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The effect of free-electron laser pulse structure on mid-infrared soft-tissue ablation: biological effects.
Mackanos MA, Kozub JA, Hachey DL, Joos KM, Ellis DL, Jansen ED
(2005) Phys Med Biol 50: 1885-99
MeSH Terms: Animals, Cornea, Dermatologic Surgical Procedures, Dose Fractionation, Radiation, Dose-Response Relationship, Radiation, Electrons, Infrared Rays, Laser Therapy, Light, Mice, Radiation Dosage, Radiation Injuries, Radiometry, Skin, Treatment Outcome
Show Abstract · Added March 20, 2014
Previous studies have shown that changing the pulse structure of the free electron laser (FEL) from 1 to 200 ps and thus reducing the peak irradiance of the micropulse by 200 times had little or no effect on both the ablation threshold radiant exposure and the ablated crater depth for a defined radiant exposure. This study focuses on the ablation mechanism at 6.1 and 6.45 microm with an emphasis on the role of the FEL pulse structure. Three different experiments were performed to gain insight into this mechanism. The first was an analysis of the ablation plume dynamics observed for a 1 ps micropulse compared with a 200 ps micropulse as seen through bright-field analysis. Negligible differences are seen in the size, but not the dynamics of ablation, as a result of this imaging. The second experiment was a histological analysis of corneal and dermal tissue to determine whether there is less thermal damage associated with one micropulse duration versus another. No significant difference was seen in the extent of thermal damage on either canine cornea or mouse dermis for the micropulse durations studied at either wavelength. The final set of experiments involved the use of mass spectrometry to determine whether amide bond breakage could occur in the proteins present in tissue as a result of direct absorptions of mid-infrared light into the amide I and amide II absorption bands. This analysis showed that there was no amide bond breakage due to irradiation at 6.45 microm on protein.
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15 MeSH Terms
Kinetic analysis of oxidation of coumarins by human cytochrome P450 2A6.
Yun CH, Kim KH, Calcutt MW, Guengerich FP
(2005) J Biol Chem 280: 12279-91
MeSH Terms: 7-Alkoxycoumarin O-Dealkylase, Anticoagulants, Aryl Hydrocarbon Hydroxylases, Binding Sites, Binding, Competitive, Carbon, Catalysis, Chromatography, High Pressure Liquid, Coumarins, Cytochrome P-450 CYP2A6, Cytochromes b5, Electron Transport, Electrons, Humans, Hydrogen, Hydrogen Bonding, Hydroxylation, Kinetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mixed Function Oxygenases, Models, Chemical, Oxygen, Protein Binding, Protein Structure, Tertiary, Spectrophotometry, Substrate Specificity, Time Factors, Ultraviolet Rays
Show Abstract · Added March 5, 2014
Human cytochrome P450 (P450) 2A6 catalyzes 7-hydroxylation of coumarin, and the reaction rate is enhanced by cytochrome b5 (b5). 7-Alkoxycoumarins were O-dealkylated and also hydroxylated at the 3-position. Binding of coumarin and 7-hydroxycoumarin to ferric and ferrous P450 2A6 are fast reactions (k(on) approximately 10(6) m(-1) s(-1)), and the k(off) rates range from 5.7 to 36 s(-1) (at 23 degrees C). Reduction of ferric P450 2A6 is rapid (7.5 s(-1)) but only in the presence of coumarin. The reaction of the ferrous P450 2A6 substrate complex with O2 is rapid (k > or = 10(6) m(-1) s(-1)), and the putative Fe2+.O2 complex decayed at a rate of approximately 0.3 s(-1) at 23 degrees C. Some 7-hydroxycoumarin was formed during the oxidation of the ferrous enzyme under these conditions, and the yield was enhanced by b5. Kinetic analyses showed that approximately 1/3 of the reduced b5 was rapidly oxidized in the presence of the Fe2+.O2 complex, implying some electron transfer. High intrinsic and competitive and non-competitive intermolecular kinetic deuterium isotope effects (values 6-10) were measured for O-dealkylation of 7-alkoxycoumarins, indicating the effect of C-H bond strength on rates of product formation. These results support a scheme with many rapid reaction steps, including electron transfers, substrate binding and release at multiple stages, and rapid product release even though the substrate is tightly bound in a small active site. The inherent difficulty of chemistry of substrate oxidation and the lack of proclivity toward a linear pathway leading to product formation explain the inefficiency of the enzyme relative to highly efficient bacterial P450s.
