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751.
Cytochrome P450 (CYP) 3A4 is responsible for the oxidative degradation of more than 50% of clinically used drugs. By means of molecular dynamics simulations with the newly developed force field parameters for the heme-thiolate group and its dioxygen adduct, we examine the differences in structural and dynamic properties between CYP3A4 in the resting form and its complexes with the substrate progesterone and the inhibitor metyrapone. The results indicate that the broad substrate specificity of CYP3A4 stems from the malleability of a loop (residues 211-218) that resides in the vicinity of the channel connecting the active site and bulk solvent. However, the high-amplitude motion of the flexible loop is found to be damped out upon binding of the inhibitor or the substrate in the active site. In the resting form of CYP3A4, a structural water molecule is bound to the sixth coordination position of the heme iron, stabilizing the octahedral coordination geometry. In addition to the direct coordination of metyrapone to the heme iron, the hydrogen bond interaction between the inhibitor carbonyl group and the side chain of Ser119 also contributes significantly to stabilizing the CYP3A4-metyrapone complex. On the other hand, progesterone is stabilized in the active site by the formation of two hydrogen bonds with Ser119 and Arg106, as well as by the van der Waals interactions with the heme and hydrophobic residues. The structural and dynamic features of the CYP3A4-progesterone complex indicate that the oxidative degradation of progesterone occurs through hydroxylation at the C16 position by the reactive oxygen coordinated to the heme iron. 相似文献
752.
Songyi Seo Mi-Kyung Kim Ryul-I Kim Yeongju Yeo Koung Li Kim Wonhee Suh 《Experimental & molecular medicine》2020,52(10):1744
Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 diabetes mellitus (DM). Recent studies have shown that beyond their effect in lowing glucose, DPP-4 inhibitors mitigate DM-related microvascular complications, such as diabetic retinopathy. However, the mechanism by which pathological retinal neovascularization, a major clinical manifestation of diabetic retinopathy, is inhibited is unclear. This study sought to examine the effects of evogliptin, a potent DPP-4 inhibitor, on pathological retinal neovascularization in mice and elucidate the mechanism by which evogliptin inhibits angiogenesis mediated by vascular endothelial growth factor (VEGF), a key factor in the vascular pathogenesis of proliferative diabetic retinopathy (PDR). In a murine model of PDR, an intravitreal injection of evogliptin significantly suppressed aberrant retinal neovascularization. In human endothelial cells, evogliptin reduced VEGF-induced angiogenesis. Western blot analysis showed that evogliptin inhibited the phosphorylation of signaling molecules associated with VEGF-induced cell adhesion and migration. Moreover, evogliptin substantially inhibited the VEGF-induced activation of adenosine 5′-diphosphate ribosylation factor 6 (Arf6), a small guanosine 5′-triphosphatase (GTPase) that regulates VEGF receptor 2 signal transduction. Direct activation of Arf6 using a chemical inhibitor of Arf-directed GTPase-activating protein completely abrogated the inhibitory effect of evogliptin on VEGF-induced activation of the angiogenic signaling pathway, which suggests that evogliptin suppresses VEGF-induced angiogenesis by blocking Arf6 activation. Our results provide insights into the molecular mechanism of the direct inhibitory effect of the DPP-4 inhibitor evogliptin on pathological retinal neovascularization. In addition to its glucose-lowering effect, the antiangiogenic effect of evogliptin could also render it beneficial for individuals with PDR.Subject terms: Vascular diseases, Growth factor signalling 相似文献
753.
To improve the degree of phase separation between polymer and LC in LC microcapsules, poly(methylmethacrylate-co-vinylacetate) substrate particles were acetalized by using aldehydes having a different chain length. LC microcapsules were prepared by the solute co-diffusion method (SCM). The phase separation behavior was evaluated with a differential scanning calorimeter (DSC). The degree of phase separation between LC and substrate particles modified with butyl aldehyde was relatively high in comparison with those modified with hexanal and octanal. This means that poly(vinylbutyral) (PVB) moiety in substrate particles causes the complete phase separation and a single LC domain formation. On the contrary, as the aldehyde chain lengthened, the phase separation of LC domain was inhibited. 相似文献
754.
