Ezra R. Lowe
University of Michigan
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Featured researches published by Ezra R. Lowe.
Journal of Biological Chemistry | 2002
Scott S. Billecke; Andrew T. Bender; Kimon C. Kanelakis; Patrick J. M. Murphy; Ezra R. Lowe; Yasuhiko Kamada; William B. Pratt; Yoichi Osawa
It is established that neuronal NO synthase (nNOS) is associated with the chaperone hsp90, although the functional role for this interaction has not been defined. We have discovered that inhibition of hsp90 by radicicol or geldanamycin nearly prevents the heme-mediated activation and assembly of heme-deficient apo-nNOS in insect cells. This effect is concentration-dependent with over 75% inhibition achieved at 20 μm radicicol. The ferrous carbonyl complex of nNOS is not formed when hsp90 is inhibited, indicating that functional heme insertion is prevented. We propose that the hsp90-based chaperone machinery facilitates functional heme entry into apo-nNOS by the opening of the hydrophobic heme-binding cleft in the protein. Previously, it has been reported that the hsp90 inhibitor geldanamycin uncouples endothelial NOS activity and increases endothelial NOS-dependent O 2 ⨪ production. Geldanamycin is an ansamycin benzoquinone, and we show here that it causes oxidant production from nNOS in insect cells as well as with the purified protein. At a concentration of 20 μm, geldanamycin causes a 3-fold increase in NADPH oxidation and hydrogen peroxide formation from purified nNOS, whereas the non-quinone hsp90 inhibitor radicicol had no effect. Thus, consistent with the known propensity of other quinones, geldanamycin directly redox cycles with nNOS by a process independent of any action on hsp90, cautioning against the use of geldanamycin as a specific inhibitor of hsp90 in redox-active systems.
Drug Metabolism and Disposition | 2011
Joel W. Proksch; Ezra R. Lowe; Keith W. Ward
Mapracorat is a selective glucocorticoid receptor agonist in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat after topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.01 to 3000 μg/eye (rabbit) or 50 to 3000 μg/eye (monkey). All animals received a single instillation, and monkeys also received repeated (three times per day for 4 days) instillations. At predetermined intervals through at least 24 h after dosing, ocular tissues and plasma were collected and analyzed for mapracorat by liquid chromatography-tandem mass spectrometry. Mapracorat was rapidly absorbed and widely distributed into ocular tissues after topical ocular administration, with measurable levels sustained through ≥24 h. In both species, mapracorat concentrations were highest in tears followed by conjunctiva and cornea, with lower levels observed in iris/ciliary body and aqueous humor. Mapracorat concentrations in conjunctiva, cornea, and iris/ciliary body increased linearly with increasing dose levels. Ocular exposure was higher after repeated dosing to monkeys than after a single dose. Systemic exposure to mapracorat was low after a single administration, with an average maximal concentration of ≤2.0 ng/ml at the highest dose tested (3000 μg/eye). In comparison with the traditional glucocorticoids, dexamethasone (0.1%) and prednisolone acetate (1%), mapracorat (3%) demonstrated similar or higher levels in ocular tissues with lower systemic exposure. The favorable pharmacokinetic profile of mapracorat supports further clinical investigation and suggests that a convenient daily dosing regimen may be efficacious for this novel ophthalmic anti-inflammatory therapy.
Plant Signaling & Behavior | 2007
Yoichi Osawa; Miranda Lau; Ezra R. Lowe
Cigarette smoking is known to cause a decrease in NO production in man resulting in a variety of pathological effects, including vascular dysfunction. Aqueous extracts of cigarette and cigarette smoke contain chemical inhibitors to NO-synthases, a heme-containing cytochrome P450 enzymes. More recently, it was shown that freshly harvested leaves from the tobacco plant (Nicotiana tabacum, Solanaceae) also contain chemical inhibitors to neuronal NO-synthase (nNOS). Examination of leaves from 32 other plants representing diverse members of the plant kingdom showed that 17 other plants, besides tobacco, contain these chemical inhibitors. Of all these plants, 16 are members of the core asterids flowering plant group and 6 are members of the Solanaceae family. Although the identity of the chemicals is not known, perhaps the closely related plants contain the same or similar compounds that inhibit nNOS. The inhibitory effects are not attributable to nicotine. The discovery of these chemicals and their further characterization may help to explain the loss of nNOS in smokers. In this addendum, we discuss these results in light of the effect of tobacco-derived chemicals in inhibiting P450 cytochromes, as well as our thoughts on how the inactivation of nNOS leads to its selective downregulation through proteolytic degradation.
Journal of Biological Chemistry | 2003
Yoshihiro Morishima; Kimon C. Kanelakis; Patrick J. M. Murphy; Ezra R. Lowe; Gary J. Jenkins; Yoichi Osawa; Roger K. Sunahara; William B. Pratt
Journal of Pharmacology and Experimental Therapeutics | 2003
Yoichi Osawa; Ezra R. Lowe; Andrew C. Everett; Anwar Y. Dunbar; Scott S. Billecke
Molecular Pharmacology | 2004
Anwar Y. Dunbar; Yasuhiko Kamada; Gary J. Jenkins; Ezra R. Lowe; Scott S. Billecke; Yoichi Osawa
Drug Metabolism and Disposition | 2004
Ezra R. Lowe; Andrew C. Everett; Anthony J. Lee; Miranda Lau; Anwar Y. Dunbar; Vladimir Berka; Ah Lim Tsai; Yoichi Osawa
Molecular Brain Research | 2005
Yasuhiko Kamada; Gary J. Jenkins; Miranda Lau; Anwar Y. Dunbar; Ezra R. Lowe; Yoichi Osawa
Molecular Pharmacology | 2002
Jennifer L. Vuletich; Ezra R. Lowe; Suree Jianmongkol; Yasuhiko Kamada; Ute M. Kent; Andrew T. Bender; Damon R. Demady; Paul F. Hollenberg; Yoichi Osawa
Drug Metabolism and Disposition | 2003
Damon R. Demady; Ezra R. Lowe; Andrew C. Everett; Scott S. Billecke; Yasuhiko Kamada; Anwar Y. Dunbar; Yoichi Osawa