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Biomedical subjects

S M Swanson

Publications and source records attributed to S M Swanson.

18 recordsLinked to original sources
PubMed1992

Incidence of c-Ki-ras activation in N-methyl-N-nitrosourea-induced mammary carcinomas in pituitary-isografted mice.

We found previously that mouse mammary epithelial cells cultured in the presence of the mammogenic hormones progesterone and prolactin and treated with the carcinogen N-methyl-N-nitrosourea produced a high frequency of hyperplastic alveolar nodules and carcinomas with squamous metaplasia upon transplantation to syngeneic mice. The majority of these mammary transformants had an activated c-Ki-ras proto-oncogene with a specific point mutation in codon 12 (G35 to A35). To determine whether these in vitro findings parallel mammary carcinogenesis in vivo, virgin female mice were pituitary isografted to increase their circulating levels of progesterone and prolactin. The pituitary isograft results in an increase in proliferation, leading to lobulo-alveolar development and differentiation of the mammary epithelial cells. Five weeks after pituitary isografting, the mice were treated with a single injection of N-methyl-N-nitrosourea (50 micrograms/g body weight). Greater than 90% of the N-methyl-N-nitrosourea-treated mice developed mammary carcinomas between 3 and 7 months after treatment. The majority (75%) of the carcinomas had histopathology identical to that of tumors induced in vitro in the presence of progesterone and prolactin. A number of the mammary cancers (17%) induced in pituitary-isografted mice also had the identical point mutation in the c-Ki-ras proto-oncogene found in the in vitro studies. These results suggest that the hormonal milieu around the time of carcinogen exposure affects not only the incidence and phenotype of the mammary transformants but also the molecular events associated with mammary carcinogenesis.

Animals↗
PubMed1990

Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation.

Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the O gamma-H group (Ser 195) and nitrogen N, (His 57). A cluster of ordered water molecules effectively competes with the H-O gamma group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.

Animals↗
PubMed1990

Simulations of dynamical properties of a Michaelis complex: porcine pancreatic elastase and the hexapeptide, Thr-Pro-n Val-Leu-Tyr-Thr.

Molecular dynamic simulations (30ps) of the Michaelis complex of hexapeptide (Thr-Pro-nVal-Leu-Tyr-Thr) bound to porcine pancreatic elastase (PPE) hydrated by about 2000 water molecules have been performed using the AMBER 3.0 program package. Dynamical properties of the conformation of the active site have been examined. A comparison with previously reported simulations of native PPE shows that after the substrate is bound, the catalytically crucial H-bond between O gamma-H group of (Ser 195) and nitrogen N epsilon (His 57) is more readily formed. These results show, however, that the H-bond does not adopt the most favorable conformation. The O gamma-H group of Ser 195 has a statistical preference for an attractive interaction with the O = C carbonyl (Ser 214) rather than the nitrogen N epsilon (His 57).

Amino Acid Sequence↗
PubMed1989

Animation: a useful tool for protein molecular dynamicists, applied to hydrogen bonds in the active site of elastase.

Massive amounts of coordinate data result from molecular dynamics calculations. The animation program MDKINO is a simple but powerful tool for previewing or reviewing the results. In recent simulations of elastase, we have examined hydrogen bonding patterns, conformational changes involving shifts in ring positions and rotations of amino acid side chains, electric fields in interatomic space, and electric forces acting on chosen nuclei. Animation is also useful for checking on the stability of calculations in progress. Simple programming techniques achieve acceptable levels of animation with readily available hardware (PS330 or PS390 display with a serial interface to a laboratory VAX). In about half an hour, it is possible to make and watch a color stereo "movie" of a selected subsystem of a simulation (up to 1,000 frames of about 100 atoms each).

Binding Sites↗
PubMed1988

Evaluation of the cytotoxic potential of catechols and quinones structurally related to butylated hydroxyanisole.

