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141.
Cyrille S. Kounde Hui-Quan Yeo Qing-Yin Wang Kah Fei Wan Hongping Dong Ratna Karuna Ina Dix Trixie Wagner Bin Zou Oliver Simon Ghislain M.C. Bonamy Bryan K.S. Yeung Fumiaki Yokokawa 《Bioorganic & medicinal chemistry letters》2017,27(6):1385-1389
A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC50 < 0.1 μM. Cross-resistant analysis confirmed that the virus NS4B protein remained the target of the new oxopiperazine analogs obtained via scaffold morphing from the HTS hit 4. 相似文献
142.
Mink SN Kasian K Santos Martinez LE Jacobs H Bose R Cheng ZQ Light RB 《American journal of physiology. Heart and circulatory physiology》2008,294(4):H1724-H1735
In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock. 相似文献
143.
Microbial pretreatment of cotton stalks by solid state cultivation of Phanerochaete chrysosporium 总被引:3,自引:0,他引:3
White rot fungi degrade lignin and have biotechnological applications in conversion of lignocellulose to valuable products. Pretreatment is an important processing step to increase the accessibility of cellulosic material in plant biomass, impacting efficiency of subsequent hydrolysis and fermentation. This study investigated microbial pretreatment of cotton stalks by solid state cultivation (SSC) using Phanerochaete chrysosporium to facilitate the conversion into ethanol. The effects of substrate moisture content (M.C.; 65%, 75% and 80% wet-basis), inorganic salt concentration (no salts, modified salts without Mn(2+), modified salts with Mn(2+)) and culture time (0-14 days) on lignin degradation (LD), solids recovery (SR) and availability of carbohydrates (AOC) were examined. Moisture content significantly affected lignin degradation, with 75% and 80% M.C. degrading approximately 6% more lignin than 65% M.C. after 14 days. Within the same moisture content, treatments supplemented with salts were not statistically different than those without salts for LD and AOC. Within the 14day pretreatment, additional time resulted in greater lignin degradation, but indicated a decrease in SR and AOC. Considering cost, solid state cultivation at 75% M.C. without salts was the most preferable pretreatment resulting in 27.6% lignin degradation, 71.1% solids recovery and 41.6% availability of carbohydrates over a period of 14 days. Microbial pretreatment by solid state cultivation has the potential to be a low cost, environmentally friendly alternative to chemical approaches. Moisture relationships will be significant to the design of an effective microbial pretreatment process using SSC technology. 相似文献
144.
Young male albino mice of Swiss strain were exposed to nickel by oral route of 20 mg nickel sulfate/kg body weight for 5 d/wk
for 6 mo. A decrease in normal (testosterone-dependent) proteinuria was shown, and morphological examination of the seminal
vesicles revealed a lower weight and smaller size as well as a histological indication of lower secretory activity of the
epithelium compared to controls. The findings are consistent with a theory implying a decreased testosterone activity in nickel-treated
animals. 相似文献
145.
Male reproductive effect of nickel sulphate in mice 总被引:5,自引:0,他引:5
Nickel sulphate was administered orally to adult male mice at dose level of 5 and 10 mg/kg body weight (5 days per week) for 35 days. There was no change in body weight. However a significant decrease in absolute and organ-to-body weight ratios of testes, epididymides, seminal vesicles and prostate gland was observed. The sperm abnormality, associated with decrease in sperm motility and sperm count was also observed. Significant alterations in the activities of marker testicular enzymes, viz. sorbitol dehydrogenase (decreases), lactate dehydrogenase (increases) and -glutamyl transpeptidase (increases) associated with histopathological changes in testes, epididymides and seminal vesicles, were also observed. Accumulation of nickel in testes, epididymides and seminal vesicles was also observed. The study reveals that the oral exposure to nickel may affect the histology of testes, epididymides, seminal vesicles and sperms morphology. These testicular and spermatotoxic changes may be responsible for observed male mediated developmental toxic effects. 相似文献
146.
