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Biomedical subjects

E Lee

Publications and source records attributed to E Lee.

At least 163 records · Page 9Linked to original sources
PubMed1999

Anti-tumor-promoting activities of selected pungent phenolic substances present in ginger.

Ginger (Zingiber officinale Roscoe, Zingiberaceae) has been widely used as a dietary spice, as well as in traditional oriental medicine. The rhizome of ginger contains pungent vanillyl ketones, including [6]-gingerol and [6]-paradol, and has been reported to possess a strong anti-inflammatory activity. These pungent substances have a vanilloid structure found in other chemopreventive phytochemicals, including curcumin. In our study, we found anti-tumor-promoting properties of [6]-gingerol and [6]-paradol. Thus, topical application of [6]-gingerol or [6]-paradol 30 min prior to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) attenuated the skin papillomagenesis initiated by 7,12-dimethylbenz[a]anthracene in female ICR mice. These substances also significantly inhibited the tumor-promoter-stimulated inflammation, TNF-alpha production, and activation of epidermal ornithine decarboxylase in mice. In another study, [6]-gingerol and [6]-paradol suppressed the superoxide production stimulated by TPA in differentiated HL-60 cells. Taken together, these findings suggest that pungent vanilloids found in ginger possess potential chemopreventive activities.

Animals↗
PubMed1998

Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol.

[6]-Gingerol, a major pungent ingredient found in the rhizome of ginger, has been reported to possess a strong antiinflammatory activity, which is considered to be closely associated with its cancer chemopreventive potential. [6]-Paradol, another pungent phenolic substance found in ginger and other Zingiberaceae plants, also has a vanilloid structure found in other chemopreventive phytochemicals including curcumin. In the present study, [6]-gingerol and [6]-paradol were found to exert inhibitory effects on the viability and DNA synthesis of human promyelocytic leukemia (HL-60) cells. The cytotoxic and antiproliferative effects of both compounds were associated with apoptotic cell death. The above results suggest that [6]-gingerol and [6]-paradol possess potential cytotoxic/cytostatic activities.

Anticarcinogenic Agents↗
PubMed1998

Life without white fat: a transgenic mouse.

We have generated a transgenic mouse with no white fat tissue throughout life. These mice express a dominant-negative protein, termed A-ZIP/F, under the control of the adipose-specific aP2 enhancer/promoter. This protein prevents the DNA binding of B-ZIP transcription factors of both the C/EBP and Jun families. The transgenic mice (named A-ZIP/F-1) have no white adipose tissue and dramatically reduced amounts of brown adipose tissue, which is inactive. They are initially growth delayed, but by week 12, surpass their littermates in weight. The mice eat, drink, and urinate copiously, have decreased fecundity, premature death, and frequently die after anesthesia. The physiological consequences of having no white fat tissue are profound. The liver is engorged with lipid, and the internal organs are enlarged. The mice are diabetic, with reduced leptin (20-fold) and elevated serum glucose (3-fold), insulin (50- to 400-fold), free fatty acids (2-fold), and triglycerides (3- to 5-fold). The A-ZIP/F-1 phenotype suggests a mouse model for the human disease lipoatrophic diabetes (Seip-Berardinelli syndrome), indicating that the lack of fat can cause diabetes. The myriad of consequences of having no fat throughout development can be addressed with this model.

Adipose Tissue↗
PubMed1998

Human lymphocyte heme oxygenase 1 as a response biomarker to inorganic arsenic.

We propose the use of human lymphocyte heme oxygenase 1 (HO1) as a biomarker of response to environmental arsenic exposure. We report the induction of HO1 in human lymphoblastoid cells (LBs) by arsenite in a dose-related manner. HO1 was identified by SDS-PAGE from its molecular weight and from its detection by Western blotting with anti-HO1. HO1 levels in LBs treated with arsenite increased by de novo synthesis as demonstrated by incorporation of 35S-methionine and by inhibition of HO1 synthesis by actinomycin D. The amount of HO1 in LBs was estimated by quantifying Western blots. HO1 was also induced by 10 microM cadmium or mercuric chloride. We suggest that circulating lymphocyte HO1 levels may be useful in assessing the biological activity of arsenic exposure in vivo under properly controlled conditions of simultaneous urinalysis for arsenic, cadmium, and mercury.

