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PubMedDate not supplied

Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca(2+) ionophore) nor veratridine (a Na(+) ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca(2+) concentration and Na(+) accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [(14)C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides.

Androgens↗
PubMed1976

Acylated Steryl Glycoside Synthesis in Seedlings of Nicotiana tabacum L.

In tobacco seedlings (Nicotiana tabacum L.), glucose from supplied uridine diphosphate-[U-(14)C]glucose was first incorporated into steryl glycosides and later into acylated steryl glycosides. However, when [(14)C]cholesterol was used as substrate, the acylated steryl glycosides became labeled earlier than the steryl glycosides. With [(14)C]cholesteryl glucoside as substrate, most of the radioactive label was recovered as free sterol, and the acylated steryl glycosides were not readily labeled; however, palmitoyl [(14)C]cholesteryl glucoside was rapidly converted to steryl glycoside. In feeding experiments with free sterol, an unknown, highly radioactive steroid component was isolated. Incorporation of radioactivity into the unknown occurred before the acylated steryl glycosides were labeled.IT IS POSTULATED THAT TWO PATHWAYS EXIST FOR THE BIOSYNTHESIS OF ACYLATED STERYL GLYCOSIDE: one through steryl glycosides, and the other through an unidentified steroid component. It is the latter pathway which appears to be dominant in the in vivo tobacco system.

Journal Article↗
PubMed1980

Biosynthesis of daunorubicin glycosides: role of epsilon-rhodomycinone.

Daunorubicin (daunomycin; NSC 82151) is a fermentation-derived anthracycline antibiotic that is clinically useful in the treatment of human leukemias. Daunorubicin itself is found rarely in microbial fermentations, but is present normally in the form of glycoside derivatives that yield the free drug on simple acid hydrolysis. A major by-product of daunorubicin fermentations is usually the structurally related anthracyclinone epsilon-rhodomycinone. We have used mutants of a daunorubicin-producing Streptomyces species to study the biosynthetic relationship between epsilon-rhodomycinone and daunorubicin. We found that exogenously added epsilon-rhodomycinone can be converted to daunorubicin glycosides by a nonproducing mutant and by a mutant that produces daunorubicin glycosides but not epsilon-rhoeomycinone. Molar conversion efficiences were in the 15 to 30% range. The latter mutant was also shown to convert exogenous 14C-labeled epsilon-rhodomycinone to 14C-labeled daunorubicin glycosides, again at conversion efficiencies of about 25%. The same biotransformation was observed with daunorubicin production strain C5, which normally accumulates both epsilon-rhodomycinone and daunorubicin glycosides. A significant percentage (16 to 37%) of exogenously added epsilon-[14C]rhodomycinone was metabolized by strain C5, and 22 to 32% of the metabolized radioactivity could be recovered as daunorubicin glycosides. A mathematical model of epsilon-rhodomycinone metabolism was constructed based on plausible assumptions concerning the kinetics of epsilon-rhodomycinone accumulation and catabolsim. When analyzed according to this model, our data indicate that most (63 to 73%), but not all, of the daunorubicin glycosides accumulated in the experiments with production strain C5 derived from epsilon-rhodomycinone. A pathway network for the biosynthesis of daunorubicin glycosides is proposed that is in agreement with these data. In this proposed pathway network, epsilon-rhodomycinone is an intermediate in one of at least two pathways which yield daunorubicin glycosides.

Anthracyclines↗
PubMed2001

Sterol glycosides and cerebrosides accumulate in Pichia pastoris, Rhynchosporium secalis and other fungi under normal conditions or under heat shock and ethanol stress.

