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91.
Feng-Shiun Shie Young-Ji Shiao Chih-Wen Yeh Chien-Hung Lin Tsai-Teng Tzeng Hao-Chieh Hsu Fong-Lee Huang Huey-Jen Tsay Hui-Kang Liu 《PloS one》2015,10(8)
Diabesity-associated metabolic stresses modulate the development of Alzheimer’s disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson’s correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD. 相似文献
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93.
Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine. While human IDO is able to oxidize both L- and D-Trp, human TDO (hTDO) displays major specificity for L-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the L-Trp-bound enzyme, but not in the D-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH(3)(+) group and epoxide oxygen of the ferryl-indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops, loop(250-260) and loop(117-130), critical for substrate binding. 相似文献
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95.
Condensation of 2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-α-
-galactopyranosyl bromide (3) with methyl 2,3,4-tri-O-acetyl-β-
-galactopyranoside (4) gave a fully acetylated (1→6)-β-
-galactobiose fluorinated at the 3′-position which was deacetylated to give the title disaccharide. The corresponding trisaccharide was obtained by reaction of 4 with 2,3,4-tri-O-acetyl-6-O-chloroacetyl-α-
-galactopyranosyl bromide (5), dechloroacetylation of the formed methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β-
-galactopyranosyl)-(1→6)- 2,3,4-tri-O-acetyl-β-
-galactopyranoside to give methyl O-(2,3,4-tri-O-acetyl-β-
-galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β-
-galactopyranoside (14), condensation with 3, and deacetylation. Dechloroacetylation of methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β-
-galactopyranosyl)-(1→6)-O-(2,3,4-tri-O-acetyl- β-
-galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β-
-galactopyranoside, obtained by condensation of disaccharide 14 with bromide 5, was accompanied by extensive acetyl migration giving a mixture of products. These were deacetylated to give, crystalline for the first time, the methyl β-glycoside of (1→6)-β-
-galactotriose in high yield. The structures of the target compounds were confirmed by 500-MHz, 2D, 1H- and conventional 13C- and 19F-n.m.r. spectroscopy. 相似文献
96.
Interactions of permeant cations with sodium channels of squid axon membranes. 总被引:5,自引:1,他引:5 下载免费PDF全文
To determine how the permeant cations interact with the sodium channel, the instantaneous current-voltage (I-V) relationship, conductance-ion concentration relationship, and cation selectivity of sodium channels were studied with internally perfused, voltage clamped squid giant axons in the presence of different permeant cations in the external solution. In Na-containing media, the instantaneous I-V curve was almost linear between +60 and -20 mV, but deviated from the linearity in the direction to decrease the current at more negative potentials. The linearity of instantaneous I-V curve extended to more negative potentials with lowering the external Ca concentration. The I-V curve in Li solution was almost the same as that in Na solution. The linearity of the I-V curve improved in NH4 solution exhibiting only saturation at -100 mV with no sign of further decrease in current at more negative potentials. Guanidine and formamidine further linearized the instantaneous I-V curve. The conductance of the sodium channels as measured from the tail current saturated at high concentrations of permeant cations. The apparent dissociation constants determined from the conductance-ion concentration curve at -60 mV were as follows: Na, 378 mM; Li, 247 mM; NH4, 174 mM; guanidine, 111 mM; formamidine, 103 mM. The ratio of the test cation permeability to the sodium permeability as measured from the reversal potentials of tail currents varied with the test cation concentration and/or the membrane potential. These observations are incompatible with the independence principle, and can be explained on the basis of the Eyring's rate theory. It is suggested that the slope of the instantaneous I-V curve is determined by the relative affinity of permeant cations and blocking ions (Ca) for the binding site in the sodium channel. The ionic selectivity of the channel depends on the energy barrier profile of the channel. 相似文献
97.
Hou-Wen Cheng Hsiao-Wen Wang Tsung-Yun Wong Hsien-Wei Yeh Yi-Chun Chen Der-Zen Liu Pi-Hui Liang 《Bioorganic & medicinal chemistry》2018,26(9):2262-2270
S-NeuAc-α(2-6)-di-LacNAc (5) was efficiently synthesized by a [2+2] followed by a [1+4] glycosylation, and later conjugated with 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE) to form both single-layer and multi-layer homogeneous liposomes in the presence of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol. These liposomes were found to be weak inhibitors in both the influenza virus entry assay and the hemagglutination inhibition assay. The single layer liposome was found to more efficiently interfere with the entry of the H1N1 influenza virus into MDCK cells than the multilayer liposome containing 5. 相似文献
98.
Yen-Chu Huang Ho-Ling Liu Jiann-Der Lee Jen-Tsung Yang Hsu-Huei Weng Meng Lee Mei-Yu Yeh Yuan-Hsiung Tsai 《PloS one》2013,8(7)
Background
The aim of this study was to evaluate whether arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) can reliably quantify perfusion deficit as compared to dynamic susceptibility contrast (DSC) perfusion MRI.Methods
Thirty-nine patients with acute ischemic stroke in the anterior circulation territory were recruited. All underwent ASL and DSC MRI perfusion scans within 30 hours after stroke onset and 31 patients underwent follow-up MRI scans. ASL cerebral blood flow (CBF) and DSC time to maximum (Tmax) maps were used to calculate the perfusion defects. The ASL CBF lesion volume was compared to the DSC Tmax lesion volume by Pearson''s correlation coefficient and likewise the ASL CBF and DSC Tmax lesion volumes were compared to the final infarct sizes respectively. A repeated measures analysis of variance and least significant difference post hoc test was used to compare the mean lesion volumes among ASL CBF, DSC Tmax >4–6 s and final infarct.Results
Mean patient age was 72.6 years. The average time from stroke onset to MRI was 13.9 hours. The ASL lesion volume showed significant correlation with the DSC lesion volume for Tmax >4, 5 and 6 s (r = 0.81, 0.82 and 0.80; p<0.001). However, the mean lesion volume of ASL (50.1 ml) was significantly larger than those for Tmax >5 s (29.2 ml, p<0.01) and Tmax >6 s (21.8 ml, p<0.001), while the mean lesion volumes for Tmax >5 or 6 s were close to mean final infarct size.Conclusion
Quantitative measurement of ASL perfusion is well correlated with DSC perfusion. However, ASL perfusion may overestimate the perfusion defects and therefore further refinement of the true penumbra threshold and improved ASL technique are necessary before applying ASL in therapeutic trials. 相似文献99.
Lee HY Ge WP Huang W He Y Wang GX Rowson-Baldwin A Smith SJ Jan YN Jan LY 《Neuron》2011,72(4):630-642
How transmitter receptors modulate neuronal signaling by regulating voltage-gated ion channel expression remains an open question. Here we report dendritic localization of mRNA of Kv4.2 voltage-gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by fragile X mental retardation protein (FMRP) linked to fragile X syndrome (FXS), the most common heritable mental retardation. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice and in neurons expressing Kv4.2-3'UTR that binds FMRP. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation induced by moderate stimuli. Surprisingly, recovery of Kv4.2 after N-methyl-D-aspartate receptor (NMDAR)-induced degradation also requires FMRP, likely due to NMDAR-induced FMRP dephosphorylation, which turns off FMRP suppression of Kv4.2. Our study of FMRP regulation of Kv4.2 deepens our knowledge of NMDAR signaling and reveals a FMRP target of potential relevance to FXS. 相似文献
100.