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PubMed1988

Endogenous cardiac glycoside-like substances in newborns, adults, pregnant women and patients with hypertension or renal insufficiency.

In an attempt to confirm the presence of endogenous substances with cardiac glycoside-like activity, the biological and immunological cardiac glycoside-like activity was measured by a sensitive solid-phase radioimmunological assay (RIA), two radioreceptor assays (RRA), and a 86Rb uptake method in normal subjects and in some pathophysiological conditions characterized by sodium retention and volume expansion. Significant concentrations of digoxin-like immunoreactive substances (DLIS) were measured in plasma (or serum) of normal subjects while significantly higher levels were found in pregnant women, newborns and in patients with renal impairment, and in some with essential hypertension. Concentrations in urine of normal adults or newborns were several times higher than in plasma. The results obtained by RIA correlated with those obtained by RRA and 86Rb uptake methods. In 88 normal subjects, DLIS excretion rates (overnight urine collection) in men were significantly higher than in women (68.6 +/- 23.6 pg/min vs 50.9 +/- 21.0 pg/min, p less than 0.01). The DLIS excretion rates correlated with creatinine, Na and K urinary excretion rates, and also with the subjects' body weight, height, body mass index, and systolic blood pressure. These findings confirm the presence of endogenous substances with immunological and biological activity similar to cardiac glycosides in human body fluids and also confirm the hypothesis that these endogenous factors may be involved in fluid and electrolyte regulation in man. In addition, the present data indicate that urinary excretion of DLIS is dependent on body mass and renal glomerular filtration.

Adult↗

PubMed1984

Synthesis of nucleotides with specific radiolabels in ribose. Primary 14C and secondary 3H kinetic isotope effects on acid-catalyzed glycosidic bond hydrolysis of AMP, dAMP, and inosine.

Adenosine 5'-phosphate was synthesized with 3H or 14C label specifically located as [1'-3H]AMP, [1'-14C] AMP, [5'-3H]AMP, and [5'-14C]AMP. The synthesis was accomplished from adenine and glucose or adenine and ribose using enzymes from the pentose pathway and/or from the purine salvage pathways. Structural analysis of the compounds confirmed the locations of the radiolabels. The methods provide a general scheme for the efficient synthesis of adenine nucleotides of high purity with 3H or 14C at any stable position on the ribose ring. Synthesis of [5'-14C]dAMP and [1'-3H] dAMP from the corresponding ribonucleotides was accomplished with ribonucleotide reductase. Labeled inosine was prepared by enzymatic dephosphorylation and deamination of labeled AMP. These compounds have been used to measure the secondary kinetic isotope effects on the acid-catalyzed hydrolysis of the N-glycosidic bond of AMP, dAMP, and inosine and the corresponding primary kinetic isotope effects with AMP. Acid hydrolysis in 0.1 or 0.2 N HCl at 50 degrees C gave 1H/3H secondary kinetic isotope effects of 1.23 +/- 0.01, 1.26 +/- 0.01, and 1.230 +/- 0.003 for AMP, dAMP, and inosine, respectively. The primary kinetic isotope effect for 12C/14C was 1.049 +/- 0.010 for AMP. The apparent rate constants for hydrolysis under these conditions were similar for inosine and AMP and were in the range 10(-6)-10(-5)s-1. Acid hydrolysis of dAMP is approximately 1000-fold faster than AMP but gives a similar 1H/3H kinetic isotope effect. The results of secondary isotope effects indicate that the transition states for the acid-catalyzed hydrolysis of the N-glycosidic bonds of inosine, AMP, and dAMP have similar bonding to 1'-3H in the transition state and have considerable carboxonium character. Results with [1'-14C]AMP demonstrate that a significant primary isotope effect can be measured in the acid solvolysis of the N-glycosidic bond of AMP.

Adenosine Monophosphate↗

PubMed1995

Glycoside-bearing liposomal delivery systems against macrophage-associated disorders involving Mycobacterium leprae and Mycobacterium tuberculosis.

Asiaticoside, a plant glycoside with rhamnose as end sugar and having microbicidal properties was tested against Mycobacterium leprae and Mycobacterium tuberculosis both in vivo and in vitro. As rhamnose is reported to have no tissue specificity, corchorusin D having glucose as end sugar was used for targeting with an equimolar proportion of asiaticoside in liposomal form for testing the drug value. Results showed that liposomal asiaticoside had better microbicidal property against M. leprae and M. tuberculosis when compared to that of free asiaticoside whereas liposomes containing asiaticoside and corchorusin D were found to be equally or more active in comparison to liposomal asiaticoside alone. It is inferred that appropriate glycosides, if used in liposomal form (incorporated or covalently grafted) have enhanced drug efficacy and such glycoside bearing liposomes as targeted delivery systems could be used for chemotherapeutic control of several other diseases.