The cytotoxicity of 2- and 3-butylated hydroxyanisole (BHA) and 18 related aromatic compounds has been determined employing cultured P388 and KB cells. The phenolic compounds, 3-BHA and 2-BHA, had moderately low cytotoxic activity. Their corresponding catechols had ED50 values that were much lower than those of the parent compounds. This substantial increase in the cytotoxic activity is attributed to the presence of the catechol group, which is known to undergo one-electron oxidation readily to give the corresponding semiquinone radical. Other related catechols had similar cytotoxic activity. In general, derivatization of the catechol functionality resulted in a decrease of the cytotoxic potential of the compounds. Monoacetylation or monomethylation of the catechols gave products that were less potent cytotoxic agents than the parent compounds. Further loss of activity was observed when both hydroxy groups of the catechol function were blocked. Substitution of a methoxy group in place of a hydrogen atom in these compounds resulted in a significant increase of cytotoxicity, whereas the replacement of a methoxy group with a methyl group reduced the cytotoxicity. The catechols and quinones derived from 2-BHA were more active when compared with those derived from 3-BHA. The t-butyl group adjacent to the catechol or quinone moiety in the 3-BHA derivatives appeared to exert a significant steric effect toward the cytotoxic potential of these compounds. These results suggest the potential use of o-quinones and catechols as cytotoxic and antitumor agents.

Butylated Hydroxyanisole↗
PubMed1988

C1q binding by a high affinity anti-fluorescein murine monoclonal IgM antibody and monomeric subunits.

Comparative interactions of purified rabbit C1q with 18-2-3, a high affinity (2-3 X 10(10) M-1) anti-fluorescein (anti-F1) murine monoclonal IgM antibody (pentamer) and constitutive monomeric subunits (IgMs) were studied. Using a solid phase radioimmunoassay (SPRIA), based on immobilized polyvalent antigen, it was shown that the mechanism of C1q binding to IgM was characteristically multiphasic while IgMs yielded monophasic binding curves. The latter compared qualitatively and quantitatively with a monoclonal IgG2a anti-fluorescein antibody with the same intrinsic affinity of 2-3 X 10(10) M-1. C1q binding efficiency to antibodies was significantly enhanced when the immunoglobulins interacted with immobilized multivalent antigen. Monoclonal IgM antibody bind identically to six F1-carrier protein conjugates independent of epitope (F1) density. In contrast, the C1q-antibody interaction binding was dependent upon epitope density. An average distance between F1 epitopes of 80 A was optimal for C1q binding by IgM. At low concn of IgM, when fluorescein was bound by antigen-binding sites on adjacent subunits of an intact pentamer, C1q appeared to bind IgM intramolecularly.

Animals↗
PubMed1988

Evaluation of the mutagenic and cytostatic potential of aristolochic acid (3,4-methylenedioxy-8-methoxy-10-nitrophenanthrene-1-carboxylic acid) and several of its derivatives.

Aristolochic acid (1), a constituent of Aristolochia species, has been used for medicinal purposes since the Graeco-Roman period. Following the observation that the compound was mutagenic and carcinogenic, it was removed from pharmaceutical products. Consistent with previous reports, we have found that 1 serves as a direct-acting mutagen in Salmonella typhimurium strains TA100, TA102, TA1537 and TM677, but was not active in the nitroreductase-deficient strains TA98NR and TA100NR. However, aristolic acid (2), a compound that differs in structure only by the absence of the nitro group, was also found to be a direct-acting mutagen in Salmonella strains TA98, TA100, TA102, TA1537, and TM677, as well as strains TA98NR and TA100NR. Both compounds (1 and 2) were active mutagens when evaluated with cultured Chinese hamster ovary cells. Thus, in contrast to previous suggestions, the nitro group at position 10 is not required to induce a mutagenic response. Also, a series of structural relatives (the methyl esters of 1 and 2 (3 and 4, respectively), aristolochic acid-D (5), aristolactam (6), aristolactam A-II (7), and aristolactam-N-beta-D-glucoside (8)) were evaluated for mutagenic potential with Salmonella typhimurium strain TM677 and found to be inactive. Since compounds 3 and 4 were found to be active mutagens with Salmonella typhimurium strains TA98, TA100, TA102 and TA1537 (sufficient quantities of compounds 5-8 were not available for testing), differential sensitivity of the tester strains unrelated to mutagenic potential is suggested. Further, compounds 1, 2, and 6-8 were evaluated for potential to inhibit growth with cultured KB or P388 cells. P388 cells were substantially more sensitive, and compound 1 was the most active of the materials tested (ED5 = 0.58 microM). Compound 6 also demonstrated appreciable activity (ED50 = 4.2 microM), as did compound 8 (ED50 = 6.0 microM). It therefore appears that phenanthrene-ring substituents, in addition to the nitro group at position 10, serve important roles for biological potential. In considering the carcinogenic event induced by aristolochic acid, these functionalities should also be taken into account.