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29 MeSH Terms
New insights regarding the autoxidation of polyunsaturated fatty acids.
Yin H, Porter NA
(2005) Antioxid Redox Signal 7: 170-84
MeSH Terms: Animals, Arteriosclerosis, Electrons, Fatty Acids, Unsaturated, Free Radicals, Humans, Isoprostanes, Leukotrienes, Lipid Peroxidation, Lipid Peroxides, Lipids, Mass Spectrometry, Models, Chemical, Neoplasms, Oxygen, Peroxides, Silver, Spectrometry, Mass, Electrospray Ionization, Time Factors
Show Abstract · Added May 29, 2014
Free radical-initiated autoxidation of polyunsaturated fatty acids (PUFAs) has been implicated in numerous human diseases, including atherosclerosis and cancer. This review covers the free radical mechanisms of lipid oxidation and recent developments of analytical techniques to analyze the lipid oxidation products. Autoxidation of PUFAs generates hydroperoxides as primary oxidation products, and further oxidation leads to cyclic peroxides as secondary oxidation products. Characterization of these oxidation products is accomplished by several mass spectrometric techniques. Ag+ coordination ion spray mass spectrometry has proven to be a powerful tool to analyze the intact lipid peroxides. Monocyclic peroxides, bicyclic endoperoxides, serial cyclic peroxides, and a novel class of endoperoxides (dioxolane-isoprostane peroxides) have been identified from the oxidation of arachidonate. Electron capture atmospheric pressure chemical ionization mass spectrometry has been applied to study lipid oxidation products after derivatization. All eight possible diastereomeric isoprostanes are observed from the oxidation of a single hydroperoxide precursor. 5- and 15-series isoprostanes are more abundant than the 8- and 12-series because the precursors that lead to 8- and 12-series compounds can undergo further oxidation and form dioxolane-isoprostane peroxides. Furthermore, formation of isoprostanes from 15-hydroperoxyeicosatetraenoate occurs from beta-fragmentation of the corresponding peroxyl radical to generate a pentadienyl radical rather than a "dioxetane" intermediate, as previously suggested.
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19 MeSH Terms
The alpha1.alpha2 network of collagen IV. Reinforced stabilization of the noncollagenous domain-1 by noncovalent forces and the absence of Met-Lys cross-links.
Vanacore RM, Shanmugasundararaj S, Friedman DB, Bondar O, Hudson BG, Sundaramoorthy M
(2004) J Biol Chem 279: 44723-30
MeSH Terms: Animals, B-Lymphocytes, Basement Membrane, Binding Sites, Cattle, Chromatography, High Pressure Liquid, Collagen Type IV, Crystallography, X-Ray, Dimerization, Electrons, Epitopes, Hydrogen Bonding, Ions, Lens, Crystalline, Lysine, Mass Spectrometry, Metals, Methionine, Models, Molecular, Peptides, Placenta, Potassium, Promoter Regions, Genetic, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Time Factors, Trypsin
Show Abstract · Added December 10, 2013
Collagen IV networks are present in all metazoa and underlie epithelia as a component of basement membranes. The networks are essential for tissue function and are defective in disease. They are assembled by the oligomerization of triple-helical protomers that are linked end-to-end. At the C terminus, two protomers are linked head-to-head by interactions of their trimeric noncollagenous domains, forming a hexamer structure. This linkage in the alpha1.alpha2 network is stabilized by a putative covalent Met-Lys cross-link between the trimer-trimer interface (Than, M. E., Henrich, S., Huber, R., Ries, A., Mann, K., Kuhn, K., Timpl, R., Bourenkov, G. P., Bartunik, H. D., and Bode, W. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 6607-6612) forming a nonreducible dimer that connects the hexamer. In the present study, this cross-link was further investigated by: (a) comparing the 1.5-A resolution crystal structures of the alpha1.alpha2 hexamers from bovine placenta and lens capsule basement membranes, (b) mass spectrometric analysis of monomer and nonreducible dimer subunits of placenta basement membrane hexamers, and (c) hexamer dissociation/re-association studies. The findings rule out the novel Met-Lys cross-link, as well as other covalent cross-links, but establish that the nonreducible dimer is an inherent structural feature of a subpopulation of hexamers. The dimers reflect the reinforced stabilization, by noncovalent forces, of the connection between two adjoining protomers of a network. The reinforcement extends to other types of collagen IV networks, and it underlies the cryptic nature of a B-cell epitope of the alpha3.alpha4.alpha5 hexamer, implicating the stabilization event in the etiology and pathogenesis of Goodpasture autoimmune disease.