Arsenic↗
PubMed1998

Electrophoretic Mobility of a Sphere in a Spherical Cavity.

The electrophoretic behavior of a spherical particle in a spherical cavity is analyzed theoretically, taking the effect of double layer polarization into account. We show that for the case where the particle is positively charged and the cavity uncharged if the surface potential of particle is high, the variation of the mobility of the particle as a function of kappaa has a minimum, kappa and a being respectively the reciprocal Debye length and particle radius. This minimum does not appear if the effect of double layer polarization is neglected. The variation of the mobility as a function of kappaa has a minimum for a medium value of lambda (= particle radius/cavity radius); it becomes negligible if lambda is either small or large. In the case where the particle is uncharged and the cavity positively charged, if the surface potential is high, the variation of mobility as a function of kappaa has a maximum; if it is low, the mobility increases monotonically with kappaa. Here, the mobility is mainly determined by the drag force, rather than by the electric force, acting on the particle as in the case where the particle is positively charged and the cavity uncharged. If both the particle and the cavity are charged, the electrophoretic behavior of the particle can be deduced from the results of the above two cases. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II.

We have used gene targeting to create a mouse model of glycogen storage disease type II, a disease in which distinct clinical phenotypes present at different ages. As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice have markedly reduced mobility and strength. They grow normally, however, reach adulthood, remain fertile, and, as in the human adult disease, older mice accumulate glycogen in the diaphragm. By 8-9 months of age animals develop obvious muscle wasting and a weak, waddling gait. This model, therefore, recapitulates critical features of both the infantile and the adult forms of the disease at a pace suitable for the evaluation of enzyme or gene replacement. In contrast, in a second model, mutant mice with deletion of exon 6 (Delta6/Delta6), like the recently published acid alpha-glucosidase knockout with disruption of exon 13 (Bijvoet, A. G., van de Kamp, E. H., Kroos, M., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., and van der Ploeg, A. T. (1998) Hum. Mol. Genet. 7, 53-62), have unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathological changes. The genetic background of the mouse strains appears to contribute to the differences among the three models.

Alleles↗
PubMed1998

Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene.

Albright hereditary osteodystrophy (AHO), an autosomal dominant disorder characterized by short stature, obesity, and skeletal defects, is associated with heterozygous inactivating mutations of GNAS1, the gene encoding the heterotrimeric G protein alpha-subunit (Gsalpha) that couples multiple receptors to the stimulation of adenylyl cyclase. It has remained unclear why only some AHO patients present with multihormone resistance and why AHO patients demonstrate resistance to some hormones [e.g., parathyroid hormone (PTH)] but not to others (e.g., vasopressin), even though all activate adenylyl cyclase. We generated mice with a null allele of the mouse homolog Gnas. Homozygous Gs deficiency is embryonically lethal. Heterozygotes with maternal (m-/+) and paternal (+/p-) inheritance of the Gnas null allele have distinct phenotypes, suggesting that Gnas is an imprinted gene. PTH resistance is present in m-/+, but not +/p-, mice. Gsalpha expression in the renal cortex (the site of PTH action) is markedly reduced in m-/+ but not in +/p- mice, demonstrating that the Gnas paternal allele is imprinted in this tissue. Gnas is also imprinted in brown and white adipose tissue. The maximal physiological response to vasopressin (urinary concentrating ability) is normal in both m-/+ and +/p- mice and Gnas is not imprinted in the renal inner medulla (the site of vasopressin action). Tissue-specific imprinting of Gnas is likely the mechanism for variable and tissue-specific hormone resistance in these mice and a similar mechanism might explain the variable phenotype in AHO.

Alleles↗
PubMed1998

Chemoprotective properties of some pungent ingredients present in red pepper and ginger.

There has been a substantial body of data, supporting that dietary factors have a profound impact on prevention as well as etiology of human cancer. Capsaicin has been tested by many investigators for its effects on experimental carcinogenesis and mutagenesis. Data in the literature indicate that capsaicin has dual effects on carcinogenic and mutagenic processes. At present, there is no solid evidence that hot red and chili peppers or their principal pungent ingredient capsaicin are carcinogenic in humans although results of early investigations with experimental animals exhibit the moderate tumorigenicity of this compound. In contrast, recent studies reveal substantial antigenotoxic and anticarcinogenic effects of capsaicin, suggesting this compound as another important dietary phytochemical with a potential chemopreventive activity. Some pungent constituents present in ginger and other zingiberaceous plants have potent antioxidant and anti-inflammatory effects, and some of them exhibit anti-tumor promotional activity in experimental carcinogenesis.

