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1.
ACS Appl Mater Interfaces ; 13(2): 2230-2244, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33403850

RESUMO

Efficient reconstruction of a fully functional skin after wounds requires multiple functionalities of wound dressing due to the complexity of healing. In these regards, topical administration of functionalized nanoparticles capable of sustainably releasing bioactive agents to the wound site may significantly accelerate wound repair. Among the various nanoparticles, superparamagnetic iron oxide (Fe3O4) nanoparticles gain increasing attractiveness due to their intrinsic response to an external magnetic field (eMF). Herein, based on the Fe3O4 nanoparticle, we developed a fibroblast growth factor (bFGF)-loaded Fe3O4 nanoparticle using a simple mussel-inspired surface immobilization method. This nanoparticle, named as bFGF-HDC@Fe3O4, could stabilize bFGF in various conditions and exhibited sustained release of bFGF. In addition, an in vitro study discovered that bFGF-HDC@Fe3O4 could promote macrophage polarization toward an anti-inflammatory (pro-healing) M2 phenotype especially under eMF. Further, in vivo full-thickness wound animal models demonstrated that bFGF-HDC@Fe3O4 could significantly accelerate wound healing through M2 macrophage polarization and increased cell proliferation. Therefore, this approach of realizing sustained the release of the growth factor with magnetically macrophage regulating behavior through modification of Fe3O4 nanoparticles offers promising potential to tissue-regenerative applications.


Assuntos
Preparações de Ação Retardada/química , Dopamina/análogos & derivados , Fatores de Crescimento de Fibroblastos/administração & dosagem , Heparina/química , Nanopartículas de Magnetita/química , Cicatrização/efeitos dos fármacos , Animais , Materiais Biomiméticos/química , Bivalves/química , Fatores de Crescimento de Fibroblastos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Propriedades de Superfície
2.
Eur J Endocrinol ; 183(2): 129-139, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32413848

RESUMO

Background: In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome. Objective: To evaluate the diagnostic utility of ratios to creatinine of 'spot' uMNs. Methods: Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components. Results: In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529-1), plasma: 0.929 (0.874-0.984) and output: 0.858 (0.764-0.952)). Conclusions: Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.


Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Metanefrina/sangue , Metanefrina/urina , Paraganglioma/urina , Feocromocitoma/urina , Adolescente , Neoplasias das Glândulas Suprarrenais/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Creatinina/urina , Dopamina/análogos & derivados , Dopamina/sangue , Dopamina/urina , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Normetanefrina/sangue , Normetanefrina/urina , Paraganglioma/sangue , Feocromocitoma/sangue , Curva ROC , Valores de Referência , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
3.
Chemosphere ; 254: 126715, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32334245

RESUMO

Perinatal exposure to bisphenol A (BPA) contributes to neurological disorders in offspring, but the underlying mechanisms are still poorly understood. The abnormal release of neuroactive metabolites in the tryptophan (TRP) and dopamine (DA) pathways is considered to be closely associated with some disorders. Thus, in this study, TRP and DA pathways in adult female mouse offspring were investigated when the pregnant mice were given either vehicle or BPA (2, 10, or 100 µg/kg/d) from day 6 of gestation until weaning. Then, the serum and brain samples of offspring were collected at 3, 6 and 9 months, and 12 neuroactive metabolites in the TRP and DA pathways were detected. The results showed that, in the TRP pathway, TRP levels decreased, whereas kynurenine (KYN) levels and TRP turnover increased in the brain. In the serum, TRP, KYN and 5-hydroxytryptamine (5-HT) levels decreased significantly. For the DA pathway, DA and DA metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), reduced significantly in the brain and serum. DA turnover decreased dramatically in the brain but enhanced in the serum. The disturbance of these two metabolic pathways might be one of the potential mechanisms of BPA-induced neuropsychiatric disorders.