Animals↗

PubMed1993

Amino acid residues of the Na,K-ATPase involved in ouabain sensitivity do not bind the sugar moiety of cardiac glycosides.

The identification of amino acid substitutions in the alpha subunit of the Na,K-ATPase that alter cardiac glycoside sensitivity provides a unique opportunity to examine the role these residues play in binding to the structural domains of these drugs. Substitution of a residue(s) involved in binding to the sugar moiety of cardiac glycosides would be expected to yield similar affinities for ouabain and its aglycone, ouabagenin. Sheep Na,K-ATPase alpha 1 subunit amino acid substitutions previously shown to influence ouabain sensitivity were tested for activity in the presence of ouabain and ouabagenin. These substitutions included both transmembrane and extracellular regions: C104F, D121E, N122D, Q111K, N122K, and Q111R, A112S. Na,K-ATPase activity versus drug concentration curves yielded I50 values over a 1000-fold range for wild type HeLa and HeLa transfectants. Interestingly, the I50 ratio for ouabagenin to ouabain in all mutants tested indicated a 19-24-fold lower affinity of the Na,K-ATPase for ouabagenin. This constant ratio among all mutations tested implies that the first transmembrane region and the first extracellular loop (H1-H2) do not participate in the binding of the sugar moiety of cardiac glycosides.

Amino Acid Sequence↗

PubMed1993

Glycoside antibiotics alone and combined with tetracyclines for prophylaxis of experimental cryptosporidiosis in neonatal BALB/c mice.

Glycoside antibiotics including the macrolide antibiotics azithromycin, clarithromycin, and erythromycin and the aminoglycoside paromomycin were administered alone or combined with doxycycline, minocycline, or tetracycline to neonatal BALB/c mice experimentally infected with Cryptosporidium parvum. Glycosides at 100 or 200 mg/kg of body weight and tetracyclines at 50 mg/kg of body weight were dissolved in dimethylsulfoxide (DMSO), which was then diluted with phosphate-buffered saline (PBS) and given orally by gavage. Drugs were administered at 0, 24, 48, and 72 hr postinfection (PI) for prophylaxis. Histologic sections of ileum, cecum, and colon from tissues fixed at 96 hr PI were examined microscopically to determine the number of developing parasites and assign a quantitative score based on infectivity. All groups that received glycosides had significantly (P < 0.01) lower scores than controls that received only DMSO/PBS. A range in efficacy was apparent. None or extremely few parasites were found in paromomycin- and azithromycin-treated groups, whereas few to moderate numbers of parasites were found in erythromycin- and clarithromycin-treated groups. The addition of tetracyclines did not consistently result in significantly lower scores.

Animals↗

PubMed1977

[Clinico-electrocardiographic, morphological and biochemical manifestations of glycoside poisoning in patients with myocardial infarct].

The clinical manifestations of glycoside toxicosis were compared with the character of myocardial ultrastructural changes and the electrolyte shifts outside the infarction zone. Accumulation of glycogen in the cytoplasm of the muscle cells with simultaneous gross destruction of the myocardial ultrastructure in the pre-infarction zones are morphological manifestations of glycoside toxicosis on the ultrastructural level. The administration of strophanthin to patients with extremely severe cardiac insufficiency due to myocardial infarction may lead to disturbance in the mitochondrial energy-producing activity and the development of nodes of myofibril over-contractility with subsequent death of the cell, even to the development of smallfocal necrosis in the myocardium. The use of lidocaine and panangin in sufficiently high doses is an effective measure in the prevention and elimination of extrasystolic arrhythmias caused by glycoside toxicosis.

Acute Disease↗

PubMed2000

Profile of glycosaminoglycan-degrading glycosidases and glycoside sulfatases secreted by human articular chondrocytes in homeostasis and inflammation.

