RESUMO
Although some endocrine disruptors (EDs) act at steroid receptors, it is now apparent that compounds may have ED potential if they alter steroid synthesis or metabolism, particularly if they affect Phase 1 or Phase 2 pathways. In the ENDOMET project (EU-funded 5th Framework programme), 23 different assays were used on a wide range of EDs. Cluster analysis of the matrix results enabled identification of four integrated test systems that can be used to pinpoint compounds that are able to alter steroid metabolism or function. Critical pathways were shown to include oestrogen synthesis and sulphonation, synthesis of sulphate/PAPS and thyroid hormone regulation so that the activity profiles of some Phase 1 and Phase 2 reactions can be used as biomarkers for detection of compounds with ED potential.
Assuntos
Biomarcadores/metabolismo , Disruptores Endócrinos/farmacologia , Plastificantes/farmacologia , Esteroides/metabolismo , Algoritmos , Análise por Conglomerados , Sistema Enzimático do Citocromo P-450/metabolismo , Poluentes Ambientais/análise , Poluentes Ambientais/farmacologia , União Europeia , Genoma Humano/efeitos dos fármacos , Ácido Glucurônico/metabolismo , Humanos , Cooperação Internacional , Fosfoadenosina Fosfossulfato/metabolismo , Receptores de Esteroides/metabolismo , Sulfotransferases/metabolismo , Hormônios Tireóideos/metabolismoRESUMO
Endocrine disruptors frequently bear little structural relationship to the hormone whose actions they disrupt. Consequently, the threat of an uninvestigated chemical cannot easily be assessed. Here three different approaches to assessment are discussed. The first presumes an endocrine-disrupting property, following which a cell model capable of responding to such a hormone is used. Although simple and cheap, it provides limited data. A second approach involves multiple assays to detect multiple hormones. Increasing the amount of data increased the difficulty in assessing the significance of results. To meet this problem, cluster analysis based on a simple mathematical matrix was adopted. The matrix was used to determine (i) a limited number of assays to identify a maximum number of endocrine disruptors and (ii) the chemicals with the most wide-ranging effects. A third approach was a whole genome expression analysis based on expression of mRNAs in human TE671 medulloblastoma cells. Expression of individual mRNAs was assessed using the Affymetrix GeneChip(®) Human Genome U133 Plus 2.0 chip. The significance of differential expressed genes was assessed based on gene ontology and pathways analyses using DAVID and GenMaPP programs. The results illustrated the very wide-ranging effects of these chemicals across the genome.
Assuntos
Disruptores Endócrinos/análise , Disruptores Endócrinos/farmacologia , Alternativas aos Testes com Animais , Neoplasias da Mama/metabolismo , Catecol O-Metiltransferase/análise , Linhagem Celular Tumoral , Análise por Conglomerados , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica/métodos , Genoma Humano , Humanos , Plastificantes/análise , Receptores de Estrogênio/antagonistas & inibidores , Regulação para CimaRESUMO
BACKGROUND: Idiopathic inflammatory demyelinating disorders (IIDD) affect the central nervous system. In classical multiple sclerosis (CMS), brain, optic nerves [optic neuritis (ON)] and spinal cord [acute transverse myelitis (ATM)] are affected. In neuromyelitis optica (NMO), optic nerves and spinal cord are predominantly affected. NMO-IgG, an autoantibody targeting aquaporin-4, is a marker for NMO. We studied the frequency and clinical relevance of NMO-IgG seropositivity in IIDD patients. METHODS: Neuromyelitis optica-IgG was detected by indirect immunofluorescence using primate cerebellum. RESULTS: Neuromyelitis optica-IgG was detected in six of 10 NMO patients (60%), six of 10 idiopathic relapsing transverse myelitis (IRTM) patients (60%), two of nine idiopathic relapsing ON patients (22%), one of 11 patients (9%) having single ON attack, one of 30 CMS patients (3%), and none of patients having single ATM attack or controls. Comparing NMO-IgG seropositive (n = 12) with NMO-IgG seronegative (n = 8) patients having NMO or IRTM, NMO-IgG seropositivity was associated with a higher relapse rate in first 2 years, 1.5 and 0.6 attacks/year for seropositive and seronegative groups respectively (P = 0.006), and non-significant trend towards more severe ON and myelitis with poorer clinical outcome. CONCLUSION: Neuromyelitis optica -IgG facilitates diagnosis of NMO spectrum disorders. NMO-IgG seropositivity is associated with higher relapse rate in first 2 years.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Desmielinizantes/imunologia , Imunoglobulina G/sangue , Neuromielite Óptica/imunologia , Adulto , Idoso , Aquaporina 4/imunologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Mielite Transversa/imunologia , Neurite Óptica/imunologia , Recidiva , Adulto JovemRESUMO