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29 MeSH Terms
Molecular dynamics investigation of membrane-bound bundles of the channel-forming transmembrane domain of viral protein U from the human immunodeficiency virus HIV-1.
Lopez CF, Montal M, Blasie JK, Klein ML, Moore PB
(2002) Biophys J 83: 1259-67
MeSH Terms: Carbon, Cell Membrane, Computer Simulation, Electrons, HIV-1, Human Immunodeficiency Virus Proteins, Lipid Bilayers, Magnetic Resonance Spectroscopy, Models, Molecular, Octanes, Phosphatidylethanolamines, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Software, Time Factors, Viral Regulatory and Accessory Proteins, Water
Show Abstract · Added March 10, 2014
Molecular dynamics (MD) simulations have been carried out on bundles of the channel-forming transmembrane (TM) domain of the viral protein U (VPU(1-27) and VPU(6-27)) from the human immunodeficiency virus (HIV-1). Simulations of hexameric and pentameric bundles of VPU(6-27) in an octane/water membrane mimetic system suggested that the pentamer is the preferred oligomer. Accordingly, an unconstrained pentameric helix bundle of VPU(1-27) was then placed in a hydrated palmitoyl-oleyl-3-n-glycero-phosphatidylethanolamine (POPE) lipid bilayer and its structural properties calculated from a 3-ns MD run. Some water molecules, initially inside the channel lumen, were expelled halfway through the simulation and the bundle adopted a conical structure reminiscent of previous MD results obtained for VPU(6-27) in an octane/water system. The pore constriction generated may correspond to a closed state of the channel and underlies the relocation of the W residue toward the pore lumen. The relative positions of the helices with respect to the bilayer and their interactions with the lipids are discussed. The observed structure is stabilized via specific interactions between the VPU helices and the carbonyl oxygen atoms of the lipid molecules, particularly at the Q and S residues.
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18 MeSH Terms
Mitochondrial recycling of ascorbic acid from dehydroascorbic acid: dependence on the electron transport chain.
Li X, Cobb CE, May JM
(2002) Arch Biochem Biophys 403: 103-10
MeSH Terms: Animals, Ascorbic Acid, Dehydroascorbic Acid, Electrons, Ferricyanides, Free Radicals, Intracellular Membranes, Mitochondria, Models, Biological, Muscle, Skeletal, Muscles, Rats, Succinic Acid, Temperature, Time Factors, alpha-Tocopherol
Show Abstract · Added December 10, 2013
Mitochondria can regenerate ascorbic acid from its oxidized forms, which may help to maintain the vitamin both in mitochondria and in the cytoplasm. In this work, we sought to determine the site and mechanism of mitochondrial ascorbate recycling from dehydroascorbic acid. Rat skeletal muscle mitochondria incubated for 3 h at 37 degrees C with 500 microM dehydroascorbic acid and energy substrates maintained ascorbate concentrations more than twice those observed in the absence of substrate. Succinate-dependent mitochondrial reduction of dehydroascorbic acid was blocked by inhibitors of mitochondrial Complexes II and III. Neither cytochrome c nor the outer mitochondrial membrane were necessary for the effect. The ascorbate radical was generated by mitochondria during treatment with dehydroascorbic acid and was abolished by ferricyanide, which does not penetrate the mitochondrial inner membrane. Together, these results show that energy substrate-dependent ascorbate recycling from dehydroascorbic acid involves an externally exposed portion of mitochondrial complex III.
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16 MeSH Terms
Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity.
