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Estudo de diferentes parâmetros de estresse oxidativo na adrenoleucodistrofia ligada ao X

Deon, Marion
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Dissertação Formato: application/pdf
Português
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17.51%
A adrenoleucodistrofia ligada ao cromossomo X (X-ALD) é uma doença peroxissomal bioquimicamente caracterizada pelo acúmulo de ácidos graxos de cadeia muito longa (“Very Long Chain Fatty Acids” - VLCFA), principalmente os ácidos hexacosanóico (C26:0) e tetracosanóico (C24:0), em diferentes tecidos e fluidos orgânicos. A doença é clinicamente caracterizada por progressiva desmielinização central e periférica e insuficiência adrenal. Os mecanismos exatos do dano cerebral na X-ALD são pouco conhecidos. O tratamento usual para X-ALD com a mistura gliceroltrioleato/gliceroltrierucato na proporção 4:1, conhecido como óleo de Lorenzo (OL), em combinação com uma dieta de restrição dos VLCFA normaliza os níveis de VLCFA, mas em pacientes sintomáticos os sintomas neurológicos persistem ou progridem. Os radicais livres parecem estar envolvidos em um grande número de enfermidades no ser humano, tais como nas doenças neurodegenerativas (como doença de Parkinson, doença de Alzheimer e esclerose múltipla), nas doenças crônico-inflamatórias, nas doenças vasculares e no câncer. Considerando que a geração de radicais livres está envolvida em várias desordens neurodegenerativas, no presente estudo foram avaliados vários parâmetros de estresse oxidativo em plasma...

Avaliação da funcionalidade mitocondrial na cardiomiopatia diabética

Guerra, Gabriela Maria Pereira Carvalho
Fonte: Universidade de Aveiro Publicador: Universidade de Aveiro
Tipo: Dissertação de Mestrado
Português
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17.51%
A cardiomiopatia diabética é uma das complicações mais comuns da diabetes mellitus, sendo a principal causa de insuficiência cardíaca entre os pacientes diabéticos. Nesta patologia está subjacente a disfunção mitocondrial e, dada a importante função da mitocôndria no metabolismo, esta constitui um foco de interesse e de estudo no âmbito da diabetes. Assim, o presente trabalho teve como objetivo avaliar a funcionalidade mitocondrial cardíaca numa fase inícial da patogênese da diabetes e a sua possivel relação com a suscetibilidade das proteínas e dos lípidos à oxidação. Nesse sentido, utilizou-se um modelo animal de diabetes tipo 1 obtido por administração de streptozotocina (STZ). Após um mês da administração deste fármaco (DMT1) ou de veículo (CONT), os animais foram sacrificados e isolou-se a fração mitocondrial do músculo cardíaco. Posteriormente foi avaliado o efeito da administração de STZ na atividade da cadeia respiratória mitocondrial e na suscetibilidade das proteínas e lípidos mitocondriais ao dano oxidativo e as possiveis alterações estruturais. Os resultados obtidos evidenciaram uma diminuição significativa da atividade dos complexos IV e V da cadeia respiratória do músculo cardíaco dos animais DMT1...

Indeterminate results of the second-generation hepatitis C virus (HCV) recombinant immunoblot assay: significance of high-level c22-3 reactivity and influence of HCV genotypes.

Zein, N N; Germer, J J; Wendt, N K; Schimek, C M; Thorvilson, J N; Mitchell, P S; Persing, D H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1997 Português
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A second-generation recombinant immunoblot assay (RIBA 2.0) is used in the United States to confirm infection with hepatitis C virus (HCV) in samples that are anti-HCV (enzyme immunoassay) positive. In some cases, indeterminate results of RIBA 2.0, which are defined as reactivity to a single antigen species or reactivity limited to two proteins derived from the same coding region of the HCV genome, are encountered. This study was performed to establish the significance of indeterminate RIBA 2.0 results in relation to HCV RNA detection, high positivity for the c22-3 band, and the HCV genotype as determined by direct DNA sequencing. Ninety-six samples with indeterminate RIBA 2.0 results were studied. HCV RNA was detected in 21 of 34 (62%) samples with high reactivity to c22-3 and in 8 of 62 (13%) samples with low reactivity to c22-3. The HCV genotype distribution in samples that were RIBA 2.0 indeterminate and HCV RNA positive was significantly different from that in samples of a control group with positive results for both the RIBA 2.0 and HCV PCR. These results suggest that highly positive c22-3 samples are likely to be associated with HCV viremia and that infection with less common HCV genotypes is more commonly associated with indeterminate RIBA 2.0 results.

