Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.263
Filtrar
1.
Chem Commun (Camb) ; 56(20): 3039-3042, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048637

RESUMO

We report synthesis and enzymatic assays on human histone lysine methyltransferase catalysed methylation of histones that possess lysine and its geometrically constrained analogues containing rigid (E)-alkene (KE), (Z)-alkene (KZ) and alkyne (Kyne) moieties. Methyltransferases G9a and GLP do have a capacity to catalyse methylation in the order K ≫ KE > KZ ∼ Kyne, whereas monomethyltransferase SETD8 catalyses only methylation of K and KE.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Lisina/metabolismo , Alcenos/química , Alcenos/metabolismo , Alquinos/química , Alquinos/metabolismo , Biocatálise , Humanos , Lisina/análogos & derivados , Lisina/química , Metilação , Conformação Molecular
2.
Int J Radiat Oncol Biol Phys ; 106(3): 546-555, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730876

RESUMO

PURPOSE: Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease. METHODS AND MATERIALS: A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized. RESULTS: Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score <7 (95%). Median prostate-specific antigen at diagnosis was 7.4 ng/mL and at relapse was 4.8 ng/mL. DI detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 9 out of 79 (11%), distant disease in 12 out of 79 (15%), and no disease in 26 out of 79 (33%). 18F-DCFPyL PET/CT detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 21 out of 79 (27%), distant disease in 24 out of 79 (30%), and no disease in 10 out of 79 (13%). DI identified 8 out of 79 (10%) patients to have oligometastatic disease, compared with 21 out of 79 (27%) with 18F-DCFPyL PET/CT. 18F-DCFPyL PET/CT changed proposed management in 34 out of 79 (43%) patients. CONCLUSIONS: 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men.


Assuntos
Lisina/análogos & derivados , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/sangue , Radioisótopos de Flúor , Glutamato Carboxipeptidase II/sangue , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia
3.
Ecotoxicol Environ Saf ; 190: 110077, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31864122

RESUMO

Nε-(carboxymethyl)lysine (CML) is a potentially noxious compound that is causing widespread concern due to its use in various food products. In this study, we investigated CML neurotoxicity via an in vivo experiment with mice, and an in vitro experiment using a 3D microvascular network model (with human brain vascular endothelial cell and human astrocyte) that simulated the blood-brain barrier. We found that CML could induce cell survival status variations, and histopathological changes to the brain. In addition, CML increased levels of oxidative stress, prompted the protein expression of the receptor for advanced glycation end-products (RAGE). CML up-regulated both the gene expression of RAGE, the activating protein-1 (AP-1), the inflammatory cytokines Interleukin-6 (IL-6), vascular cell adhesion molecule1 (VCAM-1), monocyte chemotactic protein1 (MCP-1). We, therefore, postulated that CML has the potential to deleteriously affect the nervous system through oxidative stress and that activation of the p38 MAPK-AP-1 signaling pathway might be implicated in this pathological process.


Assuntos
Lisina/análogos & derivados , Síndromes Neurotóxicas , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Técnicas de Cultura de Células , Células Cultivadas , Citocinas/genética , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Manipulação de Alimentos , Humanos , Lisina/toxicidade , Camundongos , Microvasos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Transcrição AP-1/metabolismo
4.
Food Chem ; 307: 125554, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648176

RESUMO

The reaction of Nε-(carboxymethyl) lysine (CML) with eight kinds of non-flavonoid o-benzoquinones and five kinds of flavonoid o-benzoquinones were investigated by cyclic voltammetry at pH 5.0, 7.0 and 8.0 and scan rate of 10, 50 and 100 mV/s. The reactivity of o-benzoquinones towards CML is weakened by the electron-donating substituent and strengthened by the electron-withdrawing substituent on the o-benzoquinone rings. The steric hindrance of the substituents on o-benzoquinone rings also weakens the quinone reactivity. Reaction of 4-methylbenzoquinone with CML (38.0 ±â€¯1.3%) was found to be faster than that with l-lysine (31.3 ±â€¯1.5%) and Nα-acetyl-l-lysine (14.5 ±â€¯0.1%) but slower than that with l-cysteine (≥100.0%) and Nα-acetyl-l-cysteine (≥100.0%) at pH 7.0 and scan rate of 10 mV/s. Products obtained by the reaction of CML with o-benzoquinones were found to include a CML-quinone adduct according to the cyclic voltammetry and UPLC-QTOF-MS/MS analysis.


