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S Barnes

Publications and source records attributed to S Barnes.

At least 109 records · Page 6Linked to original sources
PubMed1996

Peroxynitrite-dependent tryptophan nitration.

Peroxynitrite (ONOO-), the reaction product of superoxide (O2.-) and nitric oxide (.NO), nitrates tyrosine and other phenolics. We report herein that tryptophan is also nitrated by peroxynitrite in the absence of transition metals to one predominant isomer of nitrotryptophan, as determined from spectral characteristics and liquid chromatography-mass spectrometry analysis. At high peroxynitrite to tryptophan ratios, other oxidation products were detected as well. The amount of nitrotryptophan formed from peroxynitrite increased at acidic pH, with an apparent pKa of 7.8. High concentrations of Fe(3+)-EDTA were required to enhance peroxynitrite-induced nitrotryptophan formation, while addition of up to 15 microM Cu/Zn superoxide dismutase had a minimal effect on tryptophan nitration. Cysteine, ascorbate, and methionine decreased nitrotryptophan yield to an extent similar to that predicted by their reaction rates with ground-state peroxynitrite, and typical hydroxyl radical scavengers partially inhibited nitration. Plots of the observed rate constant of nitrotryptophan formation vs tryptophan concentration presented downward curvatures. Thus, the kinetics of metal-independent nitration reactions were interpreted in terms of two parallel mechanisms. In the first one, ground-state peroxynitrous acid nitrated tryptophan with a second-order rate constant of 184 +/- 11 M-1 s-1 at 37 degrees C. The activation enthalpy was 9.1 +/- 0.3 kcal mol-1, and the activation entropy was -19 +/- 1 cal mol-1 K-1. In the second mechanism, ONOOH*, an activated intermediate derived from trans-peroxynitrous acid formed in a steady state, was the nitrating agent.

Deferoxamine↗
PubMed1996

The dihydropyridine-sensitive calcium channel subtype in cone photoreceptors.

High-voltage activated Ca channels in tiger salamander cone photoreceptors were studied with nystatin-permeabilized patch recordings in 3 mM Ca2+ and 10 mM Ba2+. The majority of Ca channel current was dihydropyridine sensitive, suggesting a preponderance of L-type Ca channels. However, voltage-dependent, incomplete block (maximum 60%) by nifedipine (0.1-100 microM) was evident in recordings of cones in tissue slice. In isolated cones, where the block was more potent, nifedipine (0.1-10 microM) or nisoldipine (0.5-5 microM) still failed to eliminate completely the Ca channel current. Nisoldipine was equally effective in blocking Ca channel current elicited in the presence of 10 mM Ba2+ (76% block) or 3 mM Ca2+ (88% block). 15% of the Ba2+ current was reversibly blocked by omega-conotoxin GVIA (1 microM). After enhancement with 1 microM Bay K 8644, omega-conotoxin GVIA blocked a greater proportion (22%) of Ba2+ current than in control. After achieving partial block of the Ba2+ current with nifedipine, concomitant application of omega-conotoxin GVIA produced no further block. The P-type Ca channel blocker, omega-agatoxin IVA (200 nM), had variable and insignificant effects. The current persisting in the presence of these blockers could be eliminated with Cd2+ (100 microM). These results indicate that photoreceptors express an L-type Ca channel having a distinguishing pharmacological profile similar to the alpha 1D Ca channel subtype. The presence of additional Ca channel subtypes, resistant to the widely used L-, N-, and P-type Ca channel blockers, cannot, however, be ruled out.

Ambystoma↗
PubMed1996

Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats.