Guengerich FP
(2001) Chem Res Toxicol 14: 611-50
MeSH Terms: Aldehydes, Animals, Biotransformation, Catalysis, Cytochrome P-450 Enzyme System, Electrons, Esters, Fatty Acids, Humans, Kinetics, Oxidation-Reduction, Peroxidases, Phospholipase D, Xenobiotics
Show Abstract · Added March 5, 2014
Cytochrome P450 (P450) enzymes catalyze a variety of reactions and convert chemicals to potentially reactive products as well as make compounds less toxic. Most of the P450 reactions are oxidations. The majority of these can be rationalized in the context of an FeO(3+) intermediate and odd electron abstraction/rebound mechanisms; however, other iron-oxygen complexes are possible and alternate chemistries can be considered. Another issue regarding P450-catalyzed reactions is the delineation of rate-limiting steps in the catalytic cycle and the contribution to reaction selectivity. In addition to the rather classical oxidations, P450s also catalyze less generally discussed reactions including reduction, desaturation, ester cleavage, ring expansion, ring formation, aldehyde scission, dehydration, ipso attack, one-electron oxidation, coupling reactions, rearrangement of fatty acid and prostaglandin hydroperoxides, and phospholipase activity. Most of these reactions are rationalized in the context of high-valent iron-oxygen intermediates and Fe(2+) reductions, but others are not and may involve acid-base catalysis. Some of these transformations are involved in the bioactivation and detoxication of xenobiotic chemicals.
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14 MeSH Terms
Evidence for a 1-electron oxidation mechanism in N-dealkylation of N,N-dialkylanilines by cytochrome P450 2B1. Kinetic hydrogen isotope effects, linear free energy relationships, comparisons with horseradish peroxidase, and studies with oxygen surrogates.
Guengerich FP, Yun CH, Macdonald TL
(1996) J Biol Chem 271: 27321-9
MeSH Terms: Alkylation, Aniline Compounds, Animals, Cytochrome P-450 CYP2B1, Electrons, Horseradish Peroxidase, Kinetics, Microsomes, Liver, Models, Chemical, Oxidation-Reduction, Phenobarbital, Rats, Substrate Specificity
Show Abstract · Added March 5, 2014
Many enzymes catalyze N-dealkylations of alkylamines, including cytochrome P450 (P450) and peroxidase enzymes. Peroxidases, exemplified by horseradish peroxidase (HRP), are generally accepted to catalyze N-dealkylations via 1-electron transfer processes. Several lines of evidence also support a 1-electron mechanism for many P450 reactions, although this view has been questioned in light of reported trends for kinetic hydrogen isotope effects for N-demethylation with a series of 4-substituted N,N-dimethylanilines. No continuous trend for an increase of isotope effects with the electronic parameters of para-substitution was seen for the P450 2B1-catalyzed reactions in this study. The larger value seen with the 4-nitro derivative is consistent with a shift in mechanism due to either a reversible electron transfer step preceding deprotonation or to a hydrogen atom abstraction mechanism. With HRP, the trend is to lower isotope effects with para electron-withdrawing substituents, due to an apparent shift in rate-limiting steps. Biomimetic model high-valent porphyrins showed reduction rates with variously 4-substituted N,N-dialkylanilines that were consistent with a positively charged intermediate; such relationships were not seen for anisole O-demethylation with P450 2B1. In contrast to the case with the NADPH-supported P450 reactions, high deuterium isotope effects ( approximately 7) were seen in the N-dealkylations supported by the oxygen surrogate iodosylbenzene. With iodosylbenzene, colored aminium radicals were observed in the oxidations of aminopyrine, N,N-dimethyl-4-aminothioanisole, and 4-methoxy-N,N-dimethylaniline. With the latter compound, a substantial intermolecular deuterium isotope effect was observed for N-demethylation. In the N-dealkylation of N-ethyl,N-methylaniline by P450 2B1 (NADPH-supported), the ratio of N-demethylation to N-deethylation was 16. Although it is probably possible for P450s to catalyze amine N-dealkylations via hydrogen atom abstraction when such a course is electronically or sterically favored, we interpret the evidence to favor a 1-electron pathway with N,N-dialkylamines with P450 2B1 as well as HRP and several biomimetic models.
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13 MeSH Terms
Radiation therapy dosimetry using magnetic resonance imaging of polymer gels.
