Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel fluorescent probe N-(N-(2-(4-morpholinyl)ethyl)-4-acridinecarboxamide)-alpha-alanine (N-(N-(ME)-4-ACA)-alpha-ALA) was synthesized. The structure was characterized by 1H NMR, MS, elemental analysis, fluorescent and ultraviolet spectra. This new compound exhibited high binding affinity to DNA, intense fluorescence and high water solubility. Experiment indicated that the fluorescent intensity was quenched when DNA was added. A method for DNA determination based on the quenching fluorescence (lambda(ex)=258nm, lambda(em)=451nm) of N-(N-(ME)-4-ACA)-alpha-ALA was established. Under optimal conditions (pH 7.2, CN-(N-(ME)-4-ACA)-alpha-ALA)=3 x 10(-6) mol L(-1)), the linear range is 0.1-4.0 microg mL(-1) for both fish semen (fsDNA) and calf thymus DNA (ct-DNA). The corresponding determination limits are 4.6 ng mL(-1) for fsDNA and 5.1 ng mL(-1) for ct-DNA, respectively. The relative standard deviation is 1.0%. Thus this compound can be used as a DNA fluorescent probe. The experiments proved that the interaction mode between N-(N-(ME)-4-ACA)-alpha-ALA and DNA was groove binding. The modified Rosenthal's graphical method gave the binding constant of 1.0 x 10(6) L mol(-1) and a binding size of 0.31 base pairs per bound drug molecule.
Spectrochim Acta A Mol Biomol Spectrosc 2008 Dec 15
PMID:Synthesis of a novel fluorescent probe and investigation on its interaction with nucleic acid and analytical application. 1851 36

Erythropoietic Protoporphyria (EPP) is an inherited deficiency of ferrochelatase, the last enzyme of the heme pathway. Under general anaesthesia, some patients develop neurological dysfunction suggesting upregulation in heme biosynthesis similar to that described for acute porphyrias after xenobiotic administration. Our aim has been to evaluate whether Isoflurane induces alterations in the heme pathway in a mouse model for EPP. Administration of Isoflurane (a single dose of 2 ml/kg, i.p) to wild-type (+/+), heterozygous (+/Fechm1Pas) and homozygous (Fechm1Pas/Fechm1Pas) mice, was evaluated by measuring the activity of delta-aminolevulinic acid synthetase (ALA-S) and Porphobilinogen-deaminase (PBG-D) in different tissues, as well as Heme oxygenase (HO), cytochrome P-450, CYP2E1 and glutathione levels in liver. Porphyrin precursors were measured in 24 h-urine samples. Fechm1Pas/Fechm1Pas mice receiving anaesthesia show enhanced ALA-S and CYP2E1 activities in the liver and increased urinary excretion of porphyrin precursors. No alterations were found in either PBG-D or HO activities. Diminished glutathione levels suggest that anaesthesia may produce oxidative stress in these animals. In conclusion, Isoflurane induces ALA-S activity and increased excretion of porphyrin precursors in EPP mice. These findings appear to confirm our previous hypothesis and indicate that Isoflurane may be an unsafe anaesthetic not only for patients with acute porphyrias but also for individuals with non acute porphyrias.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Induction of hepatic aminolevulinate acid synthetase activity by isoflurane in a genetic model for erythropoietic protoporphyria. 1926

Porphyrin precursors and porphyrins were measured in three patients with recurrent attacks of acute intermittent porphyria and end-stage renal disease (ESRD): two patients on hemodialysis and one on peritoneal dialysis. Plasma porphobilinogen (PBG) and porphyrins were considerably increased in the three patients. In a previous study, the mean urinary and plasma PBG/ALA ratio in biochemically active AIP patients with conserved renal function was 2.0 (normal 0.3) and plasma porphyrin levels were normal (< 10 nmol/L). In this study we show that the progression to ESRD was paralleled by an increase in urinary and plasma PBG/ALA ratio reaching levels above 6 and higher. Plasma porphyrin increased to levels above 1000 nmol/L causing cutaneous lesions resembling porphyria cutanea tarda. The porphyrin precursors were readily filtered by dialysis membranes but not the porphyrins. The development of kidney failure was a devastating complication in these AIP patients with chronic active disease, leading to unavoidable deterioration of peripheral veins, progression of peripheral neuropathy, dialysis treatment and secondary cutaneous lesions. The clinical course could not be reversed by medical treatment in any of the cases. Today, combined liver and kidney transplantation should be considered as a therapeutic option.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes. 1926 4

The aim of this study was to investigate the hepatoprotective effect of 3-alkynyl selenophene (compound a), a selenophene compound, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in rats. The animals received compound a (25 and 50 mg/kg; per oral, p.o.) in the first day of treatment. In the second day, the rats received D-GalN (500 mg/kg; intraperitoneal, i.p.) and LPS (50 microg/kg; intraperitoneal, i.p.). Twenty-four hours after D-GalN/LPS administration animals were euthanized to the biochemical and histological analysis. Compound a (25 and 50 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by D-GalN/LPS. Compound a at 50 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by D-GalN/LPS. The inhibition of delta-aminolevulinic dehydratase (delta-ALA-D) activity and the decrease of ascorbic acid levels caused by D-GalN/LPS were protected by compound a (25 and 50 mg/kg). Glutathione S-transferase (GST) and catalase activities were not altered in all groups. The histological data showed that sections of liver from D-GalN/LPS-treated rats presented massive hemorrhage, the presence of inflammatory cells and necrosis. Compound a attenuated D-GalN/LPS-induced hepatic histopathological alterations. Based on the results, we demonstrated the hepatoprotective effect of compound a on acute liver injury induced by D-GalN/LPS.
Exp Mol Pathol 2009 Aug
PMID:Hepatoprotective effect of 3-alkynyl selenophene on acute liver injury induced by D-galactosamine and lipopolysaccharide. 1934 11

We report a simple algorithm to scan interfaces in protein-protein complexes for identifying binding 'hot spots'. The change in side-chain solvent accessible area (DeltaASA) of interface residues has been related to change in binding energy due to mutating interface residues to Ala (DeltaDeltaG (X --> ALA)) based on two criteria-hydrogen bonding across the interface and location in the interface core-both of which are major determinants in specific, high-affinity binding. These relationships are used to predict the energetic contribution of individual interface residues. The predictions are tested against 462 experimental X --> ALA mutations from 28 interfaces with an average unsigned error of 1.04 kcal/mol. More than 80% of interface hot spots (with experimental DeltaDeltaG > or = 2 kcal/mol) could be identified as being energetically important. From the experimental values, Asp, Lys, Tyr and Trp are found to contribute most of the binding energy, burying >45 A2 on average. The method described here would be useful to understand and interfere with protein interactions by assessing the energetic importance of individual interface residues.
J Comput Aided Mol Des 2009 Sep
PMID:Empirical estimation of the energetic contribution of individual interface residues in structures of protein-protein complexes. 1947 23

Toxicological and pharmacological studies demonstrated that the introduction of functional groups into the aromatic ring of diphenyl diselenide alter its effect. The aim of this study was to evaluate the in vitro effect of m-trifluoromethyl-diphenyl diselenide (m-CF(3)-C(6)H(4)Se)(2), p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) and p-methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) on delta-aminolevulinate dehydratase (delta-ALA-D) and Na(+), K(+)-ATPase activities in rat brain homogenates. Diselenides inhibited delta-ALA-D activity (IC(50) 4-6 microM [concentration inhibiting 50%]), and dithiothreitol (DTT) restored the enzyme activity. ZnCl(2) (100 microM) did not restore delta-ALA-D inhibition caused by (p-Cl-C(6)H(4)Se)(2) and (m-CF(3)-C(6)H(4)Se)(2). Na(+), K(+)-ATPase activity was more sensitive to (p-Cl-C(6)H(4)Se)(2) and (m-CF(3)-C(6)H(4)Se)(2) (IC(50) 6 microM) than (p-CH(3)O-C(6)H(4)Se)(2) and (PhSe)(2) (IC(50) 45 and 31 microM, respectively). DTT restored the activity of Na(+), K(+)-ATPase inhibited by diselenides. The effect of diselenides on Na(+)/K(+)-ATPase is dependent on their substitutions in the aromatic ring. The mechanism through which diselenides inhibit delta-ALA-D and Na(+), K(+)-ATPase activities involves the oxidation of thiol groups.
Mol Cell Biochem 2009 Dec
PMID:Disubstituted diaryl diselenides inhibit delta-ALA-D and Na+, K+-ATPase activities in rat brain homogenates in vitro. 1950 2

We investigated the pigment composition and the transcriptome of albina (alb-e ( 16 ) and alb-f ( 17 )) and xantha (xan-s ( 46 ) and xan-b ( 12 )) barley mutants to provide an overall transcriptional picture of genes whose expression is interconnected with chloroplast activities and to search for candidate genes associated with the mutations. Beside those encoding plastid-localized proteins, more than 3,000 genes involved in non-chloroplast localized metabolism were up-/down-regulated in the mutants revealing the network of chloroplast-dependent metabolic pathways. The alb-e ( 16 ) mutant was characterized by overaccumulation of protoporphyrin IX upon ALA (5-amino levulinic acid) feeding and down-regulation of the gene encoding one subunit of Mg-chelatase, suggesting a block of the chlorophyll biosynthetic pathway before Mg-protoporphyrin IX biosynthesis, while alb-f ( 17 ) overaccumulated Mg-protoporphyrin IX and repressed PorA expression, without alterations in Mg-chelatase mRNA level. The alb-f ( 17 )mutant also showed overexpression of several genes involved in phytochrome and in phytochrome-dependent pathways. The results indicate that the down-regulation of Lhcb genes in alb-e ( 16 ) cannot be mediated by the accumulation of Mg-protoporphyrin IX. After ALA treatment, xan-s ( 46 ) showed overaccumulation of Mg-protoporphyrin IX, while the relative porphyrin composition of xan-b ( 12 ) was similar to wild type. The transcripts encoding the components of several mitochondrial metabolic pathways were up-regulated in albina/xantha leaves to compensate for the absence of active chloroplasts. The mRNAs encoding gun3, gun4, and gun5 barley homologous genes showed significant expression variations and were used to search for co-expressed genes across all samples. These analyses provide additional evidences on a chloroplast-dependent covariation of large sets of nuclear genes.
Plant Mol Biol 2009 Sep
PMID:Parallel pigment and transcriptomic analysis of four barley albina and xantha mutants reveals the complex network of the chloroplast-dependent metabolism. 1955 21

The photodynamic activity of three photosensitizers (PS): AL-induced PPIX, the porphyrin derivative 5-(4-trimethylammoniumphenyl)-10, 5, 20-tris (2,4,6- trimethoxyphenyl) porphyrin (CP) and the molecular dyad porphyrin-C(60) (P-C(60)), the last two incorporated into liposomal vesicles, was evaluated on Hep-2 human larynx carcinoma cell line. ALA-induced accumulation of the endogenous PS PPIX, reached saturation values between 5 and 24 h incubation time; the maximal PPIX content was 5.7 nmol/106 cells. The same intracellular level was accumulated when the cationic porphyrin CP was used, while the amount of P-C(60) attained was 1.5 nmol/106 cells. Under violet-blue exciting light, the fluorescence of PPIX and P-C(60) was found in the cytoplasm showing a granular appearance indicating lysosomal localization. CP was mainly detected as a filamentous pattern characteristic of mitochondrial localization. No dark cytotoxicity was observed using 1mM ALA, 5 microM CP and 1 microM P-C(60) after 24 h incubation. Cell morphology was analyzed using Hoechst-33258, toluidine blue staining, TUNEL assay and DNA fragmentation, 24 h after irradiation with 54 J/cm2. When photosensitized with ALA and P-C(60), chromatine condensation characteristic of apoptotic cell death was found; instead, 58 % of necrotic cells were observed with CP. The results show that in the Hep-2 cells, of the three PS analyzed, the molecular dyad P-C(60) was more efficient than CP and PPIX, and confirm that PDT can induce different mechanisms of cell death depending on the PS and the irradiation dose.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Endogenous and exogenous porphyrins as photosensitizers in the Hep-2 human carcinoma cell line. 1965 45

Variegate Porphyria (VP) is an autosomal dominant disorder found worldwide but is rare in Italy. In this study we provide an overview of clinical, biochemical and genetic background of 33 Italian VP patients diagnosed in the last fifteen years. About 70% of patients had experienced clinical symptoms: 43.4% had photosensivity, 8.7% acute attacks and 47.8% both. Among the 33 patients, 14 different mutations were identified. Of these only 6 defects have been previously described in other countries and 8 are unique having been identified for the first time in Italy. Two of these, the c.851G>T and the c.1013C>G, were found in two and four unrelated families respectively. No mutation has been found in homozygosis and no significant correlation has been observed between specific clinical and biochemical manifestations and the type of mutation. In contrast, normal faecal protoporphyrin excretion was high predictive of silent phenotype. Normal urinary excretion of PBG and ALA, predicted absence of neurovisceral symptoms. This paper represents the first compilation of data on genotype-phenotype relation in Italian patients with VP.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Clinical, biochemical and genetic characteristics of Variegate Porphyria in Italy. 1965 55

Erythropoietic Protoporphyria (EPP) is a disease associated with ferrochelatase deficiency, which produces accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver and skin. In some cases, a severe hepatic failure and cholestasis was observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in animals. The aim of this work was to further characterize this model studying its effect on different metabolisms in mice Gris feeding (0-2.5%, 7 and 14 days). PROTO IX accumulation in liver, blood and feces, induction of ALA-S activity, and a low rate of Holo/Apo tryptophan pyrrolase activity was produced, indicating a reduction of free heme pool. The progressive liver injury was reflected by the aspect and the enlargement of liver and the induction of hepatic damage. Liver redox balance was altered due to porphyrin high concentrations; as a consequence, the antioxidant defense system was disrupted. Heme oxygenase was also induced, however, at higher concentrations of antifungal, the free heme pool would be so depleted that this enzyme would not be necessary. In conclusion, our model of Protoporphyria produced liver alterations similar to those found in EPP patients.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Hepatic damage and oxidative stress induced by Griseofulvin in mice. 1965 61


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