Catabolism of Naphthalenesulfonic Acids by Pseudomonas sp. A3 and Pseudomonas sp. C22

Brilon, C.; Beckmann, W.; Knackmuss, H.-J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1981 Português
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Naphthalene and two naphthalenesulfonic acids were degraded by Pseudomonas sp. A3 and Pseudomonas sp. C22 by the same enzymes. Gentisate is a major metabolite. Catabolic activities for naphthalene, 1-naphthalenesulfonic acid, and 2-naphthalenesulfonic acid are induced by growth with naphthalene, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, methylnaphthalene, or salicylate. Gentisate is also an inducer in strain A3. Inhibition kinetics show that naphthalene and substituted naphthalenes are hydroxylated by the same naphthalene dioxygenase. Substrates with nondissociable substituents such as CH3, OCH3, Cl, or NO2 are hydroxylated in the 7,8-position, and 4-substituted salicylates are accumulated. If CO2H, CH2CO2H, or SO3H are substituents, hydroxylation occurs with high regioselectivity in the 1,2-position. Thus, 1,2-dihydroxy-1,2-dihydronaphthalene-2-carboxylic acids are formed quantitatively from the corresponding naphthalenecarboxylic acids. Utilization of naphthalenesulfonic acids proceeds by the same regioselective 1,2-dioxygenation which labilizes the C—SO3− bond and eliminates sulfite.

Significance of highly positive c22-3 "indeterminate" second-generation hepatitis C virus (HCV) recombinant immunoblot assay (RIBA) and resolution by third-generation HCV RIBA.

Pawlotsky, J M; Fleury, A; Choukroun, V; Deforges, L; Roudot-Thoraval, F; Aumont, P; Duval, J; Dhumeaux, D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1994 Português
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Second-generation recombinant immunoblot assay (RIBA) is widely used for the validation of anti-hepatitis C virus (HCV) antibody detection. The aims of this work were (i) to determine, in terms of liver disease and HCV replication, the significance of a peculiar "indeterminate" second-generation RIBA pattern characterized by the presence of high titers of antibodies directed to c22-3, a protein bearing core epitopes and (ii) to determine whether a more advanced version of the same strip assay, namely a third-generation RIBA, may solve the problem of such indeterminate patterns. Sixty patients for which c22-3 indeterminate second-generation RIBAs were highly positive were studied. Forty-two of them (70%) were immunocompromised. Serum transaminases were increased in 46 cases (77%), and HCV RNA was detected by PCR in 50 cases (83%). Third-generation RIBA remained highly positive c22 indeterminate for 9 patients (15%) but was positive for 51 (85%), mostly because of increased sensitivity for the detection of both anti-c100 and anti-c33c antibodies. These results suggest that third-generation RIBA may achieve resolution of most of these cases but that highly positive c22 indeterminate third-generation RIBA may persist when used with some patients with very low titers of anti-HCV nonstructural protein antibodies.

Long Chain (C20 and C22) Fatty Acid Biosynthesis in Developing Seeds of Tropaeolum majus: AN IN VIVO STUDY 1

Pollard, Michael R.; Stumpf, Paul K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1980 Português
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The storage triacylglycerols of nasturtium (Tropaeolum majus) seeds are composed principally of cis-11-eicosenoate and cis-13-docosenoate. To investigate the biosynthesis of these C20 and C22 fatty acids, developing seed tissue was incubated with various 14C-labeled precursors. Incubation with [1-14C]acetate produced primarily cis-11-[1-14C]eicosenoate and cis-13-[1,3-14C]docosenoate in the triacylglycerol fraction, the odd-carbon [U-14C]oleate also formed from [14C] acetate was in the polar lipid fraction. Kinetic data showed that this oleate was not channeled into cis-11-eicosenoate nor cis-13-docosenoate over a 24-hour period. Under suitable conditions, nasturtium seed could also produce [14C]stearate, [14C]eicosenoate, and [14C]docosenoate from [1-14C]acetate. The results are discussed in terms of the number of pathways producing fatty acids. From pool size and other considerations, the results can be rationalized only in terms of different de novo systems for oleate biosythesis, one supplying oleate for incorporation into phospholipids and the other supplying oleate for chain elongation and subsequent esterification into triacylglycerols. Because of the probable heterogeneous nature of the seed tissue, it is not known if these two systems are operating in different cell types...

