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PubMed2006

Synthesis of new amino sugar derivatives from keto-sugars of D-xylose.

Several amino sugars and imino sugar derivatives were synthesized from keto-sugars of D-xylose through a series of reactions such as the Henry reaction, hydrogenation reactions, and nucleophilic addition reactions or substitution reactions. Thiazine derivative 15 was obtained by the reaction of the keto-sugar with NH(2)CSNH(2). Higher carbon sugar 16 was accidentally prepared at room temperature from the keto-sugar in the presence of NH(2)CONH(2). The structures of the compounds were confirmed by spectral analysis. The absolute configurations of all asymmetric carbon atoms of 6 and 8 were confirmed by X-ray crystallographic analysis.

Amino Sugars↗
PubMed2004

Decolorization of synthetic dyes using a copper complex with glucaric acid.

Selected azo, acridine, triphenyl methane, anthraquinone and thiazine-based dyes were decolorized using a catalytic system consisting of Cu(II)/glucaric acid/H(2)O(2). More than 90% decolorization was obtained with 100 ppm Acridine Orange, Azure B, Chicago Sky Blue, Crystal Violet, Methyl Orange, Poly B-411, Reactive Black 5, Reactive Blue 2, and Remazol Brilliant Blue R within 24 h. Seventy to eighty percent decolorization was achieved within the first 6 h. The decolorizaton was not affected by pH. The involvement of hydroxyl radicals produced in the system in the decolorization of the dye molecules was confirmed by electron spin resonance study.

Catalysis↗
PubMed2004

Copper-ligand complex for the decolorization of synthetic dyes.

The reaction system containing Cu(II), hydrogen peroxide and D-arabinono-1,4-lactone was found to be effective in the decolorization and reduction of toxicity of azo, thiazine-, triphenylmethane- and anthraquinone-based synthetic dyes. More than 85% decolorization was obtained with 100ppm Acridine Orange, Azure B, Chicago Sky Blue 6B, Crystal Violet, Evans Blue, Poly B-411, Reactive Blue 2, Reactive Blue 5, and Remazol Brilliant Blue R incubated for 24h in the presence of 10mM CuSO(4), 20mM D-arabinono-1,4-lactone and 80 mM H(2)O(2). The rate of decolorization was not affected by pH in the range of 3-9. The rapid decolorization was accompanied by a fast decomposition of H(2)O(2) in the reaction mixture and by a fast production of hydroxyl radicals.

Coloring Agents↗
PubMed2005

Putative role of nitric oxide synthase isoforms in the changes of nitric oxide concentration in rat brain cortex and cerebellum following sevoflurane and isoflurane anaesthesia.

We have previously observed an increase in nitric oxide (NO) content in rat brain cortex following halothane, sevoflurane or isoflurane anaesthesia. This study was undertaken in order to determine whether isoform-specific nitric oxide synthase (NOS) inhibitors and inducers could modify these increases in NO contents. Rats were subjected to isoflurane and sevoflurane anaesthesia with concomitant administration of neuronal nitric oxide synthase (nNOS) inhibitor 7-Nitro-indazole (7-NI), inducible nitric oxide synthase (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) or lipopolysaccharide. NO concentration in different organs was measured by electron paramagnetic resonance (EPR) spectroscopy. 7-NI significantly decreased NO concentration in cerebellum but not in brain cortex, whereas AMT decreased NO in all the organs studied. Anaesthesia significantly increased NO concentration in brain cortex and decreased that in cerebellum. AMT abolished the NO increase in brain cortex. Anaesthesia enhanced the drastic increase in NO concentration in brain cortex after intraventricular lipopolysaccharide administration. Isoflurane was found to inhibit recombinant nNOS and iNOS activities at high concentrations (EC50=20 mM). Our data suggest a putative role for iNOS in the increase in NO levels produced by isoflurane and sevoflurane, whereas nNOS activity is probably inhibited during anaesthesia.

Anesthetics, Inhalation↗
PubMed2005

Thiourea, triazole and thiadiazine compounds and their metal complexes as antifungal agents.

Many currently available antifungal and antibacterial agents have undesirable toxic effects, and a wide spread use of these drugs has lead to rapid development of drug resistant strains which are the leading cause for treatment failure in both clinical and agricultural applications. The present article provides a synopsis of recent progress in investigations of new classes of antifungal compounds: disubstituted aliphatic and aromatic thioureas, triazole and thiazine compounds which act as ligands for transition metals. Antifungal effects of these compounds and selected metallic complexes versus representative plant pathogenic fungi are reviewed.

