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PubMed1979

Neuraminidase deficiency in the original patient with the Goldberg syndrome.

Homogenates of cultured skin fibroblasts from a non-ambulatory, 20-year-old male with cherry-red spots, corneal clouding, seizures, mental retardation, dysostosis multiplex, dwarfism, coarse facies and loss of vision, originally described by Goldberg et al. (1971), have diminished neuraminidase activity and an excess of neuraminic acid-rich compounds. Specifically, these cells have 2-17% normal neuraminidase when measured with 2-(3' methoxyphenyl)-N-acetyl-alpha-neuraminic acid, N-acetyl-neuramin-lactose and fetuin. Activities of 12 other lysosomal enzymes were either at or above the range of normal control fibroblasts. Total neuraminic acid concentration was 44.3 nmol/mg protein versus an average control value of 14.2. It is concluded that the Goldberg syndrome should be considered, along with mucolipidosis I and the cherry-red spot -- myoclonus syndrome, as resulting from a primary neuraminidase deficiency.

Abnormalities, Multiple↗

PubMed1977

Effect of neuraminidase on the chromatographic behaviour of eleven acid hydrolases from human liver and plasma.

1. The elution profiles of eleven acid hydrolases from human liver and plasma were directly compared using a system whereby a single salt gradient was simultaneously applied to two DEAE-cellulose chromatographic columns. 2. Plasma alpha-L-fucosidase, alpha-mannosidase, alpha-galactosidase and alpha-glucosidase isoenzymes were eluted at higher salt concentrations than the corresponding liver isoenzymes whereasbeta-N-acetylglucosaminidase, beta-galactosidase, beta-glucosidase, exo-1,4-beta-xylosidase and alpha-L-arabinofuranosidase isoenzymes were eluted at lower salt concentrations. The elution profiles of beta-glucuronidase and acid phosphatase weremore complex. 3. After incubation with neuraminidase most plasma hydrolases were eluted at lower salt concentrations, however the elution patterns of beta-glucosidase, beta-xylosidase and acid phosphatase were not altered. 4. Preincubation with neuraminidase had no effect on the elution profiles of six liver hydrolases whereas the major isoenzymes of alpha-mannosidase, beta-galactosidase and alpha-L-arabinofuranosidase were eluted at markedly lower salt concentrations. Liver alpha-fucosidase and alpha-galactosidase were eluted at slightly lower salt concentrations afterincubation with neuraminidase. 5. The results are discussed in relation to thepathogenesis of Mucolipidosis II (I-cell disease), and the synthesis and packaging of lysosomal enzymes.

Acetylglucosaminidase↗

PubMed1979

Monomer-micelle transition of the ganglioside GM1 and the hydrolysis by Clostridium perfringens neuraminidase.

The action of Clostridium perfringens neuraminidase on the ganglioside Gm1 tritiated in the ceramide moiety was studied. The rates of hydrolysis of the Gm1 ganglioside were determined from radioactivity in the neutral glycolipid product, which was separated from the substrate on DEAE-Sephadex columns. In order to study the physical state of the substrate in the conditions used in the neuraminidase treatment, the critical micelle concentrations of the Gm1 ganglioside were determined using formation of the triiodide anion in aqueous iodine solution as an indicator. The critical micelle concentrations were also obtained by determining the non-sedimenting radioactivity at different concentrations of the labeled ganglioside per total volume used in ultracentrifugation experiments. In addition, the concentrations of the monomeric ganglioside were concluded from the results of the ultra-centrifugation studies. The increase in the reaction rate of the Gm1 hydrolysis as the function of the substrate concentration was leveled off at 25-28 microM ganglioside. The abrupt change at this concentration is interpreted as reflecting the monomer-micelle transition of the ganglioside in the conditions used (50mM sodium acetate buffer, pH 4.6). The critical micelle concentration was 29 microM on the basis of the triiodide test, and ultracentrifugation revealed the critical micelle concentration 28 microM. The reaction velocity of the hydrolysis was decreased immediately above the critical micelle concentration, and became constant at higher concentrations of the ganglioside. A close correlation to these changes in the reaction rate is suggested to exist in the concentrations of the monomeric Gm1 ganglioside. Saturation of the buffer used in the neuraminidase assays with butanol effected a striking change in the plot of reaction rate versus ganglioside concentration. The reaction rate increased up to 100-110 microM Gm1 ganglioside. The shift of the inflexion point in the rate plot from 25-28 microM to 100-110 microM ganglioside concentration is suggested to be due to a respective change in the critical micelle concentration effected by butanol. N-Acetylneuraminyllactosyl ceramide, lactosyl ceramide and asialo-Gm1 ganglioside had an inhibitory effect on the reaction. In contrast, N-acetylneuraminyllactose, lactose and some other free saccharides were not inhibitory. The results demonstrate that factors other than the saccharide structure must be taken into account when substrate specificity of a glycosidase is studied using competition experiments. It is suggested that the inhibition effected by the glycolipids is due to an increase in the micellar state of the Gm1 ganglioside.