Anticarcinogenic Agents↗
PubMed1998

Assessment of covariate effects in Aalen's additive hazard model.

We study the properties of test statistics for a covariate effect in Aalen's additive hazard model and propose several new test statistics. The proposed statistics are derived by using the weights from linear rank statistics for comparing two survival curves. We compare these statistics with the two statistics proposed by Aalen using Monte Carlo simulations. Several different survival configurations are considered in the simulation study: proportional hazards; crossing hazards; hazard differences early in time, and hazard differences for large survival times. Of the proposed test statistics, one is superior for detecting hazard differences for large survival times and another is superior for detecting early hazard differences and crossing hazards.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Use of a fusion protein between GFP and an actin-binding domain to visualize transient filamentous-actin structures.

Many important processes in eukaryotic cells involve changes in the quantity, location and the organization of actin filaments [1] [2] [3]. We have been able to visualize these changes in live cells using a fusion protein (GFP-ABD) comprising the green fluorescent protein (GFP) of Aequorea victoria and the 25 kDa highly conserved actin-binding domain (ABD) from the amino terminus of the actin cross-linking protein ABP-120 [4]. In live cells of the soil amoeba Dictyostelium that were expressing GFP-ABD, the three-dimensional architecture of the actin cortex was clearly visualized. The pattern of GFP-ABD fluorescence in these cells coincided with that of rhodamine-phalloidin, indicating that GFP-ABD specifically binds filamentous (F) actin. On the ventral surface of non-polarized vegetative cells, a broad ring of F actin periodically assembled and contracted, whereas in polarized cells there were transient punctate F-actin structures; cells cycled between the polarized and non-polarized morphologies. During the formation of pseudopods, an increase in fluorescence intensity coincided with the initial outward deformation of the membrane. This is consistent with the models of pseudopod extension that predict an increase in the local density of actin filaments. In conclusion, GFP-ABD specifically binds F actin and allows the visualization of F-actin dynamics and cellular behavior simultaneously.

Actins↗
PubMed1998

Formation of F-actin aggregates in cells treated with actin stabilizing drugs.

We have electroporated Dictyostelium amoebae with fluorescent phalloidin in order to visualize the localization and behavior of F-actin filaments in living cells. Immediately after electroporation with phalloidin, cells became round and showed bright staining in the cortical region. Over time, the cortical staining disappeared and was replaced by a large aggregate of actin filaments. The aggregates were predominantly localized to the apical posterior of actively moving cells and in the middle of dividing cells or stationary AX4 cells. Mutants lacking myosin II or ABP-120 also formed actin aggregates; however, the rate of formation of aggregates was slower in myosin II mutant cells. In order to investigate this phenomenon further, we have used jasplakinolide, a membrane-permeable drug that also stabilizes F-actin filaments. Cells treated with jasplakinolide formed actin aggregates in a concentration-dependent manner. Drug treatment led to an increase in the proportion of actin associated with the cytoskeleton. Jasplakinolide-treated cells were still motile; however, their rate of movement was less than that of untreated cells. Cytochalasin B and nocodazole had inhibitory effects on aggregate formation, while azide blocked the process completely. We hypothesize that aggregates are formed from the cortical flow of F-actin filaments. These filaments would normally be depolymerized but are artificially stabilized by phalloidin or jasplakinolide binding. The localization of the aggregate is likely to be an indication of the direction of cortical flow.

Actins↗
PubMed1998

Inhibition of immediate type allergic reactions by the aqueous extract of Kum-Hwang-San.

We studied the effect of aqueous extract of Kum-Hwang-San (KHS) on mast cell-mediated immediate type allergic reactions. KHS (1-100 microg/site) inhibited concentration-dependently mast cell-dependent ear swelling response induced by compound 48/80 (200 microg/site) in mice by both topical and intradermal application. KHS (0.1-100 microg/site) inhibited concentration-dependently passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) IgE in rats by both topical and intradermal application. KHS also inhibited concentration-dependently the histamine release from the rat peritoneal mast cells (RPMC) by compound 48/80 and anti-DNP IgE. Moreover, KHS had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-alpha (TNF-alpha) secretion from RPMC. These results indicate that KHS inhibits immediate type allergic reactions by inhibition of histamine release and TNF-alpha secretion from mast cells in vivo and in vitro.