UNLABELLED: The effects of four compounds, bis(2-ethylhexyl)phthalate (BEHP); diisodecylphthalate (DIP); 4-n-octylphenol (OP); 4-chloro-3-methylphenol (CMP), on gene expression (steady-state mRNA levels) across the whole human genome were studied in human TE671 cells. Effects were studied using the Affymetrics GeneChip Human Genome U133 Plus 2.0, HG-U133 Plus 2.0 arrays, The array analyses the expression of 47,000 transcripts and variants, including approximately 38,500 well characterised. All four compounds exerted statistically significant actions, affecting between 4 and 6.5% of all genes. Each compound had its own expression signature. In most instances where there was an effect, steady-state mRNA levels were decreased, although not always. CMP treatment caused most increases in mRNA levels. A mixture of DIP and CMP caused fewer changes in mRNA levels than either of the individual compounds. CONCLUSIONS: These plasticisers affected the steady-state mRNA levels of many human genes. Exposure to these compounds over many years has the potential to influence human health.
Assuntos
Poluentes Ambientais/toxicidade , Genômica , Plastificantes/toxicidade , Biotinilação , Linhagem Celular Tumoral , Análise por Conglomerados , DNA/biossíntese , DNA/genética , Primers do DNA/farmacologia , DNA Complementar/biossíntese , DNA Complementar/genética , Desoxirribonuclease I/biossíntese , Desoxirribonuclease I/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Poli A/genética , RNA Complementar/biossíntese , RNA Complementar/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica/efeitos dos fármacosRESUMO
Previously we have shown that E2 down regulates S-COMT expression. Here the effects of four phthalate esters and 4-(tert-octyl)phenol on the intra-cellular levels of S-COMT and COMT activity were studied in MCF-7 cells as a measure of estrogenic activity of these compounds. The four phthalate esters caused significant reductions in both S-COMT protein and COMT activity levels. These effects were inhibited by the ERalpha receptor antagonist ICI182780. 4-(tert-octyl)phenol also caused reductions in these parameters, but the effects were not abolished by ICI182780. Assay of S-COMT protein levels represents a simple and convenient method of assessing the estrogenic potential of a compound.
Assuntos
Catecol O-Metiltransferase/biossíntese , Poluentes Ambientais/toxicidade , Plastificantes/toxicidade , Western Blotting , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Estradiol/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Ácidos Ftálicos/toxicidade , Bifenilos Policlorados/farmacologiaRESUMO
Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.
Assuntos
Catecol O-Metiltransferase/biossíntese , Catecóis/toxicidade , Poluentes Ambientais/toxicidade , Estrogênios não Esteroides , Neoplasias/induzido quimicamente , Fenóis/toxicidade , Bifenilos Policlorados/toxicidade , Receptores de Estrogênio/efeitos dos fármacos , Actinas/toxicidade , Western Blotting , Catecóis/metabolismo , Catecóis/farmacologia , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Poluentes Ambientais/metabolismo , Poluentes Ambientais/farmacologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Fulvestranto , Humanos , Neoplasias/epidemiologia , Fenóis/metabolismo , Fenóis/farmacologia , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/farmacologia , RiscoRESUMO
Hydrogen is the source of energy that unites the metabolisms and fuels the innovative potentials of all living organisms. Autotrophs use hydrogen emitted into hydrothermal vents, where symbiotic communities that share hydrogen thrive. On the surface, life developed using photons to cleave water, releasing hydrogen carried into a reverse Krebs cycle to produce carbohydrates, from which hydrogen and its constituent electron and proton are extracted. Fluctuant electrogenic power is harnessed by extensive exchanges and symbiotic sharing schemes of hydrogen sources and carriers. These communicate with electrostatic nuclear centres, forming a positive feedback loop. If the proton-motive circuitry fails from loss of Redox potential, premature ageing and all-category disease can result.