Assuntos
Benzoquinonas/química , Lisina/análogos & derivados , Catecóis , Cisteína/química , Flavonoides , Lisina/química
5.
Food Chem ; 309: 125708, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31683151

RESUMO

Herein, corn silk extract and its flavonoids were used to inhibit the formation of Nε-carboxymethyllysine (CML) in a casein glucose-fatty acid model system. Under these optimum extraction conditions, nine major flavonoids were identified and quantified by HPLC-MS/MS. The percent inhibition of CML formation by corn silk extract was 76.57%. The inhibitory mechanism of corn silk extract toward CML formation was further investigated by examining the trapping of glyoxal/methyl glyoxal by the major flavonoids (5 mM) using HPLC-ESI-MS, and mono-, di-, and tri-adducts were found for some flavonoid compounds. The antioxidant activity of the corn silk extract was evaluated by the DPPH and ABTS assays. The scavenging activity of the corn silk extract for DPPH and ABTS was 84.38% and 89.11%, respectively. The results suggested that corn silk extract inhibited CML formation through glyoxal/methyl glyoxal scavenging or by its antioxidant activity attributed to its flavonoid content.


Assuntos
Flavonoides/química , Glioxal/química , Lisina/análogos & derivados , Modelos Biológicos , Zea mays/química , Antioxidantes/química , Caseínas/química , Cromatografia Líquida de Alta Pressão , Ácidos Graxos/química , Flavonoides/análise , Glucose/química , Lisina/química , Lisina/metabolismo , Extratos Vegetais/química , Seda/química , Espectrometria de Massas em Tandem , Zea mays/metabolismo
6.
J Agric Food Chem ; 67(46): 12863-12874, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31670949

RESUMO

A comprehensive quantitative characterization of Maillard reaction products was carried out for conventional (CON) and lactose-hydrolyzed (LH) ultrahigh temperature (UHT) milk during storage at 20, 30, and 40 °C for 1 year. The accumulation of 3-deoxyglucosone (3-DG) and 3-deoxygalactosone (3-DGal) in LH-UHT milk ranged from 20-fold (at 20 °C) to 44-fold (at 40 °C) higher than that in CON-UHT milk. High temperature storage (40 °C) significantly accelerated the accumulation of 3-DG, 3-DGal, and 5-hydroxymethyl furfural but not the majority of the analyzed advanced glycation endproducts (AGEs). The concentrations of major AGEs including N-ε-carboxymethyllysine (CML), N-ε-carboxyethyllysine (CEL), methylglyoxal-hydroimidazolone isomers (MG-H1/H3), glyoxal-hydroimidazolone isomers (G-H1/H3), and G-H2 detected in CON milk during storage were in the range 12-700, 1-14, 8-45, 4-13, and 1-30 µM, respectively, while they were 30-570, 2-88, 17-150, 9-20, and 5-34 µM, respectively, in LH milk. Pyrraline, S-(carboxymethyl)cysteine (CMC), and glyoxal-lysine dimer were detected in lower levels, while MG-H2, methylglyoxal-lysine dimer, argpyrimidine, glyoxal-lysine-amide, glycolic acid-lysine-amide, and pentosidine were not detected in any of the milk samples. This work demonstrates for the first time that five of the analyzed AGEs (CML, CEL, MG-H1/H3, G-H1/H3, and G-H2) could be selected as markers for evaluation of the extent of the Maillard reaction in UHT milk. These results contribute to a better understanding of how Maillard reactions progress during storage of UHT milk and can be used to develop strategies to inhibit Maillard reactions in LH milk.


Assuntos
Produtos Finais de Glicação Avançada/análise , Lactose/química , Leite/química , Animais , Bovinos , Desoxiglucose/análogos & derivados , Desoxiglucose/análise , Armazenamento de Alimentos , Galactose/análogos & derivados , Galactose/análise , Isomerismo , Lisina/análogos & derivados , Lisina/análise , Reação de Maillard , Aldeído Pirúvico/análise , Temperatura Ambiente
7.
Org Biomol Chem ; 17(48): 10228-10236, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31782417

RESUMO

Hydrophobic membrane peptides/proteins having low water solubility are often difficult to prepare. To overcome this issue, temporal introduction of solubilizing tags has been demonstrated to be beneficial. Following our recent work on the solubilization of a difficult target by using a hydrophilic oligo-Lys tag bearing a trityl linker (Trt-K method), this paper describes a comparative study of the solubilizing abilities of several peptidic trityl tags containing Lys, Arg, Glu, Asn, Nε-tri-Me-Lys or Cys-sulfonate using two hydrophobic model peptides. Among the tags evaluated, that containing Nε-tri-Me-Lys exhibits superior solubilizing ability.