Biosynthesis of C20 and C22 Fatty Acids by Developing Seeds of Limnanthes alba: CHAIN ELONGATION AND Δ5 DESATURATION1

Pollard, Michael R.; Stumpf, Paul K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1980 Português
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27.15%
The storage triacylglycerols of meadowfoam (Limnanthes alba) seeds are composed essentially of C20 and C22 fatty acids, which contain an unusual Δ5 double bond. When [1-14C]acetate was incubated with developing seed slices, 14C-labeled fatty acids were synthesized with a distribution similar to the endogenous fatty acid profile. The major labeled product was cis-5-eicosenoate, with smaller amounts of palmitate, stearate, oleate, cis-5-octadecenoate, eicosanoate, cis-11-eicosenoate, docosanoate, cis-5-docosenoate, cis-13-docosenoate, and cis-5,cis-13-docosadienoate. The label from [14C]acetate and [14C]malonate was used preferentially for the elongation of endogenous oleate to produce cis-[14C]11-eicosenoate, cis-13-[14C]docosenoate, and cis-5,cis-13-[14C]docosadienoate and for the elongation of endogenous palmitate to produce the remaining C20 and C22 acyl species. The Δ5 desaturation of the preformed acyl chain and chain elongation of oleate and palmitate were demonstrated in vivo by incubation of the appropriate 1-14C-labeled free fatty acids. Using [1-14C]acyl-CoA thioesters as substrates, these enzyme activities were also demonstrated in vitro with a cell-free homogenate.

Incorporation and turnover of eicosapentaenoic and docosahexaenoic acids in human blood platelets in vitro.

Croset, M; Bayon, Y; Lagarde, M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/01/1992 Português
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Mass changes in the incorporation of linoleic (C18:2), eicosapentaenoic (C20:5) and docosahexaenoic (C22:6) acids in human blood platelet phospholipids were induced by incubating the cells and these fatty acids complexed to albumin. The remodelling of [14C]C18:2, [14C]C20:5 and [14C]C22:6 in classes, subclasses and molecular species of platelet phospholipids was studied in resting and thrombin-stimulated cells. More than 85% of the incorporation was located in phospholipids, representing 5-fold and 2.5-fold increases in the phospholipid C20:5 and C22:6 endogenous content respectively. Thrombin stimulation induced a 30% degradation of 1-acyl-2-C20:5-glycerophosphocholine (GPC) and 1-acyl-2-C22:6-GPC, but did not induce significant release of C18:2 from 1-acyl-2-C18:2-GPC. There was no change in the [14C]fatty acid composition of 1-alkyl-2-acyl-GPC. Thrombin-dependent increases in 1-alkenyl-2-C20:5-glycerophosphoethanolamine (GPE) and 1-alkenyl-2-C22:6-GPE of 2.1-fold and 2.5-fold respectively accounted for the rise in GPE radioactivity and partly compensated for the loss of these fatty acids from 1,2-diacyl-GPC: transfer to 1-alkenyl-2-acyl-GPE was 0.4 and 1.5 nmol/10(9) platelets for C20:5 and C22:6 respectively. [14C]C20:5 and [14C]C22:6 were incorporated into six different species of 1...

Surface areas of 1-palmitoyl phosphatidylcholines and their interactions with cholesterol.