Genistein, a component of soy, was administered to prepubertal female Sprague-Dawley CD rats and investigated for chemoprevention against mammary cancer. Genistein, at 500 microgram/g body wt or an equivalent volume of the vehicle, dimethylsulfoxide (DMSO), was injected (s.c.) on days 16, 18 and 20 post-partum. At day 50 post-partum all animals were exposed to 80 microgram dimethylbenz[a]anthracene (DMBA) per g body wt. Animals treated prepubertally with genistein as compared to DMSO had reduced incidence and significantly fewer adenocarcinomas per animal. Mammary whole mount analysis showed that prepubertal genistein treatment resulted in mammary glands of 50-day-old rats developing fewer terminal end buds and more lobules II. Cell proliferation studies with bromodeoxyuridine (BrdU) showed that terminal end buds from mammary glands of 50-day-old females treated prepubertally with genistein had significantly fewer cells in S-phase of the cell cycle. Serum genistein concentrations in 21- and 50-day-old females following prepubertal genistein treatment were 4.2 +/- 0.6 micromol and 102 +/- 30 nM, respectively. Animals treated prepubertally with genistein as compared to vehicle spent more time in the estrus phase of the estrus cycle, although all animals did cycle. In 50-day-old females, circulating estradiol-17 beta and progesterone concentrations were not significantly altered by the prepubertal genistein treatment. Oocyte/follicle counts and numbers of atretic follicles and corpora lutea were not significantly different between the genistein- and vehicle-treated animals. We conclude that genistein treatment during the prepubertal period can suppress the development of chemically-induced mammary cancer without significant toxicity to the endocrine/reproductive system.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A.

The basis for the differential sensitivity of cultured normal human mammary epithelial (HME) cells and a transformed human breast cancer MCF-7 cell line to growth inhibition by the isoflavone genistein and its 4'-methyl ether derivative, biochanin A, was examined. In HME cells genistein is 5-fold more potent as a growth inhibitor than biochanin A, whereas in MCF-7 cells biochanin A and genistein are equally potent as growth inhibitors. Based on its properties as an in vitro protein tyrosine kinase (PTK) inhibitor, biochanin A would be expected to be a less potent growth inhibitor than genistein. To determine whether isoflavone metabolism could account for the observed differences in growth inhibition, metabolism experiments were conducted with HME and MCF-7 cells using [4-14C]genistein and [4-14C]biochanin A. MCF-7 cells extensively metabolized both isoflavones, producing two genistein metabolites with molecular weights of 350 and 380 and three biochanin A metabolites with molecular weights of 270, 350 and 380. In contrast, significant genistein or biochanin A metabolism was not observed in HME cells. Using mass spectrometry and nuclear magnetic resonance analysis, metabolite 350 from genistein and biochanin A experiments was identified as genistein 7-sulfate; biochanin A metabolite 270 was identified as genistein. Metabolite 380 was not unequivocally identified, but appeared to be a hydroxylated and methylated form of genistein sulfate. In MCF-7 cells, genistein 7-sulfate and metabolite 380 were detected primarily in the cell media fraction, suggesting that once formed these polar metabolites were excreted from the cells. These data show that isoflavone metabolism by transformed breast epithelial cells modulates the growth inhibitory effects of genistein and biochanin A. In MCF-7 cells, genistein metabolism was correlated with a decrease in growth inhibition, whereas biochanin A metabolism was associated with an increase in growth inhibition.

Anticarcinogenic Agents↗
PubMed1996

Interleukin-1beta, tumor necrosis factor-alpha, and LPS enhance calcium channel current in isolated vascular smooth muscle cells of rat tail artery.

Cytokines, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), are thought to be responsible for the compromised blood pressure regulation after systemic infection or other antigenic challenge. Because Ca homeostasis is critical for the maintenance of vascular tone, we hypothesized that cytokines may contribute to alterations in blood pressure by a mechanism involving the voltage-sensitive Ca channel in vascular smooth muscle (VSM) cells. Using nystatin-permeabilized patch techniques we examined the effects of IL-1 beta, TNF-alpha, and lipopolysaccharide (LPS) on the Ca channel of VSM cells isolated from rat tail artery. Both IL-1 beta (0.05--1 nM) and TNF-alpha (0.1--1 nM) increased, dose-dependently, the Ba2+ current carried in VSM Ca channels, whereas heat-denatured IL-1 beta was without significant effect on the channel. LPS (0.01--1.0 ng/ml) also increased the Ba2+ current with onset kinetics similar to the two cytokines. Prostaglandins were ruled out as an intermediary in VSM Ca channel modulation, as prostaglandin E2 had no effect and indomethacin (1 microM) failed to block TNF-alpha-induced Ca channel enhancement. The role of cyclic nucleotides in mediating TNF-alpha-induced changes in Ca channel activity was also assessed. Increasing intracellular cAMP via forskolin (1 microM) did not affect the response to TNF-alpha, but pretreatment with the membrane-permeant analog of cGMP, dibutyryl cGMP (100 microM), inhibited the response to TNF-alpha. These data demonstrate that IL-1 beta, TNF-alpha, and LPS have immediate effects on VSM cells via an interaction with the voltage-sensitive Ca channel, and these effects may he regulated by intracellular cGMP. Immunomodulation of Ca channels may represent an early signaling step in VSM cells mediating kinetically slower events, such as changes in gene transcription.