Udyaningsih-Freisleben SK Kurniati V Prasetyo PB Handayani S Adhiyanto C Soegianto RR Pudiantari R Munthe BG Ramelan W Freisleben HJ 《BioFactors (Oxford, England)》2003,19(1-2):87-100
Erythrocyte membrane structural parameters were studied in transfusion-dependent beta-thalassemia patients, in long-term transfused patients (regularly transfused < 15 years), and in those who had not yet obtained transfusions. Controls were voluntary students up to 30 years of age without diagnosis or clinical signs of thalassemia. Membranes were isolated and investigated by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and electron paramagnetic resonance (EPR) spectroscopy. Data obtained from the thiol-reactive spin label N-ethyl-maleimidoproxyl reveal immobilization of protein environment in erythrocyte membranes from thalassemic patients. SDS-PAGE shows both degradation and aggregation of membrane proteins. Thalassemic erythrocyte membranes exert higher order parameters in the hydrophobic region as determined by 16-doxyl-stearic acid. Rotational correlation times of this spin label increase only in transfused patients. Polarity is higher in membranes of all patients than in controls. In the polar interface, order parameters obtained from 5-doxyl-stearic acid increase in non-transfused and decrease in transfusion-dependent patients as compared with controls. Transfused patients exert increasing membrane order in the hydrophobic region and counter-currently decreasing order in the polar interface indicating loss of membrane integrity along with the loss of fluidity and polarity gradients and the loss the energetic barrier function of the membrane. 相似文献
147.
Barnes CJ Vadlamudi RK Mishra SK Jacobson RH Li F Kumar R 《Nature structural biology》2003,10(8):622-628
The C-terminal binding protein 1 (CtBP) is a ubiquitous corepressor linking the recruitment of DNA- and histone-modifying proteins to sequence-specific DNA-binding proteins and facilitating gene regulation during development and oncogenesis. We describe here the binding, phosphorylation and functional regulation of CtBP by the p21-activated kinase 1 (Pak1). Pak1 phosphorylates CtBP selectively on Ser158 within a putative regulatory loop, triggering CtBP cellular redistribution and blocking CtBP corepressor functions. A S158A substitution in CtBP or Pak1 knockdown by short interference RNA blocked CtBP phosphorylation, redistribution and attenuation of CtBP corepressor functions in reporter and chromatin assays. In the presence of NADH, Pak1 superphosphorylates CtBP and inhibits CtBP dehydrogenase activity, suggesting that preferential phosphorylation of active CtBP may alter secondary structures and influence both enzymatic and corepressor functions. Pak1 regulation of CtBP represents a new model of corepressor regulation whereby cellular signaling cascades may influence gene expression in mammalian cells. 相似文献
148.
Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands
Wang RA Vadlamudi RK Bagheri-Yarmand R Beuvink I Hynes NE Kumar R 《The Journal of cell biology》2003,161(3):583-592
Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine beta-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and beta-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated beta-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate beta-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development. 相似文献
149.
The action of dietary phytochemicals quercetin, catechin, resveratrol and naringenin on estrogen-mediated gene expression 总被引:2,自引:0,他引:2
Hepatic expression of apolipoprotein (apo) II is in part modulated by estrogen-mediated stabilization of its mRNA. This stabilization is due to the estrogen-regulated mRNA stabilizing factor (E-RmRNASF) expressed in the liver in response to estrogen (Ratnasabapathy, 1995, Cell. Mol. Biol. Res, 41: 583-594). E-RmRNASF protects the RNA from targeted endonucleolytic degradation. The hepatic expression of E-RmRNASF is modulated by certain estrogenic and antiestrogenic nonsteroidal environmental xenobiotics (Ratnasabapathy et al. 1997, Biochem. Pharmacol., 53: 1425-1434). To determine whether dietary phytochemicals purported to prevent hormone-dependent breast and prostate cancers, and atherosclerosis, acted via the estrogen-cell-signaling pathway, roosters were administered increasing doses up to 1 mmole/kg of resveratrol, quercetin, catechin or naringenin parenterally and tested for hepatic expression of E-RmRNASF. Besides estrogen, the expression of E-RmRNASF in the liver was stimulated by resveratrol and catechin, indicating these agents to be estrogenic. A lack of E-RmRNASF expression was seen with the roosters treated with the vehicle, naringenin or quercetin. To determine whether the agents exerted partial agonistic or antagonistic effects, roosters were administered combinations of estrogen and increasing doses of the above phytochemicals. Resveratrol showed agonistic activity at all concentrations (10-1000 micromol/kg) tested. Catechin showed partial agonistic activity, while quercetin and naringenin appeared to be antagonistic. 相似文献
150.
Ratna WN 《Life sciences》2002,71(8):865-877