Evans, R W; Williams, M A; Tinoco, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/07/1987 Português
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1-Palmitoyl phosphatidylcholines (1-palmitoyl PCs), in which the 2-position was occupied respectively by C10:0, C12:0, C14:0, C14:1, n-7, C16:0, C16:1, n-7, C18:0, C18:1(t), n-9, C18:1, n-9, C18:2, n-6, C18:3, N-3, C18:3, n-6, C18:3(5t,9,12), C22:0, C22:1, n-9, C22:2, n-6, C22:3, n-3, C22:4, n-6, C22:5, n-6 or C22:6, n-3 fatty acids, were studied as monolayer films at the air/water interface. Results for molecular area indicated that the areas of the PC (phosphatidylcholine) did not continuously decrease as the length of one chain increased. For series of saturated, monoenoic and dienoic 1-palmitoyl PCs the smallest molecular area was occupied by the PC containing a 20-carbon acid at the 2-position. In the 18-carbon series, introduction of the first and third cis double bonds caused a large increase in molecular area, but in the 22-carbon series the first and second cis double bonds produced large increases in molecular area. Molecules containing three or more cis double bonds varied little in molecular area, regardless of chain length (18-22 carbon atoms). The influence of a trans double bond was intermediate between that of a saturated and a cis double bond. The 18- and 22-carbon series of PCs were studied in mixed monolayers with cholesterol and desmosterol. Condensation of molecular areas occurred in all sterol PC mixed films...

Comparative biochemistry of beta-oxidation. An investigation into the abilities of isolated heart mitochondria of various animal species to oxidize long-chain fatty acids, including the C22:1 monoenes.

Osmundsen, H; Bremer, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/08/1978 Português
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27.15%
Rates of acylcarnitine oxidation by isolated heart mitochondria from various animal species were measured polarographically, and by using a spectrophotometric assay [see Osmundsen & Bremer (1977) Biochem. J. 164, 621-633]. Polarographic measurements do not give a correct guide to abilities to beta-oxidize very-long-chain acylcarnitines, in particular C22:1 fatty acylcarnitines. 2. No significant species differences were detected in the abilities to beta-oxidize various C22:1 fatty acylcarnitines. Significant species differences were, however, detected when rates of beta-oxidation were correlated with rates of respiration brought about by very-long-chain acylcarnitines. We concluded that some aspects of oxidative metabolism (possibly the oxidation of tricarboxylic acid-cycle intermediates) are inhibited by very-long-chain fatty acids in some species (e.g. the rat and the cat but not in others (e.g. the pig and the rabbit). 3. It is proposed that the pattern of variation of rates of oxidation of various acylcarnitines (as measured spectrophotometrically) of various chain lengths can be used as a guide to the chain-length specificities of the acyl-CoA dehydrogenases of beta-oxidation (EC 1.3.99.3).

Separate effects of long-chain phosphatidylcholines on dephosphorylation of the Ca(2+)-ATPase and on Ca2+ binding.

Starling, A P; East, J M; Lee, A G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/09/1996 Português
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17.51%
The steady-state activity of the Ca(2+)-ATPase of skeletal muscle sarcoplasmic reticulum (SR) is low when reconstituted into bilayers of the long-chain phosphatidylcholines dierucyl phosphatidylcholine [di(C22:1)PC] or dinervonyl phosphatidylcholine [di(C24:1)PC]. In di(C24:1)PC the ATPase binds a single Ca2+ ion, whereas in di(C22:1)PC it binds two, as in the native SR [Starling, East and Lee (1993) Biochemistry 32, 1593-1600]. In di(C22:1)PC, rates of phosphorylation of the ATPase by ATP and the rate of ATP-induced Ca2+ dissociation are slightly lower than in the native ATPase. However, a much more marked decrease is observed in di(C22:1)PC in the rate of dephosphorylation of the phosphorylated ATPase, which explains the low steady-state ATPase activity. The level of phosphorylation of the ATPase by Pi was little affected by reconstitution in di(C22:1)PC, suggesting that the rate of phosphorylation by Pi is also decreased. The very similar effects of di(C22:1)PC and di(C24:1)PC (Starling, East and Lee (1995) Biochem. J. 310, 875-879) on phosphorylation and dephosphorylation suggest that changes in these steps and the change in Ca2+ binding stoichiometry observed in di(C24:1)PC represent independent changes on the ATPase.

Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

Hirohata, Shunsei; Arinuma, Yoshiyuki; Takayama, Maki; Yoshio, Taku
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
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17.51%
We explored the relationship of antibodies to the whole ribosomal P proteins (P0, P1, and P2) in cerebrospinal fluid (CSF) with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus (SLE). CSF samples were obtained from 71 SLE patients (52 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NP-SLE] and 19 patients with neurological syndromes or peripheral neuropathy [focal NP-SLE]) as well as from 24 patients with non-inflammatory neurological disease. Immunoglobulin G (IgG) antibodies to the C-terminal 22-amino acid ribosomal P synthetic peptide (anti-PC22) and those to purified bovine ribosomal P proteins (P0, P1, and P2) (anti-whole P) were determined by enzyme-linked immunosorbent assay; affinity-purified IgG anti-PC22 were used as the standard. The concentrations of antibodies to epitopes other than the C-terminal 22 amino acids of ribosomal P proteins were calculated by subtracting anti-PC22 from anti-whole P (anti-PEX.C22). CSF anti-whole P levels were significantly elevated in diffuse NP-SLE compared with focal NP-SLE or control patients. By contrast, there were no significant differences in CSF anti-PC22 levels among the three groups. Of note, CSF anti-PEX.C22 levels were significantly elevated in diffuse NP-SLE compared with the other two groups. CSF anti-PEX.C22 levels were not significantly correlated with CSF anti-PC22 levels...

Toward the Synthesis of Antascomicin B. Synthesis of a Model of the C22-C34 Fragment via Ireland-Claisen and Allylic Diazene Rearrangements

Qi, Wei; McIntosh, Matthias C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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26.88%
The C22-C34 fragment of antascomicin B lacking the C31 and C32 hydroxyl groups has been prepared in 11 steps from commercially available 2-OH-cyclohexanone. An Ireland-Claisen rearrangement was employed to install the C26 and C27 stereocenters. Our recently reported diastereoselective acyclic 1,3-reductive transposition was used to establish the remote C23 stereocenter. Directed hydrogenation was employed to set the C29 stereocenter. The model compound contains 5 of the stereocenters and all of the carbons of the corresponding fragment of antascomicin B.

A synthetic analog of verbenachalcone potentiates NGF-induced neurite outgrowth and enhances cell survival in neuronal cell models

Clement, Ceiléssia M.; Dandepally, Srinivasa R.; Williams, Alfred L.; Ibeanu, Gordon C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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17.62%
This study uses NeuroScreen-1 (NS-1) cells, a derivative of pheochromocytoma (PC12) cells, to examine neurite outgrowth induced by a novel synthetic verbenachalcone derivative, DSRB20-022 (C22). We treated NS-1 cells with varying concentrations of C22 in the presence of 2ng/mL nerve growth factor (NGF). A dose dependent effect of C22 was observed at concentrations of 2 μM and above, resulting in significant enhancement of NGF-dependent neurite outgrowth in NS-1 cells. C22 did not exhibit neuritogenic activity in the absence of NGF, but promoted a concentration-dependent increase in neurite-bearing cells without inducing cytotoxicity. Cell viability assays showed that C22 and the parent compound verbenachalcone (VC) are neuroprotective and enhanced survival of NS-1, PC12, and the murine neuro-2A (N2a) cell lines under conditions of serum deprivation. The results show that augmentation of NGF-induced neurite outgrowth by C22 in NS-1 was dependent on MAP kinase. Furthermore, the neuroprotective function of C22 and VC was accompanied by suppression of caspase-3/7 activation. However, C22 and VC exerted their antagonistic effects on caspase 3/7 activation through potentially different mechanisms of action.

A Clinical Isolate of Candida albicans with Mutations in ERG11 (Encoding Sterol 14α-Demethylase) and ERG5 (Encoding C22 Desaturase) Is Cross Resistant to Azoles and Amphotericin B▿