Carbohydrates↗

PubMed1976

On the activation of plasma membrane ecto-enzymes by treatment with neuraminidase.

It had been proposed that sialyl-residues on the surface of the cell control the activity of certain plasma membrane ecto-enzymes. We have tested the effects of several established (or presumptive) ecto-enzymes in tissue cultures of CNS-derived cells. Application of neuraminidases to cultured mouse neuroblastoma (N-18), neonatal Syrian hamster astrocytes (NN), human astrocytoma (Cox clone) and two lines of primary mouse astroblasts failed to change the activity of ecto-ATPase and 5'-nucleotidase. Only two of the seven neuraminidase preparations produced marked or moderate increases in inorganic pyrophosphatase, p-nitrophenylphosphatase and cholinesterase. We have concluded that the stimulation of these enzymes was not due to removal of sialyl-residues. We suggest that contaminants (haemolysins?) in neuraminidase preparations of Clostridium perfringens increased membrane permeability and facilitated substrate-product translocation.

4-Nitrophenylphosphatase↗

PubMed1991

Stimulation of neurite outgrowth in neuroblastoma cells by neuraminidase: putative role of GM1 ganglioside in differentiation.

Treatment of three neuroblastoma cell types in culture with neuraminidase resulted in enhanced neurite outgrowth. These included the mouse Neuro-2A and rat B104 and B50 lines. The morphological changes depended on the presence of exogenous Ca2+ and were accompanied by modest but statistically significant increases in 45Ca2+ influx. Neuraminidase-stimulated neuritogenesis was blocked by the B subunit of cholera toxin (cholera B) and anti-GM1 antibody, a finding suggesting the effect was due to an increased amount of GM1 on the cell surface. Cholera B also blocked the increase in 45Ca2+ influx. The mouse N1A-103 line, previously characterized as "neurite minus," did not respond to neuraminidase with either neurite outgrowth or enhanced Ca2+ influx. These results point to an influence of GM1 on neuritogenesis in cells with differentiation potential and suggest a mechanism involving modulation of Ca2+ flux.

Animals↗

PubMed1990

Role of neuraminidase-dependent adherence in Bacteroides fragilis attachment to human epithelial cells.

Of 50 B. fragilis strains isolated from clinical samples we have demonstrated that 24 (48%) possess an adhesin that mediates a neuraminidase-dependent attachment of B. fragilis to mammalian epithelial cells, but does not mediate any association with human polymorphonuclear leucocytes. This ligand interacts with a mammalian cell receptor that contains a galactoside residue, exposed after neuraminidase pretreatment. Our results suggest a possible role for cell associated neuraminidase in mediating a two step adherence mechanism.

Adhesins, Bacterial↗

PubMed1977

Detection of anti-red blood cell antibodies by treatment of the cells with neuraminidase.

Neuraminidase treated RBC were used to detect incomplete unbound anti RBC antibodies in the plasma of patients with immune diseases. 80% (48 out of 60) of the examined patients gave positive results with this method while all the 50 normal controls were negative. The indirect antiglobulin test was negative in all the patients. In the direct antiglobulin test only two RBC samples, whether treated with neuraminidase or not, gave positive results. The present study indicates that the assay of plasma on neuraminidase treated RBC may serve as a sensitive method for the detection of the presence of anti RBC antibodies in various immunological diseases.

Adolescent↗

PubMed1982

Increase of the in vitro complement-dependent cytotoxicity against autologous invasive human bladder tumor cells by neuraminidase treatment.

Complement-dependent cytotoxicity (CDC) was measured in a 51-Cr release assay against tumor cells from 13 non-invasive and 7 invasive transitional-cell tumors of the urinary bladder. CDC was compared between mechanically dispersed tumor cells and neuraminidase-treated tumor cells. Neuraminidase treatment of bladder tumor cells enhanced their susceptibility to complement-dependent cytolysis. There were no differences in CDC between autologous and allogenic sera. Mechanically dispersed tumor cells showed no significant differences in susceptibility when non-invasive and invasive tumor cells were compared, whereas significant differences in CDC were seen when neuraminidase-treated non-invasive and invasive tumor cells were used as targets. A C2 deficient serum showed significantly reduced cytotoxicity suggesting that the CDC reaction requires classical complement activation. A hypogammaglobulinemic serum showed stronger CDC compared to autologous and other allogenic sera and upon dilution of autologous sera and hypogammaglobulinemic serum CDC declined parallelly.

Adult↗

PubMed1986

Electrophoretic analysis of liver neuraminidase-1 variation in mice and additional evidence concerning the location of NEU-1.

Neuraminidase-1 (NEU-1) is one of two neuraminidase isozymes which can be detected electrophoretically in mouse liver extracts. The inheritance of variation in NEU-1 and the linkage relationships of the gene controlling this variation were studied through a backcross analysis involving the SM/J and MA/MyJ inbred strains, and by examination of NEU-1 phenotypes in three congenic strains: B10.SM, B10.SM(22R) and B10.RVB. The data indicate that NEU-1 is controlled by Neu-1, a gene previously identified by its effect on total liver neuraminidase activity in whole tissue homogenates. Analysis of the congenic strains revealed identical low activity (SM/J-type: Neu-1a/Neu-1a) NEU-1 phenotypes in all three strains. This indicates that Neu-1 lies in the segment of the SM/J-derived H-2 region that is common to all three strains: H-2E alpha to H-2D. In addition, we examined the relationship between NEU-1 and phenotypic variation in liver acid phosphatase (AP; for which a new typing method is described) and linkage order among several other enzyme-coding genes linked to H-2. In all animals that could be scored confidently for AP, the NEU-1 and AP phenotypes were concordant, adding support to the hypothesis that both phenotypes are controlled by Neu-1. Recombination rates among six H-2-linked marker loci were unexpectedly low, but were sufficient to verify the position of Upg-1 as the telomeric flanking marker relative to Glo-1, H-2 (C4), Neu-1 (Apl), Ce-2 and Pgk-2.

Acid Phosphatase↗

PubMed1987

On the action of ruthenium red and neuraminidase at the frog neuromuscular junction.

1. The actions of the polyvalent cationic dye Ruthenium Red and the enzyme neuraminidase were studied at the frog neuromuscular junction. 2. Both Ruthenium Red (0.5-40 microM) and neuraminidase (1, 2 and 4 u.) reduced the miniature end-plate potential (m.e.p.p.) amplitude irreversibly with little change in frequency. This effect could be attributed to the depressant action of these agents on the amplitude of extracellularly recorded miniature end-plate currents (m.e.p.c.s) coupled with their shortening effect on the duration of these m.e.p.c.s. For example, 10 microM-Ruthenium Red reduced the time constant of decay (tau D) of extracellular m.e.p.c.s to 35% of the control value. 3. Ruthenium Red (5, 10 and 15 microM) produced a pronounced reduction in the post-synaptic end-plate sensitivity to microiontophoretically applied acetylcholine. In some cases this effect was fully reversible on wash-out of the dye. 4. Amplitude histograms of m.e.p.c.s recorded under voltage clamp showed a similar shift of the modal value to lower levels in the presence of Ruthenium Red. Over the voltage range -70 to -110 mV the action of Ruthenium Red on the tau D was not voltage dependent. 5. The actions of Ruthenium Red on tau D were not affected by anaesthetic agents, such as the short-chain alcohols which increased tau D, or ketamine which decreased tau D. 6. Some possible modes of action of Ruthenium Red and neuraminidase are briefly discussed.

Action Potentials↗

PubMed1998

Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection.

We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.

Acetamides↗

PubMed1998

Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071.

GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (Cmaxs; Cmax <0.06 microg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high Cmaxs of GS 4071 (Cmax = 0.47 microg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Acetamides↗

PubMed1974

Effect of parainfluenza-3 virus neuraminidase on the structure of the gel phase of bovine nasal secretion.

The gel phase of bovine nasal secretion was separated from the liquid phase and exposed to parainfluenza-3 virus or Vibrio cholerae neuraminidase under optimal in vitro conditions. N-Acetylneuraminic acid was released from the gel by either neuraminidase. The release of N-acetylneuraminic acid was accompanied by a decrease in the net negative charge of the gel, as evidenced by free zone electrophoresis. Scanning electron microscopy showed that after exposure to neuraminidases the regular network structure of the untreated gel attained a coarse, irregular structure. Samples of gel incubated with 0.15 M sodium chloride under similar conditions did not show changes in the net charge or morphology.

Animals↗

PubMed1977

Extracellular neuraminidase production by group B streptococci.

Neuraminidase (sialidase) activity in concentrated culture filtrates of group B streptococci was measured with bovine submaxillary mucin as substrate. Group B streptococcal neuraminidase was not active on human alpha-1 acid glycoprotein and did not show increased activity on bovine submaxillary mucin that had been O-deacetylated by alkaline treatment. The enzyme was produced in a variety of media, including a chemically defined medium (FMC; Terleckyj et al., Infect. Immun. 11:649-655, 1975) supplemented with bovine serum albumin or human serum albumin. Maximal levels of activity were present in filtrates from cells grown in a dialyzable fraction of Todd-Hewitt broth harvested during the late exponential phase of growth. Dramatic decreases were seen when filtrates from the late stationary phase were assayed. The decrease in specific activity during the stationary phase was shown to be due to proteolytic digestion of neuraminidase and not to the elaboration of an extracellular neuraminic acid aldolase.

Cell Cycle↗

PubMed1978

Association of elevated levels of extracellular neuraminidase with clinical isolates of type III group B streptococci.

The level of total extracellular neuraminidase produced by 74 clinical isolates of group B streptococci isolated from diseased or asymptomatically colonized infants was assayed. Extracellular neuraminidase was obtained from concentrated filtrates of exponentially growing cultures of group B streptococci grown in a chemically defined medium (FMC) containing supplemental protein. The total activity of extracellular enzyme produced by these clinical isolates ranged from less than 10 to 360 nmol of sialic acid released per min per mg of cell dry weight. Strains were arbitrarily classified as either nonproducers (less than 10 nmol/min per mg of cell dry weight), low producers (greater than 10 to less than or equal 140 nmol/min per mg of cell dry weight), or high producers (greater than 140 to 360 nmol/min per mg of cell dry weight). Type III isolates from diseased infants were significantly more often classified as high producers than strains of group B streptococci of other serotypes from diseased infants (P less than 0.001). Furthermore, the serotype III strains isolated from neonatal infections were more often high producers than those of the same serotype from asymptomatically colonized infants (P less than 0.025). These results suggest that the ability to produce elevated levels of neuraminidase may be related to the frequent association of type III strains with disease among neonates.

Culture Media↗

PubMed1979

Cell-mediated immune responses to the hemagglutinin and neuraminidase antigens of influenza A virus after immunization in humans.

Humoral and cell-mediated immunity (CMI) were evaluated in groups of school children after immunization with inactivated influenza virus vaccines. A conventional biphasic strain (H3ChN2Ch) of Port Chalmers influenza virus (X-41), a recombinant influenza virus specific for the neuraminidase antigen (Heq1N2Ch) of Port Chambers influenza A virus (X-42), and a placebo were employed for immunization. The techniques of hemagglutination inhibition and neuraminidase inhibition were used to determine serum antibody titers. The CMI responses were evaluated by the in vitro lymphocyte transformation assay employing HavN2Ch, Heq1Neq1, H3ChNeq1, and H3ChN2Ch influenza A virus strains as stimulants. Specific HAI antibody and CMI responses to H3Ch were observed in X-41 but not in X-42 vaccinees. Specific anti-neuraminidase antibodies and CMI responses to N2Ch were manifested by both X-41 and X-42 vaccinees. Immunization with the placebo resulted in no influenza-specific immune responses. The CMI response was first detectable 10 days after immunization and then declined. These observations demonstrate the induction of CMI responses to the HA and NA influenza surface antigens after immunization. These responses may be important in antiviral immunity and the recovery from influenza infection.

Antibodies, Viral↗

PubMed1980

Relationship between surface antigens of two variants of influenza A (H3N2) virus, as revealed by hemagglutination inhibition, kinetic neutralization, and neuraminidase inhibition.

Rabbit antisera were raised against plaque-purified influenza virus strains of A/Victoria/75 and A/Texas/77 isolated from Seattle influenza patients. The antigenic specificity of hemagglutinins was compared by hemagglutination inhibition (HI) and kinetic neutralization tests. Anti-A/Victoria/75 had equally high HI titers and neutralization rate constants (kappa values) for A/Victoria/75 and A/Texas/77. In contrast, anti-A/Texas/77 had a high HI titer and kappa value to A/Texas/77 and a low HI titer and kappa value to A/Victoria/75. Similar results were obtained with antisera to recombinants with hemagglutinin specific for A/Victoria/3/75 or A/Texas/1/77 and with irrelevant neuraminidase. Seven wild-type isolates, three each of A/Texas and A/Victoria, and one strain characterized as a bridging strain were tested by HI and kinetic neutralization. Characterization as A/Texas or A/Victoria was confirmed by the results. No significant difference in neuraminidase specific for A/Victoria/75 or A/Texas/77 was hown when recombinants with an irrelevant hemagglutinin were compared by the neuraminidase inhibition test. These results suggest that A/Victoria/75 strains are "senior" to A/Texas/77 strains. The epidemiological implications of this observation are discussed.

Animals↗

PubMed1982

Streptococcal neuraminidase and acute glomerulonephritis.

We examined the hypothesis that streptococcal neuraminidase may alter host serum immunoglobulin G so that autoantibodies are formed which lead to immune complexes and acute glomerulonephritis. We confirmed the observation that T-type 4 and T-type 12 streptococci (both associated with acute glomerulonephritis) are the most likely of many types studied to produce neuraminidase. However, we did not find this enzyme to be produced by any of 23 streptococcal strains isolated from patients with nephritis, whereas it was produced by two strains from patients with rheumatic fever and by one strain from a patient with scarlet fever. Also, we were unable to find direct or indirect evidence of increased neuraminidase activity in the sera of six patients with acute glomerulonephritis when they were compared with the sera of six patients with acute rheumatic fever and with those of six normal subjects.

Acute Disease↗