Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The abnormal aggregation of tau protein into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease. Aggregation takes place in the cytoplasm and could therefore be cytotoxic for neurons. To find inhibitors of PHF aggregation we screened a library of 200,000 compounds. The hits found in the PHF inhibition assay were also tested for their ability to dissolve preformed PHFs. The results were obtained using a thioflavin S fluorescence assay for the detection and quantification of tau aggregation in solution, a tryptophan fluorescence assay using tryptophan-containing mutants of tau, and confirmed by a pelleting assay and electron microscopy of the products. Here we demonstrate the feasibility of the approach with several compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit PHF formation with IC50 values of 1-5 microm and to disassemble preformed PHFs at DC50 values of 2-4 microm. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere with the stabilization of microtubules by tau. Tau-inducible neuroblastoma cells showed the formation of tau aggregates and concomitant cytotoxicity, which could be prevented by inhibitors. Thus, small molecule inhibitors could provide a basis for the development of tools for the treatment of tau pathology in AD and other tauopathies.
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PMID:Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. 1552 37

In a 5-L fermentor (NBS-MF 105), Saccharomyces cerevisiae W303-181 (1.0 g dry matter/L) was inoculated into 3.0 L of liquid medium containing glucose (10 or 20 g/L), yeast nitrogen base (YNB, 3.7 or 7.4 g/L), l-histidine (0.02 g/L), l-tryptophan (0.02 g/L), uracil (0.02 g/L), and adenine (0.02 g/L). The culture was carried out batchwise for 12 or 24 h at 30 degrees C, pH 4.6 or 5.7, aeration of 0, 0.8, 1.7 or 2.2 vvm, and agitation of 400 rpm. The highest G6PDH productivity (10.5 U/L.h) and specific activity (320 U/mg of protein) occurred at aeration of 2.2 vvm, pH 5.7, 10 g/L of glucose, and 3.7 g/L of YNB. The G6PDH specific activity attained was comparable with those of commercial preparations, which are between 50 and 600 U/mg of protein.
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PMID:Production of glucose 6-phosphate dehydrogenase from genetically modified Saccharomyces cerevisiae grown by batch fermentation process. 1608 Jun 93

An extracellular pectinase (PECI) was purified to apparent homogeneity from liquid state cultures of the thermophilic fungus Acrophialophora nainiana by ultrafiltration and a combination of gel filtration and ion-exchange chromatographic procedures. The molecular masses of PECI were 35,500 and 30,749 Da, as determined by SDS-PAGE and mass spectrometry, respectively. It was more active at 60 degrees C and pH 8.0 and showed high stability at 50 degrees C with half-life of 7 days. However at 60 and 70 degrees C, PECI was much less stable with half lives of approximately 20 and 3 min, respectively. The thermostability of purified PECI was also investigated by fluorescence and circular dichroism spectroscopy. Fluorescence revealed that the unfolding transition region was observed between 45 and 70 degrees C. A major decrease in the stability was found at 70 degrees C. Circular dichroism measurements at pH between 5.0 and 9.0 showed a transition temperature (T(m)) range of 50-55 degrees . The thermodynamic analysis of these results showed that EPGI is thermal stable protein exhibiting maximum stability (DeltaG(25)) of 22.65 and 19.19 kcal/mol at pH 8.0 and 9.0, respectively. The apparent K(m) value on pectin from citrus fruits was 4.22 mgml(-1). PECI exhibited no detectable activity of pectin methylesterase, endo-polygalacturonase, mannanase, xylanase and cellulase. However, it showed exo-polygalacturonase and pectin lyase activities. The presence of carbohydrate was detected in the pure PECI. It was activated by l-tryptophan, DEPC, DTT, DTNB, DTP, l-cystein and beta-mercaptoethanol and inhibited by NBS, Fe(2+), Cu(2+), Zn(2+), Mn(2+), Al(3+) and Ca(2+). The enzyme showed homology with a pectin lyases from Xanthomonas campestris and Bacillus licheniformis.
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PMID:Purification and characterization of a novel pectinase from Acrophialophora nainiana with emphasis on its physicochemical properties. 1633 7

