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Biomedical subjects

J A Olson

Publications and source records attributed to J A Olson.

At least 19 recordsLinked to original sources
PubMed1992

Synthetic modification of a novel microbial ionophore: exploration of anticoccidial structure-activity relationships.

While fermentation-derived polyether ionophores such as salinomycin are the dominant class of anticoccidial feed additives, there is little information concerning the structural features which confer optimal potency/efficacy in this important series. The recently discovered microbial polyether 1a, featuring potent, broad-spectrum anticoccidial activity, was employed as a template to explore structure-activity relationships. A number of single-step synthetic modifications targeted structural changes in both the lipophilic carbon backbone and the ion-binding cavity of 1a. Although previous semisynthetic transformations among the polyether ionophores almost always resulted in a substantial loss of anticoccidial activity, we obtained several analogues, altered on the periphery of the ionophore-ion complex, which retain good potency and efficacy. Monoglycone 7 (semduramicin sodium) has the most impressive anticoccidial profile of this series, and is undergoing further biological testing under field conditions.

Animals↗
PubMed1992

Retinoyl beta-glucuronide: lack of binding to receptor proteins of retinoic acid as related to biological activity.

Retinoid beta-glucuronides have emerged as biologically active, water-soluble, natural retinoids with relatively few toxic and teratogenic effects. The mechanism of action of these glucuronides in the control of epithelial differentiation, growth, and tumorigenesis is unknown. Since retinoyl beta-glucuronide (RAG) contains a free carboxyl group, we studied the interactions of RAG with cellular retinoic acid-binding protein (CRABP) and nuclear receptors of retinoic acid (RARs), the possible mediators of the biological action of retinoic acid (RA). RAG did not exhibit any significant affinity to bind either CRABP or RARs. During 24- and 48-hr incubations of RAG in chick cytosol, detectable amounts of RA were generated which interacted with the RA receptors. In chick skin, the biological activity of RAG may be due to this slowly released RA. Other possible modes of action of RAG are suggested.

Animals↗
PubMed1992

Metabolism of carotenoid analogs in humans.

Single oral doses (100 mumol) in peanut oil of 4,4'-dimethoxy-beta-carotene, ethyl beta-apo-8'-carotenoate, and beta-apo-8'-carotenal were administered to healthy adult male subjects (n = 4-6). Blood samples were taken frequently thereafter, and serum carotenoids and retinoids were analyzed by HPLC. The metabolism of the three analogs was very different; 4,4'-dimethoxy-beta-carotene was oxidized at the 4 and 4' positions but apparently not cleaved, whereas ethyl beta-apo-8'-carotenoate was not detectably metabolized, and beta-apo-8'-carotenal was extensively converted to its corresponding acid, alcohol, and fatty acyl ester and detectably converted to retinyl ester and possibly to two shorter beta-apocarotenals. Serum concentrations of endogenous retinoids and carotenoids, except as noted above, were not affected in any case. Kinetically, the maximum serum concentrations, areas under the curve, and mean sojourn times for the three analogs differed by 50-, 270-, and 5-fold, respectively. For any given analog, however, the fractional standard deviations for these parameters were only 0.2-0.5.

Administration, Oral↗
PubMed1992

Enhancement of biological activity by conjugation reactions.

Conjugation reactions, such as the formation of sulfates, glucuronides and amino acid derivatives of biologically active compounds, are classically considered as detoxication processes. In essence, common nonpolar compounds are rendered less active by the formation of water-soluble metabolites, which then can readily be excreted in the urine. In the past decade, however, it has become clear that some natural metabolites become more active rather than less so by the formation of such conjugates. Several compounds in this special group will be considered in this article; namely, glucuronide and hydroxyphenylamide conjugates of retinoic acid, glutathione and cysteine conjugates of halogenated hydrocarbons, glucuronide conjugates of various xenobiotics and polyglutamates of folic acid and its inhibitors. The metabolism, biological activity and toxicity of the parent molecule is profoundly affected in complex ways by such reactions. Thus, the historical concept of conjugation reactions as general detoxication processes is no longer tenable.

Animals↗
PubMed1992

CP-72,588, a semisynthetic analog of the polyether ionophore UK-58,582 with increased anticoccidial potency.