The occurrence of glycolipids such as sterol glycosides, acylated sterol glycosides, cerebrosides and glycosyldiacylglycerols was examined in the three yeast species Candida albicans, Pichia pastoris and Pichia anomala, as well as in the six fungal species Sordaria macrospora, Pyrenophora teres, Ustilago maydis, Acremonium chrysogenum, Penicillium olsonii and Rhynchosporium secalis. Cerebroside was found in all organisms tested, whereas acylated sterol glycosides and glycosyldiacylglycerols were not found in any organism. Sterol glycosides were detected in P. pastoris strain GS115, U. maydis, S. macrospora and R. secalis. This glycolipid occurred in both yeast and filamentous forms of U. maydis but in neither form of C. albicans. This suggests that sterol glycoside is not correlated with the separately grown dimorphic forms of these organisms. Cerebrosides and sterol glycosides from P. pastoris and R. secalis were purified and characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. The cerebrosides are beta-glucosyl ceramides consisting of a saturated alpha-hydroxy or non-hydroxy fatty acid and a Delta4,8-diunsaturated, C9-methyl-branched sphingobase. Sterol glycoside from P. pastoris was identified as ergosterol-beta-D-glucopyranoside, whereas the sterol glucosides from R. secalis contain two derivatives of ergosterol. The biosynthesis of sterol glucoside in P. pastoris CBS7435 and GS115 depended on the culture conditions. The amount of sterol glucoside in cells grown in complete medium was much lower than in cells from minimal medium and a strong increase in the content of sterol glucoside was observed when cells were subjected to stress conditions such as heat shock or increased ethanol concentrations. From these data we suggest that, in addition to Saccharomyces cerevisiae, new yeast and fungal model organisms should be used to study the physiological functions of glycolipids in eukaryotic cells. This suggestion is based on the ubiquitous and frequent occurrence of cerebrosides and sterol glycosides, both of which are rarely detected in S. cerevisiae. We suggest P. pastoris and two plant pathogenic fungi to be selected for this approach.

Cerebrosides↗
PubMed2004

Modulation of suppressive activity of lipopolysaccharide-induced nitric oxide production by glycosidation of flavonoids.

Flavonoids have been demonstrated to exhibit a wide range of biological activities including anti-inflammatory and neuroprotective actions. Although a significant amount of flavonoids has been identified to be present as glycosides in medicinal plants, determinations of the biological activities of flavonoids were mainly carried out with aglycones of flavonoids. Therefore, the exact role of the glycosidation of flavonoid aglycones needs to be established. In an attempt to understand the possible role of glycosidation on the modulation of the biological activities of flavonoids, diverse glycosides of kaempferol, quercetin, and aromadendrin were examined in terms of their anti-inflammatory activity determined with the suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 microglial cells. The results indicated that glycosidation of aglycones attenuated the suppressive activity of aglycones on LPS-induced NO production. Although attenuated, some of glycosides, depending on the position and degree of glycosidation, maintained the inhibitory capability of LPS-induced NO production. These findings suggest that glycosidation of flavonoid aglycones should be considered as an important modulator of the biological activities of flavonoids.

Animals↗
PubMed1996

Potent growth inhibitory activity of a novel Ornithogalum cholestane glycoside on human cells: induction of apoptosis in promyelocytic leukemia HL-60 cells.

Growth inhibitory activities of a novel 22-homo-23-norcholestane glycoside found in bulbs of Ornithogalum saundersiae were examined in vitro using human promyelocytic leukemia HL-60 cells, human T-lymphocytic leukemia MOLT-4 cells, and mitogen-stimulated human peripheral-blood mononuclear cells (PBMC). The growth of HL-60 cells and MOLT-4 cells was strongly suppressed in the presence of the glycoside; the IC50s of which were 21.0 and 18.0 nM, respectively. Suppressive effect of the glycoside on HL-60 cell growth appears to be mediated partially through induction of apoptosis which was demonstrated by the presence of DNA fragmentation of the leukemic cells. Flow cytometric analysis of glycoside-treated HL-60 cells also demonstrated apoptotic cells with low DNA content and showed a decrease of G0/G1 cells and a concomitant increase of S and/or G2M cells. The growth inhibiting effect of the glycoside on HL-60 cells was promoted by calcium and was inhibited in the presence of zinc, which support involvement of endonuclease activation in the glycoside-induced apoptosis. The glycoside also inhibited mitogen-stimulated blastogenesis of PBMC, the IC50 of which was 6.2 nM. These results provided the first evidence ever for the potent growth inhibitory activity of Ornithogalum glycoside on human leukemia cell lines and PBMC.