Animals↗
PubMed1996

Latex allergy and anaphylaxis in a child undergoing craniofacial surgery.

This case report represents an example of latex anaphylaxis in a child with a history of multiple previous surgeries without any complications. Obviously, the patient had not shown evidence of being sensitized until this particular surgery, where she had multiple sources of latex exposure, e.g., Foley catheter, blood pressure cuff, rubber gloves, and clear adhesive tape. If a more careful history had been taken, the diagnosis of latex allergy might have been suspected, for upon further questioning after surgery, the mother reported multiple incidences of urticarial reactions to rubber gloves and clothes with elastic waist bands. In summary, this case report highlights the importance of a careful history and the need for a high index of suspicion of potential latex allergy in children who acquire sensitization to latex because they require multiple surgical procedures for anatomic correction of congenital abnormalities. One week after this episode, the patient returned to the operating room for completion of her surgery. All latex was avoided, and there were no complications.

Anaphylaxis↗
PubMed1996

Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells.

Genistein is a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor that is hypothesized to be responsible for the lower rate of breast cancer observed in Asian women consuming soy. Although genistein is a potent in vitro PTK inhibitor, its mechanism of action in vivo is not known. In vivo, breast cancer growth is regulated by estrogens and peptide growth factors, such as epidermal growth factor (EGF), the receptor of which has intrinsic PTK activity. Therefore, genistein may block mammary epithelial cell growth by interfering with signal transduction events stimulated by estradiol or growth factors. The effect of genistein, related isoflavones, and other tyrosine kinase inhibitors on fetal bovine serum-, estradiol-, and EGF-stimulated cell growth and signal transduction pathways was examined in five human breast cancer cell lines. Genistein inhibited the growth of these cells by each of the growth stimuli with IC50 values ranging from 2.6 to over 20 micrograms/ml. Growth inhibition by genistein was cytostatic and reversible at IC50 concentrations. Related isoflavones were less potent growth inhibitors than genistein, whereas the synthetic PTK inhibitor tyrphostin A25 was an equally potent growth inhibitor. The mechanism of genistein growth inhibition in human breast cancer cells did not depend on the presence of functional estrogen receptor signaling pathways or on inhibition of EGF-receptor PTK activity. Furthermore, genistein (< or = 20 micrograms/ml) did not decrease constitutive or EGF-induced tyrosine phosphorylation as determined by Western blotting with antiphosphotyrosine antibodies. These data suggest that although genistein inhibits the growth of breast cancer cells in culture, it does so without gross inhibition of PTK activity.

Animals↗
PubMed1996

Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women.

Soy foods have been reported to have protective effects against premenopausal breast cancer in Asian women. No studies have been reported on potential physiological effects of dietary soy consumption on breast gland function. We evaluated the influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to resemble those previously found in Asian women. At monthly intervals for 1 year, 24 normal pre- and postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and 24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months 4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, gross cystic disease fluid protein (GCDFP-15) concentration, and NAF cytology were used as biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study protocol was obtained. Compared with NAF volumes obtained in months 1-3, a 2-6-fold increase in NAF volume ensued during months 4-9 in all premenopausal women. A minimal increase or no response was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin, cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with concentrations found in months 1-3 (no soy), plasma estradiol concentrations were elevated erratically throughout a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in premenopausal women during the months of soy ingestion. Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women (29.2%) during the months they were consuming soy protein isolate. The findings did not support our a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells, and elevated levels of plasma estradiol. These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate.

Adult↗
PubMed1995

Nitric oxide inhibition of lipoxygenase-dependent liposome and low-density lipoprotein oxidation: termination of radical chain propagation reactions and formation of nitrogen-containing oxidized lipid derivatives.