We have employed semisynthesis to enhance the anticoccidial potency of a polyether ionophore. CP-72,588 is the alpha-methyl analog of the fermentation-derived polyether ionophore UK-58,852. The parent ionophore required a dose of 15 ppm to achieve anticoccidial efficacy in chickens equivalent to that of salinomycin at 60 ppm. CP-72,588 demonstrated substantially improved potency, with efficacy at 5 to 7.5 ppm. The intrinsic antimicrobial potencies of the two ionophores are similar; however, CP-72,588 was found in chicken tissues at higher levels than those of the parent ionophore when each was administered at the same dose (8 ppm). The enhanced potency of CP-72,588 may be partially due to enhanced uptake into tissues.

Animals↗
PubMed1992

In vivo expression of in vitro anticoccidial activity.

Large-scale screening has led to the identification of several experimental compounds that have very potent intrinsic activity against coccidia, but the lack of translation to in vivo efficacy has been a major hurdle in developing such leads into effective new drugs. We developed methods to explore the impact of oral availability and appropriate distribution in tissue, both of which are potentially important factors in the expression of activity in vivo. For the compounds that we examined, neither oral absorption nor distribution to the site of infection appeared to be the critical barrier to in vivo expression of intrinsic anticoccidial activity. Elucidation of the nature of additional factors that might be involved could assist greatly in the identification of useful new anticoccidial agents.

Administration, Oral↗
PubMed1992

Further investigation of anticoccidial activity of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine.

The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine exhibits potent activity against Eimeria tenella infections in chickens. Disease control was abrogated by a selective alpha 2 antagonist, which is consistent with the dependence of such activity upon binding to receptors with characteristics of the vertebrate alpha 2 adrenoceptor. Lack of significant activity against the parasite in tissue culture and our inability to detect significant binding of alpha 2 adrenergic ligands to E. tenella imply that the anticoccidial action may be an indirect effect mediated by the host. Efficacy varied, depending upon the Eimeria species, being greatest for the cecal species E. tenella and less for the intestinal species. The effects described differ substantially from previous accounts of adrenergic actions on parasitic protozoa. The evidence suggests that we have observed a new mechanism of action for antiparasitic drugs.

Adrenergic alpha-Agonists↗
PubMed1992

An unusual pagC::TnphoA mutation leads to an invasion- and virulence-defective phenotype in Salmonellae.

Two phenotypes believed to contribute to the pathogenesis of Salmonella infections are macrophage survival and invasion of epithelial cells. It was recently observed that the Salmonella macrophage survival factor PagC has significant amino acid similarity to the Yersinia invasion factor Ail. This observation raised the possibilities that macrophage survival is in part determined by the pathway of entry and that PagC confers an entry mechanism that does not trigger the microbicidal activities of the macrophage. Thus, we sought to investigate the role of PagC in invasion by examining (i) the invasion phenotype of pagC mutants and (ii) the invasion phenotype of Escherichia coli carrying pagC. A previously identified invasion-defective TnphoA insertion mutant of Salmonella enteritidis was found to have TnphoA inserted into the signal sequence-encoding region of pagC; the pagC allele from this mutant, SM5T, was designated pagC64. In contrast, Salmonella typhimurium carrying the pagC1 allele (a TnphoA insertion mutation, downstream of the region encoding the signal sequence) was not defective for invasion. Further analysis of these two pagC alleles suggested that the invasion-defective phenotype associated with pagC64 is not due to the loss of PagC function but rather is due to the synthesis of a hybrid PagC-alkaline phosphatase protein that is aberrantly localized, most likely to the inner membrane, and thus may prevent proper localization or function of a factor(s) required for efficient invasion. The observation that pagC did not confer an invasive phenotype to E. coli further suggests that PagC is not an invasion factor. A cloned pagC gene complemented the macrophage survival defect of S. typhimurium pagC1 mutants, but the cloned ail gene did not. Together these results suggest that the structural similarity between PagC and Ail may not extend to a similarity in function. Interestingly, S. enteritidis carrying the pagC64 allele that results in both an invasion defect and a macrophage survival defect was less virulent for mice infected intragastrically or intraperitoneally than was S. enteritidis carrying the pagC1 allele that results only in a macrophage survival defect.

Alkaline Phosphatase↗
PubMed1992

Fatty-acyl esters of retinol (vitamin A) in the liver of the harp seal (Phoca groenlandica), hooded seal (Cystophora cristata), and California sea lion (Zalophus californianus).