Assuntos
Compostos Benzidrílicos/toxicidade , Dopamina/metabolismo , Poluentes Ambientais/toxicidade , Neurotransmissores/metabolismo , Fenóis/toxicidade , Triptofano/metabolismo , Ácido 3,4-Di-Hidroxifenilacético , Animais , Encéfalo/metabolismo , Dopamina/análogos & derivados , Feminino , Masculino , Redes e Vias Metabólicas , Camundongos , Gravidez , Serotonina/metabolismo
4.
Eur J Endocrinol ; 182(5): 499-509, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187575

RESUMO

Objective: Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). Design and methods: Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. Results: Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. Conclusions: Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.


Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Dopamina/análogos & derivados , Metanefrina/urina , Paraganglioma/urina , Feocromocitoma/urina , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Dopamina/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Adulto Jovem
5.
Psychopharmacology (Berl) ; 237(6): 1577-1593, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076746

RESUMO

RATIONALE: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.


Assuntos
Ketamina/toxicidade , Atividade Motora/efeitos dos fármacos , Nootrópicos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/análogos & derivados , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Microdiálise , Atividade Motora/fisiologia , Nootrópicos/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tetra-Hidroisoquinolinas/farmacologia , Resultado do Tratamento
6.
Eur J Med Chem ; 189: 112048, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954881

RESUMO

Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.


Assuntos
Antivirais/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/metabolismo , Dopamina/metabolismo , Desenho de Fármacos , Endonucleases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Vírus da Influenza A Subtipo H1N1/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Proteínas Virais/metabolismo
7.
J Chromatogr A ; 1618: 460893, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31980263

RESUMO

Seven retention models have been selected to describe a dual-retention behavior of ten dopamine-related compounds on polymer-based monolithic stationary phase with zwitterion sulfobetaine functionality. Regression quality, as well as a statistical significance of individual regression parameters, have been evaluated. Better regression performance showed two four-parameter models when compared to three-parameter models. On the other hand, limited number of experimental points disqualified statistical robustness of four-parameter models. Among three-parameter models, retention description introduced by Horváth and Liang provided comparable quality of regression at significantly improved robustness. Multivariate analysis of the best three-parameter models provided the description of physicochemical properties of dopamine precursors and metabolites. Principal component analysis and logistic regression allowed structural characterization of dopamine-related compounds based solely on regression parameters extracted from an isocratic elution data. Both polarity and type of functional groups has been correctly assigned for 3-methoxytyramine that has not been part of an evaluation study. Among applied dual-retention models, Horváth´s model, initially developed to describe a retention of ionic compounds on nonpolar stationary phases, provided robust regression of experimental data and allowed an extraction of structural characteristics of dopamine-related compounds.


Assuntos
Dopamina/química , Modelos Químicos , Betaína/análogos & derivados , Betaína/química , Dopamina/análogos & derivados , Estrutura Molecular , Polímeros/química
8.
J Pharm Biomed Anal ; 179: 113016, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31816473

RESUMO

The hypochlorous acid produced by the innate immune system during inflammation characteristic of several neurodegenerative disorders is responsible for the generation of chlorinated byproducts of dopamine in neurons where this neurotransmitter reaches the highest concentration. Therefore, this physiological acid could play a key role in neuronal oxidative stress associated to aberrant dopamine-quinones (DQ) production. Here we report a model study simulating simplified conditions of HOCl reaction with dopamine (DA) in neurons, showing for the first time that DA is immediately converted by HOCl to the yellow colored DQ molecule. The DQ originated from dopamine oxidation results directly proportional to the total amount of the oxidant with excellent reproducibility. Furthermore, following the several evidences of the interplay between cytosolic dopamine and calcium in neurodegenerative disorders, we have verified that the presence of calcium cation influences the dopamine oxidation pathway likely due to the metal chelation by semiquinone formed in the early stage of dopamine oxidation. This experimental approach, based on the isolation of the highly reactive DQ molecule, could be useful for prelaminar investigation of the (putative) determinants of dopamine-poisoning derivatives formation.