OBJECTIVE: To determine enzymatic activities of the 8 key glycosaminoglycan-degrading glycosidases and glycoside sulfatases in cultured human articular chondrocytes and in synovial fluid from patients with osteoarthritis. METHODS: The following enzymes were analyzed: hexosaminidase and its isoenzyme A, N-acetyl-alpha-D-glucosaminidase, beta-galactosidase, beta-glucuronidase, alpha-L-iduronidase, aryl sulfatase, and galactose-6-sulfate sulfatase. Activity of the selected enzymes was analyzed by fluorometry with the aid of 4-methylumbelliferryl derivatives of the appropriate monosaccharides. RESULTS: Hexosaminidase was found to be the dominant enzyme released by chondrocytes into the extracellular compartment. Stimulation of chondrocytes with interleukin-1beta resulted in a selective increase of the extracellular hexosaminidase activity and, to a lesser degree, of the extracellular beta-galactosidase activity, without significant changes in the activity of the other studied enzymes. Analysis of the pH dependency of the enzymatic activities revealed that even at neutral pH, hexosaminidase expressed a measurable activity, much higher than the activity of the other studied enzymes. Chondrocyte apoptosis did not result in increased extracellular glycosidase activities, including hexosaminidase activity. The spectrum of glycosidase and glycoside sulfatase activities in the synovial fluid from patients with osteoarthritis was similar to that in cultured human articular chondrocytes. CONCLUSION: These data support the concept that lysosomal glycosidases, in particular hexosaminidase, represent a distinct subset of cartilage matrix-degrading enzymes that are activated by proinflammatory stimuli.

Apoptosis↗

PubMed1988

Localization and catabolism of cyanogenic glycosides.

The catabolism of cyanogenic glycosides is initiated by cleavage of the carbohydrate moiety by one or more beta-glycosidases, which yields the corresponding alpha-hydroxynitrile. Until recently, the mode by which cyanogenic disaccharides are hydrolysed was largely unclear. Investigation of highly purified beta-glycosidases from plants containing cyanogenic disaccharides has now indicated that these compounds may be degraded via two distinct pathways, depending on the plant species. beta-Glycosidases from Davallia trichomanoides and Vicia angustifolia hydrolysed (R)-vicianin and (R)-amygdalin at the aglycone-disaccharide bond producing mandelonitrile and the corresponding disaccharide. Alternatively, hydrolysis of cyanogenic disaccharides in Prunus serotina, almonds, and Linum usitatissimum involves stepwise removal of the sugar residues. The nature of these enzymes and of other beta-glycosidases responsible for hydrolysis of simple cyanogenic monosaccharides is discussed. Hydroxynitriles may decompose either spontaneously or enzymically in the presence of a hydroxynitrile lyase to produce hydrogen cyanide and an aldehyde or ketone. The major kinetic and molecular properties of hydroxynitrile lyases purified from species accumulating aromatic and aliphatic cyanogens are reviewed. Cyanogenesis occurs rapidly only after cyanogenic plant tissues are macerated, allowing glycosides access to their catabolic enzymes. The possible nature of the compartmentation which prevents cyanogenesis under normal physiological conditions is discussed in relation to our knowledge of the tissue and subcellular localizations of cyanogens and catabolic enzymes.

Aldehyde-Lyases↗

PubMed2026

Tripterygium Glycosides Alleviates Hemophagocytic Lymphohistiocytosis Accompanied With Aggressive NK Cell Leukemia and Epstein-Barr Virus Infection.

Hemophagocytic lymphohistiocytosis (HLH) is a group of hyperinflammatory disorders with a mortality rate exceeding 50%. We report a case of a female Asian patient who developed secondary HLH accompanied by aggressive natural killer cell leukemia and Epstein-Barr virus (EBV) infection, and was treated with tripterygium glycosides (TG), a Chinese patent medicine. Within 3 weeks of oral administration, the patient's recurrent high fever resolved, abdominal distension and splenomegaly improved, ascites diminished, serum soluble CD25 levels decreased, and hematopoietic and coagulation functions recovered. Triptolide, a major component of TG, exhibited cytotoxicity against the patient's ascitic cells and induced apoptosis in a dose-dependent manner ex vivo. Whole-genome and transcriptome sequencing of the patient's tumor cells revealed that TG regulated EBV-associated mutated genes such as PSMD7 and modulated inflammation-related pathways. Molecular docking further suggested direct targeting of PSMD7 by triptolide. Tripterygium glycosides quickly mitigated cytokine storm, alleviated symptoms of HLH, and showed no observed adverse effects with a good cost-benefit profile, thereby offering a potential bridge for follow-up hematopoietic stem cell transplantation.

Humans↗

PubMed1986

Cardiac glycosides with non-rotating steroid to sugar linkages: tools for the study of digitalis structure-activity relationships.

