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PubMedDate not supplied

Bis(hydroxamamide)-based bifunctional chelating agent for 99mTc labeling of polypeptides.

To develop chelating molecules that provide 99mTc-labeled polypeptides of high in vivo stability and high specific activities under mild reaction conditions, an asymmetrical bis(benzohydroxamamide) compound with an amine group, 4'-aminomethyl-N,N'-trimethylenedibenzohydroxamamide [NH2-C3(BHam)2], was designed and synthesized. The amine residue of NH2-C3(BHam)2 was converted to a maleimide group by reaction with N-succinimidyl-6-maleimidohexanoate, and the conjugation product was coupled to thiol groups of a monoclonal antibody against osteogenic sarcoma (OST7, IgG1) pretreated with 2-iminothiolane to prepare C3(BHam)2-OST7. 99mTc radiolabeling of C3(BHam)2-OST7 was performed by the exchange reaction with [99mTc]glucoheptonate. [99mTc]C3(BHam)2-OST7 was further characterized using directly radioiodinated OST7 ([125I]OST7) and [111In]labeled OST7 with 1-[4-[(5-maleimidopentyl)amidobenzyl]ethylenediamine-N,N, N'N'-tetraacetic acid (EMCS-Bz-EDTA) as references. [99mTc]C3(BHam)2-OST7 was obtained with radiochemical yields of over 94% at protein concentrations as low as 0.2 mg/mL at room temperature for 1 h. [99mTc]C3(BHam)2-OST7 remained stable after incubation in freshly prepared murine plasma and in the presence of cysteine. Similar binding affinities to tumor cells were observed between [99mTc]C3(BHam)2-OST7 and [125I]OST7. When injected into normal mice, [99mTc]C3(BHam)2-OST7 exhibited radioactivity levels in the blood similar to [111In]-EMCS-Bz-EDTA-OST7 up to 24 h postinjection with significantly faster elimination rate of the radioactivity from the liver. In nude mice bearing osteogenic sarcoma, no significant differences were observed in the radioactivity levels in the blood and the tumor between [99mTc]C3(BHam)2-OST7 and [125I]OST7 at 24 h postinjection. These findings indicated that C3(BHam)2 provided 99mTc chelate of high stability at low concentrations even when conjugated to an intact antibody. Such characteristics render bis(hydroxamamide) compounds useful as chelating molecules for preparation of 99mTc-labeled polypeptides.

Amides↗
PubMed1998

TNFalpha processing enzyme inhibitors prevent aspirin-induced TNFalpha release and protect against gastric mucosal injury in rats.

BACKGROUND: Although previous studies indicate that prevention of tumour necrosis factor alpha (TNFalpha) release protects against NSAID-induced gastric mucosal injury, intracellular pathways by which aspirin causes TNFalpha release are unknown. TNFalpha is synthesized as a precursor which is proteolytically cleaved by a specific converting enzyme, TACE, to release the mature cytokine. TACE inhibitors prevent TNFalpha release and protect against TNFalpha-mediated disease. AIM: To investigate: (i) molecular events that regulate TNFalpha secretion in response to aspirin in vivo and in vitro; (ii) whether TNFalpha secretion inhibitors prevent aspirin-induced TNFalpha release and protect against gastric mucosal damage; and (iii) whether TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells. METHODS: In vitro studies were carried out on mouse macrophages and rat gastric mucosal cells. Gastric mucosal damage was induced in rats by oral administration of 300 mg/kg aspirin. TNFalpha cytotoxicity on gastric mucosal cells was examined by treating rats with lipopolysaccharide to release TNFalpha or by incubating dispersed gastric mucosal cells with increasing concentrations of TNFalpha. RESULTS: Aspirin increases intracellular calcium (Ca2+) levels and causes a time and concentration dependent increase in macrophage TNFalpha mRNA accumulation and cytokine release. Agents that cause Ca2+ mobilization with a receptor-independent mechanism, such as ionomycin and thapsigargin, stimulate TNFalpha release. Incubating the macrophages in a Ca2+ free medium inhibited TNFalpha secretion. Agents that prevent TNFalpha mRNA transcription, e.g. lisophylline, PGE2, interleukin-10 and 8-BrcAMP, or TACE inhibitors, e.g. EDTA, TAPI-2 and BB-3103, inhibit TNFalpha release and protect rats against gastric mucosal injury induced by oral administration of aspirin. TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells as demonstrated by the reduced viability observed in gastric mucosal cells prepared from rats treated with lipopolysaccharide, or directly incubated with increasing concentrations of TNFalpha. CONCLUSIONS: (i) Aspirin directly stimulates TNFalpha gene transcription; (ii) TACE inhibitors protect against aspirin-induced gastric mucosal injury; and (iii) TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells.

Animals↗
PubMed1999

Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity.

