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1.
Artigo em Inglês | MEDLINE | ID: mdl-39284370

RESUMO

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematologic abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored. OBJECTIVE: This study comprehensively examined the BM and peripheral blood of pediatric and adult patients with DADA2 presenting with rheumatologic/immunologic symptoms or severe hematologic manifestations. METHODS: Immunophenotyping of hematopoietic stem cells (HSCs), progenitor cells, and mature cell populations was performed for 18 patients with DADA2. We also conducted a characterization of mesenchymal stromal cells. RESULTS: Our study revealed a significant decrease in primitive HSCs and progenitor cells, alongside their reduced clonogenic capacity and multilineage differentiation potential. These BM defects were evident in patients with both severe and nonsevere hematologic manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematologic symptoms. Beyond stem cells, there was a reduction in mature cell populations in the BM and peripheral blood, affecting myeloid, erythroid, and lymphoid populations. Furthermore, BM mesenchymal stromal cells in patients with DADA2 exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage. CONCLUSIONS: Our exploration into the BM landscape of patients with DADA2 sheds light on the critical hematologic dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation.

2.
Int J Mol Sci ; 24(13)2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37446391

RESUMO

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist's efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei.


Assuntos
Cocaína , Animais , Cocaína/farmacologia , Receptores de Dopamina D3 , Proteínas Proto-Oncogênicas c-akt , Condicionamento Operante , Extinção Psicológica/fisiologia , Corticosterona/farmacologia , Estresse Fisiológico , Recidiva , Quinases de Proteína Quinase Ativadas por Mitógeno , Estresse Psicológico/psicologia
3.
Pediatr Emerg Care ; 37(11): e757-e763, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31058761

RESUMO

OBJECTIVE: Guidelines adherence in emergency departments (EDs) relies partly on the availability of resources to improve sepsis care and outcomes. Our objective was to assess the management of pediatric septic shock (PSS) in Latin America's EDs and to determine the impact of treatment coordinated by a pediatric emergency specialist (PEMS) versus nonpediatric emergency specialists (NPEMS) on guidelines adherence. METHODS: Prospective, descriptive, and multicenter study using an electronic survey administered to PEMS and NPEMS who treat PSS in EDs in 14 Latin American countries. RESULTS: We distributed 2164 surveys with a response rate of 41.5%, of which 22.5% were PEMS. Overall American College of Critical Care Medicine reported guidelines adherence was as follows: vascular access obtained in 5 minutes, 76%; fluid infusion technique, 60%; administering 40 to 60 mL/kg within 30 minutes, 32%; inotropic infusion by peripheral route, 61%; dopamine or epinephrine in cold shock, 80%; norepinephrine in warm shock, 57%; and antibiotics within 60 minutes, 82%. Between PEMS and NPEMS, the following differences were found: vascular access in 5 minutes, 87.1% versus 72.7% (P < 0.01); fluid infusion technique, 72.3% versus 55.9% (P < 0.01); administering 40 to 60 mL/kg within 30 minutes, 42% versus 29% (P < 0.01); inotropic infusion by peripheral route, 75.7% versus 56.3% (P < 0.01); dopamine or epinephrine in cold shock, 87.1% versus 77.3% (P < 0.05); norepinephrine in warm shock, 67.8% versus 54% (P < 0.01); and antibiotic administration within first 60 minutes, 90.1% versus 79.3% (P < 0.01), respectively. Good adherence criteria were followed by 24%. The main referred barrier for sepsis care was a failure in its recognition, including the lack of triage tools. CONCLUSIONS: In some Latin American countries, there is variability in self-reported adherence to the evidence-based recommendations for the treatment of PSS during the first hour. The coordination by PEMS support greater adherence to these recommendations.


Assuntos
Sepse , Choque Séptico , Criança , Serviço Hospitalar de Emergência , Humanos , América Latina , Estudos Prospectivos , Sepse/tratamento farmacológico , Choque Séptico/terapia
4.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803578

RESUMO

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Cocaína/farmacologia , Condicionamento Clássico , Giro Denteado/metabolismo , Receptores de Dopamina D3/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Derrota Social , Serina-Treonina Quinases TOR/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia
5.
Int J Mol Sci ; 21(22)2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33182810

RESUMO

Breast cancer (BC) is a molecularly heterogeneous disease that encompasses five major molecular subtypes (luminal A (LA), luminal B HER2 negative (LB-), luminal B HER2 positive (LB+), HER2 positive (HER2+) and triple negative breast cancer (TNBC)). BC treatment mainly depends on the identification of the specific subtype. Despite the correct identification, therapies could fail in some patients. Thus, further insights into the genetic and molecular status of the different BC subtypes could be very useful to improve the response of BC patients to the range of available therapies. In this way, we used gold nanoparticles (AuNPs, 12.96 ± 0.72 nm) as a scavenging tool in combination with Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to quantitatively analyze the serum proteome alterations in the different breast cancer intrinsic subtypes. The differentially regulated proteins specific of each subtype were further analyzed with the bioinformatic tools STRING and PANTHER to identify the major molecular function, biological processes, cellular origin, protein class and biological pathways altered due to the heterogeneity in proteome of the different BC subtypes. Importantly, a profile of blood coagulation proteins was identified in the serum of HER2-overexpressing BC patients.


Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Mapeamento de Peptídeos/métodos , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Estudos de Casos e Controles , Feminino , Genes erbB-2 , Ouro , Humanos , Espectrometria de Massas , Nanopartículas Metálicas , Coroa de Proteína , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
6.
Int J Gynecol Cancer ; 29(6): 1050-1056, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263024

RESUMO

BACKGROUND: Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. OBJECTIVE: To evaluate neoadjuvant bevacizumab in a randomized phase II trial. METHODS: Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. RESULTS: Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. CONCLUSIONS: Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/cirurgia , Resultado do Tratamento
7.
Mol Ther ; 26(4): 1137-1153, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29503198

RESUMO

The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform that combines simplicity, inexpensive manufacture, and favorable safety features in the context of human applications. However, efficient correction of hematopoietic stem and progenitor cells (HSPCs) with non-viral vector systems, including SB, demands further refinement of gene delivery techniques. We set out to improve SB gene transfer into hard-to-transfect human CD34+ cells by vectorizing the SB system components in the form of minicircles that are devoid of plasmid backbone sequences and are, therefore, significantly reduced in size. As compared to conventional plasmids, delivery of the SB transposon system as minicircle DNA is ∼20 times more efficient, and it is associated with up to a 50% reduction in cellular toxicity in human CD34+ cells. Moreover, providing the SB transposase in the form of synthetic mRNA enabled us to further increase the efficacy and biosafety of stable gene delivery into hematopoietic progenitors ex vivo. Genome-wide insertion site profiling revealed a close-to-random distribution of SB transposon integrants, which is characteristically different from gammaretroviral and lentiviral integrations in HSPCs. Transplantation of gene-marked CD34+ cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution, which was most efficient when the SB transposase was supplied as mRNA and nucleofected cells were maintained for 4-8 days in culture before transplantation. Collectively, implementation of minicircle and mRNA technologies allowed us to further refine the SB transposon system in the context of HSPC gene delivery to ultimately meet clinical demands of an efficient and safe non-viral gene therapy protocol.


Assuntos
Elementos de DNA Transponíveis , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Animais , Sobrevivência Celular , Citometria de Fluxo , Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Retroviridae/genética , Transfecção , Transgenes
8.
Food Microbiol ; 77: 69-77, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30297058

RESUMO

The aim of this study was to evaluate the effects of Enterococcus faecalis UGRA10 and its enterocin AS-48 against the fish pathogen Lactococcus garvieae. The minimum bactericidal concentrations of AS-48 against L. garvieae CECT 5807, 5806, and 5274 were 15.62, 15.62, and 7.81 µg/ml respectively. In broth cultures, enterocin at 100, 50, and 25 µg/ml reduced 108 CFU/ml lactococci after 2, 5, and 10 h, respectively. In co-cultures of UGRA10/L. garvieae at a 1/10 CFU/ml ratio, lactococci were eliminated after 24 h. Studies on UGRA10 biosafety and AS-48 toxicity in R1 cells and in rainbow trout have shown a lack of adverse effects from both the strain and bacteriocin. Trout challenged with L. garvieae and UGRA10 administered in diet 30 days before infection had a cumulative survival rate of 50% compared with 0% for control fish. Trout inoculated with the pathogen and treated by regular dipping in AS-48 baths had a survival rate of 60% after 20 days compared with that of untreated fish (0%). These results indicate the protective effect of the UGRA10 strain and the bacteriocin AS-48 against L. garvieae and the potential of these natural products as alternatives to antibiotics for controlling diseases in aquaculture.


Assuntos
Bacteriocinas/farmacologia , Enterococcus faecalis/fisiologia , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Positivas/veterinária , Lactococcus/efeitos dos fármacos , Truta/microbiologia , Administração Oral , Ração Animal , Animais , Linhagem Celular/efeitos dos fármacos , Técnicas de Cocultura , Contenção de Riscos Biológicos , Dieta , Doenças dos Peixes/mortalidade , Doenças dos Peixes/prevenção & controle , Infecções por Bactérias Gram-Positivas/mortalidade , Infecções por Bactérias Gram-Positivas/prevenção & controle , Lactococcus/crescimento & desenvolvimento , Lactococcus/patogenicidade , Viabilidade Microbiana/efeitos dos fármacos , Probióticos/uso terapêutico , Alimentos Marinhos/microbiologia , Taxa de Sobrevida , Testes de Toxicidade
9.
J Biol Inorg Chem ; 23(3): 331-345, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29453558