Lipoxygenase-induced lipid oxidation contributes to plasma lipoprotein oxidation and may be an underlying pathogenic mechanism of atherogenesis. Since inactivation of the vasorelaxant actions of nitric oxide (.NO) plays a critical role in the impaired function of atherosclerotic vessels and because .NO reacts rapidly with other radical species, we assessed the influence of .NO on lipoxygenase-catalyzed oxidation of linoleic and linolenic acid, 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PC) liposomes, hypercholesterolemic rabbit beta-very-low-density lipoprotein, and human low-density lipoprotein. Soybean lipoxygenase (SLO)-induced lipid oxidation was assessed by accumulation of conjugated dienes, formation of lipid hydroperoxides, oxygen consumption, and liquid chromatography-mass spectrometry. Different rates of delivery of .NO to lipid oxidation systems were accomplished either by infusion of .NO gas equilibrated with anaerobic buffer or via .NO released from S-nitrosoglutathione. Nitric oxide alone did not induce lipid peroxidation, while exposure to SLO yielded significant oxidation of fatty acids, PC liposomes, or lipoproteins in a metal ion-independent mechanism. Low concentrations of .NO, which did not significantly inhibit the activity of the iron-containing lipoxygenase, induced potent inhibition of lipid peroxidation in a dose-dependent manner. Mass spectral analysis of oxidation products showed formation of nitrito-, nitro-, nitrosoperoxo-, and/or nitrated lipid oxidation adducts, demonstrating that .NO serves as a potent terminator of radical chain propagation reactions. The formation of Schiff's base fluorescent conjugates between SLO-oxidized linoleic or linolenic acid and bovine serum albumin (BSA) was also inhibited by .NO via reaction with lipid hydroperoxyl radicals (LOO.), thus preventing the reaction of LOO. with polypeptide amino groups. Mass spectrometry analysis showed that both lipid peroxidation products and nitrogen-containing oxidized lipid species decreased in the presence of BSA. We conclude that .NO can play a potent oxidant-protective role in the vessel wall by inhibiting lipoxygenase-dependent lipid and lipoprotein oxidation. This occurs via termination of lipid radical chain propagation reactions catalyzed by alkoxyl (LO.) and LOO. intermediates of lipid peroxidation rather than by inhibition of lipoxygenase-catalyzed initiation reactions.

Animals↗
PubMed1995

Nitric oxide synthase in tiger salamander retina.

Previous studies have indicated that nitric oxide, a labile freely diffusible biological messenger synthesized by nitric oxide synthase, may modulate light transduction and signal transmission in the retina. In the present work, the large size of retinal cells in tiger salamander (Ambystoma tigrinum) allowed the utilization of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry and nitric oxide synthase immunocytochemistry to delineate the cell-specific intracellular localization of nitric oxide synthase. NADPH-diaphorase activity was highly concentrated in the outer retina, in rod and cone inner segment ellipsoids, and between and adjacent to the photoreceptor cell bodies in the outer nuclear layer. Examination of enzymatically isolated retinal cells indicated that outer nuclear layer NADPH-diaphorase activity was localized to the distal processes of the retinal glial (Müller) cells and to putative bipolar cell Landolt clubs. Less intense NADPH-diaphorase activity was seen in the photoreceptor inner segment myoid region, in a small number of inner nuclear layer cells, in cap-like configurations at the distal poles of cells in the ganglion cell layer and surrounding ganglion cell layer somata, and in punctate form within both plexiform layers, the pigment epithelium, and the optic nerve. Nitric oxide synthase-like immunoreactivity was similarly localized, but was also concentrated along a thin sublamina centered within the inner plexiform layer. The potential for nitric oxide generation at multiple retinal sites suggests that this molecule may play a number of roles in the processing of visual information in the retina.

Animals↗
PubMed1995

Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer.