The fatty-acid composition of retinyl esters in the livers of two species of phocid seal, the harp seal (Phoca groenlandica, n = 20) and the hooded seal (Cystophora cristata, n = 15), and one species of otariid seal, the California sea lion (Zalophus californianus, n = 6), was determined. Vitamin A ranged in concentration from 4 to 1024 nmol retinol/g liver for the phocids and from 381 to 979 nmol/g liver for the otariids. In most of the livers, retinyl palmitate was not the principal ester, and the palmitate + stearate + oleate trio of retinyl esters represented less than 50% of the total. In all samples, the retinyl esters contained 20:1, 20:4, 20:5, and 22:6 in unusually large amounts. Retinyl esters tended to be richer than whole-liver lipids in 20:5 + 22:6, whereas whole-liver lipids were richer in 18:0 and 18:2. Therefore, the pool of acyl donors used for the esterification of retinol may be distinct from that used for other lipids. Birth-to-weaning changes were seen only in the harp seals. In the pups, the hepatic vitamin-A concentration increased 454%, while the proportion of 18:0 and 20:1 in the retinyl esters rose and that of 14:0 + 16:1 and 20:4 fell. Concomitantly, in their mothers, the proportion of 20:4 increased but that of 16:0 and 18:0 decreased.

Animals↗
PubMed1992

Angiotensin-II induction of plasminogen activator inhibitor-1 gene expression in astroglial cells of normotensive and spontaneously hypertensive rat brain.

Angiotensin-II (AII) stimulates plasminogen activator inhibitor-1 (PAI-1) gene transcription, translation, and protein secretion from astroglial cells derived from normotensive [Wistar-Kyoto (WKY)] rat brain, an effect mediated by AII type 1 (AT1) receptors. Since abnormal expression of the brain AII system has been demonstrated in spontaneously hypertensive (SH) rats, we investigated the regulation of PAI-1 gene expression by AII in astroglial cells from the brains of these animals. AII caused an increase in PAI-1 gene expression in SH rat astroglia in a manner similar to that observed in WKY-derived cultures. However, both the basal and AII-stimulated levels of PAI-1 mRNA in SH rat astroglia were only 20% of those observed in WKY rat astroglial cultures. Consequently, there was a significant reduction in the de novo synthesis and secretion of PAI-1 from astroglia of SH rat brain. The reduced synthesis and secretion of PAI-1 from SH rat brain astroglia was associated with lower numbers of AT1 receptors in these cells. However, the steady state levels of AT1 receptor mRNA were comparable in both WKY and SH rat astroglia. This reduction in AII-modulated PAI-1 levels in SH rat astroglia is consistent with a proposed role of these interactions in the development of hypertension in these animals.

Angiotensin II↗
PubMed1992

Antioxidants in health and disease: overview.

Molecular oxygen is an essential nutrient for higher forms of life. In addition to its normal physiological reactions, oxygen and its partially reduced forms can oxidize a variety of macromolecular and simpler compounds in cells and fluids of the body. Such oxidized and peroxidized compounds have been associated with, and may be causally related to, a variety of chronic diseases. As a protection against excessive oxidation, nature has developed a complex set of interactive antioxidant systems. Selected aspects of antioxidant actions are considered in this symposium.

Animals↗
PubMed1992

Anticoccidial efficacy of semduramicin in battery studies with laboratory isolates of coccidia.

The anticoccidial activity of semduramicin against laboratory isolates of five species of poultry Eimeria was investigated. In laboratory scale battery trials, semduramicin at 20 to 30 ppm demonstrated broad-spectrum anticoccidial efficacy equivalent to salinomycin at 60 ppm. Also, semduramicin at 25 ppm was fed to uninfected cockerels in batteries for 21 days, and growth rate and feed efficiency were found to be equivalent to birds fed salinomycin at 60 ppm. Semduramicin was well tolerated when coadministered with tiamulin. Semduramicin demonstrated the same activity whether produced by semisynthesis or by direct fermentation.

Animals↗
PubMed1992

Chemical synthesis, growth-promoting activity, and metabolism of all-trans retinyl beta-glucose in the rat.

Reaction of all-trans retinol with alpha-D-glucopyranosyl bromide tetrabenzoate in the presence of silver carbonate gave all-trans retinyl beta-glucose in good yield. Depending on the mode of administration, retinyl beta-glucose, which is soluble in water, showed 67-100% of the growth-promoting activity of retinyl acetate in vitamin A-deficient rats. In metabolic studies on vitamin A-deficient rats, retinyl beta-glucose was rapidly hydrolyzed to retinol. The possible therapeutic uses of retinyl glucose are discussed.

Animals↗
PubMed1992

Retinoid glucuronides do not interact with retinoid binding proteins.

