-linked Ngb-Galpha(i) complex revealed several binding regions in Ngb. Furthermore, MALDI-TOF/TOF MS analysis of the cross-linked Ngb and Galpha(i) peptides, together with the MS/MS scoring method, predicted cross-linking between Glu60 (Ngb) and Ser206 (Galpha(i)), and between Glu53 (Ngb) and Ser44 (Galpha(i)). Because Ser206 of Galpha(i) is located in the region that contacts Gbetagamma, binding of Ngb could facilitate the release of Gbetagamma from Galpha(i). Binding of Ngb to Galpha(i) would also inhibit the exchange of GDP for GTP, because Ser44 (Galpha(i)) is adjacent to the GDP-binding site and Glu53 (Ngb), which is cross-linked to Ser44 (Galpha(i)), could be located close to GDP. Thus, we have identified, for the first time, the sites of interaction between Ngb and Galpha(i), enabling us to discuss the functional significance of this binding on the GDI activity of Ngb. 相似文献
96.
97.
Nakanishi J Wada Y Matsumoto K Azuma M Kikuchi K Ueda S 《Cancer immunology, immunotherapy : CII》2007,56(8):1173-1182
PURPOSE: The programmed death-1 (PD-1)/B7-H1 (also called PD-L1) pathway negatively regulates T cell activation and has been suggested to play an important role in regulating antitumor host immunity. To investigate the clinical significance of B7-H1 expression to the tumor grade and postoperative prognosis of patients with urothelial cancer, we analyzed the relationship between B7-H1 expression and various clinicopathological features and postoperative prognosis. EXPERIMENTAL DESIGN: Sixty-five urothelial cancer cases were examined. B7-H1 expression in tumors and the numbers and phenotypes of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry and flow cytometry. RESULTS: A substantial expression of B7-H1 was observed in all urothelial cancers investigated. Tumor specimens from patients with higher WHO grade or primary tumor classifications showed significantly higher percentages of tumor-associated B7-H1. Tumor-associated B7-H1 expression was significantly associated with a high frequency of postoperative recurrence and poor survival rate. Furthermore, multivariate analysis indicated that tumor-associated B7-H1 was more significant prognostic factor than WHO grade. CONCLUSIONS: Our results demonstrate that the aberrant expression of B7-H1 in urothelial cancer is associated with aggressive tumors, suggesting a regulatory role of tumor-associated B7-H1 in antitumor immunity. Therefore, the manipulation of tumor-associated B7-H1 may become a beneficial target for immunotherapy in human urothelial cancer. 相似文献
98.
Dear Editor:
Geldanamycin is a benzoquinone ansamycin, which was originally described as a tyrosine kinase inhibitor. However, subsequent studies have revealed that geldanamycin binds to and inhibits heat-shock protein 90 (Hsp90) activity [1]. Hsp90 is a molecular chaperone involved in the conformational maturation of proteins such as mutated p53, Raf- 1, Akt, Bcr-Abl, and ErbB2. It is suggested that agents inhibiting Hsp90 have anti-cancer properties, although the precise molecular mechanisms underlying the anti-cancer effects of geldanamycin are not well understood. 相似文献
99.
Ami E Nakahara K Sato A Nguyen JT Hidaka K Hamada Y Nakatani S Kimura T Hayashi Y Kiso Y 《Bioorganic & medicinal chemistry letters》2007,17(15):4213-4217
We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir. 相似文献
100.
WooJin Kim Erin Zekas Robert Lodge Delia Susan-Resiga Edwidge Marcinkiewicz Rachid Essalmani Koichiro Mihara Rithwik Ramachandran Eugene Asahchop Benjamin Gelman éric A. Cohen Christopher Power Morley D. Hollenberg Nabil G. Seidah 《Molecular and cellular biology》2015,35(21):3684-3700
The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1β [IL-1β]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓ (where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND. 相似文献