Assuntos
Evolução Biológica , Ecossistema , Hidrogênio/fisiologia , Simbiose/fisiologia , Animais , Hidrogênio/química , Hidrogênio/deficiênciaRESUMO
Over the past five years, a number of papers have appeared describing the assay of free immunoglobulin light chains in cerebrospinal fluid to assist in the diagnosis of multiple sclerosis. The assay of kappa free immunoglobulin chains is being advocated as a technically simpler and cheaper quantitative alternative to the qualitative detection of oligoclonal bands. This article reviews the analytical and clinical characteristics of these immunoglobulin free light chain assays and places them in their historical context and possible future developments.
Assuntos
Bioensaio , Cadeias kappa de Imunoglobulina/líquido cefalorraquidiano , Cadeias lambda de Imunoglobulina/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Limite de Detecção , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologiaRESUMO
A mathematical model has been developed to determine the best approach to improving tumor targeting with antibody. The amount of antibody in the tumor (tumor content) and the tumor:normal tissue antibody concentration ratio (uptake ratio) were calculated over 12 days from injection, using the computer program FACSIMILE to solve the stiff nonlinear differential equations describing the system. Results indicate that success requires an optimal combination of dose, size, and binding affinity of antibody. Increasing the dose to 100 times that presently used for scanning increased both the percentage of injected antibody in the tumor and the uptake ratio by up to 2 orders of magnitude to maximal values determined by affinity. This result could be achieved by coinjecting unlabeled antibody. Increasing affinity from Keq = 10(9) to 10(13)M-1 increased the uptake ratio from 5 to 100 for whole antibody and to 550 for a small ligand, at the calculated optimal dose, but had no effect at the current scanning dose. With decreasing molecular size at average affinity, the same maximum tumor content and uptake ratio were achieved but progressively earlier. At high affinity there was a substantial advantage for a small ligand compared with whole antibody in terms of uptake ratio (550 versus 100) and tumor:normal tissue integral dose ratio (330 versus 60). The uptake of a small ligand was not increased by binding to plasma protein but with increasing time the tumor content was higher than without protein binding.
Assuntos
Anticorpos Antineoplásicos , Transporte Biológico , Ligantes , Modelos Teóricos , Neoplasias/metabolismo , Animais , Humanos , Imunoterapia , Cinética , Matemática , Neoplasias/imunologia , Neoplasias/terapia , Ligação Proteica , SoftwareRESUMO
BACKGROUND/OBJECTIVES: Enteral feeding will induce remission in as many as 80-90% of compliant patients with active Crohn's disease (CD), but its method of action remains uncertain. This study was designed to examine its effects on the colonic microbiome. METHODS/SUBJECTS: Healthy volunteers and patients with CD followed a regimen confined to enteral feeds alone for 1 or 2 weeks, respectively. Chemicals excreted on breath or in faeces were characterised at the start and at the end of the feeding period by gas chromatography/mass spectrometry. RESULTS: One week of feeding in healthy volunteers caused significant changes in stool colour and deterioration in breath odour, together with increased excretion of phenol and indoles on the breath. Feeding for 2 weeks in patients with CD produced significant improvements in symptoms and a decrease in the concentration of C-reactive protein. The faecal concentrations of microbial products, including short-chain fatty acids (SCFAs), and potentially toxic substances, including 1-propanol, 1-butanol and the methyl and ethyl esters of SCFAs, showed significant falls. CONCLUSIONS: A significant change occurs in the production of microbial metabolites after enteral feeding in both healthy volunteers and patients with CD. Many of those detected in CD are toxic and may feasibly lead to the immunological attack on the gut microbiota, which is characteristic of inflammatory bowel disease. The reduction in the production of such metabolites after enteral feeding may be the reason for its effectiveness in CD.