Maryanski MJ, Ibbott GS, Eastman P, Schulz RJ, Gore JC
(1996) Med Phys 23: 699-705
MeSH Terms: Acrylamide, Acrylamides, Brachytherapy, Electrons, Gels, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Muscle, Skeletal, Nitrous Oxide, Phantoms, Imaging, Polymers, Radiosurgery, Radiotherapy Dosage, Sepharose, Water, X-Ray Therapy
Show Abstract · Added December 10, 2013
Further progress in the development of polymer gel dosimetry using MRI is reported, together with examples of its application to verify treatment plans for stereotactic radiosurgery and high dose rate brachytherapy. The dose distribution image produced in the tissue-equivalent gel by radiation-induced polymerization, and encoded in the spatial distribution of the NMR transverse relaxation rates (R2) of the water protons in the gel, is permanent. Maps of R2 are constructed from magnetic resonance imaging data and serve as a template for dose maps, which can be used to verify complex dose distributions from external sources or brachytherapy applicators. The integrating, three-dimensional, tissue-equivalent characteristics of polymer gels make it possible to obtain dose distributions not readily measured by conventional methods. An improved gel formulation (BANG-2) has a linear dose response that is independent of energy and dose rate for the situations studied to date. There is excellent agreement between the dose distributions predicted using treatment planning calculations and those measured using the gel method, and the clinical practical utility of MRI-based polymer gel dosimetry is thereby demonstrated.
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17 MeSH Terms
Mechanism of hydroperoxide reduction by mangano-prostaglandin endoperoxide synthase.
Landino LM, Marnett LJ
(1996) Biochemistry 35: 2637-43
MeSH Terms: Animals, Arachidonic Acids, Electrons, Free Radicals, Hydroxyeicosatetraenoic Acids, In Vitro Techniques, Leukotrienes, Lipid Peroxides, Male, Manganese, Molecular Structure, Oxidation-Reduction, Prostaglandin-Endoperoxide Synthases, Sheep, Substrate Specificity
Show Abstract · Added March 5, 2014
Reaction of manganese-reconstituted prostaglandin endoperoxide synthase (Mn-PGHS) with 15-hydroperoxyeicosatetraenoic acid (15-HPETE) generates two products in nearly equal amounts: 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-ketoeicosatetraenoic acid (15-KETE) [Kulmacz et al. (1994) Biochemistry 33, 5428-5439]. Their proposed mechanism to explain 15-KETE formation, namely oxidation of 15-HETE by the peroxidase activity of MnPGHS, was tested and found not to occur. Instead, 15-KETE may arise by one-electron reduction of 15-HPETE followed by oxidation of an intermediate alkoxyl radical. The mechanism of hydroperoxide reduction by Mn-PGHS was investigated using 10-hydroperoxyoctadeca-8,12-dienoic acid (10-OOH-18:2), a diagnostic probe of hydroperoxide reduction pathways. Reaction of Mn-PGHS with 10-OOH-18:2 generated the two-electron reduced product, 10-hydroxyoctadeca-8,12-dienoic acid (10-OH-18:2), as well as the one-electron reduction products, 10-oxooctadeca-8,12 dienoic acid (10-oxo-18:2) and 10-oxodec-8-enoic acid (10-oxo-10:1) in relative yields of 82, 10, and 7%, respectively. The identity of the one-electron reduction products was confirmed by electrospray ionization mass spectrometry. The detection of 10-oxo-10:1 provides strong evidence for the production of an alkoxyl radical during 10-OOH-18:2 reduction by Mn-PGHS. Like 15-HPETE, reaction of Mn-PGHS with 13-hydroperoxyoctadeca-8,12-dienoic acid (13-OOH-18:2) generated two products in equal amounts: 13-hydroxyoctadeca-8,12-dienoic acid (13-OH-18:2) and the keto fatty acid 13-oxooctadeca-8,12-dienoic acid (13-oxo-18:2). Comparison of the three hydroperoxides demonstrates that 15-HPETE is a much better substrate for Mn-PGHS than 10-OOH-18:2 or 13-OOH-18:2 with 10-fold greater turnovers. The results show that Mn-PGHS catalyzes both one- and two-electron hydroperoxide reduction and that the pathway of alkoxyl radical decomposition is influenced by the protein component of Mn-PGHS and the structure of the alkoxyl radical intermediate.
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15 MeSH Terms