Pharmacologists have realized that tyrosine kinase inhibitors (TKI) have potential as anti-cancer agents, both in prevention and therapy protocols. Nonetheless, concern about the risk of toxicity caused by synthetic TKIs restricted their development as chemoprevention agents. However, a naturally occurring TKI (the isoflavone genistein) in soy was discovered in 1987. The concentration of genistein in most soy food materials ranges from 1-2 mg/g. Oriental populations, who have low rates of breast and prostate cancer, consume 20-80 mg of genistein/day, almost entirely derived from soy, whereas the dietary intake of genistein in the US is only 1-3 mg/day. Chronic use of genistein as a chemopreventive agent has an advantage over synthetic TKIs because it is naturally found in soy foods. It could be delivered either in a purified state as a pill (to high-risk, motivated patient groups), or in the form of soy foods or soy-containing foods. Delivery of genistein in soy foods is more economically viable ($1.50 for a daily dose of 50 mg) than purified material ($5/day) and would require no prior approval by the FDA. Accordingly, investigators at several different sites have begun or are planning chemoprevention trials using a soy beverage product based on SUPRO, an isolated soy protein manufactured by Protein Technologies International of St. Louis, MO. These investigators are examining the effect of the soy beverage on surrogate intermediate endpoint biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining potential SIEBs in patients at risk for prostate cancer, and determining whether the soy beverage reduces the incidence of cancer recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticarcinogenic Agents↗
PubMed1995

Genistein suppresses mammary cancer in rats.

Female Sprague-Dawley CD rats were injected s.c. with 5 mg genistein, a soy phytoestrogen, or 20 microliters of the vehicle, dimethylsulfoxide (DMSO), on days 2,4 and 6 postpartum. At day 50, they were exposed to 80 micrograms dimethylbenz[a]anthracene (DMBA)/g body wt. Animals treated neonatally with genistein as compared to DMSO had increased latency and reduced incidence and multiplicity of DMBA-induced mammary adenocarcinomas. Mammary whole mount analysis showed that 50 day old female rats treated neonatally with genistein had fewer terminal end buds. Cell proliferation studies revealed that 50 day old genistein-treated rats had lower percentages and total numbers of cells in the S-phase of the cell cycle in terminal end buds, terminal ducts, lobules I and lobules II. In genistein-treated as compared to vehicle-treated female rats, vaginal openings occurred earlier, the estrus cycle was disrupted and the uterine-ovarian weights were smaller. In 50 day old genistein-treated females there were atretic antral follicles, fewer corpora lutea, and lower circulating progesterone but not estradiol-17 beta concentrations. In 21 day old rats treated neonatally with genistein, mammary glands were larger and there were more terminal end buds and terminal ducts, and more proliferative activity in all terminal ductals structures. It appears that neonatal genistein-treatment exerted its chemoprevention action by acting directly to enhance maturation of terminal ductal structures and by altering the endocrine system to reduce cell proliferation in the mammary gland.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Effect of genistein on in vitro and in vivo models of cancer.

In two-thirds of studies on the effect of genistein-containing soy materials in animal models of cancer, the risk of cancer (incidence, latency or tumor number) was significantly reduced. In addition, purified genistein delayed mammary tumor appearance in association with increased cell differentiation in mammary tissue in rats treated with 7, 12-dimethylbenz[a]anthracene when administered neonatally, inhibited phorbol ester-induced H2O2 production in a model of skin cancer, and inhibited aberrant crypt formation in a model of colonic cancer. In in vitro models, genistein inhibited the proliferation of human tumor cell lines in culture with a wide variation in IC50 values (2.6-79 mumol/L, or 1-30 micrograms/mL). In only a few cases was the IC50 below 13.2 mumol/L (5 micrograms/mL), the presumed upper limit for the serum genistein concentration in those on a high soy diet. In future studies, greater emphasis should be placed on the effect of genistein on nontransformed, normal cell lines from the tissues where cancer can occur rather than established tumor cell lines. Similarly, the effect of genistein on the progression and/or promotion of cancer may be more clearly examined using nontransformed cell lines transfected with specific oncogenes thought to be activated during oncogenesis.

Animals↗
PubMed1995

Biochemical targets of the isoflavone genistein in tumor cell lines.

Dietary intake of soy is associated with a decreased risk of both hormone-dependent and hormone-independent cancers. It has been proposed that genistein, the predominant isoflavone in soy foods, is responsible for this effect. In this review, the potential mechanisms of action of genistein at the cellular level are critically examined to determine which are physiologically relevant. We concluded that (i) only those mechanisms requiring genistein concentrations below 5 micrograms/ml (18 microM) should be considered, and (ii) more emphasis should be placed on the effects of genistein on events in normal cells or those from the early stages of the cancer process.

Animals↗
PubMed1995

Neonatal genistein chemoprevents mammary cancer.