Animals↗
PubMed1998

Stability of alkoxycarbonylamidine prodrugs.

PURPOSE: Alkoxycarbonylamidine prodrug modification was used to mask the positively-charged amidine moiety of an Arg-Gly-Asp peptidomimetic and enhance oral bioavailability. The aqueous stability of ethoxycarbonylamidine (ECA), ethanethiocarbonylamidine (ETCA) and phenoxycarbonylamidine (PCA) prodrugs was examined. METHODS: Degradation was followed by RP-HPLC and rate constants were determined from a degradation scheme defined by product analysis. RESULTS: ECA gave a pH of maximum stability at pH approximately 7 and was independent of pH below pH approximately 4. A novel degradation pathway of ECA, conversion to ethoxycarbonyl- aminocarbonyl, was observed below pH 7. The relative rates below pH 7 were ECA approximately ETCA < PCA, in the same order of decreasing pKa of the conjugate acid of the substituted amidino group. Base-catalyzed cleavage of ECA to yield the amidine derivative gave the relative rates ECA < ETCA < PCA, in agreement with the decreasing pKa of the leaving groups. CONCLUSIONS: The observed rate constants at all pHs were small enough that only 5-30% (depending on the substituent) undesirable degradation is predicted during transit time of the gut. The spontaneous post-absorptive conversion to the amidine drugs at neutral pH is predicted to be 6x greater for the PCA than the ECA prodrugs.

Amidines↗
PubMed1998

Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle.

Mutation of RPE65 can cause severe blindness from birth or early childhood, and RPE65 protein is associated with retinal pigment epithelium (RPE) vitamin A metabolism. Here, we show that Rpe65-deficient mice exhibit changes in retinal physiology and biochemistry. Outer segment discs of rod photoreceptors in Rpe65-/- mice are disorganized compared with those of Rpe65+/+ and Rpe65+/- mice. Rod function, as measured by electroretinography, is abolished in Rpe65-/- mice, although cone function remains. Rpe65-/- mice lack rhodopsin, but not opsin apoprotein. Furthermore, all-trans-retinyl esters over-accumulate in the RPE of Rpe65-/- mice, whereas 11-cis-retinyl esters are absent. Disruption of the RPE-based metabolism of all-trans-retinyl esters to 11-cis-retinal thus appears to underlie the Rpe65-/- phenotype, although cone pigment regeneration may be dependent on a separate pathway.

Animals↗
PubMed1998

Identification of a calcium channel modulator using a high throughput yeast two-hybrid screen.

The interaction of the N-type calcium channel beta3 subunit with the alpha1B subunit alters the activation/inactivation kinetics and the maximal conductance of the channel. The defined protein-protein interaction of the human alpha1B and beta3 subunits provides a target for small-molecule modulation of N-type channel activity. We describe a high throughput screen based on a counterselection yeast two-hybrid assay, which was used to identify small molecules that disrupt alpha1B-beta3 subunit interactions and inhibit N-type calcium channel activity. These small molecules may be a new class of calcium channel antagonists with therapeutic potential.

Calcium Channel Blockers↗
PubMed1998

Inhibition of the induction of the inducible nitric oxide synthase in murine brain microglial cells by sodium salicylate.

The induction of the inducible nitric oxide synthase (iNOS) has been proposed to play a role in a variety of inflammatory diseases. Sodium salicylate (NaSal) is the most commonly used anti-inflammatory agent. We investigated whether NaSal can diminish the induction of iNOS in murine brain microglial cells. In primary cultures, interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) separately did not stimulate nitric oxide (NO) production, whereas IFN-gamma combined with LPS synergistically induced iNOS. NaSal inhibited both the production of NO and expression of iNOS in microglial cells. Synergy between IFN-gamma and LPS was mainly dependent on tumour necrosis factor-alpha (TNF-alpha) secretion as the increase of the induction of the iNOS by IFN-gamma plus LPS was associated with the increase of TNF-alpha secretion and IFN-gamma plus LPS-induced TNF-alpha secretion by microglial cells was decreased by the treatment with NaSal. These results suggest a possible use of NaSal in managing inflammation of the central nervous system through inhibition of the iNOS induction.

Animals↗