Assuntos
Colorimetria/métodos , Dopamina/análogos & derivados , Ácido Hipocloroso/metabolismo , Estresse Oxidativo/fisiologia , Dopamina/análise , Dopamina/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Oxirredução , Reprodutibilidade dos Testes
9.
Eur J Pharmacol ; 866: 172826, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31790652

RESUMO

Many reports have indicated that dopamine has immunomodulatory effects on peripheral immune cells. The purpose of this study was to reveal the immunomodulatory effect of dopamine on the expression of proinflammatory cytokines in microglial cells, which are the immune cells of the central nervous system. In murine microglial cell line BV-2 cells, pretreatment with dopamine for 24 h attenuated the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines such as tumor-necrosis factor-α, interleukin-1ß, and interleukin-6. Neither (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol; hydrochloride (SCH-23390) nor sulpiride, which are dopamine D1-like and D2-like receptor antagonists, respectively, affected the attenuation of LPS-induced expression of cytokines by dopamine. In addition, pretreatment with neither (-)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY208-243) nor bromocriptine, dopamine D1-like and D2-like receptor agonists, respectively, was effective in doing so. However, N-acetylcysteine (NAC), which inhibits dopamine oxidation to dopamine quinone, did inhibit this attenuated expression. Dopamine increased the level of quinoproteins, and this increase was inhibited by NAC. Western blot and immunocytochemical analyses revealed that dopamine inhibited LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Dopamine also attenuated the expression of cytokines and the nuclear translocation of NF-κB p65 induced by LPS in mouse microglial cells in primary culture. These results suggest that dopamine attenuated LPS-induced expression of cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglial cells.


Assuntos
Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/metabolismo , Dopamina/análogos & derivados , Dopamina/farmacologia , Microglia/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Linhagem Celular , Dopamina/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/metabolismo
10.
Pediatr Blood Cancer ; 67(2): e28081, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31724812

RESUMO

BACKGROUND: Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA. PROCEDURE: Plasma concentrations of 3-methoxytyramine, normetanephrine, and metanephrine were measured in two pediatric cohorts: (i) 96 children with confirmed neuroblastoma and (ii) 41 children with signs and symptoms of a catecholamine-producing tumor or other neoplasms and in whom neuroblastoma was excluded. Additional measurements of plasma 3-O-methyldopa and relationships of metabolites to MYCN amplification were examined in patient subgroups. RESULTS: Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P < 0.0001) than that of 82.2% for HVA and VMA. One of the two patients with normal plasma results showed an elevation of plasma 3-O-methyldopa. Diagnostic specificities were, respectively, 95.1% and 84.8%. Areas under receiver-operating characteristic curves confirmed the superior diagnostic power of the plasma than the urinary test (0.994 vs 0.945; P = 0.0095). Ratios of plasma 3-methoxytyramine to normetanephrine were 7.2-fold higher (P < 0.0001) for patients who had neuroblastomas with MYCN amplification than without MYCN amplification. CONCLUSIONS: Measurements of plasma 3-methoxytyramine and normetanephrine provide a highly accurate diagnostic test for neuroblastoma and also offer potential for prognostic risk stratification.


Assuntos
Biomarcadores Tumorais/análise , Dopamina/análogos & derivados , Neuroblastoma/diagnóstico , Normetanefrina/análise , Tirosina/análogos & derivados , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dopamina/análise , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neuroblastoma/sangue , Neuroblastoma/urina , Prognóstico , Estudos Retrospectivos , Tirosina/análise
11.
J Pharmacol Exp Ther ; 372(2): 157-165, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31744850

RESUMO

Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein α-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT: Interactions of the protein α-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPAL-induced protein modifications.


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Dopamina/análogos & derivados , Dopamina/química , Doença de Parkinson/metabolismo , alfa-Sinucleína/química , Ácido 3,4-Di-Hidroxifenilacético/efeitos adversos , Ácido 3,4-Di-Hidroxifenilacético/química , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Acetilcisteína/química , Antioxidantes/química , Linhagem Celular , Cobre/química , Cobre/metabolismo , Dopamina/efeitos adversos , Dopamina/metabolismo , Humanos , Monoaminoxidase/metabolismo , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Oligodendroglia/citologia , Oxirredução , Ligação Proteica , Conformação Proteica , Tolcapona/metabolismo , alfa-Sinucleína/metabolismo
12.
Sci Rep ; 9(1): 19338, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853095

RESUMO

IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.