RESUMO

Nanoparticles are being actively developed for biomolecular profiling of cancer biomarkers, tumor imaging in vivo, and targeted drug delivery. These nanotechnology-based techniques can be applied widely in the management of different malignant diseases, such as breast cancer. Although the number of different types of nanoparticles is increasing rapidly, most can be classified into two major types: particles that contain organic molecules as a major building material (such as dendrimers, micelles, liposomes and carbon nanotubes, and other polymers); and those that use inorganic elements, usually metals, as a core. In particular, inorganic nanoparticles have received increased attention in the recent past as potential diagnostic and therapeutic systems in the field of oncology. This review primarily discusses progress in applications of inorganic nanoparticles for breast cancer imaging and treatment.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Compostos Inorgânicos/análise , Compostos Inorgânicos/uso terapêutico , Nanopartículas Metálicas/análise , Nanopartículas Metálicas/uso terapêutico , Feminino , Ouro/química , Humanos , Nanopartículas Metálicas/química , Pontos Quânticos
11.
Addict Biol ; 21(2): 374-86, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25522207

RESUMO

Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.


Assuntos
Dopamina/metabolismo , Dependência de Morfina/etiologia , Morfina/farmacologia , Entorpecentes/farmacologia , Síndrome de Abstinência a Substâncias/etiologia , Doença Aguda , Animais , Biomarcadores/metabolismo , Doença Crônica , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Implantes de Medicamento , Proteínas de Homeodomínio , Masculino , Dependência de Morfina/metabolismo , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Núcleo Accumbens/metabolismo , RNA Mensageiro/metabolismo , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Fatores de Transcrição , Área Tegmentar Ventral/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
12.
Addict Biol ; 20(1): 104-19, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23927484

RESUMO

Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction.


Assuntos
Analgésicos Opioides/farmacologia , Proteínas Argonautas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , Morfina/farmacologia , RNA Mensageiro/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Encéfalo/metabolismo , Expressão Gênica/efeitos dos fármacos , Masculino , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , MicroRNAs/genética , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , RNA Mensageiro/metabolismo , Ratos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
13.
Chemistry ; 20(22): 6684-92, 2014 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-24782336

RESUMO

A new 3,5-disubstituted pyridine with two porphyrin moieties was prepared through an efficient synthetic approach involving 2-formyl-5,10,15,20-tetraphenylporphyrin (1), piperidine, and catalytic amounts of [La(OTf)3]. 3,5-Bis(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)pyridine (2) was fully characterized and its sensing ability towards Zn(2+), Cu(2+), Hg(2+), Cd(2+), and Ag(+) was evaluated in solution by absorption and fluorescence spectroscopy and in gas phase by using matrix-assisted laser desorption/ionization (MALDI)-TOF mass spectrometry. Strong changes in the ground and excited state were detected in the case of the soft metal ions Zn(2+), Cd(2+), Hg(2+), and Cu(2+). A three-metal-per-ligand molar ratio was obtained in all cases and a significant ratiometric behavior was observed in the presence of Zn(2+) with the appearance of a new band at 608 nm, which can be assigned to a metal-to-ligand charge transfer. The system was able to quantify 79 ppb of Zn(2+) and the theoretical calculations are in accordance with the stoichiometry observed in solution. The gas-phase sensorial ability of compound 2 towards all metal ions was confirmed by using MALDI-TOF MS and in solid state by using polymeric films of polymethylmethacrylate (PMMA) doped with ligand 2. The results showed that compound 2 can be analytically used to develop new colorimetric molecular devices that are able to discriminate between Hg(2+) and Zn(2+) in solid phase. The crystal structure of Zn(II) complex of 3,5-bisporphyrinylpyridine was unequivocally elucidated by using single-crystal X-ray diffraction studies.


Assuntos
Porfirinas/química , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Zinco/análise , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Gases/química , Íons/química , Conformação Molecular , Piperidinas/química , Polimetil Metacrilato/química , Porfirinas/síntese química
14.
Nitric Oxide ; 37: 17-27, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24365975