Assuntos
Lisina/análogos & derivados , Peptídeos/síntese química , Sequência de Aminoácidos , Aminoácidos/química , Interações Hidrofóbicas e Hidrofílicas , Lisina/química , Solubilidade , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Água
8.
Nat Commun ; 10(1): 4792, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636263

RESUMO

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. Here, we report the synthesis of an enantiomeric block co-beta-peptide, poly(amido-D-glucose)-block-poly(beta-L-lysine), with high yield and purity by one-shot one-pot anionic-ring opening (co)polymerization. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and also disperses biofilm biomass. It is active towards community-acquired and hospital-associated MRSA strains which are resistant to multiple drugs including vancomycin and daptomycin. Its antibacterial activity is superior to that of vancomycin in MRSA mouse and human ex vivo skin infection models, with no acute in vivo toxicity in repeated dosing in mice at above therapeutic levels. The copolymer displays bacteria-activated surfactant-like properties, resulting from contact with the bacterial envelope. Our results indicate that this class of non-toxic molecule, effective against different bacterial sub-populations, has promising potential for the treatment of S. aureus infections.


Assuntos
Biofilmes/efeitos dos fármacos , Glucose/síntese química , Lisina/análogos & derivados , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , beta-Lactamas/síntese química , Células 3T3 , Animais , Farmacorresistência Bacteriana Múltipla , Glucose/farmacologia , Glucose/uso terapêutico , Humanos , Técnicas In Vitro , Lisina/síntese química , Lisina/farmacologia , Lisina/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Polimerização , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico
9.
Cell Host Microbe ; 26(4): 463-477.e8, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31585844

RESUMO

Dramatic increases in processed food consumption represent a global health threat. Maillard reaction products (MRPs), which are common in processed foods, form upon heat-induced reaction of amino acids with reducing sugars and include advanced glycation end products with deleterious health effects. To examine how processed foods affect the microbiota, we fed gnotobiotic mice, colonized with 54 phylogenetically diverse human gut bacterial strains, defined sugar-rich diets containing whey as the protein source or a matched amino acid mixture. Whey or ϵ-fructoselysine, an MRP in whey and many processed foods, selectively increases Collinsella intestinalis absolute abundance and induces Collinsella expression of genomic loci directing import and metabolism of ϵ-fructoselysine to innocuous products. This locus is repressed by glucose in C. aerofaciens, whose abundance decreases with whey, but is not repressed in C. intestinalis. Identifying gut organisms responding to and degrading potentially harmful processed food components has implications for food science, microbiome science, and public health.


Assuntos
Actinobacteria/metabolismo , Fast Foods/análise , Inocuidade dos Alimentos , Produtos Finais de Glicação Avançada/metabolismo , Lisina/análogos & derivados , Actinobacteria/genética , Animais , Qualidade dos Alimentos , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Lisina/metabolismo , Reação de Maillard , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Soro do Leite/metabolismo
10.
Int J Nanomedicine ; 14: 6339-6356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496690

RESUMO

Objective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy. Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP). Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively. Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.


Assuntos
Ácido Desoxicólico/química , Composição de Medicamentos , Intestinos/efeitos dos fármacos , Pemetrexede/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Humanos , Íons , Lisina/análogos & derivados , Lisina/química , Camundongos Endogâmicos BALB C , Pemetrexede/administração & dosagem , Pemetrexede/sangue , Pemetrexede/farmacocinética , Permeabilidade , Ratos Sprague-Dawley
11.
Amino Acids ; 51(9): 1259-1271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31388851