Anti-Bacterial Agents↗
PubMed2005

NF-kappaB-dependent production of nitric oxide by astrocytes mediates apoptosis in differentiated PC12 neurons following exposure to manganese and cytokines.

Neuronal injury in manganism is accompanied by activation of astroglia within the basal ganglia that is thought to increase production of inflammatory mediators such as nitric oxide (NO). The present studies postulated that astroglial-derived NO mediates neuronal apoptosis induced by manganese (Mn) and pro-inflammatory cytokines. Pheochromocytoma (PC12) cells differentiated with nerve growth factor (NGF) were co-cultured with primary astrocytes and exposed to Mn and tumor necrosis factor-alpha (TNF-alpha) plus interferon-gamma (IFN-gamma). Mn enhanced cytokine-induced expression of inducible nitric oxide synthase (NOS2, EC 1.14.13.39) and production of NO in astrocytes that correlated with apoptosis in co-cultured neurons, as determined by caspase activity, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), and nuclear morphology. Apoptosis in PC12 neurons required the presence of astrocytes and was blocked by overexpression of a phosphorylation-deficient mutant of IkappaBalpha (S32/36A) in astrocytes that prevented induction of NOS2. Pharmacologic inhibition of NOS2 with (+/-)-2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) significantly reduced neuronal apoptosis, and the addition of low concentrations of the NO donor, S-nitroso-N-acetylpenicillamine (SNAP), to neurons cultured without astrocytes was sufficient to recover the apoptotic phenotype following exposure to Mn and TNF-alpha/IFN-gamma. It is concluded that Mn- and cytokine-dependent apoptosis in PC12 neurons requires astroglial-derived NO and NF-kappaB-dependent expression of NOS2.

Animals↗
PubMed2006

Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum.

Methylene blue (MB) is a thiazine dye with cationic and lipophilic properties that acts as an electron transfer mediator in the mitochondria. Due to this metabolic improving activity and free radicals scavenging effects, MB has been used in the treatment of methemoglobinemia and ifosfamide-induced encephalopathy. Considering that methylmalonic acidemia consists of a group of inherited metabolic disorders biochemically characterized by impaired mitochondrial oxidative metabolism and reactive species production, we decided to investigate whether MB, protects against the behavioral and neurochemical alterations elicited by the intrastriatal injection of methylmalonate (MMA). In the present study we showed that intrastriatal injection of MB (0.015-1.5nmol/0.5microl) protected against seizures (evidenced by electrographic recording), protein carbonylation and Na(+),K(+)-ATPase inhibition ex vivo induced by MMA (4.5micromol/1.5microl). Furthermore, we investigated whether convulsions elicited by intrastriatal MMA administration are accompanied by striatal protein carbonyl content increase and changes in Na(+),K(+)-ATPase activity in rat striatum. The effect of MB (0.015-1.5nmol/0.5microl) and MMA (4.5micromol/0.5microl) on striatal NO(x) (NO(2) plus NO(3)) content was also evaluated. Statistical analysis revealed that the MMA-induced NO(x) content increase was attenuated by intrastriatal injection of MB and the duration of convulsive episodes correlated with Na(+),K(+)-ATPase inhibition, but not with MMA-induced total protein carbonylation. In view of that MB decreases MMA-induced neurotoxicity assessed by behavioral and neurochemical parameters, the authors suggest that MB may be of value to attenuate neurological deficits of methylmalonic acidemic patients.

Animals↗
PubMed2001

Role of nitric oxide on in vitro human eosinophil migration.

Eosinophils purified from the rat peritoneal cavity have been found to contain nitric oxide synthase (NOS) functionally coupled to a cyclic GMP transduction pathway that is involved in in vitro eosinophil migration, but no studies on cell locomotion have been done with purified human eosinophils. Therefore, this study was carried out to investigate the effects of N(omega) -nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor), 1-(2-trifluoromethylphenyl) imidazole (TRIM; a type I/type II NOS inhibitor), 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; a selective type II NOS inhibitor), and 1H-[1,2,4]-oxidiazolo[4,3-a] quinoxalin-1-one (ODQ; a soluble guanylate cyclase inhibitor) on human eosinophil migration induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP). Human eosinophils were purified from peripheral blood of healthy volunteers using a Percoll gradient followed by an immunomagnetic cell separator. Chemotaxis was evaluated using a 48-well microchemotaxis chamber. The fMLP (1.0 x 10(-7) M)-induced eosinophil migration was reduced significantly by l-NAME (0.1 and 1.0 mM), whereas the inactive enantiomer N(omega)-nitro-D-arginine methyl ester (D-NAME) had no effect. The inhibition by l-NAME was restored by sodium nitroprusside (0.25 mM). The NOS inhibitors AMT and TRIM (0.05 to 0.25 mM each) also markedly attenuated fMLP-induced chemotaxis. Additionally, ODQ (0.01 to 0.5 mM) concentration-dependently inhibited fMLP-induced migration, and the inhibition was restored by 2.0 mM dibutyryl cyclic GMP. In conclusion, this study demonstrates that human eosinophils present a nitric oxide-cyclic GMP pathway that is involved in the in vitro locomotion of this cell type.

