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PubMed2005

Use of nitisinone in patients with alkaptonuria.

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria. We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels. We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.

Adult↗
PubMed2004

Lasianthionosides A-C, megastigmane glucosides from leaves of Lasianthus fordii.

From the leaves of Lasianthus fordii, three megastigmane glucosides, lasianthionosides A, B and C, were isolated together with the known iridoid glucoside, asperuloside, deacetylasperuloside and methyl deacetyl-asperulosidate, and a megastigmane glucoside, citroside A. The structures have been elucidated based on spectroscopic analyses and/or X-ray crystallographic analysis.

Crystallography, X-Ray↗
PubMed2004

Biosynthetic experiments with tall plants under field conditions. 18O2 incorporation into humulone from Humulus lupulus.

Five segments of a large hop plant (Humulus lupulus var. Hallertauer Magnum) carrying several cones were enclosed in sealed glass vessels that were gassed with (18)O(2). After 14 days, the segments were harvested and humulone and cohumulone were analysed by NMR spectroscopy and mass spectroscopy. The oxygen atoms in position 6 of humulone and cohumulone showed 9% (18)O enrichment, respectively. It follows that the C-6 hydroxy groups were introduced by oxygenase catalysis.

Cyclohexanones↗
PubMed2004

Two compounds from allelopathic rice accession and their inhibitory activity on weeds and fungal pathogens.

A flavone (5,7,4'-trihydroxy-3',5'-dimethoxyflavone), a cyclohexenone (3-isopropyl-5-acetoxycyclohexene-2-one-1) and a liquid mixture of low polarity, containing long-chain and cyclic hydrocarbons, were isolated from leaves of allelopathic rice accession PI 312777 using column chromatography. Their structures and constituents were identified by means of HR-MS, NMR and GC/MS analyses, respectively. Bioassays showed that both the flavone and cyclohexenone significantly inhibited the growth of weeds Echinochloa crus-galli, Cyperus difformis and Cyperus iris, and the spore germination of fungal pathogens Pyricularia oryzae and Rhizoctonia solani at all tested concentrations. Moreover, the combination of the inactive mixture of low polarity and the active flavone or cyclohexenone significantly enhanced the inhibitory activities on weed growth. In addition, the two compounds and the mixture of low polarity from the leaves of PI312777 did not inhibit the rice growth at the same concentrations. It was also established that both compounds could be released into the soil, and was especially induced by E. crus-galli. The results suggest that 5,7,4'-trihydroxy-3',5'-dimethoxyflavone and 3-isopropyl- 5-acetoxycyclohexene-2-one-1 may act as allelochemicals participating in the defense of rice against weeds and pathogens.

Agriculture↗
PubMed2006

Accumulation of apocarotenoids in mycorrhizal roots of Ornithogalum umbellatum.

Colonization of roots of Ornithogalum umbellatum by the arbuscular mycorrhizal fungus Glomus intraradices induced the accumulation of different types of apocarotenoids. In addition to the mycorrhiza-specific occurrence of cyclohexenone derivatives and the "yellow pigment" described earlier, free mycorradicin and numerous mycorradicin derivatives were detected in a complex apocarotenoid mixture for the first time. From the accumulation pattern of the mycorradicin derivatives their possible integration into the continuously accumulating "yellow pigment" is suggested. Structure analyses of the cyclohexenone derivatives by MS and NMR revealed that they are mono-, di- and branched triglycosides of blumenol C, 13-hydroxyblumenol C, and 13-nor-5-carboxy-blumenol C, some of which contain terminal rhamnose as sugar moiety.

Carotenoids↗
PubMed2006

Bridelionosides A-F: Megastigmane glucosides from Bridelia glauca f. balansae.

The chemical investigation of leaves of Bridelia glauca f. balansae afforded six megastigmane glucosides, named bridelionosides A-F, along with seven known megastigmane glucosides. Their structures were determined by a combination of spectroscopic analyses and by application of the modified Mosher's method.

Cyclohexanones↗
PubMed2006

Mycosporine-like amino acids in the zooxanthella-ciliate symbiosis Maristentor dinoferus.

Coral reef organisms living in mutualistic symbioses with phototrophic dinoflagellates are widespread in shallow UV-transparent waters. Maristentor dinoferus is a recently discovered species of marine benthic ciliate that hosts symbiotic dinoflagellates of the genus Symbiodinium. In this study, we tested this ciliate for the occurrence of mycosporine-like amino acids, a family of secondary metabolites that minimize damage from exposure to solar UV radiation by direct screening. Using high-performance liquid chromatography and liquid chromatography coupled to mass spectrometry, five mycosporine-like amino acids (shinorine, palythenic acid, palythine, mycosporine-2-glycine, and porphyra-334) were identified in aqueous methanolic extracts of the symbiosis. This is the first report of mycosporine-like amino acids in a marine ciliate.

Amino Acids↗
PubMed2005

Structural assignment of Diels-Alder adducts: an experimental and theoretical approach.

A detailed NMR analysis with total assignment of (1)H and (13)C NMR data for the endo and the exo adducts, obtained by Diels-Alder reaction between 2-cyclohexenone and cyclopentadiene, is described. The unequivocal assignment of the endo and exo structures was performed by (1)H and (13)C NMR. These assignments were supported by theoretical chemical shift calculations at GIAO/HF level using 6-311 + g(2d, p) from optimized structures at the B3LYP/6-31g(d) level.

Cyclohexanones↗
PubMed2006

Solid-state linear-dichroic IR-spectroscopy of isophorone derivatives with potential non-linear optical application.

Possibilities of linear-dichroic infrared (IR-LD) spectroscopy based on oriented solid samples as suspension in nematic liquid crystal have been applied for detailed experimental IR-band assignment and structural information of 2-[5,5-dimethyl-3-(2-phenyl-vinil)-cyclohex-2-enylidene]-malononitrile, 2-[5,5-dimethyl-3-[2-(2-methoxyphenyl)vinyl]cyclo-hex-2-enylidene]malononitrile and 2-[3-[2-(2,4-dimethoxyphenyl)vinyl]-5,5-dimethylcyclohex-2-enylidene]malononitrile. The data of last two compounds have been compared with known crystallographic ones, thus determining the validity of conclusions made.

Cyclohexanones↗
PubMed2006

Tyrosinemia produced by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) in experimental animals and its relationship to corneal injury.

2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.

Animals↗
PubMed2006

Prooxidant action of rhodizonic acid: transition metal-dependent generation of reactive oxygen species causing the formation of 8-hydroxy-2'-deoxyguanosine formation in DNA.

Rhodizonic acid, a six-membered cyclic hydroxyquinone, produced reactive oxygen species as a complex with transition metals. Addition of rhodizonic acid with ferrous ion caused an inactivation of aconitase the most sensitive enzyme to oxidative stress in permeabilized yeast cells. The iron-dependent inactivation of aconitase implies the rhodizonic acid/iron-mediated generation of reactive oxygen species. Spectrophotometric analysis of the interaction of rhodizonic acid with FeSO4 showed that addition of superoxide dismutase could inhibit the oxidation of rhodizonic acid, suggesting that reactive oxygen species produced from rhodizonic acid is superoxide radical. Rhodizonic acid further acted as a prooxidant causing a copper-dependent DNA damage. Treatment of DNA from plasmid pBR322 and calf thymus with rhodizonic acid plus copper caused strand scission and the formation of 8-hydroxy-2'-deoxyguanosine in DNA. Addition of catalase protected DNA from the rhodizonic acid-mediated strand scission, indicating that hydroxyl radical may participate in the DNA damage. Rhodizonic acid also showed a potent copper-reducing activity. These results indicate that copper ion reduced by rhodizonic acid may participate in the formation of superoxide radical that converts to hydrogen peroxide and hydroxyl radical. Other cyclic hydroxyquinones such as four-membered squaric acid and five-membered croconic acid did not show any prooxidant and reducing effects. Cytotoxic effects of tetrahydroquinone the precursor of rhodizonic acid may be related to the prooxidant properties of rhodizonic acid formed in cells.

Copper↗
PubMed2004

D-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism.

D-serine selectively damages renal proximal tubule cells in rats by a mechanism that is not fully understood. Recent proteomic analysis identified that D-serine elevated plasma fumarylacetoacetate hydrolase (FAH). FAH is involved in tyrosine catabolism; hence, this pathway may be involved in mediating the toxicity. This work examines whether 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC), a potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) located upstream of FAH, modulates D-serine-induced nephrotoxicity. Rats were pretreated with NTBC (0.5 mg/kg p.o.) or corn oil and then 30 min later given either D-serine (250 mg/kg i.p.) or water. Urine was collected every 12 h until termination (48 h) and analysed by 1H NMR spectroscopy and principal component analysis (PCA). Markers of proximal tubule injury were evident in urine following treatment with D-serine and NTBC + D-serine. PCA could not distinguish between these urine samples suggesting that NTBC does not effect the development of nephrotoxicity. Clinical chemistry analysis of urine and terminal plasma samples and histopathological examination of the kidneys confirmed this. NTBC alone caused a marked increase in the excretion of 4-hydroxyphenylpyruvate (HPPA) and 4-hydroxyphenyllactate (HPLA); however, HPPA and HPLA excretion was minimal following NTBC + D-serine. Instead marked tyrosinuria was observed suggesting that D-serine-induced renal damage markedly affects the handling of increased levels of HPPA and HPLA resulting from the inhibition of HPPD.

Animals↗
PubMed2004

Chemical modification of arginine residues of Notechis scutatus scutatus notexin.

Notexin, a presynaptic phospholipase A2 (PLA2) neurotoxin isolated from Notechis scutatus scutatus venom, was inactivated by arginine-specific reagents, phenylglyoxal and 1,2-cyclohexanedione. Kinetic analyses of the modification reaction revealed that the inactivation of notexin followed pseudo-first order kinetics and the loss of PLA2 activity was correlated with the incorporation of one molecule of modification reagent per toxin molecule. However, the results of amino acid analysis and sequence determination revealed that two arginine residues at positions 43 and 79 of notexin were modified simultaneously. Modification of the arginine residues was accompanied with a decrease in the ability to inhibit the indirectly evoked contraction of chick biventer cervicis muscle and bind with synaptic membranes. The secondary structure of the toxin molecule did not significantly change after modification with phenylglyoxal as revealed by the CD spectra. The modified derivative retained its affinity for Ca2+, indicating that the modified arginine residues did not participate in Ca2+ -binding. Together with the notion that Arg-43 and Arg-79 of notexin are located in the proximity of its catalytic site and toxic site, respectively, our results suggest that modification of Arg-43 and Arg-79 should differently contribute to the observed decrease in the PLA2 activity and neurotoxic effect of notexin.

Animals↗
PubMed2004

Display of heterologous antigens on the Bacillus subtilis spore coat using CotC as a fusion partner.

We report the use of CotC, a major component of the Bacillus subtilis spore coat, as a fusion partner for the expression of two heterologous antigens on the spore coat. Recombinant spores expressing tetanus toxin fragment C (TTFC) of Clostridium tetani or the B subunit of the heat-labile toxin of Escherichia coli (LTB) were used for oral dosing and shown to generate specific systemic and mucosal immune responses in a murine model. This report, expanding the previously described expression of TTFC on the spore surface by fusion to CotB [J Bacteriol 183 (2001) 6294] and its use for oral vaccination [Infect Immun 71 (2003) 2810] shows that different antigens can be successfully presented on the spore coat and supports the use of the spore as an efficient vehicle for mucosal immunisation.

Amino Acid Sequence↗
PubMed2006

Tyrosinemia type I treated by NTBC: how does AFP predict liver cancer?

BACKGROUND: Tyrosinemia type I is associated with an increased risk of liver cancer development. The formation of the pathogenic fumarylacetoacetate is prevented by 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC). Still, some patients with NTBC treatment develop liver cancer. A rise of alpha-fetoprotein (AFP) is an indicator of liver cancer. AIM: To study the predictive value of AFP in tyrosinemia type I patients for the discrimination between patients at high and low risk of liver cancer development. METHODS: We examined the course of AFP values of 11 Dutch patients with tyrosinemia type I treated by NTBC, of whom four were diagnosed with liver cancer. RESULTS: The four patients with liver cancer had a course of AFP different from the other patients in either velocity of the decrease of AFP, achieving normal AFP and/or having a rise of AFP concentrations. CONCLUSION: Apart from a rise of AFP, a slow AFP decrease, and never normalizing levels of AFP are important predictors of liver cancer development in further life.

Child↗
PubMed2000

The role of diacylglycerol as a modulator of oxytocin-stimulated phasic contractions in myometrium from pregnant and nonpregnant rats.

OBJECTIVE: The role of diacylglycerol in the phosphatidylinositol-signaling pathway is to activate protein kinase C. In the myometrium, protein kinase C activation leads to inhibition of phasic contractions. These studies are designed to determine why stimulation of the phosphatidylinositol-signaling pathway caused by oxytocin does not cause a paradoxical suppression of contractions through diacylglycerol production and protein kinase C activation. Specifically, these studies were performed to test the hypothesis that diacylglycerol catabolism is significant in myometrial tissue, thereby precluding its availability for the activation of protein kinase C. STUDY DESIGN: For these studies, uterine tissue was obtained from Sprague-Dawley rats both nonpregnant and with timed gestations. In vitro contraction studies were performed with cumulative additions of oxytocin (8-64 nmol/L) with and without R59022 (a diacylglycerol kinase inhibitor) or RHC80267 (a diacylglycerol lipase inhibitor). The contraction data were computer-digitalized, analyzed for total contractile activity, normalized for tissue cross-sectional area, and reported as the percentage of spontaneous activity. RESULTS: In myometrium from nonpregnant animals, inhibition of diacylglycerol lipase with RHC80267 had little effect on oxytocin-stimulated contractile activity, whereas inhibition of diacylglycerol kinase with R59022, although producing an increase in contractile frequency, markedly suppressed total oxytocin-stimulated contractile activity. In contrast, in myometrium from near-term pregnant animals both RHC80267 and R59022 produced marked suppression of oxytocin-stimulated contractile activity. CONCLUSIONS: These studies have demonstrated that prevention of diacylglycerol degradation, especially in response to inhibition of myometrial diacylglycerol kinase, results in the paradoxic oxytocin-mediated suppression of total myometrial contractile activity. These observations support the hypothesis that, when its catabolism is prevented, diacylglycerol produced in response to stimulation of the phosphatidylinositol-signaling pathway by oxytocin becomes available for protein kinase C activation, resulting in inhibition of myometrial contractile activity.

Animals↗
PubMed2002

Corneal opacities associated with NTBC treatment.

PURPOSE: To describe a patient with hereditary tyrosinemia type I (HHT-I) treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) who developed corneal opacities. METHODS: A 14-month-old patient was diagnosed with HHT-I and began treatment with NTBC. Her serial ocular examinations were normal until age 4 years, when she developed ocular discomfort and was found to have bilateral, linear, branching subepithelial corneal opacities. RESULTS: Over the next 3 years, the extent of the opacities fluctuated, and increased opacities correlated with periods of poor compliance with a restricted protein diet. Serum tyrosine levels remained elevated at 238 to 602 umol/L (normal 26 to 83) throughout the duration of NTBC treatment. CONCLUSION: Corneal opacities are a potential consequence of NTBC treatment for HHT-I. The lesions probably result from elevated serum and ocular tyrosine levels due to inhibition of the tyrosine catabolic pathway and poor dietary compliance.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1998

The effect of ATP-depletion on the inhibition of glucose exits from human red cells.

The effect of ATP-depletion or its consequence, by metabolic inhibition, on the inhibition of glucose transport by various inhibitors was studied in human red cells. In cells depleted of ATP, glucose exit times were longer than in normal cells and the times increased with the duration of depletion. The Km for external glucose was higher in ATP-depleted cells than in normal undepleted cells (3.0 mM c.f. 2.5 mM at 30 degrees C). In contrast, the apparent Ki for cytochalasin B decreased from 0.85 microM in the normal cells to 0.5 microM after ATP-depletion. Half-maximal rates of glucose exit in the absence, and in the presence of 2 microM cytochalasin B were found at ATP concentrations of 0.43 and 0.68 microM, respectively. Although glucose exits from ATP-depleted cells exposed to the irreversible inhibitor of glucose transport, 1-fluoro-2,4-dinitrobenzene (FDNB) were slower than in normal cells, the relative degrees of inhibition were not significantly different. However, normal and ATP-depleted cells responded differently to treatment with 1,2-cyclohexanedione, a modifier of arginine residues which inhibits glucose exit. While normal cells were markedly inhibited, depleted cells were much less affected and the inhibitory effect of cytochalasin B seen in normal cells was reduced. These findings demonstrate that the glucose transport system of human red cells is affected by intracellular ATP and that ATP alters the affinity of the transporter for certain inhibitors. The implications of these findings are discussed.

Adenosine Triphosphate↗