Assuntos
Colo , Doença de Crohn/terapia , Nutrição Enteral , Microbioma Gastrointestinal , 1-Butanol/metabolismo , 1-Propanol/metabolismo , Adolescente , Adulto , Idoso , Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Proteína C-Reativa/metabolismo , Colo/metabolismo , Colo/microbiologia , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Ésteres/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Thyroid hormones regulate the transcription of a number of genes in the anterior pituitary gland. A thyroid hormone response element in the regulatory region of the rat growth hormone gene has previously been shown to mediate the effects of thyroid hormones on growth hormone gene transcription. The 5' flanking regions of the thyrotrophin alpha and beta subunit and prolactin genes have now been examined for the presence of sequences similar to this response element. Southern blotting reveals that no such sequences are present in the regions of the thyrotrophin subunit and prolactin genes examined, suggesting that the thyroid response elements of these genes differ from that of the rat growth hormone gene.
Assuntos
Hormônio do Crescimento/genética , Hormônios Adeno-Hipofisários/genética , Sequências Reguladoras de Ácido Nucleico , Hormônios Tireóideos/fisiologia , Animais , Southern Blotting , DNA/genética , Subunidade alfa de Hormônios Glicoproteicos/genética , Humanos , Sondas de Oligonucleotídeos , Prolactina/genética , Tireotropina/genéticaRESUMO
The base sequence of cDNA encoding the complete human liver cysteine dioxygenase type I (CDO-I; EC 1.13.11.20) message, and the derived amino-acid sequence are reported. CDO-I is encoded on a single mRNA species (approx. 1.5 kb). Human CDO-I clones were identified by screening a liver cDNA library, and inserts were isolated and sequenced. In addition, human liver total RNA was reverse-transcribed and CDO-I cDNA amplified by PCR using a modified poly-T primer and specific CDO-I primers to give a second source of sequencing template. The CDO-I message encodes a 200 amino-acid residue protein, the sequence of which has greater than 90% homology with the equivalent rat enzyme. The message was not expressed in a human hepatoma cell line (Hep G2).
Assuntos
Dioxigenases , Oxigenases/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Cisteína Dioxigenase , Sondas de DNA , DNA Complementar , Biblioteca Gênica , Humanos , Fígado/enzimologia , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , DNA Polimerase Dirigida por RNA , Ratos , Homologia de Sequência de Aminoácidos , Células Tumorais CultivadasRESUMO
Thyroglobulin, a 660 kDa glycoprotein, is the major product of protein synthesis in the thyroid gland. It has been suggested that modifications of thyroglobulin glycosylation occur in various thyroid disorders. In order to study possible changes in glycosylation of tissue thyroglobulin associated with thyroid disease, we have developed a lectin affinity electrophoresis system which allows characterization of small (less than 1 microgram) quantities of thyroglobulin. Human thyroglobulin was extracted and purified. Agarose gels were cast containing concanavalin A, Ricinus communis agglutinin, L-phytohaemagglutinin and pokeweed mitogen at various concentrations. Purified human thyroglobulin was serially diluted, loaded onto lectin gels and electrophoresed. Concanavalin A, R. communis agglutinin and phytohaemagglutinin all bound thyroglobulin in a concentration-dependent manner. Pokeweed mitogen did not bind thyroglobulin. Purified thyroglobulin was treated with neuraminidase and endoglycosidase H. Two-dimensional immunoelectrophoresis revealed the migration of thyroglobulin to be modified by neuraminidase but not by endoglycosidase H. Lectin affinity electrophoresis of purified human thyroglobulin with and without enzyme treatment indicated the presence of: oligomannose structures as shown by concanavalin A reactivity and modification by endoglycosidase H, and complex oligosaccharides as shown by affinity for R. communis agglutinin and modification by neuraminidase. These structures are in keeping with the proposed patterns of glycosylation of human thyroglobulin and indicate suitability of the method for characterizing the glycosylation of small quantities of thyroglobulin.