The 5 alpha H-cardenolide, gomphoside, is one of a small group of naturally occurring cardiac glycosides in which the sugar residue is bilinked to the steroid ring system. This arrangement prevents the sugar moiety from rotating and this makes gomphoside and related compounds potentially useful for structure-activity relationship (SAR) studies. When gomphoside was tested for inotropic activity using guinea pig left atria, the compound was found to have very high potency comparable to the most active 5 beta H-cardenolides. Removal of the sugar moiety reduced inotropic activity almost 500-fold indicating that it was the presence of the sugar moiety that was mainly responsible for the drug's high potency. Modification of the steroid or sugar residue of gomphoside reduced activity in all cases. It would thus appear that gomphoside with its high potency and non-rotatable glycosidic linkage is an excellent tool for SAR studies.

Animals↗

PubMed2005

Hydrolysis of terpenyl glycosides in grape juice and other fruit juices: a review.

The importance of monoterpenes on varietal flavour of must and other fruit juices has been reviewed. These compounds were mainly found linked to sugar moieties in grape juice and wines, showing no olfactory characteristics. In this way, analytical techniques developed to study these compounds, in both free or glycosidically forms, are discussed. Mechanisms to liberate terpenes were studied, making a comparative study between acidic and enzymic hydrolysis of terpene glycosides; as enzymic hydrolysis seems to be the most natural way to liberate terpenes, the ability to use glycosidases from grapes, yeasts, bacterial or exogenous, i.e. fungal commercial preparations, were reviewed. Re-arrangements of terpenes after acidic hydrolysis of glycoconjugated are discussed as well as potential adverse effects of enzyme preparations.

Bacteria↗

PubMed2026

Unlocking the molecular engineering of Geobacillus glycoside hydrolases as a source of industrial biocatalysts.

This review examines Geobacillus sensu stricto as a source of thermostable glycoside hydrolases (GH) for biomass conversion, food processing, and enzyme engineering. Recent peer-reviewed literature was assessed with emphasis on taxonomy, genome-based Carbohydrate-Active Enzymes (CAZyme) prediction, biochemical validation, structural data, and engineering case studies. Taxonomic boundaries were interpreted using current Anoxybacillaceae frameworks, with Parageobacillus treated as a related comparator rather than as Geobacillus. The strongest evidence supports GH13 alpha-amylases, xylan-active systems, beta-xylosidases, and selected accessory enzymes. Recent studies also show that genome mining must be coupled with enzymatic assays and product profiling because CAZyme annotation alone does not prove industrial function. Molecular engineering has improved relevant traits, including the longer thermal half-life of engineered G. stearothermophilus alpha-amylase variants, the increased catalytic efficiency of oligo-alpha-1,6-glucosidase variants, and improved AmyS expression in Bacillus subtilis. Geobacillus glycoside hydrolases are best interpreted as process-specific, engineerable biocatalytic templates. Their translation requires reliable taxonomy, functional validation, structural interpretation, scalable expression and testing on realistic substrates. This synthesis also recognises current limitations: many predicted CAZymes still lack biochemical validation, complete cellulolytic systems remain less mature than xylan- and starch-active systems, and scale-up data remain scarce.

Geobacillus↗

PubMed1990

Enzymic synthesis of HexNAc-containing disaccharide glycosides.

The following disaccharide glycosides were obtained from the appropriate donor and acceptor glycosides by employing glycosidases from the mollusc Chamelea gallina as catalysts: alpha-D-Galp-OMe (N-acetyl-alpha-D- galactosaminidase), beta-D-GalpNAc-(1----3)-beta-D-Galp-OMe, beta-D-GlcpNAc-(1----3)-beta-D-Galp-OMe, and beta-D-GlcpNAc-(1----6)-alpha-D-Manp-OMe (N-acetyl-beta-D-hexosaminidase). The regioselectivity of the N-acetyl-beta-D-hexosaminidase-catalysed reactions depended on the anomeric configuration of the acceptor. Thus, alpha-D-Galp-OMe gave beta-D-GlcpNAc- (1----6)-alpha-D-Galp-OMe almost exclusively, whereas beta-D-Galp-OMe gave beta-D-GlcpNAc-(1----3)-beta-D-Galp-OMe and beta-D-GlcpNAc-(1----6)-beta-D-Galp-OMe in almost equal amounts. The isolation of the products by chromatography was straightforward.

Animals↗

PubMed1988

Isolation of alkaloids and glycosides from tissue following enzymic digestion.