Antineoplastic Agents↗
PubMed2006

Biosynthesis of malonylated flavonoid glycosides on the basis of malonyltransferase activity in the petals of Clitoria ternatea.

The crude malonyltransferase from the petals of Clitoria ternatea was characterized enzymatically to investigate its role on the biosynthetic pathways of anthocyanins and flavonol glycosides. In C. ternatea, a blue flower cultivars (DB) and mauve flower variety (WM) accumulate polyacylated anthocyanins (ternatins) and delphinidin 3-O-(6''-O-malonyl)-beta-glucoside which is one of the precursors of ternatins, respectively. Moreover, WM accumulates minor delphinidin glycosides - 3-O-beta-glucoside, 3-O-(2''-O-alpha-rhamnosyl)-beta-glucoside, 3-O-(2''-O-alpha-rhamnosyl-6''-O-malonyl)-beta-glucoside of delphinidin. These glycosidic patterns for minor anthocyanins in WM are also found among the minor flavonol glycosides in all the varieties including a white flower variety (WW) although the major flavonol glycosides are 3-O-(2''-O-alpha-rhamnosyl)-beta-glucoside, 3-O-(6''-O-alpha-rhamnosyl)-beta-glucoside, 3-O-(2'',6''-di-O-alpha-rhamnosyl)-beta-glucoside of kaempferol, quercetin, and myricetin. How do the enzymatic characteristics affect the variety of glycosidic patterns in the flavonoid glycoside biosynthesis among these varieties? While the enzyme from DB highly preferred delphinidin 3-O-beta-glucoside in the presence of malonyl-CoA, it also has a preference for other anthocyanidin 3-O-beta-glucosides. It could use flavonol 3-O-beta-glucosides in much lower specific activities than anthocyanins; however, it could not utilize 3-O-(2''-O-alpha-rhamnosyl)-beta-glucosides of anthocyanins and flavonols, and 3,3'-di- and 3,3',5'-tri-O-beta-glucoside of delphinidin - other possible precursors in ternatins biosynthesis. It highly preferred malonyl-CoA as an acyl donor in the presence of delphinidin 3-O-beta-glucoside. The crude enzymes prepared from WM and WW had the same enzymatic characteristics. These results suggested that 3-O-(2''-O-alpha-rhamnosyl-6''-O-malonyl)-beta-glucosides of flavonoids were synthesized via 3-O-(6''-O-malonyl)-beta-glucosides rather than via 3-O-(2''-O-alpha-rhamnosyl)-beta-glucosides, and that malonylation proceeded prior to glucosylation at the B-ring of delphinidin in the early biosynthetic steps towards ternatins. It seemed that the substrate specificities largely affected the difference in the accumulated amount of malonylated glycosides between anthocyanins and flavonols although they are not simply proportional to the accumulation ratio. This enzyme might join in the production of both malonylanthocyanins and flavonol malonylglycosides as a result of broad substrate specificities towards flavonoid 3-O-beta-glucosides.

Acyltransferases↗
PubMed1992

Comparison of N-glycosides of fetuins from different species and human alpha 2-HS-glycoprotein.

Complex type N-glycosides of commercial bovine fetuin preparations from pooled fetal calf serum have been shown to contain comparable amounts of Gal4,4,4TRI (see structure A below) and Gal4,4,3TRI (structure B) as major asialo-structures. To investigate whether there is a clear genetic specificity for synthesis of these oligosaccharides, N-glycosides from two preparations of bovine fetuin, each from a single calf, were examined. Both of these structures were present in each calf, and there was only a subtle quantitative difference in the ratio of these two structures between the calves. Thus, a specific galactosyltransferase, presumably required for the biosynthesis of the Gal4,4,3TRI structure, may exist in both of these individual calves. Comparison of fetuin N-glycosides was also extended to sheep, pig, and human alpha 2-HS-glycoprotein, the human counterpart of bovine fetuin, using high-pH anion-exchange chromatography of the reducing oligosaccharides as well as HPLC of their pyridinylamino derivatives. The N-glycosides of ovine fetuin also have both Gal4,4,4TRI and Gal4,4,3TRI structures in a ratio similar to that of bovine fetuin. However, the major N-glycoside of porcine fetuin is of a fucosyl biantennary complex type structure (structure C below) and human alpha 2-HS-glycoprotein has an N-glycoside which is almost exclusively a nonfucosylated biantennary structure (structure D). This species-specific presence of N-glycosides of fetuins and comparison with N-glycosides of other glycoproteins suggest that the polypeptide sequence of a glycoprotein may affect its N-glycan structure by regulating the activity of specific glycosyltransferases. [formula: see text]