Assuntos
Tireoglobulina/metabolismo , Acetilglucosaminidase , Fenômenos Químicos , Química , Eletroforese/métodos , Glicosilação , Humanos , Imunoeletroforese/métodos , Lectinas , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase , NeuraminidaseRESUMO
All-trans retinoic acid is a potent inhibitor of [125I]-thyroxine (T4) binding to human erythrocyte membranes and can block the activation by thyroid hormone of erythrocyte Ca(2+)-ATPase [J. Biol. Chem. (1989) 264, 687-689]. In the present studies, retinoic acid was examined for its ability to displace thyroxine from binding sites on human transthyretin (TTR). Scatchard analysis of [125I]T4 binding to purified TTR, determined by equilibrium dialysis, revealed two classes of binding sites with association constants of 3.2 x 10(9) M-1 and 8.1 x 10(6) M-1. All-trans retinoic acid also displaced [125I]T4; 40% of the specifically bound [125I]T4 was displaced at a retinoic acid concentration of 2 x 10(-5) M. Analysis of the high affinity T4 binding site suggests that the Ka for retinoic acid to that site is approx. 10(7) M-1. 8-Anilinonaphthalene-1-sulfonate (ANS), a strongly fluorescing dye, binds to the thyroxine binding sites on TTR. T4 and 3,5,3'-L-triiodothyronine (T3) shifted the fluorescence emission maximum and intensity of an ANS-TTR solution toward the spectrum obtained from uncomplexed ANS. All-trans retinoic acid caused a similar shift in the emission spectrum of ANS, but was less potent than T4. Retinol failed to quench the emission intensity of the ANS-TTR complex, while 13-cis-retinoic acid was less effective than all-trans retinoic acid.
Assuntos
Pré-Albumina/química , Tiroxina/química , Tretinoína/farmacologia , Naftalenossulfonato de Anilina/química , Sítios de Ligação , Corantes Fluorescentes , Humanos , Radioisótopos do Iodo , Pré-Albumina/farmacologia , Tiroxina/farmacologiaRESUMO
A portion of the human X-chromosome (> 5 kb) encoding the translated portion of the thyroxine-binding globulin (TBG) gene was sequenced. The primary templates for sequencing were isolated from a human X-chromosome library (two positive plaques from 400,000 screened initially with a TBG cDNA probe) or were produced by PCR amplification using leucocyte genomic DNA as the amplification template. Potential hormone response elements (HREs) were identified at either end of the gene. These HREs have sequences based on the consensus half-site of thyroid hormone response elements, although it is unclear whether the structures are functional HREs. Other potential regulatory elements also were identified towards the 3' end of the gene.
Assuntos
Hominidae/genética , Proteínas de Ligação a Tiroxina/genética , Cromossomo X , Animais , Sequência de Bases , Sequência Consenso , Sondas de DNA , Éxons , Humanos , Dados de Sequência Molecular , Oligonucleotídeos Antissenso , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , Moldes GenéticosRESUMO
Phenotypic differences in nicotinamide N-methyltransferase (NNMT, E. C. 2.1.1.1) activity may be due to a genetic polymorphism. We report the characterisation of the hepatic NNMT activity in cytosol from normal human livers, enzyme protein levels determined by Western blotting and ELISA and mRNA levels determined by SDS-PAGE/Northern blotting. Subjects with high NNMT activity had high levels of NNMT protein and NNMT mRNA levels in hepatic cytosol and the converse was true for individuals with low NNMT activity. No differences in sequences were seen when cDNAs of individuals with high and low NNMT activity were compared. Thus phenotypic differences in the general population are due to differences in steady-state mRNA levels and not because of a polymorphism in the coding region of the NNMT gene.