Assuntos
Moléculas de Adesão Celular/metabolismo , Dopamina/análogos & derivados , Antígenos de Histocompatibilidade Classe II/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Interferon gama/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Adesão Celular/efeitos dos fármacos , Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Antígenos HLA-DR/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Integrina alfa4beta1/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Transativadores/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
13.
Dokl Biochem Biophys ; 488(1): 354-356, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768859

RESUMO

A mass spectrometric method has been developed for determining the content of dopamine and serotonin derivatives, which allows evaluating the efficiency of their penetration through artificial membranes depending on the structure of their peptide fragment. In this case, the diffusion of dopamine and serotonin derivatives through the membrane occurred as a result of competitive interactions. It was shown which compounds in this mixture more easily penetrate through artificial membranes. It was found that the most promising in terms of overcoming the BBB are Boc-Pro-Srt and Boc-Pro-DOPA.


Assuntos
Dopamina , Membranas Artificiais , Peptídeos , Serotonina , Barreira Hematoencefálica/química , Barreira Hematoencefálica/metabolismo , Dopamina/análogos & derivados , Dopamina/química , Dopamina/farmacocinética , Dopamina/farmacologia , Humanos , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Serotonina/análogos & derivados , Serotonina/química , Serotonina/farmacocinética , Serotonina/farmacologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31670057

RESUMO

Catecholamines [dopamine (DA), epinephrine (E), and norepinephrine (NE)] and their metabolites [metanephrine (MN), normetanephrine (NMN), and 3-methoxytyramine (3-MT)] are functionally important in humans. Their overexpression can indicate the presence of neuroendocrine tumors. Accurate and rapid quantitation of catecholamines and their metabolites may function in differential diagnosis of neuroendocrine tumors. Herein, we diluted 200 µL plasma using isotope labelled internal standards (IS), and extracted using solid phase extraction. The performance of isotope diluted liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) was evaluated and applied to quantify the level of catecholamines and metabolites in clinical samples from 73 apparently healthy adults. The total analysis time of the ID-LC-MS/MS method was 4 min. The improved method was highly sensitive, with a limit of quantification (LOQ) for MN, NMN, 3-MT, and E of 1 pg/mL, a LOQ for DA of 5 pg/mL, and for NE of 10 pg/mL. After correction using IS, no significant matrix effects were observed. Good reproducibility was obtained, with total CVs of 3.2-13.1% (DA), 4.8-10.0% (E), 6.2-6.9% (NE), 3.8-7.9% (MN), 4.1-8.8% (NMN), 3.4-8.9% (3-MT). Recoveries were in the range of 91.1-109.7% for the six analytes. Also, the mean concentration of catecholamines were as follows: MN, 22.9 ±â€¯7.2 pg/mL; NMN, 41.4 ±â€¯17.2 pg/mL; 3-MT, 2.34 ±â€¯2.01 pg/mL; DA, 10.2 ±â€¯4.6 pg/mL; E, 29.3 ±â€¯14.2 pg/mL and NE 427.0 ±â€¯190.6 pg/mL. A reliable ID-LC-MS/MS method for the determination of catecholamines and their metabolites using small volumes of plasma was verified. This method is rapid, simple, and may serve as an essential diagnostic tool for neuroendocrine tumors in clinical practice.