Retinoid glucuronides have recently been described as water soluble, biologically active retinoids. In mouse mammary gland organ cultures retinoyl glucuronide, a retinoic acid counterpart, inhibited hormone induced differentiation. In this report we examined whether the effects of retinoyl and retinyl glucuronides are mediated by specific retinoid binding protein in mammary glands in organ culture. Results indicated that neither retinoyl nor retinyl glucuronide competed for cytosolic retinoic acid or retinol binding proteins respectively. These results indicate that either the effects of retinoid glucuronides are independent of retinoid binding proteins or they have to be metabolized to an active component which may in turn bind to retinoid binding protein for the glucuronide action.

Animals↗
PubMed1991

Metabolism in vivo of all-trans-[11-3H]retinoic acid after an oral dose in rats. Characterization of retinoyl beta-glucuronide in the blood and other tissues.

Soon after [11-3H]retinoic acid (RA) (1.1 x 10(8) d.p.m.) was administered orally to rats either as a large dose (115 micrograms = 0.38 mumol/rat) or mixed with unlabelled RA as a huge dose (22 mg = 73.33 mumol/rat), retinoyl beta-glucuronide (RAG) was identified and characterized as a significant metabolite in the serum and small intestine. Of the administered dose, 70% remained unchanged as retinoic acid in the stomach up to 1 h. Significant amounts of 5,6-epoxyretinoic acid, 4-hydroxyretinoic acid, esters of retinoic acid and several polar retinoids, including 4-oxoretinoic acid, were also detected in the stomach. No significant difference was observed in the nature of the retinoids found after a large or a huge dose; however, the ratio of RAG/RA was higher after a huge dose than after a large dose. Thus RAG, which is biologically active in vivo and in vitro, is formed quickly in significant amounts in tissues after a dose of RA.

Administration, Oral↗
PubMed1991

Angiotensin II induces secretion of plasminogen activator inhibitor 1 and a tissue metalloprotease inhibitor-related protein from rat brain astrocytes.

The present study investigates angiotensin (Ang) II effects on secretory protein synthesis in brain astrocytes cultured from neonatal and 21-day-old rats. Ang II-induced changes in the de novo synthesis of [35S]methionine-labeled secretory proteins were visualized using two-dimensional NaDodSO4/PAGE. Astrocytes from 21-day-old rat brain possess specific high-affinity receptors for Ang II. These cells express two Ang II-induced secretory proteins with Mr 55,000 (AISP-55K) and Mr 30,000 (AISP-30K), which were time- and dose-dependent (EC50, 1 nM). [Sar1, Ile8]Ang II (where Sar is sarcosine) inhibited Ang II-induced secretion of AISP-55K but not AISP-30K. N-terminal amino acid sequencing indicates that AISP-55K is identical to rat plasminogen activator inhibitor 1, whereas AISP-30K exhibits 72-81% identity to three closely related proteins: human tissue inhibitor of metalloproteases, a rat phorbol ester-induced protein, and the murine growth-responsive protein 16C8. Immunofluorescent staining with rat plasminogen activator inhibitor 1 antibody was induced in the majority of cells in culture after Ang II treatment of astrocytes from 21-day-old rat brains. Absence of this response to Ang II in astrocytes from neonatal rat brain provides evidence that this action of Ang II on astrocytes is developmentally regulated.

Aging↗
PubMed1991

Induction of HL-60 cell differentiation by water-soluble and nitrogen-containing conjugates of retinoic acid and retinol.

Retinoids induce the promyelocytic cell line, HL-60, to differentiate along the granulocytic pathway in vitro. A number of water-soluble and nitrogen-containing retinoids were synthesized in our laboratory [retinoyl-glucose (RAGL), retinyl-glucose (ROGL), retinoyl-adenosine (RADS), retinoyl-adenine (RAD), retinoyl-beta-glucuronide (beta RAG), and retinoyl-alpha-glucuronide (alpha RAG)]. These retinoids (10(-5) to 10(-8) M), as well as retinoic acid (RA) and retinol (ROL), were tested for their ability to induce the differentiation of HL-60 cells in vitro and to affect cell growth and viability during a 24- to 72-h incubation period. Differentiation was assessed by measuring the percentage of cells expressing the Mac-1 antigen on their cell surfaces. RA and the conjugates of RA were all quite active in inducing HL-60 cell differentiation, whereas ROL and ROGL had much less activity at equimolar concentrations. beta RAG, alpha RAG, RADS, and RAD were less toxic, whereas the glucose conjugates of retinol and retinoic acid (ROGL and RAGL) were both considerably more toxic than either RA or ROL at equimolar concentrations. All retinoids affected cell growth in a dose-dependent fashion. At 24 h, free RA or ROL was not detected in the cells after incubation with any of the retinoid conjugates.

Cell Differentiation↗