Lee MJ Cho SS Jang HS Lim YS You JR Park J Suh H Kim JA Park JS Kim DK 《Experimental & molecular medicine》2002,34(4):265-272
In vivo electroporation has emerged as a leading technology for developing nonviral gene therapies, and the various technical parameters governing electroporation efficiency have been optimized by both theoretical and experimental analysis. However, most electroporation parameters focused on the electric conditions and the preferred vehicle for plasmid DNA injections has been normal saline. We hypothesized that salts in vehicle for plasmid DNA must affect the efficiency of DNA transfer because cations would alter ionic atmosphere, ionic strength, and conductivity of their medium. Here, we show that half saline (71 mM) is an optimal vehicle for in vivo electroporation of naked DNA in skeletal muscle. With various salt concentrations, two reporter genes, luciferase and beta-galactosidase were injected intramuscularly under our optimal electric condition (125 V/cm, 4 pulses x 2 times, 50 ms, 1 Hz). Exact salt concentrations of DNA vehicle were measured by the inductively coupled plasma-atomic emission spectrometer (ICP-AES) and the conductivity change in the tissue induced by the salt in the medium was measured by Low-Frequency (LF) Impedance Analyzer. Luciferase expression increased as cation concentration of vehicle decreased and this result can be visualized by X-Gal staining. However, at lower salt concentration, transfection efficiency was diminished because the hypoosmotic stress and electrical injury by low conductivity induced myofiber damage. At optimal salt concentration (71 mM), we observed a 3-fold average increase in luciferase expression in comparison with the normal saline condition (p < 0.01). These results provide a valuable experimental parameter for in vivo gene therapy mediated by electroporation. 相似文献
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Hexanuclear, octanuclear, and decanuclear manganese metalladiazamacrocycles have been prepared by reacting a series of pentadentate ligands, N-acylsalicylhydrazides (N-(3-methylbutanoyl)salicylhydrazide (H(3)3-mbshz), N-(phenylacetyl)salicylhydrazide (H(3)pashz), N-(3,3-dimethylbutanoyl)salicylhydrazide (H(3)3-dmbshz), N-(2-methylpropanoyl)salicylhydrazide (H(3)2-mpshz), N-((R,S)-2-methylbutanoyl)salicylhydrazide (H(3)RS-2-mbshz), N-((S)-2-methylbutanoyl)salicylhydrazide (H(3)S-2-mbshz), and N-(2,2-dimethylpropanoyl)salicylhydrazide (H(3)2-dmpshz)), with manganese(II) acetate tetrahydrate. The self-assembled, supramolecular complexes assume a nearly planar cyclic structure with an -(Mn-N-N)(n) backbone and measure approximately 2.1, approximately 2.3, and approximately 2.6 nm in outer diameters for n = 6, 8, and 10, respectively. The chiralities of the manganese centers on the metalladiazamacrocycle occur in alternating ...LambdaDeltaLambdaDelta... configurations. While beta-branched N-acylsalicylhydrazides (H(3)3-mbshz, H(3)pashz, H(3)3-dmbshz) with a sterically flexible Calpha methylene group yield 18-membered hexanuclear manganese metalladiazamacrocycles of S(6) point group symmetry, alpha-branched N-acylsalicylhydrazides lead to 24-membered octanuclear manganese metalladiazamacrocycles or 30-membered decanuclear manganese metalladiazamacrocycles depending on the size of the N-acyl substituents. The alpha-branched H(3)2-mpshz ligand with the sterically least demanding isopropyl tail at the N-acyl position yields a 24-membered octanuclear manganese metalladiazamacrocycle of S(8) point group symmetry, but other alpha-branched N-acylsalicylhydrazides such as H(3)RS-2-mbshz, H(3)S-2-mbshz, and H(3)2-dmpshz lead to 30-membered decanuclear manganese metalladiazamacrocycles of S(10) point group symmetry. The magnetic properties of the metalladiazamacrocycles are characterized by a weak antiferromagnetic exchange interaction, with J(eff) = -8.5 to -3.8 K between the Mn(3+) ion spins with S = 2 in the cyclic system. 相似文献
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