Animals↗
PubMed1986

Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid (steviol) and several structurally-related derivatives and evaluation of potential to induce glutathione S-transferase in mice.

Stevioside is a sweet-tasting diterpene glycoside that is derived from Stevia rebaudiana (Bertoni) Bertoni (Compositae). It is used commercially in Japan and other parts of the world as a sucrose substitute. Whereas stevioside demonstrates no mutagenic activity in a variety of test systems, the aglycone, steviol (13-hydroxy-ent-kaurenoic acid), is mutagenic toward Salmonella typhimurium strain TM677 in the presence of a metabolic activating system derived from the liver of Aroclor 1254-pretreated rats. The required activating component is localized in the microsomal fraction of rat liver, suggestive of a cytochrome P-450-mediated reaction. Partially purified epoxide hydrolase does not inhibit steviol-induced mutagenicity, indicating that an active metabolite is not an epoxide that serves as a substrate for this enzyme preparation. The 13-hydroxy group of steviol is required for the expression of mutagenicity since ent-kaurenoic acid is nonmutagenic, and acetylation of steviol at this position negates mutagenicity. Similarly, diterpenes bearing a strong structural resemblance to steviol, cafestol and kahweol, were found to demonstrate no mutagenic activity toward Salmonella typhimurium TM677, as were their respective acetates and palmitic acid esters. Conversely, 19-O-beta-D-glucopyranosyl steviol, a potential hydrolysis product of stevioside, is mutagenic and bactericidal in the presence of a metabolic activating system. Additionally, in contrast to the nonmutagenic diterpenes cafestol and kahweol that are effective as inducers of glutathione S-transferase activity, evaluation by administration to mice proved steviol, isosteviol and various steviol glycosides to be inactive in this process. Thus, structural differences among these naturally occurring and semi-synthetic diterpenes appear to impart major differences in biological activity that may relate to human health upon dietary ingestion.

Animals↗
PubMed1985

Metabolically activated steviol, the aglycone of stevioside, is mutagenic.

Stevioside, a constituent of Stevia rebaudiana, is commonly used as a noncaloric sugar substitute in Japan. Consistent with reports in the literature, we have found that stevioside is not mutagenic as judged by utilization of Salmonella typhimurium strain TM677, either in the presence or in the absence of a metabolic activating system. Similar negative results were obtained with several structurally related sweet-tasting glycosides. However, steviol, the aglycone of stevioside, was found to be highly mutagenic when evaluated in the presence of a 9000 X g supernatant fraction derived from the livers of Aroclor 1254-pretreated rats. Expression of mutagenic activity was dependent on both pretreatment of the rats with Aroclor 1254 and addition of NADPH; unmetabolized steviol was not active. The structurally related species, isosteviol, was not active regardless of metabolic activation. Similarly, chemical reduction of the unsaturated bond linking the carbon-16 and -17 positions of steviol resulted in the generation of two isomeric products, dihydrosteviol A and B, that were not mutagenic. In addition, ent-kaurenoic acid was found to be inactive. It is therefore clear that a metabolite of an integral component of stevioside is mutagenic; structural features of requisite importance for the expression of mutagenic activity include a hydroxy group at position 13 and an unsaturated bond joining the carbon atoms at positions 16 and 17. A potential metabolite of steviol, steviol-16 alpha,17-epoxide, was synthesized chemically and found to be ineffective as a direct-acting mutagen. Thus, although stevioside itself appears innocuous, it would seem prudent to expeditiously and unequivocally establish the human metabolic disposition of this substance.

