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941.
Hsieh CT Hsieh TJ El-Shazly M Chuang DW Tsai YH Yen CT Wu SF Wu YC Chang FR 《Bioorganic & medicinal chemistry letters》2012,22(12):3912-3915
Chalcones bearing electron donating or electron withdrawing substitutions were prepared and their glucose uptake activity was evaluated. Chalcone derivatives were synthesized in one step protocol with high purity and yield. Chalcones with chloro, bromo, iodo and hydroxy substitutions at position 2 on A-ring exhibited the highest activity with glucose medium concentration (210 to 236 mg/dl) compared to pioglitazone and rosiglitazone (230 and 263 mg/dl, respectively). Also chalcones with iodo substitution at position 3 on A-ring were comparably active (≤238 mg/dl). The structure-activity relationship of the tested chalcones was studied and the findings were supported statistically. 相似文献
942.
943.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Therefore, developing the early, high-sensitivity diagnostic biomarkers to prevent HCC is urgently needed. Serum a-fetoprotein (AFP), the clinical biomarker in current use, is elevated in only ~60% of patients with HCC; therefore, identification of additional biomarkers is expected to have a significant impact on public health. In this study, we used glycan microarray analysis to explore the potential diagnostic value of several cancer-associated carbohydrate antigens (CACAs) as biomarkers for HCC. We used glycan microarray analysis with 58 different glycan analogs for quantitative comparison of 593 human serum samples (293 HCC samples; 133 chronic hepatitis B virus (HBV) infection samples, 134 chronic hepatitis C virus (HCV) infection samples, and 33 healthy donor samples) to explore the diagnostic possibility of serum antibody changes as biomarkers for HCC. Serum concentrations of anti-disialosyl galactosyl globoside (DSGG), anti-fucosyl GM1 and anti-Gb2 were significantly higher in patients with HCC than in chronic HBV infection individuals not in chronic HCV infection patients. Overall, in our study population, the biomarker candidates DSGG, fucosyl GM1 and Gb2 of CACAs achieved better predictive sensitivity than AFP. We identified potential biomarkers suitable for early detection of HCC. Glycan microarray analysis provides a powerful tool for high-sensitivity and high-throughput detection of serum antibodies against CACAs, which may be valuable serum biomarkers for the early detection of persons at high risk for HCC. 相似文献
944.
945.
Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2-3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain-mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission. 相似文献
946.
H M'kada H Perazzo M Munteanu Y Ngo N Ramanujam B Fautrel F Imbert-Bismut V Ratziu I Schuppe-Koistinen V Leblond JY Delattre Y Samson OL Caen F Bricaire D Khayat C Pierrot-Deseilligny S Herson Z Amoura P Tilleul O Deckmyn P Coriat VN Delpech P Boulogne D Bonnefont-Rousselot T Poynard;for the Drug Induced Liver Injury Groupe Hospitalier Pitié-Salpêtrière 《PloS one》2012,7(8):e42418
Objective
Identification of drug-induced liver disease (DILI) is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening.Design
We prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN) and notified the designated hepatologists, who then went to the patients'' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium).Results
During the 24-week period of the standard strategy, 12 (0.04%) patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498%) [odds ratio vs. standard = 12.1 (95% CI, 3.9–32.3); P<0.0001] were identified with possible DILI, and 5 were included in the protocol.Conclusion
A simple strategy based on the daily analysis of cases with ALT >3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy.This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70. 相似文献947.
J Zhou GB Chen YC Tang Y Wu CS Yap G Wang J Hu X Xia P Tan LK Goh PM Yen R Anthonysinha 《BMC medical genomics》2012,5(1):34-8
ABSTRACT: BACKGROUND: While there is strong evidence for phosphatidylinositol 3-kinase (PI3K) involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene encodes the PI3K regulatory subunit p55 gamma, is over-expressed in glioblastoma and ovarian cancers, but its expression in gastric cancer (GC) is not known. We thus used genetic and bioinformatic approaches to examine PIK3R3 expression and function in GC, the second leading cause of cancer mortality world-wide and highly prevalent among Asians. METHODS: Primary GC and matched non-neoplastic mucosa tissue specimens from a unique Asian patient gastric cancer library were comprehensively profiled with platforms that measured genome-wide mRNA expression, DNA copy number variation, and DNA methylation status. Function of PIK3R3 was predicted by IPA pathway analysis of co-regulated genes with PIK3R3, and further investigated by siRNA knockdown studies. Cell proliferation was estimated by crystal violet dye elution and BrdU incorporation assay. Cell cycle distribution was analysed by FACS. RESULTS: PIK3R3 was significantly up-regulated in GC specimens (n=126, p<0.05), and 9.5 to 15% tumors showed more than 2 fold increase compare to the paired mucosa tissues. IPA pathway analysis showed that PIK3R3 promoted cellular growth and proliferation. Knockdown of PIK3R3 decreased the growth of GC cells, induced G0/G1 cell cycle arrest, decreased retinoblastoma protein (Rb) phosphorylation, cyclin D1, and PCNA expression. CONCLUSION: Using a combination of genetic, bioinformatic, and molecular biological approaches, we showed that PIK3R3 was up-regulated in GC and promoted cell cycle progression and proliferation; and thus may be a potential new therapeutic target for GC. 相似文献
948.
doi: 10.1111/j.1741‐2358.2012.00632.x Evaluation of a self‐assessed screening test for masticatory ability of Taiwanese older adults Objectives: The aim of this study was to evaluate a screening test based on a food intake questionnaire to discriminate the masticatory ability of Taiwanese older adults with 20 and more natural teeth and at least 8 functional tooth units (FTUs) from the masticatory ability of those with fewer than 20 natural teeth and 8 FTUs. Materials and Methods: The subjects were 2244 patients (mean age, 60.4±10.0 years) recruited from 23 counties and cities in Taiwan. Information about their demographic data, dentition, and masticatory ability was collected. Masticatory ability was measured for 23 food groups comprising 35 common Taiwanese foods, and receiver operation characteristic curve analysis was performed. Results: The results showed that the final questionnaire included 14 food groups and a subject choosing ’difficult to eat‘ responses for 4 and more of these food groups had the same masticatory ability as individuals with fewer than 20 natural teeth and 8 FTUs. Conclusion: In conclusion, foods that are the most difficult to eat are not necessarily good discriminatory indicators. Hence, the 14‐food group questionnaire can be considered the best screening test for masticatory ability of Taiwanese older adults in terms of the presence of 20 and more natural teeth and at least 8 FTUs. 相似文献
949.
Kovalevich J Corley G Yen W Kim J Rawls SM Langford D 《Journal of neurochemistry》2012,120(2):302-313
The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter-1 (TAT-1), which is an ortholog of a mammalian P-type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus-dependent learning, but no hyper-anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM-APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (V(max) ) of PM-APLT without any change in its signature parameter K(m) in the neuronal N18 cells. Conversely, expression of a P-type phosphorylation-site mutant of Atp8a1 (Atp8a1*) caused a decrease in V(max) of PM-APLT without significantly altering its K(m) . The Atp8a1*-expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM-APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells. 相似文献
950.