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1.
Nat Commun ; 12(1): 5993, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645808

RESUMO

Metabolic biomonitoring in humans is typically based on the sampling of blood, plasma or urine. Although established in the clinical routine, these sampling procedures are often associated with a variety of compliance issues, which are impeding time-course studies. Here, we show that the metabolic profiling of the minute amounts of sweat sampled from fingertips addresses this challenge. Sweat sampling from fingertips is non-invasive, robust and can be accomplished repeatedly by untrained personnel. The sweat matrix represents a rich source for metabolic phenotyping. We confirm the feasibility of short interval sampling of sweat from the fingertips in time-course studies involving the consumption of coffee or the ingestion of a caffeine capsule after a fasting interval, in which we successfully monitor all known caffeine metabolites as well as endogenous metabolic responses. Fluctuations in the rate of sweat production are accounted for by mathematical modelling to reveal individual rates of caffeine uptake, metabolism and clearance. To conclude, metabotyping using sweat from fingertips combined with mathematical network modelling shows promise for broad applications in precision medicine by enabling the assessment of dynamic metabolic patterns, which may overcome the limitations of purely compositional biomarkers.


Assuntos
Monitoramento Biológico/métodos , Café/metabolismo , Metabolômica/métodos , Suor/química , Adulto , Monitoramento Biológico/normas , Biotransformação , Cafeína/análise , Cafeína/metabolismo , Ácido Clorogênico/análise , Ácido Clorogênico/metabolismo , Cromatografia Líquida , Feminino , Dedos , Humanos , Masculino , Metabolômica/normas , Pessoa de Meia-Idade , Análise de Componente Principal , Espectrometria de Massas em Tandem , Teobromina/análise , Teobromina/metabolismo , Teofilina/análise , Teofilina/metabolismo
2.
Cancers (Basel) ; 11(5)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137558

RESUMO

In high grade serous ovarian cancer patients with peritoneal involvement and unfavorable outcome would benefit from targeted therapies. The aim of this study was to find a druggable target against peritoneal metastasis. We constructed a planar-scale free small world-co-association gene expression network and searched for clusters with hub-genes associated to peritoneal spread. Protein expression and impact was validated via immunohistochemistry and correlations of deregulated pathways with comprehensive omics data were used for biological interpretation. A cluster up-regulated in miliary tumors with NECTIN4 as hub-gene was identified and impact on survival validated. High Nectin 4 protein expression was associated with unfavorable survival and (i) reduced expression of HLA genes (mainly MHC I); (ii) with reduced expression of genes from chromosome 22q11/12; (iii) higher BCAM in ascites and in a high-scoring expression cluster; (iv) higher Kallikrein gene and protein expressions; and (v) substantial immunologic differences; locally and systemically; e.g., reduced CD14 positive cells and reduction of different natural killer cell populations. Each three cell lines with high (miliary) or low NECTIN4 expression (non-miliary) were identified. An anti-Nectin 4 antibody with a linked antineoplastic drug-already under clinical investigation-could be a candidate for a targeted therapy in patients with extensive peritoneal involvement.

3.
Mol Nutr Food Res ; 60(12): 2529-2541, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27425673

RESUMO

SCOPE: Anti-inflammatory effects of coffee consumption have been reported to be caused by caffeine and adenosine receptor signaling. However, contradictory effects have been observed. Many kinds of chronic diseases are linked to inflammation; therefore a profound understanding of potential effects of coffee consumption is desirable. METHODS AND RESULTS: We performed ex vivo experiments with eight individuals investigating peripheral blood mononuclear cells isolated from venous blood before and after coffee consumption, as well as in vitro experiments applying caffeine on isolated cells. After in vitro inflammatory stimulation of the cells, released cytokines, chemokines, and eicosanoids were determined and quantified using targeted mass spectrometric methods. Remarkably, the release of inflammation mediators IL6, IL8, GROA, CXCL2, CXCL5 as well as PGA2, PGD2, prostaglandin E2 (PGE2), LTC4, LTE4, and 15S-HETE was significantly affected after coffee consumption. While in several individuals coffee consumption or caffeine treatment caused significant downregulation of most inflammation mediators, in other healthy individuals exactly the opposite effects were observed. CONCLUSION: Ruling out age, sex, coffee consumption habits, the metabolic kinetics of caffeine in blood and the individual amount of regulatory T cells or CD39 expression as predictive parameters, we demonstrated here that coffee consumption may have significant pro- or anti-inflammatory effects in an individual fashion.


