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61.
Wioletta Rozpdek-Kamiska Grzegorz Galita Natalia Siwecka Steven L. Carroll John Alan Diehl Ewa Kucharska Dariusz Pytel Ireneusz Majsterek 《International journal of molecular sciences》2021,22(9)
Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG. 相似文献
62.
Rodrigo F. Ortiz-Meoz Liping Wang Rosalie Matico Anna Rutkowska-Klute Martha De la Rosa Sabrina Bedard Robert Midgett Katrin Strohmer Douglas Thomson Cunyu Zhang Makda Mebrahtu Jeffrey Guss Rachel Totoritis Thomas Consler Nino Campobasso David Taylor Tia Lewis Kurt Weaver Marcel Muelbaier John Seal Richard Dunham Wieslaw Kazmierski David Favre Giovanna Bergamini Lisa Shewchuk Alan Rendina Guofeng Zhang 《Chembiochem : a European journal of chemical biology》2021,22(3):516-522
Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters. 相似文献
63.
Cinkilic Emre Moodispaw Michael Zhang Jianyue Miao Jiashi Luo Alan A. 《Metallurgical and Materials Transactions A》2022,53(8):2861-2873
Metallurgical and Materials Transactions A - The use of secondary aluminum for structural components in the automotive industry is limited by the high Fe contents in recycled alloys which often... 相似文献
64.
通过研究基片种类、加热温度、保温时间、冷却速度及是否加入催化剂等不同工艺参数对低维Ga2O3,纳米材料形貌的影响,确定出合成5种不同形貌β-Ga2O3纳米材料的工艺条件。场发射扫描电镜(FE-SEM)表明5种不同形貌α-Ga2O3纳米材料分别为纳米线、纳米棒、纳米带、纳米环及纳米片。X射线衍射(X-ray)分析结果表明不同形貌纳米材料均为晶格常数日=1.223nm,b=0.304nm,c=0.58nm,a=90°,β=103.7°,γ=90°的单斜晶系β-Ga2O3晶体。 相似文献
65.
An examination of the influence of pressure and heating rate on the thermoplastic properties of a weakly coking coal and of coal with various pitch-like additives was carried out using a high pressure dilatometer. Pressure up to 4 MPa markedly increased the swelling properties and increased the plastic range by decreasing the softening temperature, but the effects of pressure were strongly influenced by rate of heating with high heating rates enhancing the effects. Additions of tar or pitch also enhanced swelling at low pressure. The solid carbonization residues from the dilatometer were examined by polarized light microscopy to determine the content and composition of optically anisotropic species. The anisotropic content was increased by increases in pressure and heating rate and pitch additives enhanced the anisotropic content, especially at low pressure, without affecting the composition of the anisotropy. No direct correlations exist between the dilatometric parameters and the optical anisotropy but their dependence on the conditions emphasizes that when considering high pressure gasification of coal, it is necessary to obtain data under appropriate conditions. 相似文献
66.
Aromaticities determined by 13C n.m.r. are reported for five shale oil samples (Green River formation) prepared under widely different pyrolysis conditions. In the absence of high-pressure hydrogen, the total amount of aromatic carbon in the products is nearly twice that in the raw shale. This is true for a wide range of pyrolysis conditions, although the distribution of aromatic carbon between the oil and carbonaceous residue changes. High-pressure hydrogen appears to inhibit both the formation of additional aromatic carbon during pyrolysis and the coking of aromatic oil. An improved kerogen decomposition mechanism is reported that accounts for these effects and provides for changes in the aromaticity of the liquid product with pyrolysis conditions. Further work is necessary to make it quantitative and account for gas formation. 相似文献
67.
Male rats were fed 100 nM dichlorodiphenyltrichloroethane-14C in oil by gastric tube. Recovery of dichlorodiphenyltrichloroethane-14C in thoracic duct lymph was 60% in 12 hr. Lymph dichlorodiphenyltrichloroethane-14C (97%) occurred in lipoproteins of d<1.006, designated chylomicrons. Mechanical separation of chylomicron triglyceride core
(labeled with triglyceride-3H) from chylomicron membrane (labeled with phospholipid-32P) showed that 97% dichlorodiphenyltrichloroethane-14C was present in triglyceride core. To investigate possible association of plasma clearance of the two core lipids, rats were
pulse injected with chylomicrons, doubly labeled with triglyceride-3H and dichlorodiphenyltrichloroethane-14C. The decay of dichlorodiphenyltrichloroethane-14C in sequential serum samples was rapid (T1/2=2 min) and was independent of triglyceride-3H decay. In tissues removed 14 min after injection of chylomicrons, 30% administered dichlorodiphenyltrichloroethane-14C was found in liver but only 1% in adipose tissue. In hepatectomized (eviscerated) rats, the decay of serum dichlorodiphenyltrichloroethane-14C (T1/2=10 min) was also independent of and more rapid than triglyceride-3H decay. With sucrose density gradients, it was shown that chylomicron dichlorodiphenyltrichloroethane-14C transferred to higher density serum proteins in vitro and in vivo and to bovine albumin in vitro. Thus, dichlorodiphenyltrichloroethane
was transported from intestine largely in the triglyderide phase of chylomicrons; disappearance of chylomicron-dichlorodiphenyltrichloroethane
from the systemic circulation was rapid and partly independent of the presence of the liver and of triglyceride hydrolysis;
some dichlorodiphenyltrichloroethane was transported from serum chylomicrons to albumin or other plasma proteins before tissue
uptake. 相似文献
68.
The diffusion of solutions of ethyl centralite (EC), dibutylphthalate (DBP), and dinitrotoluene (DNT) into a nitrocellulose (NC) propellant is investigated. DBP and EC penetrate the propellant in a way consistent with Case II diffusion. The diffusion of DNT solutions is Fickian. The apparent activation energy for Case II diffusion is 62 kJ/mol for DBP and 66 kJ/mol for EC. Changes to coating solvent polarity have little effect on DNT and DBP penetration and merely alter the rate, not the mechanism, of EC diffusion into the propellant. 相似文献
69.
Theresa E. Gentle Alan R. Bassindale 《Journal of Inorganic and Organometallic Polymers》1995,5(3):281-294
We have recently reported the synthesis of octopus molecules of defined shape and size with molecular weights well into the thousands. These octopus molecules were made by placing eight pendant groups symmetrically about a central silsesquioxane core via the H2PtCl6 catalyzed hydrosilylation of 1-alkenes as well as vinyl- and allyl-siloxanes by T8 hydrogen silsesquioxane, (HSiO32)8. The chemistry of addition was studied and it was found that while the addition of the 1-alkenes to T8 was regioprecise with only -addition being observed, both - and -addition occurred with vinyl-siloxane. In addition, H-vinyl exchange on silicon was observed to occur with addition of vinyl-siloxane to T8. In the current studies, the effect of the hydrosilylation catalyst. homogeneous and heterogeneous, on the regioselectivity of addition and on the extent of exchange on silicon was evaluated. It was found that the heterogeneous catalysts Pt–C, sulfided Pt–C, and Rh–C required higher temperature and longer times to get complete reaction than the homogeneous catalysts. H2PtCl6 and the tetramethyldivinyldisiloxane complex of Pt. Pd supported catalysts were not effective catalysts for this hydrosilylation. The extent of exchange on silicon and the degree of the second mode of addition occurring were higher with the heterogenous catalysts and may be a result of the higher reaction temperatures. 相似文献
70.