Assuntos
Catecolaminas/sangue , Catecolaminas/metabolismo , Dopamina/análogos & derivados , Metanefrina/sangue , Normetanefrina/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Cromatografia Líquida de Alta Pressão/métodos , Dopamina/sangue , Feminino , Humanos , Limite de Detecção , Masculino , Metaboloma , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Extração em Fase Sólida/métodos
15.
Pharmacol Res ; 150: 104503, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31629091

RESUMO

The major source of heart transplantation comes from brain-dead (BD) donors. However, brain death and myocardial ischemia/reperfusion injury during transplantation may lead to cardiac dysfunction and hemodynamic instability. A previous work demonstrated that pre-treatment of BD donors with dopamine improved the graft survival of heart allograft in recipient after transplantation. However, low-dose dopamine treatment might result in tachycardia and hypertension. Our previous experimental study showed that pre-treatment of BD donor rats with the dopamine derivate N-octanoyl dopamine (NOD), devoid of any hemodynamic effects, improved graft function after transplantation. Herein, we hypothesized that NOD confers superior myocardial protection than dopamine, in terms of graft function. Male Lewis donor rats were either subjected to sham-operation or brain death via a subdurally placed balloon followed by 5.5 h monitoring. Then, the hearts were explanted and heterotopically transplanted into Lewis recipient rats. Shortly before the onset of reperfusion, continuous intravenous infusion of either NOD (14.7 µg/kg/min, BD + NOD group, n = 9), dopamine (10 µg/kg/min, BD + Dopamine group, n = 8) or physiological saline vehicle (sham, n = 9 and BD group, n = 9) were administered to the recipient rats. In vivo left-ventricular (LV) graft function was evaluated after 1.5 h reperfusion. Additionally, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE, an indicator of oxidative stress) and nitrotyrosine (a nitro-oxidative stress marker), was performed. After heart transplantation, systolic and diastolic functions were significantly decreased in the BD group compared to sham. Treatment with NOD but not dopamine, resulted in better LV graft systolic functional recovery (LV systolic pressure BD + NOD 90 ±â€¯8 vs BD + Dopamine 66 ±â€¯5 vs BD 65 ±â€¯4 mmHg; maximum rate of rise of LV pressure dP/dtmax BD + NOD 2686 ±â€¯225 vs BD + Dopamine 2243 ±â€¯70 vs BD 1999 ±â€¯147 mmHg/s, at an intraventricular volume of 140 µl, p < 0.05) and myocardial work compared to BD group. The re-beating time (time to restoration of heartbeat) was significantly shorter in BD + NOD group than that of BD hearts (32 ±â€¯4 s vs. 48 ±â€¯6 s, p < 0.05), Dopamine treatment had no impact on all of these parameters. Furthermore, NOD as well as dopamine decreased HNE and nitrotyrosine immunoreactivity to the same level. NOD is superior to dopamine in terms of protecting LV graft contractile function when administered to the heart transplant recipients from BD donors.


Assuntos
Dopamina/análogos & derivados , Transplante de Coração , Substâncias Protetoras/uso terapêutico , Animais , Morte Encefálica , Dopamina/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Masculino , Ratos Endogâmicos Lew , Doadores de Tecidos , Função Ventricular Esquerda/efeitos dos fármacos
16.
Arch Insect Biochem Physiol ; 102(4): e21608, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31385627

RESUMO

Drosophila melanogaster produces fatty acid amides, and thus, provides a model to unravel the pathways for their biosynthesis. We previously demonstrated that arylalkylamine N-acetyltransferase-like 2 (AANATL2) from D. melanogaster will catalyze the formation of long-chain N-acylserotonins and N-acyldopamines in vitro. Generating silencing RNA via the UAS/GAL4 bipartite approach for targeted gene expression effectively decreased the endogenous levels of the AANATL2 transcripts in D. melanogaster, as shown by reverse transcription quantitative polymerase chain reaction. Consistent with these data, western blot analysis of the offspring of the AANATL2 knockdown flies using an anti-AANATL2 antibody revealed a significant reduction in the expression of the AANATL2 protein. Reduced expression of AANATL2 decreased the cellular levels of N-palmitoyldopamine (PALDA), providing strong evidence that AANATL2 is responsible for the biosynthesis of PALDA in vivo. This is the first time that the expression of an AANAT has been reduced in D. melanogaster to link one of these enzymes to the in vivo production of an N-acylarylalkylamide.