Martel, Claire M.; Parker, Josie E.; Bader, Oliver; Weig, Michael; Gross, Uwe; Warrilow, Andrew G. S.; Kelly, Diane E.; Kelly, Steven L.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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27.15%
A clinical isolate of Candida albicans was identified as an erg5 (encoding sterol C22 desaturase) mutant in which ergosterol was not detectable and ergosta 5,7-dienol comprised >80% of the total sterol fraction. The mutant isolate (CA108) was resistant to fluconazole, voriconazole, itraconazole, ketoconazole, and clotrimazole (MIC values, 64, 8, 2, 1, and 2 μg ml−1, respectively); azole resistance could not be fully explained by the activity of multidrug resistance pumps. When susceptibility tests were performed in the presence of a multidrug efflux inhibitor (tacrolimus; FK506), CA108 remained resistant to azole concentrations higher than suggested clinical breakpoints for C. albicans (efflux-inhibited MIC values, 16 and 4 μg ml−1 for fluconazole and voriconazole, respectively). Gene sequencing revealed that CA108 was an erg11 erg5 double mutant harboring a single amino acid substitution (A114S) in sterol 14α-demethylase (Erg11p) and sequence repetition (10 duplicated amino acids), which nullified C22 desaturase (Erg5p) function. Owing to a lack of ergosterol, CA108 was also resistant to amphotericin B (MIC, 2 μg ml−1). This constitutes the first report of a C. albicans erg5 mutant isolated from the clinic.

Drosophila lacks C20 and C22 PUFAs

Shen, Li Rong; Lai, Chao Qiang; Feng, Xiang; Parnell, Laurence D.; Wan, Jian Bo; Wang, Jing D.; Li, Duo; Ordovas, Jose M.; Kang, Jing X.
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /10/2010 Português
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Drosophila melanogaster has been considered a model organism for investigating human diseases and genetic pathways. Whether Drosophila is an ideal model for nutrigenomics, especially for FA metabolism, however, remains to be illustrated. The aim of this study was to examine the metabolism of C20 and C22 PUFAs in Drosophila. Analysis of FA composition revealed a complete lack of C20 and C22 PUFAs in the body tissue of larvae, pupae, and adult flies fed either a base or supplemented diet abundant in the PUFA precursors linoleic acid and α-linolenic acid. PUFA with >C20 could only be found in flies supplemented with specific FAs. Interestingly, the supplemented C22 PUFAs docosahexaenoic acid (22:6n-3) and docosatetraenoic acid (22:4n-6) were largely converted to the shorter chain C20 PUFAs eicosapentaenoic acid (20:5n-3) and arachidonic acid (20:4n-6), respectively. Furthermore, a genome sequence scan indicated that no gene encoding Δ-6/ Δ-5 desaturases, the key enzymes for the synthesis of C20/C22 PUFA, was present in Drosophila. These findings demonstrate that Drosophila lacks the capability to synthesize the biologically important C20 and C22 PUFAs, and thereby argue that Drosophila is not a valid model for the study of lipid metabolism and related diseases.

C22:0- and C24:0-dihydroceramides Confer Mixed Cytotoxicity in T-Cell Acute Lymphoblastic Leukemia Cell Lines

Holliday Jr., Michael W.; Cox, Stephen B.; Kang, Min H.; Maurer, Barry J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 09/09/2013 Português
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27.43%
We previously reported that fenretinide (4-HPR) was cytotoxic to acute lymphoblastic leukemia (ALL) cell lines in vitro in association with increased levels of de novo synthesized dihydroceramides, the immediate precursors of ceramides. However, the cytotoxic potentials of native dihydroceramides have not been defined. Therefore, we determined the cytotoxic effects of increasing dihydroceramide levels via de novo synthesis in T-cell ALL cell lines and whether such cytotoxicity was dependent on an absolute increase in total dihydroceramide mass versus an increase of certain specific dihydroceramides. A novel method employing supplementation of individual fatty acids, sphinganine, and the dihydroceramide desaturase-1 (DES) inhibitor, GT-11, was used to increase de novo dihydroceramide synthesis and absolute levels of specific dihydroceramides and ceramides. Sphingolipidomic analyses of four T-cell ALL cell lines revealed strong positive correlations between cytotoxicity and levels of C22:0-dihydroceramide (ρ = 0.74–0.81, P ≤ 0.04) and C24:0-dihydroceramide (ρ = 0.84–0.90, P ≤ 0.004), but not between total or other individual dihydroceramides, ceramides, or sphingoid bases or phosphorylated derivatives. Selective increase of C22:0- and C24:0-dihydroceramide increased level and flux of autophagy marker...