Amidohydrolases↗
PubMed2002

Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides.

It is well-known that micromolar to millimolar concentrations of cardiac glycosides inhibit Na/K pump activity, however, some early reports suggested nanomolar concentrations of these glycosides stimulate activity. These early reports were based on indirect measurements in multicellular preparations, hence, there was some uncertainty whether ion accumulation/depletion rather than pump stimulation caused the observations. Here, we utilize the whole-cell patch-clamp technique on isolated cardiac myocytes to directly measure Na/K pump current (I(P)) in conditions that minimize the possibility of ion accumulation/depletion causing the observed effects. In guinea pig ventricular myocytes, nanomolar concentrations of dihydro-ouabain (DHO) caused an outward current that appeared to be due to stimulation of I(P) because of the following: (1) it was absent in 0 mM [K(+)](o), as was I(P); (2) it was absent in 0 mM [Na(+)](i), as was I(P); (3) at reduced [Na(+)](i), the outward current was reduced in proportion to the reduction in I(P); (4) it was eliminated by intracellular vanadate, as was I(P). Our previous work suggested guinea pig ventricular myocytes coexpress the alpha(1)- and alpha(2)-isoforms of the Na/K pumps. The stimulation of I(P) appears to be through stimulation of the high glycoside affinity alpha(2)-isoform and not the alpha(1)-isoform because of the following: (1) regulatory signals that specifically increased activity of the alpha(2)-isoform increased the amplitude of the stimulation; (2) regulatory signals that specifically altered the activity of the alpha(1)-isoform did not affect the stimulation; (3) changes in [K(+)](o) that affected activity of the alpha(1)-isoform, but not the alpha(2)-isoform, did not affect the stimulation; (4) myocytes from one group of guinea pigs expressed the alpha(1)-isoform but not the alpha(2)-isoform, and these myocytes did not show the stimulation. At 10 nM DHO, total I(P) increased by 35 +/- 10% (mean +/- SD, n = 18). If one accepts the hypothesis that this increase is due to stimulation of just the alpha(2)-isoform, then activity of the alpha(2)-isoform increased by 107 +/- 30%. In the guinea pig myocytes, nanomolar ouabain as well as DHO stimulated the alpha(2)-isoform, but both the stimulatory and inhibitory concentrations of ouabain were approximately 10-fold lower than those for DHO. Stimulation of I(P) by nanomolar DHO was observed in canine atrial and ventricular myocytes, which express the alpha(1)- and alpha(3)-isoforms of the Na/K pumps, suggesting the other high glycoside affinity isoform (the alpha(3)-isoform) also was stimulated by nanomolar concentrations of DHO. Human atrial and ventricular myocytes express all three isoforms, but isoform affinity for glycosides is too similar to separate their activity. Nevertheless, nanomolar DHO caused a stimulation of I(P) that was very similar to that seen in other species. Thus, in all species studied, nanomolar DHO caused stimulation of I(P), and where the contributions of the high glycoside affinity alpha(2)- and alpha(3)-isoforms could be separated from that of the alpha(1)-isoform, it was only the high glycoside affinity isoform that was stimulated. These observations support early reports that nanomolar concentrations of glycosides stimulate Na/K pump activity, and suggest a novel mechanism of isoform-specific regulation of I(P) in heart by nanomolar concentrations of endogenous ouabain-like molecules.

Animals↗
PubMed1991

No upregulation of digitalis glycoside receptor (Na,K-ATPase) concentration in human heart left ventricle samples obtained at necropsy after long term digitalisation.