RESUMO

Cardiovascular disease (CVD) and chronic kidney disease (CKD) constitute substantial burdens for public health. The identification and validation of risk markers for CVD and CKD in epidemiological studies requires frequent adaption of existing analytical methods as well as development of new methods. In this study, an analytical procedure to simultaneously quantify ten endogenous biomarkers for CVD and CKD is described. An easy-to-handle sample preparation requiring only 20 µL of human plasma is followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was successfully validated according to established guidelines meeting required criteria for accuracy, precision, recovery, linearity, selectivity, and limits of quantification. The scalability of the method for application in larger cohorts was assessed using a set of plasma samples from healthy volunteers (n = 391) providing first reference values for the recently established biomarker Nɛ-acetyllysine (Nɛ-AcLys). Other biomarkers analyzed were creatinine, ß-aminoisobutyric acid (ß-AIB), carnitine, 1-methylnicotinamide (1-MNA), citrulline, symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), homoarginine (hArg), and ornithine. All obtained results are within reference values specified elsewhere. Overall, these results demonstrate the suitability of the method for simultaneous quantification of ten endogenous biomarkers for CVD and CKD in plasma samples from larger cohorts and allow validation of Nɛ-AcLys as a biomarker in large cohorts.


Assuntos
Cromatografia Líquida/métodos , Lisina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Carnitina/sangue , Citrulina/sangue , Creatinina/sangue , Feminino , Homoarginina/sangue , Humanos , Lisina/sangue , Lisina/normas , Masculino , Pessoa de Meia-Idade , Ornitina/sangue , Valores de Referência , Insuficiência Renal Crônica/sangue , Adulto Jovem
12.
Bioanalysis ; 11(14): 1359-1373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31368790

RESUMO

Aim: The first method on urinary excreted amounts of lipoyllysine (LLys) after lipoic acid (LA) supplementation was developed and validated. The suggested procedure allowed simultaneous determination of LLys and LA. Methodology & results: After the conversion of analytes into their reduced forms with tris(2-carboxyethyl)phosphine and derivatization via thiol group with 1-benzyl-2-chloropyridinium bromide, separation of analytes derivatives was performed on C18 column using a gradient mobile phase consisting of acetic acid and acetonitrile. The calibration curves for LA and LLys were linear (R2 > 0.999) in the range of 0.4-12 µM concentration and all validation results were acceptable, according to the US FDA bioanalytical method guidelines. Conclusion: This method was effectively applied for LA and LLys quantification in human urine after oral LA supplementation.


Assuntos
Suplementos Nutricionais , Lisina/análogos & derivados , Ácido Tióctico/análogos & derivados , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacologia , Urinálise/métodos , Administração Oral , Adulto , Métodos Analíticos de Preparação de Amostras , Feminino , Voluntários Saudáveis , Humanos , Lisina/urina , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Ácido Tióctico/urina
13.
Int J Mol Sci ; 20(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366014

RESUMO

As one of the Maillard reaction products, furosine has been widely reported in a variety of heat-processed foods, while the toxicity of furosine on the reproductive system and related mechanisms are unclear. Here, we constructed an intragastric gavage male mice model (42-day administration, 0.1/0.25/0.5 g furosine/Kg body weight per day) to investigate its effects on mice testicle index, hormones in serum, and mice sperm quality. Besides, the lipid metabonomics analysis was performed to screen out the special metabolites and relatively altered pathways in mice testicle tissue. Mice primary sertoli cells were separated from male mice testicle to validate the role of special metabolites in regulating pathways. We found that furosine affected testicle index, hormones expression level and sperm quality, as well as caused pathological damages in testicle tissue. Phosphatidylethanolamine (PE) (18:0/16:1) was upregulated by furosine both in mice testicle tissue and in primary sertoli cells, meanwhile, PE(18:0/16:1) was proved to activate Cep55/NF-κB/PI3K/Akt/FOX01/TNF-α pathway, and as a functional protein in dairy products, lactoferrin could inhibit expression of this pathway when combined with furosine. In conclusion, for the first time we validated that furosine posed toxic effects on mice sperms and testicle tissue through upregulating PE(18:0/16:1) and activating Cep55/NF-κB/PI3K/Akt/FOX01/TNF-α pathway.