Biochemical characterization of protein quality control mechanisms during disease progression in the C22 mouse model of CMT1A

Chittoor, Vinita G.; Sooyeon, Lee; Rangaraju, Sunitha; Nicks, Jessica R.; Schmidt, Jordan T.; Madorsky, Irina; Narvaez, Diana C.; Notterpek, Lucia
Fonte: American Society for Neurochemistry Publicador: American Society for Neurochemistry
Tipo: Artigo de Revista Científica
Publicado em 03/12/2013 Português
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26.88%
Charcot–Marie–Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axonal pathology is not fully understood, but likely involves subcellular alterations in protein homoeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin–proteasome system (UPS), autophagosomes and heat-shock proteins (HSPs). Here we assessed biochemical markers of these protein homoeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2 and 12 months to ascertain their potential contribution to disease progression. In nerves of 3-week-old mice, using endoglycosidases and Western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are up-regulated. Moreover...

Low C24-OH and C22-OH sulfatides in human renal cell carcinoma

Kim, Il Chan; Bang, Geul; Lee, Jeong Hwa; Kim, Kwang Pyo; Kim, Young Hwan; Kim, Hark Kyun; Chung, Jinsoo
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
26.88%
Histopathologic diagnosis of renal cell carcinoma (RCC) may sometimes be difficult with small biopsy samples. We applied histology-directed matrix-assisted laser desorption/ionization mass spectrometry to RCC samples to evaluate whether and how lipid profiles are different between RCC and normal tissue. We evaluated 59 RCC samples and 24 adjacent normal tissue samples collected from patients who underwent surgery. Five peaks were significantly differently expressed (p < 10−7) between RCCs and adjacent normal tissue samples. C24-OH sulfatide (ST-OH {18:1/24:0}[M-H]−; m/z 906.7 in the negative ion mode) and C22-OH sulfatide (ST-OH {18:1/22:0}[M-H]−; m/z 878.6 in the negative ion mode) were most significantly underexpressed in RCC samples, compared with adjacent normal tissue samples. With 100 random training-to-test partitions within these samples, the median prediction accuracy (RCC vs. normal) ranged from 96.3% to 100% at p cutoff values for feature selection ranging from 0.001 to 10−7. Two oncocytoma samples were predicted as normal tissue by five lipids that were differentially expressed between RCC and normal tissue at p < 10−7. Clear-cell, papillary, and chromophobe RCCs were different in lipid profiles. Permutation p- values for 0.632+ bootstrap cross-validated misclassification rates were less than 0.05 for all the classifiers. Thus...

Induction of Mitochondrial Changes Associated with Oxidative Stress on Very Long Chain Fatty Acids (C22:0, C24:0, or C26:0)-Treated Human Neuronal Cells (SK-NB-E)

Zarrouk, Amira; Vejux, Anne; Nury, Thomas; El Hajj, Hammam I.; Haddad, Madouda; Cherkaoui-Malki, Mustapha; Riedinger, Jean-Marc; Hammami, Mohamed; Lizard, Gérard
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
27.15%
In Alzheimer's disease, lipid alterations point towards peroxisomal dysfunctions. Indeed, a cortical accumulation of saturated very long chain fatty acids (VLCFAs: C22:0, C24:0, C26:0), substrates for peroxisomal β-oxidation, has been found in Alzheimer patients. This study was realized to investigate the effects of VLCFAs at the mitochondrial level since mitochondrial dysfunctions play crucial roles in neurodegeneration. On human neuronal SK-NB-E cells treated with C22:0, C24:0, or C26:0 (0.1–20 μM; 48 h), an inhibition of cell growth and mitochondrial dysfunctions were observed by cell counting with trypan blue, MTT assay, and measurement of mitochondrial transmembrane potential (Δψm) with DiOC6(3). A stimulation of oxidative stress was observed with DHE and MitoSOX used to quantify superoxide anion production on whole cells and at the mitochondrial level, respectively. With C24:0 and C26:0, by Western blotting, lower levels of mitochondrial complexes III and IV were detected. After staining with MitoTracker and by transmission electron microscopy used to study mitochondrial topography, mass and morphology, major changes were detected in VLCFAs treated-cells: modification of the cytoplasmic distribution of mitochondria...