STUDY OBJECTIVE: The aim was to evaluate the hypothesis that digitalis glycosides increase the concentration of their specific receptor (Na,K-ATPase) in human myocardial tissue, thereby possibly reducing the inotropic effect of long term digitalis treatment. DESIGN: Intact samples of left ventricle were obtained at necropsy from patients who had been on long term treatment with digoxin and from patients not previously given digoxin. Digitalis glycoside receptors were quantified using vanadate facilitated 3H-ouabain binding before and after washing samples in buffer containing excess digoxin antibody fragments for 16 h at 30 degrees C. This washing procedure has previously been shown to reduce prior specific digoxin binding in human left ventricle by 95% and to allow subsequent vanadate facilitated complete quantification of 3H-ouabain binding sites. In this context it was performed to reduce occupancy of digitalis glycoside receptors by digoxin, caused by digitalisation before 3H-ouabain binding. SUBJECTS: 11 patients who had been on long term treatment with digoxin and eight who had not previously been given digoxin were studied. Left ventricle samples were obtained at necropsy at around 15 h after death. MEASUREMENTS AND MAIN RESULTS: Standard 3H-ouabain binding was 39% less in samples from digitalised than from undigitalised subjects (p less than 0.001). Washing samples in buffer containing excess digoxin antibody fragments induced an increase in 3H-ouabain binding from 174(SEM 10) to 265(20) pmol.g-1 wet weight (n = 11, p less than 0.001) in samples from digitalised patients. After washing, the digitalis glycoside receptor concentration in left ventricle samples showed a tendency to a lower value (14%, p greater than 0.10) in patients exposed to digoxin compared to left ventricle samples from individuals unexposed to digitalis glycoside treatment. Calculating 3H-ouabain binding relative to dry ventricular muscle weight confirmed the results obtained using wet weight as reference. CONCLUSIONS: The results suggest that digoxin treatment in life is associated with a 34% occupancy of digitalis glycoside receptors with digoxin. In the human heart there was no evidence for upregulation of digitalis glycoside receptor concentration due to long term digitalisation. Thus at receptor level there was no evidence for development of tolerance to digoxin therapy. The lower digitalis glycoside receptor concentration in the left ventricle observed in the heart failure patients may support the report of a relationship between Na,K-ATPase concentration as evaluated by 3H-ouabain binding and left ventricular function.

Aged↗
PubMed1992

The reactions of beta- and alpha-pyranose peracetates with PCl5, and utilization of the products to construct sarsasapogenin glycosides.

The reactions of beta- and alpha-pyranose peracetates with PCl5 gave products regioselectively chlorinated. The reactions of 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose (5) and -beta-D-galactopyranose (6) with PCl5 in CCl4 and that of methyl 2,3,4-tri-O-acetyl-beta-D-glucuronatopyranose (7) with PCl5 in toluene gave 2-O-trichloroacetyl-beta-D-pyranosyl chlorides 4, 12 and 14, respectively, as major products, and alpha-D-pyranosyl chlorides 11, 13 and 15, respectively, as minor products. On the other hand, the reactions of compounds 8 and 9 which were alpha-anomers of 5 and 6, respectively, with PCl5 gave as major products transformed acetyl groups at C-6 to -C(Cl) = CCl2 or -C(Cl)2-CCl3 group (16 and 17 from 8 and 18 from 9). The same reaction of 10, which was alpha-anomer of 7, gave alpha-chloride 15 as a major product. The glycosidation of sugar derivative 4 with sarsasapogenin 23 gave beta-glycoside 24 (29.1%) and alpha-glycoside 25 (46.9%), and that of 12 with 23 gave beta-glycoside 26 (24.0%) and alpha-glycoside 27 (40.8%). The improvement of the yields of beta-glycosides 24 and 26 (66.9 and 62.1% for 24 and 26, respectively) in the glycosidations were accomplished by the employment of alpha-bromides 28 and 29 obtained from 4 and 6, respectively. The glycosidations of monoglycosides 30 and 31 obtained by the treatment 24 and 26, respectively, with ammonia-saturated ether with sugar acetate bromides 32 and 34 gave diglycoside derivatives 35 and 33, respectively.