Four enzymic digestion methods have been evaluated for their efficiency in releasing certain alkaloids and glycosides from spiked liver tissue. Enzymic digestion gives better recoveries of all the plant poisons studied than those obtained by conventional methods. A flow diagram for the enzymic methods of drug isolation and quantitation by HPLC is presented. Enzymic digestion for the release of glycosides is reported for the first time. It is concluded that papain digestion is the most suitable method for the analysis of broad spectrum of compounds of forensic and clinical importance.

Alkaloids↗

PubMed2026

Validated UPLC-MS/MS quantification and intracellular PK-PD Modeling of periplocin-related cardiac glycosides in H/R-injured H9c2 cells.

Reliable intracellular quantification is essential for characterizing the target-site disposition and exposure-response relationships of bioactive natural products. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of periplocin and four related cardiac glycoside metabolites in H9c2 cell lysates. Acceptable linearity, precision, recovery, and stability were achieved for intracellular quantification. Cells were treated with each compound at 50 μM, and intracellular concentrations and cell viability were monitored over 48 h. In hypoxia/reoxygenation (H/R) -injured cells, the time to maximum intracellular concentration was shortened for all five compounds, indicating altered cellular disposition under injury conditions. Cell viability was improved by all compounds during the observation period. Pharmacokinetic-pharmacodynamic (PK-PD) integration was performed using a sigmoid Emax model, and acceptable model fits were obtained, with Akaike information criterion (AIC) values ranging from 79.22 to 130.46. Low apparent EC50 values were estimated under this single-dose design, whereas the estimated Ke0 values suggested delayed equilibration with the effect compartment. These findings indicate that sustained cytoprotective responses can be produced by periplocin and related metabolic markers in injured cardiomyocytes. This intracellular bioanalytical strategy provides a quantitative approach for linking cellular exposure to pharmacodynamic response and may support further evaluation of periplocin-related cardiac glycosides.

Tandem Mass Spectrometry↗

PubMed1990

Glycosidic bond cleavage of 5-fluoro-2'-deoxyuridine and 5-fluorouridine by amino acyl-tRNA synthetases.

Lysyl-tRNA synthetase isolated from rat liver cleaves glycosidic bond of 5-Fluorouridine and 5-Fluoro-2'-deoxyuridine to generate 5-Fluorouracil. The generation of 5-Fluorouracil was monitored by cellulose thin layer chromatography and by spectrophotometry. The enzyme was found to be 1.4 fold more efficient in cleaving the glycosidic bond of 5-Fluoro-2'-deoxyuridine than 5-Fluorouridine.

Animals↗

PubMed2000

A general approach to the synthesis of dideoxy and trideoxyiminoalditols from beta-D-glycosides.

Imino sugars (also called azasugars), a class of compounds of which the 1,5-dideoxy and 1,5,6-trideoxyiminoalditols are members, are important glycosidase inhibitors with very high potential as drugs. Their potential therapeutic applications range from the treatment of diabetes to cancer and AIDS. We present here a general method for the preparation of such compounds with the D-gluco and D-galacto configurations starting from beta-D-glycosides. The procedure is especially appealing because of its high stereoselectivity and straightforwardness. The key steps are the selective oxidation of the glycosides to hexulosonic acids and reduction of the oxime derivatives to lactams, which are further reduced to the target compounds. The C-6 position can be deoxygenated during the reduction if it bears an acetoxy group. Trideoxy imino sugars are then produced. Deacetylation prior to oxime reduction gives dideoxy compounds.

Aza Compounds↗

PubMed1991

Interaction of progesterone derivatives with the digitalis target enzyme: impact of glycosidation on inhibitory potency.

As a function of the structural modification of the steroid nucleus, the inhibitory interaction of 11 progesterone derivatives with human Na/K-ATPase (Na+/K(+)-transporting ATPase, EC 3.6.1.37), through C3-O-rhamnosylation, is either much decreased or weakly up to strongly increased, so that the rhamnosyl residue contributes to the complementary Gibbs energy of interaction, at the most, the same Gibbs energy increment as realized in ouabain. After C3 beta-O-rhamnosylation, the activity of some progesterone derivatives considerably surpasses that of 3 beta-O-rhamnosyl-chlormadinolacetate, which has been known to elicit positive inotropy in cats. The progesterone derivatives (aglycons and glycosides), that have been analysed more closely, produce their effects by the same molecular mechanism of interaction with Na/K-ATPase as characteristic for digitalis aglycons and glycosides. The results promise to pave the way for the identification of the chemical nature of endogenous digitalis and for the design of novel inotropic drugs.

Biotransformation↗