Assuntos
Produtos Finais de Glicação Avançada/toxicidade , Lisina/análogos & derivados , Fosfatidiletanolaminas/metabolismo , Células de Sertoli/efeitos dos fármacos , Transdução de Sinais , Animais , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Proteína Forkhead Box O1/metabolismo , Lisina/toxicidade , Masculino , Camundongos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Sertoli/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Clin Nucl Med ; 44(10): e588-e589, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31274553

RESUMO

Literature shows that prostate-specific membrane antigen (PSMA) PET/CT may detect biochemical recurrence of prostate cancer at low prostate-specific antigen (PSA) levels, including detection of oligometastatic disease and hence direct metastasis-directed therapy. Although it is generally accepted that higher PSA values indicate higher disease burden, few data are available on the relation between PSA levels and number of detected metastases on PSMA PET/CT. This report demonstrates a patient with high PSA levels (856 ng/mL) at time of biochemical recurrence that showed only 1 metastasis on PSMA PET/CT. Combined androgen deprivation therapy and radiation therapy resulted in a complete biochemical response.


Assuntos
Lisina/análogos & derivados , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Ureia/análogos & derivados , Idoso , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/metabolismo
15.
Nucleic Acids Res ; 47(19): e114, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31361892

RESUMO

Application of viral vectors in gene delivery is attracting widespread attention but is hampered by the absence of control over transduction, which may lead to non-selective transduction with adverse side effects. To overcome some of these limitations, we proposed an unnatural amino acid aided caging-uncaging strategy for controlling the transduction capability of a viral vector. In this proof-of-principle study, we first expanded the genetic code of the lentiviral vector to incorporate an azido-containing unnatural amino acid (Nϵ-2-azidoethyloxycarbonyl-l-lysine, NAEK) site specifically within a lentiviral envelope protein. Screening of the resultant vectors indicated that NAEK incorporation at Y77 and Y116 was capable of inactivating viral transduction upon click conjugation with a photo-cleavable chemical molecule (T1). Exposure of the chimeric viral vector (Y77-T1) to UVA light subsequently removed the photo-caging group and restored the transduction capability of lentiviral vector both in vitro and in vivo. Our results indicate that the use of the photo-uncage activation procedure can reverse deactivated lentiviral vectors and thus enable regulation of viral transduction in a switchable manner. The methods presented here may be a general approach for generating various switchable vectors that respond to different stimulations and adapt to different viral vectors.


Assuntos
Vetores Genéticos/genética , Lentivirus/genética , Lisina/análogos & derivados , Transdução Genética , Azidas/efeitos da radiação , Linhagem Celular , Terapia Genética/métodos , Vetores Genéticos/efeitos da radiação , HIV-1/genética , Humanos , Lentivirus/efeitos da radiação , Lisina/genética , Lisina/efeitos da radiação , Raios Ultravioleta , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/efeitos da radiação
16.
Molecules ; 24(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336585

RESUMO

A series of 12 polysubstituted pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αß-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αß-tubulin. In consequence, it was determined that hydrophobic-aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand-target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αß-tubulin.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lisina/análogos & derivados , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
17.
Clin Nucl Med ; 44(10): 797-798, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348079

RESUMO

We report a case of a 75-year-old man with concomitant metastatic prostate cancer and progressive follicular lymphoma and the utility of molecular imaging in differentiating these 2 conditions. F-FDG PET/CT can offer accurate staging in many cancers, although its role in prostate cancer is limited. The role of F-DCFPyL (PSMA) PET/CT in prostate cancer is evolving and has been demonstrated to have a higher sensitivity than conventional bone scan and CT scan. Together, FDG and PSMA PET/CT studies may offer a noninvasive approach to individually characterize concomitant malignancies, aiding optimization of management and follow-up.


Assuntos
Fluordesoxiglucose F18 , Linfoma Folicular/diagnóstico por imagem , Lisina/análogos & derivados , Segunda Neoplasia Primária/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Idoso , Humanos , Linfoma Folicular/patologia , Masculino , Metástase Neoplásica , Segunda Neoplasia Primária/patologia , Neoplasias da Próstata/patologia
18.
J Bone Miner Metab ; 37(6): 1067-1074, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31214839