Acetates↗
PubMed1993

Preparation of glycyrrhetic acid beta-glycosides having beta (1-->2)-linked disaccharides by the use of 2-O-trichloroacetyl-beta-D-pyranosyl chlorides and their cytoprotective effects on hepatic injury in vivo.

Stepwise glycosidation was adopted for the construction of glycyrrhetic acid beta-glycosides (27-30) having beta (1-->2)-linked disaccharides such as 2-O-beta-D-glucuronopyranosyl-beta-D-glucopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucopyranosyl-beta-D-glucuronopyranose and 2-O-beta-D-galactopyranosyl-beta-D-glucuronopyranose. In the first glycosidation, 2-O-trichloroacetyl-beta-D-payranosyl chlorides (9-11) were utilized as starting sugar derivatives to react with methyl glycyrrhetinate (5): Glycosidation of 5 with 9 and 10 gave beta- and alpha-monoglycosides (12) and (13), and (15) and (16), respectively. Treatment of the beta-glycosides 12 and 15 with ammonia-saturated ether gave products (14) and (17), respectively. The glycosidation of 5 with 11 followed by treatment with ammonia-saturated ether gave compounds (18) and (19), respectively. The second step glycosidations of 14 and 17 with methyl 2,3,4-tri-O-acetyl-alpha-D-glucuronatopyranosyl bromide (20) gave diglycoside derivatives (23) and (24), respectively, and that of 18 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (21) and -alpha-D-galactopyranosyl bromide (22) gave diglycoside derivatives (25) and (26), respectively. The removal of the protecting groups of 23-26 gave diglycosides 27-30, respectively, having a beta-D-glucuronopyranose (beta-D-glcUA) as one of two sugar components in the molecules. The cytoprotective effects of the synthesized glycosides 27-30 on carbon tetrachloride (CCl4)-induced hepatotoxicity in vivo were compared with diglycosides 31-33 having only neutral sugar components and naturally occurring glycyrrhizin (34) having two acidic sugar components (beta-D-glcUA).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Sublethal effects of resin glycosides from the periderm of sweetpotato storage roots on Plutella xylostella (Lepidoptera: Plutellidae).

Resin glycoside material extracted from the periderm tissue of storage roots from sweetpotato, Ipomoea batatas (L.) Lam., was bioassayed for effects on survival, development, and fecundity of the diamondback moth, Plutella xylostella (L.). The resin glycoside was incorporated into an artificial diet and fed to P. xylostella larvae. First instars were placed individually into snap-top centrifuge vials containing artificial diet with one of six concentrations of resin glycoside material (0.00, 0.25, 0.50, 1.00, 1.50, and 2.00 mg/ml). Each replication consisted of 10 individuals per concentration, and the experiment was repeated 13 times. Vials were incubated at 25 degrees C and a photoperiod of 14:10 (L:D) h in a growth chamber. After 6 d, surviving larvae were weighted and their sex determined, then returned to their vials. Later, surviving pupae were weighed and incubated at 25 degrees C until moths emerged. Females were fed, mated with males from the laboratory colony, and allowed to lay eggs on aluminum foil strips. Lifetime fecundity (eggs/female) was measured. There were highly significant negative correlations between resin glycoside levels and survival, and between glycoside levels and larval weight after 6 d of feeding. For larvae that lived at least 6 d, there was no additional mortality that could be attributed to the resin glycoside material. However, there was a significant positive correlation between glycoside dosages and developmental time of larvae (measured as days until pupation). Lifetime fecundity also was negatively affected at sublethal doses. Resin glycosides may contribute to the resistance in sweetpotato breeding lines to soil insect pests.

Animals↗
PubMed2001

Glycoside in schizophrenic patients sera affects behavior of mouse forced swimming.

We found a glycoside in sera of schizophrenic patients. This glycoside increased climbing of mouse forced swimming and the climbing was decreased by dopamine D1 receptor antagonist SCH-23390 with a dose dependent manner. This glycoside had much reactivity of GalNAc alpha1-3GalNAc, but not that of polymannoses nor that of Gal beta1-3GlcNAc alpha1-serine or threonine. This strongly suggests that the glycoside is an isolated O-glycoside, but not N-glycoside nor O-glycoside having core 1 or 2. The present findings suggest that schizophrenic patients have the special glycoside affecting the D1 receptor activity in their serum.