Metalloprotease disintegrins are a family of membrane-anchored glycoproteins that are known to function in fertilization, myoblast fusion, neurogenesis, and ectodomain shedding of tumor necrosis factor (TNF)-alpha. Here we report the analysis of the intracellular maturation and catalytic activity of the widely expressed metalloprotease disintegrin MDC9. Our results suggest that the pro-domain of MDC9 is removed by a furin-type pro-protein convertase in the secretory pathway before the protein emerges on the cell surface. The soluble metalloprotease domain of MDC9 cleaves the insulin B-chain, a generic protease substrate, providing the first evidence that MDC9 is catalytically active. Soluble MDC9 appears to have distinct specificities for cleaving candidate substrate peptides compared with the TNF-alpha convertase (TACE/ADAM17). The catalytic activity of MDC9 can be inhibited by hydroxamic acid-type metalloprotease inhibitors in the low nanomolar range, in one case with up to 50-fold selectivity for MDC9 versus TACE. Peptides mimicking the predicted cysteine-switch region of MDC9 or TACE inhibit both enzymes in the low micromolar range, providing experimental evidence for regulation of metalloprotease disintegrins via a cysteine-switch mechanism. Finally, MDC9 is shown to become phosphorylated when cells are treated with the phorbol ester phorbol 12-myristate 13-acetate, a known inducer of protein ectodomain shedding. This work implies that removal of the inhibitory pro-domain of MDC9 by a furin-type pro-protein convertase in the secretory pathway is a prerequisite for protease activity. After pro-domain removal, additional steps, such as protein kinase C-dependent phosphorylation, may be involved in regulating the catalytic activity of MDC9, which is likely to target different substrates than the related TNF-alpha-convertase.

ADAM Proteins↗
PubMed1987

Inhibition of Spinach Leaf NADPH(NADH)-Glyoxylate Reductase by Acetohydroxamate, Aminooxyacetate, and Glycidate.

Acetohydroxamate (AHA) and aminooxyacetate (AOA) were found to be potent inhibitors of purified NADPH(NADH)-dependent glyoxylate reductase from spinach (Spinacia oleracea) leaves. AHA was a noncompetitive (ro mixed) inhibitor of the NADPH-dependent activity of the reductase with a K(i) of 0.33 millimolar. With NADH serving as a cofactor, AHA preferentially bound to the same form of the enzyme as glyoxylate, exhibiting a K(i) of 0.31 millimolar. Glycine hydroxamate and l-glutamic acid-gamma-hydroxamate were also inhibitory, but to a lesser extent than AHA. Inhibition by AOA (K(i) of 1.8 millimolar) was enhanced by increased concentrations of glyoxylate, indicating that the inhibitor preferentially reacted with the glyoxylate-bound form of the enzyme. Glycidate, an effector of glycolate metabolism in leaves, was found to be a much weaker inhibitor of the enzyme with a K(i) of 21 millimolar. While the inhibition by both AHA and AOA was fully reversible, glycidate acted as a tight-binding inhibitor. These findings are discussed with respect to the use of AHA, AOA, and glycidate as inhibitors of photorespiratory carbon metabolism in leaves. Caution is recommended in the use of these inhibitors with intact tissue experiments due to their lack of specificity.

Journal Article↗
PubMed1975

Evidence for common binding sites for ferrichrome compounds and bacteriophage phi 80 in the cell envelope of Escherichia coli.

Mutants ton A and ton B of Escherichia coli K12, known to be resistant to bacteriophage phi80, were found to be insensitive as well to albomycin, an analogue of the specific siderochrome ferrichrome. Ferrichrome at micromolar concentrations strongly inhibited plaque production by phi80. Preincubation with ferrichrome did not inactivate the phage. At a concentration at which ferrichrome allowed 90% inhibition of plaque formation, the chromium analogue of ferrichrome showed no detectable activity. Similarly, ethylenediaminetetraacetic acid, ferrichrome A, and certain siderochromes structurally distinct from ferrichrome, such as ferrioxamine B, schizokinen, citrate, and enterobactin, did not show detectable inhibitory activity. However, rhodotorulic acid showed moderate activity. A host range mutant of phi80, phi80h, was also inhibited by ferrichrome, as was a hybrid of phage lambda possessing the host range of phi80. However, phage lambdacI- and a hybrid of phi80 possessing the host range of lambda were not affected by ferrichrome. Finally, ferrichrome and chromic deferriferrichrome were shown to inhibit adsorption of phi80 to sensitive cells, ferrichrome giving 50% inhibition of adsorption at a minimal concentration of 8 nM. It is suggested that a component of the ferrichrome uptake system may reside in the outer membrane of E. coli K12 and may also function as a component of the receptor site for bacteriophage phi80, and that ferrichrome inhibition of the phage represents a competition for this common site.

Adsorption↗
PubMedDate not supplied

[Features of oxidation of reserve lipids in liver mitochondria during starvation: the role of non-heme iron and free radical fatty acid oxidation].

Structure-functional transformation fo respiratory chain, developed in response to 72 hrs starvation involved the following alterations: 1. in mitochondria of starved rats distinct increase ws observed in sensitivity of palmitocarnitine oxidation, but not of succinate, to benzhydroxamic acid--chelator of non-heme iron; 2. as compared with controls accumulation of malonic dialdehyde was completely inhibited in liver mitochondria of the starved rats in presence of benzhydroxamic acid; 3. considerable alteration in sensitivity of respiration and ATP synthesis to the effect of some inhibitors was found in liver mitochondria of starved rats. Results of the experiment are discussed on the basis of the assumption that existence of additional pathways of ATP synthesis, essential for adaptation-restoration processes, is biologically important under conditions of stress.

Adenosine Triphosphate↗