Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0393754 (HSA)
 2,996 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action.
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PMID:Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron. 217 23

Many lead compounds bind to serum albumin and exhibit markedly reduced efficacy in vivo as compared to their potency in vitro. To aid in the design of compounds with reduced albumin binding, we performed nuclear magnetic resonance (NMR) structural and binding studies on the complex between domain III of human serum albumin (HSA-III) and diflunisal, a cyclooxygenase inhibitor with antiinflammatory activity. The structural studies indicate that the aromatic rings of diflunisal are involved in extensive and specific interactions with hydrophobic residues that comprise the binding pocket in subdomain IIIA. The carboxylic acid of diflunisal forms electrostatic interactions with the protein similar to those observed in the X-ray structure of HSA complexed to myristic acid. In addition to the structural studies, NMR-derived binding constants were obtained for diflunisal and closely related analogues to develop a structure-affinity relationship for binding to subdomain IIIA. On the basis of the structural and binding data, compounds were synthesized that exhibit more than a 100-fold reduction in binding to domain III of HSA, and nearly a 10-fold reduction in affinity for full length albumin. Significantly, several of these compounds maintain activity against cyclooxygenase-2. These results suggest a rational strategy for designing out albumin binding in potential drug molecules by using structure-based design in conjunction with NMR-based screening.
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PMID:Rational design of diflunisal analogues with reduced affinity for human serum albumin. 1167 72

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.
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PMID:Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV) complexes as antitumor agents. 3098 7