Animals↗
PubMed1985

Food-chain transfer of U-series radionuclides in a northern Saskatchewan aquatic system.

Levels of TotalU, 226Ra, and 210Pb in water, sediments, insects and fish were measured in a stream and a lake affected by U mill effluents and in three uncontaminated systems (one creek and two lakes). Radionuclide levels were significantly elevated in water, sediments and biota at contaminated sites. Radionuclide concentration declined with each successive trophic level due primarily to very low assimilation efficiency. Fish radionuclide concentrations varied with season but did not vary with age or year of sampling. Distribution coefficients were high; therefore, a large proportion of radionuclides entering the systems go to the solid phase. Organisms feeding on or near sediments had higher radionuclide levels than pelagic species. There is a potential for long-term cycling of radionuclides from sediments through food chains due to low flux and sedimentation rates. With the exception of water----insects and water----fish all transfer coefficients (TC) were low, usually less than one. Control TCs were greater than TCs in contaminated areas. Radium-226 and 210Pb TCs declined dramatically at the insect-fish level. Uranium uptake from water by insects and fish was much less than 226Ra or 210Pb uptake. Uptake from sediments was similar for all nuclides in insects but 210Pb sediment-fish TCs differed from 226Ra or U TCs. The critical pathway in the contaminated area was sediments----insects----forage fish----whitefish----man. Estimated internal dose rates to large fish in the contaminated area were 1-2 rad/y. Dose to humans from consumption of one fish serving per week for 1 y was 2% of the International Commission on Radiological Protection (ICRP) annual limit for the general public.

Animals↗
PubMed1984

Evaluation of the mutagenic potential of endod (Phytolacca dodecandra), a molluscicide of potential value for the control of schistosomiasis.

Extracts of the fruit of Phytolacca dodecandra (endod) demonstrate molluscicidal and other biological activities. Since this plant is indigenous to some countries where schistosomiasis is a common problem, it has been proposed that it may be socioeconomically feasible to employ endod as an aid in the control of this disease through its use to control the snail vector. As an initial step in the safety assessment of this substance, its mutagenic potential was determined utilizing Salmonella typhimurium strain TM677. The seeds and fruit of Phytolacca americana, also molluscicidal, were additionally evaluated for mutagenic potential. Using a variety of conditions, no mutagenic activity could be demonstrated for any of the extracts tested. Thus, subject to the results of future safety assessment, endod remains a viable candidate as a useful molluscicide.

Biotransformation↗
PubMed1983

Levels of 226Ra, 210Pb and total U in fish near a Saskatchewan uranium mine and mill.

Radionuclide levels in fish from the Beaverlodge Lake area, Saskatchewan, Canada, varied significantly among lakes, species and tissues, but did not vary with fish sex or age. Fish from lakes affected by an operating uranium mine and mill had radionuclide levels one to two orders of magnitude above levels in fish from an uncontaminated control lake. Concentrations were greatest in white suckers, intermediate in lake whitefish, and low in lake trout. Skin and bone contained the highest radionuclide levels; levels in flesh were much lower. The mean ash-weight concentration of 226Ra in non-control, eviscerated, whole fish was 9.3, 1.8 and 0.8 pCi X g-1 in white suckers, lake whitefish and lake trout respectively. Mean 210Pb levels for those species were 4.0, 1.4 and 0.5 pCi X g-1, while U content was 96.8, 28.2 and 5.8 micrograms X g-1, respectively. Radium-226 content in forage fish ranged from 9.7-70 pCi X g-1. Lead-210 levels ranged from 3.9-55.0 pCi X g-1, while U levels ranged from 15-119 micrograms X g-1. Bioconcentration factors varied among sites, species and tissues. The primary radionuclide transfer pathway appears to be via sediments, either through direct contact or through food organisms. Bottom-feeding species had the highest radionuclide levels while piscivorous fish had the lowest levels. The internal dose rate to non-control fish are comparatively low; any effects are likely to occur at the genetic level.