An expedient synthesis of enantiomerically pure threo-beta-hydroxy-alpha-amino acid derivatives of phenylalanine, tyrosine, histidine, and tryptophan is described. The NBS-mediated radical bromination of the N,N-di-tert-butoxycarbonyl protected alpha-amino acids and subsequent treatment with silver nitrate in acetone provided the trans-oxazolidinones predominantly. Cesium carbonate catalyzed hydrolysis then generated the beta-hydroxy amino acid derivatives in excellent overall yield.
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PMID:Expedient synthesis of threo-beta-hydroxy-alpha-amino acid derivatives: phenylalanine, tyrosine, histidine, and tryptophan. 1693 77

alpha-mannosidase from Erythrina indica seeds is a Zn(2+) dependent glycoprotein with 8.6% carbohydrate. The enzyme has a temperature optimum of 50 degrees C and energy of activation calculated from Arrhenius plot was found to be 23 kJ mol(-1). N-terminal sequence up to five amino acid residues was found to be DTQEN (Asp, Thr, Gln, Glu, and Asn). In chemical modification studies treatment of the enzyme with NBS led to total loss of enzyme activity and modification of a single tryptophan residue led to inactivation. Fluorescence studies over a pH range of 3-8 have shown tryptophan residue to be in highly hydrophobic environment and pH change did not bring about any appreciable change in its environment. Far-UV CD spectrum indicated predominance of alpha-helical structure in the enzyme. alpha-Mannosidase from E indica exhibits immunological identity with alpha-mannosidase from Canavalia ensiformis but not with the same enzyme from Glycine max and Cicer arietinum. Incubation of E. indica seed lectin with alpha-mannosidase resulted in 35% increase in its activity, while no such activation was observed for acid phosphatase from E. indica. Lectin induced activation of alpha-mannosidase could be completely abolished in presence of lactose, a sugar specific for lectin.
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PMID:Characterization of alpha-mannosidase from Erythrina indica seeds and influence of endogenous lectin on its activity. 1693 28

Hsp22/HspB8 is a member of the small heat-shock protein family, whose function is not yet completely understood. Our immunolocalization studies in a human neuroblastoma cell line, SK-N-SH, using confocal microscopy show that a significant fraction of Hsp22 is localized to the plasma membrane. We therefore investigated its interactions with lipid vesicles in vitro. Intrinsic tryptophan fluorescence is quenched in the presence of lipid vesicles derived from either bovine brain lipid extract or purified lipids. Time-resolved fluorescence studies show a decrease in the lifetimes of the tryptophan residues. Both of these results indicate burial of some tryptophan residues of Hsp22 upon interaction with lipid vesicles. Membrane interactions also lead to increase in fluorescence polarization of Hsp22. Gel-filtration chromatography shows that Hsp22 binds stably with lipid vesicles; the extent of binding depends on the nature of the lipid. Hsp22 binds more strongly to vesicles made of lipids containing a phosphatidic acid, phosphatidylinositol or phosphatidylserine headgroup (known to be present in the inner leaflet of plasma membrane) compared with lipid vesicles made of a phosphatidylcholine head-group alone. Far-UV CD spectra reveal conformational changes upon binding to the lipid vesicles or in membrane-mimetic solvent, trifluoroethanol. Thus our fluorescence, CD and gel-filtration studies show that Hsp22 interacts with membrane and this interaction leads to stable binding and conformational changes. The present study therefore clearly demonstrates that Hsp22 exhibits potential membrane interaction that may play an important role in its cellular functions.
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PMID:Interaction of mammalian Hsp22 with lipid membranes. 1702 May 37