We have investigated the potential of genistein, an estrogenic component of soy, when administered neonatally, to manifest a protective effect against chemically induced mammary cancer. Female Sprague-Dawley rats were treated on Day 2, 4, and 6 postpartum with genistein or dimethylsulfoxide (vehicle). To induce mammary carcinogenesis, all animals were subsequently exposed on Day 50 postpartum to dimethylbenz(a)anthracene. Animals treated neonatally with genistein had increased latency and reduced incidence and multiplicity of mammary tumors compared with vehicle-treated animals. Cell differentiation studies in mammary whole mounts revealed that neonatal genistein treatment resulted in decreased numbers of terminal end buds and increased numbers of lobular structures. A precocious maturation of undifferentiated terminal end buds to more differentiated lobules may account for neonatal genistein treatment protecting against chemically induced mammary cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Antioxidant and antipromotional effects of the soybean isoflavone genistein.

Antioxidant and antipromotional effects of the soybean isoflavone genistein have been studied in HL-60 cells and the mouse skin tumorigenesis model. Effects of structure-related flavone/isoflavones on hydrogen peroxide (H2O2) production by 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated HL-60 cells and superoxide anion (O2-) generation by xanthine/xanthine oxidase were compared. Of tested isoflavones, genistein is the most potent inhibitor among TPA-induced H2O2 formation by (dimethyl sulfoxide) DMSO-differentiated HL-60 cells, daidzein is second, and apigenin and biochanin A show little effect. In contrast, genistein, apigenin, and prunectin are equally potent in inhibiting O2- generation by xanthine/xanthine oxidase, with daidzein showing a moderate inhibitory effect and biochanin A exhibiting no effect. These results suggest that the antioxidant properties of isoflavones are structurally related and the hydroxy group at Position 4' is crucial in both systems. Dietary administration of 250 ppm genistein for 30 days significantly enhances the activities of antioxidant enzymes in the skin and small intestine of mice. Further studies show that genistein significantly inhibits TPA-induced proto-oncogene expression (c-fos) in mouse skin in a dose-dependent manner. In a two-stage skin carcinogenesis study, low levels of genistein (1 and 5 mumol) significantly prolong tumor latency and decrease tumor multiplicity by approximately 50%. We conclude that genistein's antioxidant properties and antiproliferative effects may be responsible for its anticarcinogenic effect. Its high content in soybeans and relatively high bioavailability favor genistein as a promising candidate for the prevention of human cancers.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Imaging biliary lipid secretion in the rat: ultrastructural evidence for vesiculation of the hepatocyte canalicular membrane.

Physical-chemical and biological studies of hepatic bile suggest that biliary phospholipid molecules are secreted as unilamellar vesicles. Systematic ultrastructural studies of bile canaliculi were undertaken to visualize this event. Liver tissue was obtained from normal adult male rats (control), from bile salt-depleted rats (by overnight biliary diversion), and from depleted rats infused intravenously with a hydrophilic-hydrophobic congener series of common taurine-conjugated bile salts. Livers were fixed in situ either by modified chemical methods or by ultrarapid cryofixation. In control rats, chemical fixation revealed unilamellar vesicles 63 +/- 17 (+/- SD) nm in diameter, mostly free within canalicular lumena. Vesicles were infrequent in canaliculi of bile salt-depleted rats, but were present in canaliculi of rats infused with taurocholate. In cryofixed liver tissue, vesicles 67 +/- 13 nm in diameter were observed in canaliculi of control rats and bile-salt depleted rats infused with common bile salts. The majority of these vesicles were affixed to the luminal side of the canalicular membrane. The average number of vesicles per bile canaliculus was in agreement with that estimated on the basis of biliary phospholipid secretion rates, mean vesicle size, and area of close-packed phosphatidylcholine molecules. By immunoelectron microscopy, canalicular vesicles were free of actin and of a 100 kDa canalicular membrane protein. We conclude that biliary phospholipid molecules are secreted from hepatocytes into bile canalicular lumena as unilamellar vesicles approximately 63-67 nm in average diameter. We postulate that this secretion mechanism involves lumenal bile salt-induced vesiculation of lipid microdomains in the exoplasmic hemileaflet of the canalicular membrane.

Animals↗