Animals↗
PubMed1979

Reproducibility of ejection-fraction determinations by equilibrium radionuclide angiography in response to supine bicycle exercise: concise communication.

Sixteen patients with stable, chronic coronary artery disease were studied twice within and average of 15 days to evaluate the reproducibility of ejection fraction (EF) determined by equilibrium radionuclide angiography (EQ) at rest, during supine bicycle exercise (ex), and in the recovery period (rec). Following injection of 20--25 mCi of Tc-99m-tagged human serum albumin, data were analyzed for 2-min periods at rest, during several stages of exercise (submax, max), and during recovery (rec1 = minutes 2 + 3, rec2 = minutes 9 + 10). Each patient reached similar (heart rate) X (blood pressure) products in the two studies: 21280 +/- 5200 compared with 20390 +/- 4140 mmHg/min. Mean EFs for the first and second studies were: at rest (53.0 +/- 10.8)%, 52.5 +/- 10.4)% (r = 0.95; submax ex (51.4 +/- 12.0)%, (52.1 +/- 12.8)%, (r = 0.91); max ex (50.6 +/- 12.6)%, (51.6 +/- 12.9)% (r = 0.97); rec1 (62.7 +/- 11.6)%, (62.4 +/- 12.2)% (r = 0.95); rec2 (55.5 %/- 10.8)%, (57.2 +/- 11.7)% (r = 0.91). In stable patients, the reproducibility of EF determined by EQ is excellent during rest, supine bicycle exercise, and recovery from exercise.

Adult↗
PubMedDate not supplied

A rapid and sensitive bioassay involving cultured rat glioma cells to screen for substances capable of elevating intracellular cyclic AMP concentration.

Cultured rat glioma (ASK) cells are morphologically converted from a spindle to an astrocyte form when treated with dibutyryl cAMP. This morphologic transformation is discernible by light microscopy and can be visually quantitated. As described herein, dose-dependent astrocyte generation was demonstrated by treatment of confluent monolayers with forskolin [1], a compound known to activate adenylate cyclase, and the potency of four forskolin derivatives was found to correlate with previously established biologic potential. Neither a crude ginseng extract nor purified ginsenosides were active in the process, but supplementation of the otherwise inactive ginseng extract with 1 demonstrated 50% of the cells were morphologically converted to the astrocyte form at a concentration of approximately 0.0008%. Retinoic acid was also active in this test system; the morphologic transformation was reversed on treatment with colchicine, and intracellular cAMP concentration was elevated approximately 10-fold. Evaluation of 15 retinoids established a general correlation between the activity in this system and other systems reported in the literature. Thus, the astrocyte formation assay appears to provide several advantages that make it attractive as a screen for the detection or evaluation of substances capable of elevating intracellular cAMP concentration. In addition to technical ease, the procedure is rapid, sensitive, and relatively inexpensive.

Animals↗
PubMedDate not supplied

Antimicrobial and cytotoxic activity of rottlerin-type compounds from Hypericum drummondii.

Hexane extracts of Hypericum drummondii showed significant activity against the Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis, and the acid-fast bacterium Mycobacterium smegmatis in an agar well diffusion assay. Employing bioassay-directed fractionation procedures, four new rottlerin-type compounds (drummondins A, B, C[1-3], and F [4]) were isolated and identified by spectral and physical characterization. The antimicrobial activity of these compounds was comparable to or greater than that demonstrated by streptomycin and generally correlated with cytotoxic activity determined with cultured P-388, KB, or human cancer cell lines (breast, colon, lung, melanoma). No cell-type selectivity was observed. In addition, two known compounds, albaspidins A-A [5] and P-P [6], were isolated and structured characterized. Neither demonstrated appreciable antimicrobial or cytotoxic activity.

Anti-Bacterial Agents↗