Novel trinuclear complexes C23H31N6O6CuSn2Cl5 [1], C23H31N6O6CuZr2Cl5 [2], C23H31N6O6ZnSn2Cl5 [3], and C23H31N6O6ZnZr2Cl5 [4] were synthesized and characterized by spectroscopic (IR, 1H, 13C, 2D COSY, and 119Sn NMR, EPR, UV-vis, ESI-MS) and analytical methods. In complexes 1-4, the geometry of copper and zinc metal ions were described as square-based pyramidal with l-tryptophan coordinated to copper/zinc via carboxylate group while Sn/Zr was present in the hexacoordinate environment. The interaction of 1 and 2 with calf thymus DNA in Tris buffer was studied by electronic absorption titration, luminescence titration, cyclic voltammetry, circular dichroism, and viscometric measurements. The emission quenching of these complexes by [Fe(CN)6]4- depressed greatly when bound to DNA. Observed changes in the circular dichoric spectra of DNA in presence of 1 and 2 support the strong binding of complexes with DNA. The relative specific viscosity of DNA bound to 1 and 2 decreased, indicating that the complexes bind to DNA via covalent binding. The results reveal that the extent of DNA binding of 1 was greater than that of 2. To evaluate the mechanistic pathway of DNA inhibition, counting experiments and MTT assay were employed to assess the induction of apoptosis by 1. Western blot analysis of whole cell lysates and mitochondrial fractions with Bcl-2 and p-53 family proteins and caspase-3 colorimetry assay were also carried out on a human neuroblastoma cell line SY5Y.
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PMID:DNA binding studies of novel Copper(II) complexes containing L-tryptophan as chiral auxiliary: in vitro antitumor activity of Cu-Sn2 complex in human neuroblastoma cells. 1737 49

beta-Carbolines (BCs) derive from tryptophan and its derivatives. They are formed endogenously in humans and mammals and occur inter alia in cooked meat and tobacco smoke. They have been detected in human brain, cerebrospinal fluid, and plasma. Up to now they were predominantly identified as compounds exhibiting neurotoxic actions. Since significantly higher amounts are present in parkinsonian patients, they are regarded as potential pathogenetic factors in Parkinson's disease. We identified for the first time a BC (9-methyl-BC; 9-me-BC) exerting neuroprotective and neuron-differentiating effects. Treatment of primary mesencephalic dopaminergic cultures with 9-me-BC inhibited the basal release of lactate dehydrogenase and reduced the number of cells stained with propidium iodide. Caspase-3 activity was decreased, the total protein content was unchanged and ATP content was increased. Furthermore, the expression of inflammation-related genes was reduced. The number of differentiated dopaminergic neurones was significantly increased and a wide array of neurotrophic/transcription factors (Shh, Wnt1, Wnt5a, En1, En2, Nurr1, Pitx3) and marker genes (Th, Dat, Aldh1a1) decisive for dopaminergic differentiation was stimulated. Consistently, the dopamine content was slightly, although non-significantly, increased and the dopamine uptake capacity was elevated. An anti-proliferative effect was observed in human neuroblastoma SH-SY5Y cells which is consistent with a reduced incorporation of bromodesoxyuridine into the DNA of primary mesencephalic cells. Whether the additional dopaminergic neurones in primary culture derive from dopaminergic precursor cells, previously tyrosine hydroxylase negative dopaminergic neurones or are the result of a transdifferentiation process remains to be established.
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PMID:9-Methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture. 1791 2

The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.
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PMID:Characterization of the kynurenine pathway in human neurons. 1803 61

Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against various insults. However, the molecular mechanism of this protective effect has not been identified. In this study, we examined the protective effects of KYNA against 1-methyl-4-phenylpyridinium (MPP(+)), the best-characterized toxin inducing pathological changes resembling Parkinson's disease (PD), using SH-SY5Y and SK-N-SH human neuroblastoma cells. Pre-treatment of KYNA attenuated MPP(+)-induced neuronal cell death in SH-SY5Y and SK-N-SH cells. MPP(+)-induced cell death was preceded by increases in Bax expression and mitochondrial dysfunction, such as collapse of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c from mitochondria into the cytoplasm, and increases in caspase-9/-3 activities. KYNA effectively inhibited all of these mitochondrial apoptotic processes. Our results indicate that KYNA plays a protective role by down-regulating Bax expression and maintaining mitochondrial function in MPP(+)-induced neuronal cell death, and suggest that KYNA may have therapeutic potential in PD.
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PMID:Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway. 1846 30


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