Assuntos
Café/química , Inflamação/sangue , Adulto , Cafeína/administração & dosagem , Células Cultivadas , Quimiocinas/sangue , Quimiocinas/genética , Citocinas/sangue , Citocinas/genética , Eicosanoides/sangue , Eicosanoides/genética , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
PLoS One ; 10(10): e0140367, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26496078

RESUMO

Classical drug assays are often confined to single molecules and targeting single pathways. However, it is also desirable to investigate the effects of complex mixtures on complex systems such as living cells including the natural multitude of signalling pathways. Evidence based on herbal medicine has motivated us to investigate potential beneficial health effects of Mucor racemosus (M rac) extracts. Secondary metabolites of M rac were collected using a good-manufacturing process (GMP) approved production line and a validated manufacturing process, in order to obtain a stable product termed SyCircue (National Drug Code USA: 10424-102). Toxicological studies confirmed that this product does not contain mycotoxins and is non-genotoxic. Potential effects on inflammatory processes were investigated by treating stimulated cells with M rac extracts and the effects were compared to the standard anti-inflammatory drug dexamethasone on the levels of the proteome and metabolome. Using 2D-PAGE, slight anti-inflammatory effects were observed in primary white blood mononuclear cells, which were more pronounced in primary human umbilical vein endothelial cells (HUVECs). Proteome profiling based on nLC-MS/MS analysis of tryptic digests revealed inhibitory effects of M rac extracts on pro-inflammatory cytoplasmic mediators and secreted cytokines and chemokines in these endothelial cells. This finding was confirmed using targeted proteomics, here treatment of stimulated cells with M rac extracts down-regulated the secretion of IL-6, IL-8, CXCL5 and GROA significantly. Finally, the modulating effects of M rac on HUVECs were also confirmed on the level of the metabolome. Several metabolites displayed significant concentration changes upon treatment of inflammatory activated HUVECs with the M rac extract, including spermine and lysophosphatidylcholine acyl C18:0 and sphingomyelin C26:1, while the bulk of measured metabolites remained unaffected. Interestingly, the effects of M rac treatment on lipids were orthogonal to the effect of dexamethasone underlining differences in the overall mode of action.


Assuntos
Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Dexametasona/farmacologia , Metabolômica/métodos , Mucor/química , Proteômica/métodos , Sequência de Aminoácidos , Anti-Inflamatórios/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Células Cultivadas , Cromatografia Líquida , Citocinas/metabolismo , Eletroforese em Gel Bidimensional , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Dados de Sequência Molecular , Mucor/metabolismo , Testes de Mutagenicidade , Proteoma/metabolismo , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Espectrometria de Massas em Tandem
5.
Menopause ; 19(4): 426-32, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240636

RESUMO

OBJECTIVE: The aim of this study was to investigate the potential effects of pomegranate seed oil (PGS) on menopausal symptoms. METHODS: The prospective randomized, placebo-controlled, double-blinded trial was completed by 81 postmenopausal women, who received two daily doses of either 30 mg PGS containing 127 µg of steroidal phytoestrogens per dose or a placebo for 12 weeks. The participants reported their number of hot flashes and completed the Menopause Rating Scale II at baseline and at weeks 4, 8, 12, and 24. At baseline and after 12 weeks, hormonal status was determined. RESULTS: After 12 weeks of treatment, PGS reduced the number of hot flashes per day by 4.3 (38.7%), whereas placebo reduced it by 2.5 (25.6%). Both groups were significant compared with baseline, but the treated group was not significant compared with the placebo group (P = 0.17). After 24 weeks, the treated group showed a mean of 7.1 (interquartile range, 4.0) hot flashes per day compared with the placebo group with a mean of 8.8 (interquartile range, 5.0; P = 0.02). Although the overall sum score of the Menopause Rating Scale II parameters at week 12 decreased in the treated group from 16.0 to 9.0 at week 12 and in the placebo group from 18.0 to 14.5 (P = 0.08), the sum score of the vegetative somatic symptoms subgroup decreased strongly versus placebo (P < 0.03), attributable mainly to an improvement in sleeping disorders. PGS did not affect the hormone status, and no adverse effects were reported. CONCLUSIONS: In postmenopausal women, PGS does not significantly reduce hot flashes within a 12-week observation period, but further studies are needed to investigate the long-term effect.


Assuntos
Fogachos/tratamento farmacológico , Lythraceae , Menopausa/efeitos dos fármacos , Óleos de Plantas/administração & dosagem , Sementes , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Saúde da Mulher
6.
Toxicol Lett ; 205(2): 173-82, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21704138

RESUMO

Several lines of evidence suggest that besides antioxidant also prooxidant properties are crucially involved in cytotoxic and protective activities of the major green tea catechin epigallocatechin-3-gallate (EGCG) in vitro (Elbling et al., 2011). Furthermore recent data suggest that EGCG induces oxidative stress also in vivo (Li et al., 2010). Here we set out to identify factors modulating cellular effects of EGCG in vitro. Using the HaCat keratinocytes model, we demonstrate that the cytotoxic, genotoxic and signal-activating effects of EGCG are significantly dependent on the ratio of cell number to working volume. Treatment with identical EGCG concentrations at altered experimental settings resulted in IC(50) values differing up to orders of magnitude and could even exert contradictory effects. This effect was based on cell-mediated clearance of autooxidation-derived H(2)O(2) from the supernatant. In order to estimate EGCG/H(2)O(2) concentrations equally effective under different settings, we have rationally derived and experimentally verified a simple algorithm relating concentration, working volume, cell number and - indirectly - exposure time. Algorithm application resulted in similar H(2)O(2) clearance curves from cell supernatants as well as comparable EGCG/H(2)O(2) effects at different settings. Our results demonstrate the importance of standardized experimental settings when investigating cytotoxic and/or beneficial effects of autooxidizing compounds.