RESUMO

To evaluate whether or not the urinary pentosidine level has clinical value in the assessment of the osteoporotic fracture risk, a novel ELISA for pentosidine was used in clinical samples. This study employed a cross-sectional design to analyze a subset of postmenopausal women in the Nagano Cohort Study. A total of 517 urine samples were analyzed using an ELISA system, which can measure urinary pentosidine without hydrolysis. Patients were asked about their history of non-vertebral osteoporotic fracture and the prevalence of vertebral fracture was semi-quantitatively assessed on X-ray films. A 10-year increase in age was related to a 1.09-fold increase in the urinary pentosidine level (95% CI 1.05-1.13, P < 0.001), prevalent fracture (+) was related to a 1.10-fold increase in the urinary pentosidine level (95% CI 1.03-1.18, P = 0.006). Patients with prevalent fracture who had a normal bone mineral density (BMD) showed higher pentosidine levels (median 34.3 pM/mg Cr) than patients with a low BMD without fracture (median 31.4 pM/mg Cr). A multivariable logistic regression analysis revealed that urinary pentosidine was significantly associated with the prevalence of fracture after adjustment for known risk factors for fracture (odds ratio 1.92, 95% CI 1.09-3.37, P = 0.023). The present results indicated a significant association between urinary pentosidine and fracture after adjustment for age and BMD, suggesting that urinary pentosidine may be useful for assessing the fracture risk in postmenopausal women.


Assuntos
Arginina/análogos & derivados , Lisina/análogos & derivados , Osteoporose Pós-Menopausa/urina , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/urina , Idoso , Envelhecimento/urina , Arginina/urina , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Lisina/urina , Pessoa de Meia-Idade , Análise Multivariada , Prevalência
19.
Cancer Sci ; 110(8): 2408-2420, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215094

RESUMO

Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC-DR, established from a metastatic thoracic lesion. ESCC-DRtca2M was prepared by treating ESCC-DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose-6-phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF-κB) (p65) and O-linked N-Acetylglucosamine (O-GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O-GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line-based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF-κB (p65) and O-GlcNAc were expressed more highly in ESCC-DRtca2M than in the other cell lines. Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF-κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line-based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.


Assuntos
Ácidos e Sais Biliares/metabolismo , Vias Biossintéticas/fisiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Hexosaminas/metabolismo , Via de Pentose Fosfato/fisiologia , Acetilglucosamina/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/análogos & derivados , Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
20.
J Diabetes Res ; 2019: 6289831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218233

RESUMO

Advanced glycation end products (AGEs) accumulate in fatty livers and may contribute to low-grade inflammation (LGI), potentially via their receptor, RAGE. It is unknown if the AGE accumulation in fatty livers results in elevated circulating AGEs. In a cohort study, we investigated the association of liver fat and hepatocellular damage with circulating AGEs and soluble RAGE (sRAGE) and subsequently the association of circulating AGEs and sRAGE with LGI. Cross-sectional associations of liver fat percentage (eLF%; ln-transformed) and liver enzymes (LE score; standardized) with circulating AGEs (free CML, CEL, and MG-H1 in nM and protein-bound CML, CEL, and pentosidine in nmol/mmol lysine; ln-transformed) and sRAGE (pg/ml, ln-transformed) and additionally of AGEs and sRAGE with LGI (standardized) were determined by multiple linear regression. eLF% was positively associated with circulating free CEL (ß = 0.090; 95% CI 0.041; 0.139) but inversely with protein-bound CML (ß = -0.071; 95% CI -0.108; -0.034). Similarly, the LE score was positively associated with free CML (ß = 0.044; 95% CI 0.012; 0.076) and CEL (ß = 0.040; 95% CI 0.009; 0.072) but inversely with protein-bound CML (ß = -0.037; 95% CI -0.060; -0.013). Free CML (ß = 0.297; 95% CI 0.049; 0.545) was positively associated with LGI, while protein-bound CML (ß = -0.547; 95% CI -0.888; -0.207) was inversely associated, although this association was absent after adjustment for BMI. eLF% and LE score were not associated with sRAGE and sRAGE not with LGI after adjustment for BMI. Liver fat and enzymes were positively associated with circulating free AGEs, which were associated with LGI. In contrast, inverse relations were observed of liver fat and enzymes with circulating protein-bound AGEs and of protein-bound AGEs with LGI. These data suggest that hepatic steatosis and inflammation affect the formation and degradation of hepatic protein-bound AGEs resulting in elevated circulating free AGE levels. These alterations in AGE levels might influence LGI, but this is likely independent of RAGE.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Inflamação , Fígado/patologia , Idoso , Arginina/análogos & derivados , Arginina/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Fígado Gorduroso/metabolismo , Feminino , Humanos , Fígado/enzimologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Análise de Regressão , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA