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Biomedical subjects

C Salerno

Publications and source records attributed to C Salerno.

At least 19 recordsLinked to original sources
PubMed2005

Inhibition of defective adenylosuccinate lyase by HNE: a neurological disease that may be affected by oxidative stress.

Adenylosuccinate lyase is an enzyme of fumarase superfamily that participates in the purine biosynthetic pathway, catalysing the nonhydrolytic cleavage of succinyl groups from SAICA ribotide and adenylosuccinate. Enzyme defects are associated with a human inherited disease, which arises from single point mutations to the gene and results in mild to severe psychomotor retardation, epilepsy, muscle wasting, and autistic features. Adenylosuccinate lyase activity is lost to a different extent in the patients. Diminished levels of enzyme have been attributed to loss of catalytic activity, protein instability, or environmental factors. P100A/D422Y mutation represents a feasible model for studying the effect of cell milieu on the activity of the impaired enzyme. The defective enzyme is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal (HNE), a major product of membrane peroxidation that has been found to accumulate in brain tissues of patients with neurodegenerative disorders. It is suggested that inactivation of defective adenylosuccinate lyase by HNE and other membrane peroxidation products may account, at least in part, for the impairment of neurological functions and recurrent worsening of the symptoms.

Adenylosuccinate Lyase↗
PubMed2005

Inhibition of ion transport ATPases by HNE.

4-Hydroxy-2,3-trans-nonenal (HNE), a major lipid peroxidation product, has been shown to react with specific amino acid residues of proteins and alter their function. In vitro exposure of erythrocyte ghosts and neutrophil membranes to HNE results in the inhibition of ion transport ATPases. Neutrophil membrane Ca2+-ATPase is strongly inhibited by micromolar concentrations of HNE, while HNE is considerably less effective against neutrophil Mg2+-ATPase and the erythrocyte ghost enzymes.

Adenosine Triphosphatases↗
PubMed2005

Effect of carotenoid oxidation products on neutrophil viability and function.

Human neutrophils are short-lived cells that play important roles in host defense and acute inflammation by releasing hydrolytic and cytotoxic proteins and reactive oxygen derivatives. Apoptosis, a physiological mechanism for cell death, regulates both production and survival of neutrophils, representing a basic biological mechanism for this type of cells. Carotenoids may react with toxic oxygen metabolites released by neutrophils to form a multitude of carotenoid cleavage products that exert, in turn, relevant prooxidative biological effects. Recent data suggest that carotenoid oxidation products may affect neutrophil viability and function by exerting proapoptotic activity and interfering with superoxide production by activated cells. The prooxidant and proapoptotic activities of carotenoid oxidation products could account, at least in some cases, for the procancerogenic properties of carotenoid rich diet.

Apoptosis↗
PubMed2004

Urinary methylxanthine and autistic disorder: absence of previously reported correlation.

We were unable to reveal significant difference in the levels of xanthine and methylxanthines in the urine samples from 59 patients diagnosed with autistic symptoms and 64 age- and sex-matched normal volunteers. Our data suggest that abnormalities in xanthine and methylxanthine excretion (US Patent 20020019406 A1, Feb. 12, 2002) represent distincly uncommon symptoms in autism.

Autistic Disorder↗
PubMed2004

Biochemical and molecular genetic correlation in adenylosuccinate lyase deficiency.

An homology model of human adenylosuccinate lyase structure shows that P100A substitution distorts the amino acid chain of domain I in the proximity of His-86, which behaves as general acid in the catalysis, and may expose Cys-98 and Cys-99 to oxidising agents. This model is in line with the observation that the defective protein is strongly inhibited by 4-hydroxy-2-nonenal, an hydroxyalkenal that is known to form thio-ether linkage with proteins.

Adenylosuccinate Lyase↗
PubMed2003

High sensitivity of plasma membrane ion transport ATPases from human neutrophils towards 4-hydroxy-2,3-trans-nonenal.

Lipid peroxidation results in release of 4-hydroxy-2,3-trans-nonenal (HNE), which is known to conjugate to specific amino acids of proteins and may alter their function. The effect of HNE on the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase, and calmodulin-stimulated Ca(2+)-ATPase has been studied both in erythrocyte ghosts and in neutrophil membrane preparations. Neutrophil Ca(2+)-ATPase was strongly inhibited by micromolar concentrations of HNE (IC(50) = 12 microM), that means in the range of pathophysiologically relevant HNE levels. The IC(50) value for neutrophil Na(+)/K(+)-ATPase was about 40 microM. HNE was considerably less effective against neutrophil Mg(2+)-ATPase and the erythrocyte ghost enzymes (IC(50) values range from 91 to 240 microM). The data suggest that HNE may play a specific role in the regulation of neutrophil calcium homeostasis in response to oxidative stress.

Adenosine Triphosphatases↗
PubMed2001

Neurologic aspects of adenylosuccinate lyase deficiency.

Adenylosuccinate lyase deficiency is an autosomal-recessive disorder of the purine de novo synthesis pathway, diagnosed up to now in approximately 40 patients. The clinical presentation is characterized by severe neurologic involvement including seizures, developmental delay, hypotonia, and autistic features. Neonatal seizures and a severe infantile epileptic encephalopathy are often the first manifestations of this disorder. The existence of genetic heterogeneity for the adenylosuccinate lyase defect could account for variability of the clinical presentation. Deficiency of purine nucleotides, impairment of energy metabolism, and toxic effects are potential mechanisms of cerebral damage. Laboratory investigations show the presence in urine and cerebrospinal fluid of succinylpurines, which are normally undetectable. Currently, no effective treatment is available for adenylosuccinate lyase deficiency. A search for this disorder should be included in the screening program of children with unexplained neonatal seizures or severe infantile epileptic encephalopathy.

Adenylosuccinate Lyase↗
PubMed2000

Succinylpurinemic autism: increased sensitivity of defective adenylosuccinate lyase towards 4-hydroxy-2-nonenal.

We studied the effect of trans-4-hydroxy-2-nonenal on the wild-type human adenylosuccinate lyase and on the enzyme from a patient compound-heterozygous for two missense mutations (P75A/D397Y; McKusick 103050.0003/103050.0004). Both the enzymes were inhibited by 10-50 microM trans-4-hydroxy-2-nonenal in a concentration-dependent manner by means of a mixed-type co-operative mechanism. A significantly stronger inhibition was noticed in the presence of the defective enzyme. Nonanal and trans-2,3-nonenal inhibited the enzymes to a less extent and at about 10-times higher concentrations. Hydroxylamine reversed the inhibition by trans-4-hydroxy-2-nonenal, trans-2,3-nonenal or nonanal in the case of the wild-type enzyme, but it was ineffective to reverse the inhibition by trans-4-hydroxy-2-nonenal on the defective enzyme. Dithiothreitol slightly decreased the inhibition exerted by trans-4-hydroxy-2-nonenal on both the wild-type and the defective adenylosuccinate lyase, while it did not produce practically any change in the presence of trans-2,3-nonenal or nonanal.

Adenylosuccinate Lyase↗
PubMed1999

Determination of urinary orotic acid and uracil by capillary zone electrophoresis.

We describe a simple method for measuring orotic acid and uracil concentration in urine by capillary zone electrophoresis in 20 mM Na-borate buffer, pH 9.2. The method was applied for studying a patient with HHH (hyperomithinemia, hyperammonemia and homocitrullinuria) syndrome. A high value of uracil excretion was found during periods of relatively low orotic acid excretion and normal ammonemia. The orotic acid level in urine was increased by increasing protein intake.

Amino Acid Metabolism, Inborn Errors↗
PubMed1999

Effect of D-ribose on purine synthesis and neurological symptoms in a patient with adenylosuccinase deficiency.

Oral supplementation of 10 mmol/kg/day of D-ribose to a patient with an inherited deficit of adenylosuccinase, severe psychomotor retardation, and epilepsy caused a marked increase in plasma concentration and urinary excretion of urate, while minor changes in succinylpurine levels were observed. D-Ribose administration was accompanied by a slight improvement of behaviour and a progressive reduction of seizure frequency, which increased dramatically upon two attempts to withdraw the drug. Substitution of D-ribose with an equivalent amount of D-glucose did not result in an increase of seizure frequency.

Adenylosuccinate Lyase↗
PubMed1998

Identification of new mutations in the adenylosuccinate lyase gene associated with impaired enzyme activity in lymphocytes and red blood cells.

We determined the DNA sequence of the adenylosuccinate lyase (ASL) gene from a 13 year-old female, who showed a reduced ASL enzymatic activity in lymphocytes and red blood cells and suffered from severe psychomotor retardation. The patient was the offspring of a non-consanguineous marriage. She was found to be compound heterozygous for two missense-mutations located on different alleles (C300-G and G1266-T): the first mutation replaces Pro75 by Ala, the second mutation replaces Asp397 by Tyr.

Adenylosuccinate Lyase↗
PubMed1997

Effects of calmodulin antagonists on calcium pump and cytosolic calcium level in human neutrophils.

The concentration of cytosolic free calcium was monitored in suspensions of intact human neutrophils in phosphate-buffered saline by means of the fluorescent indicator Indo 1 trapped in the cytosol. Trifluoperazine and n-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide markedly reduced the amplitude of the transient increase in cytosolic Ca2+ triggered by CaCl2 as well as by N-formyl-methionyl-leucyl-phenylalanine. The effect of the calmodulin antagonists on the calcium burst observed upon cell activation was much more pronounced in the presence of extracellular free calcium than in EGTA-containing media; it was not inhibited by wortmannin or thapsigargin. Nevertheless, trifluoperazine and n-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited the plasma-membrane Ca2+ ATPase if added to plasma membrane-enriched fractions of neutrophils. These results suggest that calmodulin antagonists affect calcium ion influx even if they inhibit plasma membrane Ca2+ ATPase.

Calcium↗