Assuntos
Catequina/análogos & derivados , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/toxicidade , Queratinócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Testes de Toxicidade/métodos , Algoritmos , Western Blotting , Catequina/toxicidade , Contagem de Células , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fatores de Tempo , Testes de Toxicidade/normas
7.
J Neural Transm (Vienna) ; 118(5): 653-62, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21424576

RESUMO

Studies investigating the impact of high meat intake on cognition have yielded contradictory results as some show improved cognitive performance, whereas others report an increase of risk factors for dementia. However, few studies were designed to directly assess the effect of a high protein (HP) diet on both cognitive performance and corresponding biochemical parameters. A randomised intervention study was conducted with 23 healthy males (aged 19-31 years) to investigate the effects of a usual (UP) versus a HP diet on cognitive function and on the platelet proteome a well-established model for neurons. The study individuals were assigned to either a UP diet (15% energy) or a HP diet (30% energy) for 3 weeks with controlled intake of food and beverages. Blood samples were taken along with measurements of cognitive functions at the beginning and at the end of the intervention period. Among 908 reproducibly studied platelet proteins only the level of monoamine oxidase B (MaoB), a neurotransmitter degrading enzyme, decreased by 26% significantly (adjusted P value < 0.05) due to the HP diet. In addition, we found a correlation (r = 0.477; P < 0.02) between the decrease of MaoB expression and the shortened reaction time (cognitive function) which is in accordance with reports that dementia patients show increased MaoB activity. Plasma vitamin B(12) concentration was increased by the HP diet and correlates inversely with platelet MaoB expression (r = -0.35; P < 0.02). Healthy young males on a HP diet showed improved cognitive function and counteract well-known dementia biomarkers such as platelet MaoB and components of the methylation cycle such as vitamin B(12) and homocysteine.


Assuntos
Plaquetas/enzimologia , Cognição/fisiologia , Alimentos Fortificados , Monoaminoxidase/sangue , Proteínas/administração & dosagem , Adulto , Eletroforese em Gel Bidimensional/métodos , Jejum/sangue , Homocisteína/sangue , Humanos , Masculino , Metilação , Testes Neuropsicológicos , Proteômica/métodos , Desempenho Psicomotor/fisiologia , Tempo de Reação , Método Simples-Cego , Estatística como Assunto , Estatísticas não Paramétricas , Regulação para Cima/fisiologia , Vitamina B 12/sangue , Adulto Jovem
8.
Free Radic Biol Med ; 49(9): 1444-52, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20708679

RESUMO

The beneficial health effects of (-)-epigallocatechin-3-gallate (EGCG), the main catechin of green tea, have been attributed to complex interactions with a focus on antioxidative properties. Susceptibility to autoxidation and production of cytotoxic reactive oxygen species (ROS), mostly H(2)O(2), have been suggested to occur in vitro but also in vivo. In this study, we address whether autoxidation-derived H(2)O(2) may be involved in the cytoprotective effects of EGCG. To that end we investigated keratinocyte-derived HaCat and HL-60 promyelocytic leukemia cells with significantly different sensitivities to H(2)O(2) (IC(50) 117.3 versus 58.3 µM, respectively) and EGCG (134.1 versus 84.1 µM). HaCat cells significantly resisted cytotoxicity and DNA damage based on enhanced H(2)O(2) clearance, improved DNA repair, and reduced intracellular ROS generation. Cumulative versus bolus EGCG and H(2)O(2) treatment and H(2)O(2) pretreatment before subsequent high-dose EGCG and vice versa significantly reduced DNA damage and cytotoxicity in HaCat cells only. Addition of catalase abolished the protective activities of low-dose H(2)O(2) and EGCG. In summary, our data suggest that autoxidative generation of low-dose H(2)O(2) is a significant player in the cell-type-specific cytoprotection mediated by EGCG and support the hypothesis that regular green tea consumption can contribute as a pro-oxidant to increased resistance against high-dose oxidative stressors.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Citoproteção , Queratinócitos/efeitos dos fármacos , Estresse Oxidativo , Apoptose/efeitos dos fármacos , Catalase/farmacologia , Catequina/farmacologia , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Oxirredução/efeitos dos fármacos
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