Cell Movement↗
PubMed2003

Generation of oxidant stress in cultured endothelial cells by methylene blue: protective effects of glucose and ascorbic acid.

The thiazine dye methylene blue has long been used to stimulate cellular redox metabolism. To determine the extent to which it also generates oxidant stress in cells, its effects in cultured human-derived endothelial cells were studied. As expected, low concentrations of the dye (2-20 microM) activated the pentose phosphate pathway and oxidized both NADPH and NADH. Methylene blue enhanced extracellular ferricyanide reduction, indicating that the reduced form of the dye was present outside the cells. This reduction was greater when ferricyanide was added just before rather than 15 min after methylene blue, confirming that the dye is at least initially reduced at the cell surface. In the absence of glucose, methylene blue at concentrations above 5 microM increased intracellular oxidant stress, as manifest by oxidation of dihydrofluorescein and cellular GSH. Inclusion of glucose protected against these effects. In cells that had been loaded with ascorbate, the dye caused progressive oxidation of ascorbate, even in the presence of D-glucose. Loading cells with ascorbate also partially prevented oxidation of dihydrofluorescein by methylene blue. These results suggest that concentrations of the dye above 5 microM generated intracellular reactive oxygen species that were scavenged by ascorbate and GSH. Further, although D-glucose enhanced reduction of methylene blue, it ameliorated the oxidant stress generated by the dye.

Ascorbic Acid↗
PubMed1999

Rapid hydrolysis and slow alpha,beta-dicarbonyl cleavage of an agent proposed to cleave glucose-derived protein cross-links.

The putative protein glycation cross-link cleaving agent N-phenacylthiazolium bromide (PTB) underwent hydrolysis and cyclic hemithioacetal formation under physiological conditions to form two isomeric 2,3-dihydro-4-formyl-2-hydroxy-2-phenyl-1,4-thiazines: at pH 7.4 and 37 degrees, the rate constant k(Hydrolysis) was (2.6+/-0.1) x 10(-4) sec and the chemical half-life was ca. 44 min. The alpha,beta-dicarbonyl cleavage reaction only competed effectively with the hydrolysis when the alpha,beta-dicarbonyl substrate was at nonphysiological high levels. The high concentrations of PTB (10-30 mM) used previously to demonstrate chemical and biochemical activity also lead to acidification of incubation media. The mechanism of action of PTB now requires reappraisal.

Cross-Linking Reagents↗
PubMed1998

2-Substituted-3-oxoisothiazolo[5,4-b]pyridines as potential central nervous system and antimycobacterial agents.

The 2-[3-(substituted-amino)-2-hydroxypropyl]-4,6-dimethyl-3-oxo-2,3- dihydroisothiazolo[5,4-b]pyridines 3 were synthesized and pharmacologically evaluated in animal models. The preliminary pharmacological screening study showed that the investigated compounds were toxic and had no significant activity in central nervous system (CNS) tests. Additionally, compounds 3, and several other 2-substituted-4,6- dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridines described here (2), together with those (4) reported in a previous paper, were evaluated in vitro against Mycobacterium tuberculosis H37Rv. For comparison, products of the rearrangement of some isothiazolopyridine 1,1-dioxides (4a,b) with the corresponding pyrido[3,2-e]-1,2-thiazines (5a,b) and different N2-substituted derivatives of the latter (5c-i) were also prepared and investigated in antimycobacterial tests. The most potent antituberculars of the 23 compounds assayed are 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]-4,6-dimethyl-3-oxo- 2,3- dihydroisothiazolo[5,4-b]pyridine 3d and ethyl (4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin-2-yl)acet ate 4c (MIC < 12.5 micrograms/ml, 100 and 98% inhibition, respectively).