Assuntos
Aciltransferases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Aciltransferases/genética , Animais , Dopamina/análogos & derivados , Dopamina/biossíntese , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Drosophila melanogaster/metabolismo , Inativação Gênica
17.
Neurochem Int ; 129: 104514, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31369776

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD.


Assuntos
Dopamina/análogos & derivados , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/metabolismo , Biomarcadores , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Estresse do Retículo Endoplasmático , Humanos , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução , Estresse Oxidativo , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Enxofre/metabolismo , alfa-Sinucleína/metabolismo
18.
Cells ; 8(8)2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426448

RESUMO

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Doença de Parkinson , Polifenóis/farmacologia , Animais , Dopamina/análogos & derivados , Dopamina/toxicidade , Drosophila , Células HEK293 , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Extratos Vegetais , Chá
19.
Int J Dev Neurosci ; 78: 7-18, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31369794

RESUMO

Perinatal hypoxia-ischemia is one of the most common causes of perinatal brain injury and subsequent neurological disorders in children. The aim of this work was to evaluate the potential antioxidant and neuroprotective effects of N-arachidonoyl-dopamine (NADA) in the model of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Transcription factor HIF1-α and glutathione peroxidases GPx2 and GPx4 gene expression was increased in rat brains in the hypoxic group compared to control 1.5 h but not 4 days after ANH. There were no post-hypoxic changes in reduced (GSH) and oxidised (GSSG) glutathione levels in the brain of rat pups 1.5 h and 4 d after hypoxia. Hypoxic rats displayed retarded performance in the righting reflex and the negative geotaxis tests. ANH resulted in increased ambulation in Open field test and impaired retention in the Barnes maze task under stressful conditions as compared with the control group. Treatment with NADA significantly attenuated the delayed development of sensorimotor reflexes and stress-evoked disruption of memory retention in hypoxic rats but had no effect on the hypoxia-induced hyperactivity. In rats exposed to hypoxia, treatment with NADA decreased GPx2 gene expression and increased GSH/GSSG ratio in whole brains 1.5 h after ANH. These results suggest that the long-lasting beneficial effects of NADA on hypoxia-induced neurobehavioural deficits are mediated, at least in part, by its antioxidant properties.


Assuntos
Antioxidantes/metabolismo , Ácidos Araquidônicos/farmacologia , Encéfalo/efeitos dos fármacos , Dopamina/análogos & derivados , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Ácidos Araquidônicos/uso terapêutico , Encéfalo/metabolismo , Dopamina/farmacologia , Dopamina/uso terapêutico , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Reflexo de Endireitamento/efeitos dos fármacos
20.
Nano Lett ; 19(8): 5394-5402, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31286778

RESUMO

Multifunctional nanoplatforms featuring promising properties including excellent loading efficiency, real-time monitoring, and improved cargo bioavailability and bioselectivity are in great demand by the biomedical research community. During the development of such nanoplatforms, stimuli-responsive nanoparticles (NPs) as a smart nanoplatform have recently received extensive attention. Herein, we report small-sized octapod-shaped hollow porous manganese(II) oxide (HPMO) NPs as a stimuli-responsive T1-activatable nanoplatform for tumor-specific cargo delivery and real-time monitoring. The HPMO NPs functionalized by zwitterionic dopamine sulfonate (ZDS) can act as a versatile platform to load organic dyes or chemotherapeutic drugs with high loading efficiency. The obtained Cargo@HPMO would decompose into paramagnetic Mn2+ ions and subsequently release cargoes in mild acidic conditions, especially in tumor microenvironment and lysosome. The released Mn2+ can enhance T1 magnetic resonance signal for real-time monitoring of the cargo delivery in vivo. This octapod-shaped Cargo@HPMO can act as a smart and versatile nanoplatform with pH-responsive multimodal imaging and site-specific drug delivery for the development of accurate diagnosis and effective therapy for cancer.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Dopamina/análogos & derivados , Doxorrubicina/administração & dosagem , Compostos de Manganês/química , Óxidos/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Porosidade
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