Assuntos
Fígado/enzimologia , Metiltransferases/genética , Metiltransferases/metabolismo , Transcrição Gênica , Adolescente , Adulto , Idoso , Northern Blotting , Western Blotting , Criança , Pré-Escolar , Citosol/enzimologia , Primers do DNA , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Nicotinamida N-Metiltransferase , Fenótipo , Biossíntese de Proteínas , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Sulphation is important in xenobiotic detoxification and in steroid and thyroid hormones synthesis, transport and metabolism. Potential endocrine disrupting actions of plasticisers were assessed by studying effects on cell viability, cell proliferation and expression of enzymes (cysteine dioxygenase, sulphite oxidase, PAPS synthase I and II) involved in the synthesis of the cofactor, PAPS, for steroid sulphotransferases. TE 671 cells were used to study the effects of exposure to alkylphenols and alkylphenolethoxylates, bisphenol A, bisphenol A methacrylate, alkyladipates, dialkyl phthalates and resorcinol. The lactate dehydrogenase assay and CellTiter 96) AQ(ueous) One Solution Cell Proliferation Assay were used to measure cytotoxicity and cell proliferation, respectively. Steady-state mRNA was assessed by semi-quantitative RT-PCR and real time RT-PCR. None of the compounds tested was cytotoxic in TE 671 cells, however, cell proliferation was significantly increased with 0.005-0.5 microM dioctyl phthalate, diisodecyl phthalate (DIP) and butylbenzyl phthalate (P<0.05, n = 4). Real time RT-PCR showed dose-dependent decreases in steady-state mRNA levels of all the enzymes studied (P<0.05, n = 4) with 0.005-0.5 microM octylphenol, bis (2-ethylhexyl) phthalate and DIP treatment. Endocrine disrupting effects of some plasticisers may be a consequence of modulation of expression of enzymes supplying PAPS for hormone sulphation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Cisteína Dioxigenase/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Complexos Multienzimáticos/efeitos dos fármacos , Fosfoadenosina Fosfossulfato/biossíntese , Plastificantes/farmacologia , Sulfato Adenililtransferase/efeitos dos fármacos , Sulfito Oxidase/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisteína Dioxigenase/genética , Cisteína Dioxigenase/metabolismo , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Fenóis/farmacologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfato Adenililtransferase/genética , Sulfato Adenililtransferase/metabolismo , Sulfito Oxidase/genética , Sulfito Oxidase/metabolismoRESUMO
The roles of uncoupling proteins (UCPs) are discussed. Particular attention has been paid to the roles of UCP2 to UCP5 as agents mediating thermogenesis, and to the concept of limited or "mild" uncoupling as a means of reducing oxidative stress. The role of the endocrine system, thyroid hormones and catecholamines, in regulating expression of UCPs is also discussed.
Assuntos
Proteínas de Transporte/fisiologia , Disruptores Endócrinos/farmacologia , Proteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/fisiologia , Estresse Oxidativo/fisiologia , Termogênese/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Catecolaminas/fisiologia , Humanos , Canais Iônicos , Proteínas Mitocondriais/fisiologia , Hormônios Tireóideos/fisiologia , Desacopladores , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3RESUMO
Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
Assuntos
Doença de Parkinson/etiologia , Xenobióticos/toxicidade , Encéfalo/metabolismo , Meio Ambiente , Predisposição Genética para Doença , Humanos , Inativação Metabólica , Metiltransferases/fisiologia , Niacinamida/metabolismo , Nicotinamida N-Metiltransferase , Doença de Parkinson/metabolismo , Fatores de RiscoRESUMO
Monkeys and man are very closely related genetically. Yet intellectually there are big differences and they suffer from a broad range of different diseases. For example, monkeys do not get Parkinson's or Alzheimer's disease. The former is surprising given that both get parkinsonism from MPTP poisoning and the latter initially less surprising as the cortex predominantly affected in Alzheimer's never developed as fully in the monkey. Man is an omnivore whilst other primates are predominantly herbivores. The one primate who was almost wholly carnivorous was Neanderthal man who became extinct. Red meat has a high content of Nicotinamide, Choline, and methyl donors. The enzyme NNMT converts nicotinamide to N-methyl-nicotinamide using SAM as the methyl donor. It is not present to any degree in herbivores. It has recently been shown to be present in human brain and up regulated in Parkinson's disease. Omnivores presumably need it for nicotinamide homeostasis but the production of N-methyl-nicotinamide will also be beneficial as it will reduce the export of Choline from neurones. Both will aid brain growth and development. However, as N-methyl-nicotinamide resembles MPTP it could cause parkinsonism later in life for man but not monkeys as they would be predicted not to have as much NNMT. Humans with a diet low in Nicotinamide,Choline or methyl donors early in life and low enzyme activity may be prone to Alzheimer's as their brain and therefore its reserves may never have developed as fully. The possession of NNMT plus a diet rich in Nicotinamide, Choline and methyl providers may explain many of the advantages but also the disadvantages of the human condition. One prediction is that a diet rich in these micronutrients whilst young will improve brain development and reduce the risk of Alzheimer's but that a lower dose later in life will reduce the risk of Parkinsonism. A second prediction is that it will become clear that dietary factors including vitamins are signalers and at the head of vital biochemical pathways. A time point will be reached when errors emerge that could not be deleted by evolutionary pressures. Finding and rectifying them will be the key to preventing many common diseases.