Analgesics↗
PubMed2003

Decolorization of structurally different synthetic dyes using cobalt(II)/ascorbic acid/hydrogen peroxide system.

The cobalt(II)/ascorbic acid/hydrogen peroxide system was used for decolorization of azo, acridine, anthraquinone, thiazine and triphenylmethane dyes. More than 90% decolorization was obtained with all dyes except Remazol Brilliant Blue R (75%). With other transition metals the system was less efficient. With copper, higher concentration and prolonged incubation time was necessary to obtain the same extent of decolorization. The rate of decolorizaton was not affected by pH in the range of 3-9. The reaction is very fast, with more than 90% decolorization being attained within 15 min. The system produces hydroxyl radicals which are responsible for the decolorization.

Ascorbic Acid↗
PubMed2000

Electrophysiological characterization of CGP68730A a N-methyl-D-aspartate antagonist acting at the strychnine-insensitive glycine site.

1. Electrophysiological experiments were performed in vitro and in vivo. Voltage clamp recordings were done in Xenopus oocytes. Extracellular recordings were done in vitro in the neocortical slice and in the CA1 region of the hippocampal slice and in vivo in the CA1 region of the hippocampus of the anaesthetized rat. 2. In oocytes expressing either the human NMDAR1A/2A or 1A/2B subunit combinations, CGP68730A [sodium (-)-9-bromo-2,3,6,7-tetrahydro-5,6-dioxo-5H-pyrazino[1,2,3-de]-1,4-benzo thiazine-3-acetic acid] antagonized L-glutamate / glycine induced currents with calculated IC50s of 20.5 and 81.6 nM, respectively. 3. In vitro, CGP68730A was tested on NMDA induced depolarizations in the neocortical slice preparation and on epileptiform activity in hippocampal slices bathed in Mg2+-free-medium, which is known to be NMDA mediated. In both in vitro models CGP68730A exhibited antagonistic effects on the NMDA receptor mediated responses. 4. In vivo CGP68730A was tested on NMDA induced excitations in the CA1 region. CGP68730A abolished NMDA induced excitations when applied microiontophoretically. However, only weak effects on NMDA induced excitation were observed after systemic administration at 100 mg/kg i.v.. These results indicate that CGP68730A has poor central nervous system bioavailability. 5. In oocytes, an increase in the glycine concentration from the EC80 to the EC95.99 shifted the inhibition curves for CGP68730A to the right. Furthermore, in neocortical slices and in anaesthetized rats CGP68730A inhibited NMDA mediated depolarizations, and this effect could be reversed by the addition of the glycine mimetic D-serine. This indicates that these effects of CGP68730A are mediated by an action on the strychnine-insensitive glycine site. 6. Selectivity tests in oocytes and in the neocortical slice preparation, using NMDA, kainate and AMPA showed that CGP68730A was selective in antagonizing NMDA receptor mediated responses. In oocytes, the compound was about 1000 times less potent on the rat GluR3 and the human GluR6 receptors than on the human NMDAR1A/2A subunit combination. In the neocortical slice preparationCGP68730A had no effects on AMPA or kainate induced depolarizations at concentrations of 3 and 10 microM. At 30 microM CGP68730A reduced the effects of each of the three agonists tested. 7. Thus, CGP68730A seems to be a selective antagonist at the strychnine-insensitive glycine coagonist site of the NMDA receptor. However, the compound showed no obvious central NMDA antagonistic effects following intravenous application.

Animals↗
PubMed1999

Differential expression of nitric oxide synthase in human stomach cancer.

The level of expression and cellular localization of isoenzymes of nitric oxide synthase (NOS) was detected in human stomach tumor tissues. Tumor tissues showed 70% higher activity of NOS than that of normal tissues (P < 0.01). Poorly differentiated adenocarcinoma tend to have higher activity (P < 0.05) than well differentiated and moderately differentiated tumor tissues. Aminoguanidine (AG), 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), NG-monomethyl-L-arginine (L-NMMA), and Nomega-nitro-L-arginine (L-NNA) inhibited NOS activity in tumor tissues by 18, 14, 11 and 13%, respectively. The TNF-alpha mRNA expression was correlated with the inducible NOS (iNOS) level, which was high in adenocarcinomas and low in normal tissues. Tumor tissues showed higher expression of iNOS in gland epithelial cells but the level of eNOS was significantly decreased with an exception of concentrated localization in the proliferating capillary endothelium. These results revealed that isoforms of NOS might contribute differentially to growth and progression of human stomach tumor.

Adult↗
PubMed2001

Chemical oxidation of methylene blue using a Fenton-like reaction.

Oxidation by Fenton-like reactions is proven and economically feasible process for destruction of a variety of hazardous pollutants in wastewater. We report herein the oxidation of methylene blue, a basic dye of thiazine series using a Fenton-like reaction at normal laboratory temperature and at atmospheric pressure. The effects of different parameters like the initial concentrations of dye, Fe2+, and H2O2, pH of the solution, reaction temperature, and added electrolytes on the oxidation of the dye present in dilute aqueous solution in the concentration range (3.13-9.39)x10(-5)mol dm(-3) (10-30 mg l(-1)) have been assessed. The results indicate that the dye can be most effectively oxidized in aqueous solution at dye:Fe(2+):H2O2 molar ratio of 1:1.15:14.1. More than 98% removal of the dye could be achieved in 1h in the pH range 2.2-2.6 at 299 K which corresponds to about 81% reduction of the initial COD. The results will be useful for designing the treatment systems of various dye-containing wastewaters.

Enzyme Inhibitors↗
PubMed2001

Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin.

Nitric oxide (NO) is believed to be an important messenger molecule in signal transduction pathways that enhance nociceptive transmission in the central nervous system (CNS). The role of nitric oxide synthase (NOS) I and II, which synthesize NO, in central sensitization induced by an intradermal capsaicin injection was investigated. To elucidate whether changes in NOS I and NOS II activities caused by capsaicin injection contribute to behavioral changes, responses to von Frey filaments with two different innocuous bending forces applied on the rat foot were tested. The allodynic responses induced by capsaicin injection in the foot were partially reversed by the administration of either the selective NOS I inhibitor, 7-nitroindazole (7-NINA), or the selective NOS II inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT). To confirm changes at the level of single nociceptive neurons, extracellular recordings were made from rat dorsal horn neurons. The electrophysiological results showed that increased responses to noxious and innocuous stimuli caused by capsaicin injection were blocked by either 7-NINA or AMT delivered through a microdialysis fiber inserted through the dorsal horn. Finally, the expression of both NOS I and NOS II in the spinal cord as demonstrated by Western blots was increased by 20 min following intradermal capsaicin injection in the rat foot. These results suggest that both NOS I and NOS II are upregulated following intradermal capsaicin injection and that both cause NO release that contributes to the secondary hyperalgesia and allodynia following this noxious chemical stimulus.

Animals↗
PubMed1990

Thin-layer chromatographic analysis of myelin lipids, their differential O-deacylation by primary alkylamines and their selective staining by thionine. A limited phylogenetic study.

A silica gel thin-layer chromatographic procedure is described for the study of the myelin lipid patterns in a small phylogenetic series of nerve tissue specimens. It involves the selective staining by the thiazine dye thionine and the interpretations were facilitated by a preceding primary alkylamine O-deacylation step. Glycolipids, including sulfatides, and ethanolamine plasmalogens were the principal characterizing lipids.

Acylation↗
PubMed2001

Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's disease.

Neurofibrillary pathology is a characteristic hallmark of Alzheimer's disease that is closely correlated with cognitive decline. We have analysed the density and distribution of neurofibrillary tangles (NFTs) that are immunoreactive with the monoclonal antibody (mAb) 423 in a prospectively analysed population of Alzheimer's disease (AD) cases and age-matched controls. NFTs were examined in allocortical and isocortical areas and correlated with Braak pathological stage and clinical severity of dementia. The mAb 423 was used as it recognises a C-terminally truncated tau fragment that is a major constituent of NFTs. Our results show that extracellular NFTs and, to a lesser extent, intracellular NFTs, correlated significantly with both Braak stages and the clinical index of severity. Furthermore, a differential distribution of the two types of tangles indicates that layer II of the entorhinal cortex and the transentorhinal area are particularly vulnerable to neurofibrillary degeneration. These areas serve as a point of connection between isocortex and hippocampus. Our findings, therefore, suggest that the perforant pathway may be substantially affected by the accumulation of truncated tau protein in AD and that this represents a neuropathological predictor for the clinical severity of dementia. When neurofibrillary pathology was examined by combined labelling with mAbs 423 and Alz-50 and the dye thiazin red, we were able to demonstrate various stages of tau aggregation. The different stages may represent a sequence of conformational changes that tau proteins undergo during tangle formation in the allocortex during the early development of dementia in AD.

Aged↗