Adult↗
PubMed1976

[New aspects on the mode of action of cardiac glycosides].

A dissociation of the therapeutic from the toxic effects of cardiac glycosides has repeatedly been described. Whereas it is generally accepted that the toxic effects of cardiac glycosides are based on an inhibition of the Na+-K+-ATPase, the mechanism of action of therapeutic concentrations of cardiac glycosides still remains uncertain. To test the hypothesis, that cardiac glycosides might be transported into a distinct compartment of the myocardium with the Na+-K-ATPase acting as a carrier, the interaction of some inhibitors of this enzyme (digitoxin, dihydroouabain, cassaine, N-ethylmaleimide, p-hydroxy-mercuribenzoate, ethacrynic acid, spironolactone) with ouabain was studied at different levels of cardiac glycoside actions: Myocardial function, cardiac uptake and subcellular distribution and binding to the Na+-K+-ATPase. The following results were obtained: All cardioactive drugs (ethacrynic acid and spironolactone showed no such effects) reduced dose-dependently the inotropic action of ouabain and in high concentrations increased its toxicity. The same drugs inhibited dose-dependently the cardiac uptake of ouabain without affecting the subcellular distribution pattern of ouabain. The binding of ouabain to the Na+-K+-ATPase was influenced in a similar way by these drugs, showing a competitive type of interaction with digitoxin, dihydroouabain and cassaine and a non-competitive mechanism with N-ethylmaleimide and p-hydroxymercuribenzoate. These results support the concept of a cardiac glycoside-ATPase interaction as a basis for the therapeutic action of these drugs. This may be explained either by a direct influence of cardiac glycosides on the ATPase activity and/or by a carrier mediated cardiac glycoside-transport into a distinct compartment of the myocardial cell.

Action Potentials↗
PubMed1982

Binding and endocytosis of cluster glycosides by rabbit hepatocytes. Evidence for a short-circuit pathway that does not lead to degradation.

Synthetic cluster glycosides containing either one, two, or three galactosyl or lactosyl residues per ligand were used to test the effect of carbohydrate clustering on binding by the rabbit hepatic Gal/GalNAc-binding lectin using either isolated rabbit hepatocytes or the solubilized, affinity-purified lectin. The tris- and bis-glycosides were superior to the mono-glycosides for inhibition of 125I-asialoorosomucoid binding to rabbit hepatocytes at 0 degrees C. The concentrations of the tris-glycosides required for 50% inhibition of 125I-asialoorosomucoid binding (4-8 microM) to hepatocytes were 50-100 times lower than the concentrations of the corresponding mono-glycosides required for 50% inhibition (400-500 microM). The isolated lectin, however, did not effectively discriminate between the mono-, bis-, and tris-glycosides, possibly indicating an organizational difference between the lectin in the cell membrane and the isolated lectin. When the cluster glycosides were labeled with 125I-tyrosine, it was shown that the tris- and bis-galactosides were bound to the hepatocytes at 37 degrees C, and that binding was followed by a step that led to ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid resistance, probably internalization. The process could be specifically inhibited by the neoglycoprotein Gal44-AI-bovine serum albumin, or by IgG specific for the hepatic lectin, but not by preimmune IgG. Internalization of the cluster glycosides did not lead to accumulation of ligand inside the cell, nor to degradation. Instead, the ligands were quickly released from the cells.

Animals↗
PubMed1989

Pinpointing the sites of hydroxylysine glycosides in peptide alpha 1-CB7 of bovine corneal collagen, and their possible role in determining fibril diameter and thus transparency.

Two cyanogen bromide fragments (alpha 1-CB7 and alpha 1-CB8) of bovine corneal stromal collagen have been isolated and characterized. These added to those characterized in our previous work account for 95% of the amino acid sequence of the alpha 1(1)-chain. The hydroxylysine glycoside content of each fragment was determined and in this way the general distribution of glycoside over the entire molecule was deduced accounting for all the galactosylhydroxylysine and most of the glucosylgalactosylhydroxylysine of this heavily glycosylated type I collagen. The characterization of fragments alpha 1-CB7 and alpha 1-CB8 has enabled us to resolve the controversy over the relative mobilities of these fragments on SDS gels. Fragment alpha 1-CB7 of bovine corneal collagen was digested by trypsin and by staphylococcal proteinase V8. The resultant peptides were isolated by gel and ion-exchange chromatography and identified in relation to the known amino acid sequence of type I collagen. The hydroxylysine glycosides were determined in the relevant peptides providing a complete account of their distribution along this part of the collagen molecule. Most of the glycoside was found in the gap region of collagen especially near the edges of the axial holes where it could act as a peg to facilitate fibre formation. In addition, some glycoside was found in the overlap region where, being unable to fit into axial holes, it might impede the growth of the fibre and, with other glycoside of the overlap region, might be responsible for the narrow fibres of corneal collagen that are essential for corneal transparency. This glycoside, with that previously found in the peptide alpha 1-CB3 is the only hydroxylysine glycoside identified in the overlap region of a type I collagen.

Amino Acid Sequence↗
PubMed1997

Inhibition of peripheral blood mononuclear cell proliferation by cardiac glycosides.

INTRODUCTION: Prior studies have shown that ouabain, a cardiac glycoside that inhibits the sodium, potassium adenosine triphosphatase (Na+,K+ ATPase) enzyme, downregulates phytohemagglutinin (PHA)-induced peripheral blood mononuclear cell (PBMNC) proliferation. OBJECTIVE: This study examined and compared the effects of both ouabain and digoxin, a cardiac glycoside used therapeutically in humans, on PBMNC proliferation. METHODS: Peripheral blood mononuclear cells were isolated from healthy human subjects, incubated for 72 hours with and without PHA (2%) in the presence and absence of ouabain (10(-12) M to 10(-4) M) or digoxin (10(-9) M to 10(-6) M), and pulsed with 3H thymidine. RESULTS: For PHA-stimulated PBMNCs in the ouabain-treated group (n = 10 subjects), the mean (+/-STD) % uptake (% 3H thymidine uptake in absence of ouabain) was 80.5 +/- 6.0 at 10(-12) M ouabain, 73.1 +/- 8.4 at 10(-10) M, 47.89 +/- 13.1 at 10(-8) M, 6.9 +/- 3.2 at 10(-6) M, and 3.4 +/- 1.6 at 10(-4) M. For PHA-stimulated cells in the digoxin-treated group (n = 9 subjects), the mean (+/-STD) % uptake (% 3H thymidine uptake in absence of digoxin) was 89.8 +/- 9.8 at 10(-9) M digoxin, 92.6 +/- 8.2 at 10(-8) M, 54.3 +/- 19.8 at 10(-7) M, and 1.0 +/- 2.4 at 10(-6) M. Repeated measures ANOVA demonstrated a significant effect of concentration of both glycosides on PBMNC proliferation (P < .01). The inhibitory effect was reversible, but was largely abbrogated if ouabain was added after 48 hours of incubation with PHA. Further, the inhibitory effect extended to PBMNCs stimulated with recall antigen (tetanus) and to fractionated PBMNCs (CD4+, CD8+ and CD19+) stimulated with mitogens. Additionally, dose-response inhibitory effects of glycosides on PBMNC Na+,K+ ATPase enzyme activity and interleukin-2 (IL-2) secretion by PHA-stimulated PBMNC were also noted. Neither glycoside had an effect on spontaneous PBMNC proliferation (no PHA) or trypan blue exclusion. CONCLUSIONS: These studies demonstrate that both cardiac glycosides inhibited PHA-induced PBMNC proliferation, possibly via Na+,K+ ATPase inhibition, but not via cell toxicity. The concentration range over which inhibition was observed was similar for both glycosides. The results raise the possibility that therapeutic or toxic doses of digoxin could have an effect on cell-mediated immunity in vivo.

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