RESUMO

UNLABELLED: Our aim was to investigate the role played by endothelial nitric oxide (NO) during acute vascular response to hypoxia, as a modulator of both vascular tone (through guanylate cyclase (sGC) activation) and mitochondrial O2 consumption (through competitive inhibition of cytochrome-c-oxydase (CcO)). Organ bath experiments were performed and O2 consumption (Clark electrode) was determined in isolated aorta, mesenteric and pulmonary arteries of rats and eNOS-knockout mice. All pre-contracted vessels exhibited a triphasic hypoxic response consisting of an initial transient contraction (not observed in vessels from eNOS-knockout mice) followed by relaxation and subsequent sustained contraction. Removal of the endothelium, inhibition of eNOS (by L-NNA) and inhibition of sGC (by ODQ) abolished the initial contraction without altering the other two phases. The initial hypoxic contraction was observed in the presence of L-NNA+NO-donors. L-NNA and ODQ increases O2 consumption in hypoxic vessels and increases the arterial tone in normoxia but not in hypoxia. When L-NNA+mitochondrial inhibitors (cyanide, rotenone or myxothiazol) were added, the increase in tone was similar in normoxic and hypoxic vessels, which suggests that inhibition of the binding of NO to reduced CcO restored the action of NO on sGC. CONCLUSION: A complex equilibrium is established between NO, sGC and CcO in vessels in function of the concentration of O2: as O2 falls, NO inhibition of mitochondrial O2 consumption increases and activation of sGC decreases, thus promoting a rapid increase in tone in both pulmonary and systemic vessels, which is followed by the triggering of NO-independent vasodilator/vasoconstrictor mechanisms.


Assuntos
Aorta/metabolismo , Células Endoteliais/metabolismo , Hipóxia/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Artéria Pulmonar/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Analyst ; 139(5): 992-5, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24443721

RESUMO

The integration of ultrasound (US)-assisted sample processing on-chip in a lab-on-a-valve (LOV) format for automated high-throughput shotgun proteomic assays is herein presented for the first time. The proof of concept of this system was demonstrated with the analysis of three proteins and sera from patients with lymphoma or myeloma.


Assuntos
Biomarcadores Tumorais/análise , Espectrometria de Massas/métodos , Procedimentos Analíticos em Microchip/métodos , Técnicas Analíticas Microfluídicas/métodos , Desnaturação Proteica , Humanos
16.
Inorg Chem ; 53(12): 6149-58, 2014 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-24892845

RESUMO

New pyrazole-porphyrin conjugates were successfully prepared from a reaction of ß-porphyrin-chalcone derivatives with phenylhydrazine in acetic acid followed by an oxidative step. This fast and efficient synthetic approach provided the expected compounds in yields up to 82%. The sensing ability of the new porphyrin-pyrazole derivatives to detect the metal ions Ag(+), Na(+), K(+), Mg(2+), Ca(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), and Cr(3+) was studied by spectrophotometric and spectrofluorimetric titrations. In the presence of Zn(2+), the conjugates exhibit changes in the emission spectra that are desired for a ratiometric-type fluoroionophoric detection probe. The studies were extended to gas phase, where the pyrazole-porphyrin conjugates show ability to sense metal ions with high selectivity toward Cu(2+) and Ag(+), and in poly(methyl methacrylate) doped films with promising results for Zn(2+) detection.

17.
Nutrients ; 16(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38892611

RESUMO

BACKGROUND: Breastfeeding is the optimal nourishment for infants and it is recommended that children commence breastfeeding within the first hour of birth and be exclusively breastfed for the initial 6 months of life. Our objective was to determine which factors related to mothers could influence the degree of exclusive breastfeeding during hospitalization, as well as to assess breastfeeding mothers' attitudes towards breastfeeding. METHODS: A multicenter cross-sectional study was undertaken in the healthcare area of Santiago de Compostela, Spain. The necessary variables were collected using a specially designed ad hoc questionnaire. The researcher responsible for recruitment conducted the interviews with the participants. The reduced Iowa Infant Feeding Attitude Scale (IIFAS-s) was employed to gauge maternal attitudes toward feeding their baby. RESULTS: In total, 64 women were studied. The overall score of IIFAS-s (mean ± standard deviation) was 36.95 ± 5.17. A positive attitude towards breastfeeding was therefore observed in our sample. No use of a pacifier by the newborn was associated with a positive attitude for breastfeeding. Having previous children (Ora = 6.40; IC95% 1.26-32.51) and previous experience with breastfeeding (Ora = 6.70; IC95% 1.31-34.27) increased the likelihood of exclusive breastfeeding during admission. CONCLUSIONS: In our study, exclusive breastfeeding during hospitalization is associated with having previous children and prior breastfeeding experience.


Assuntos
Aleitamento Materno , Mães , Humanos , Aleitamento Materno/psicologia , Aleitamento Materno/estatística & dados numéricos , Estudos Transversais , Espanha , Feminino , Adulto , Recém-Nascido , Mães/psicologia , Inquéritos e Questionários , Lactente , Hospitalização , Conhecimentos, Atitudes e Prática em Saúde , Masculino , Adulto Jovem , Hospitais , Chupetas/estatística & dados numéricos
18.
J Biol Inorg Chem ; 18(6): 679-92, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23793143

RESUMO

We report the synthesis, characterization, and scope of a new versatile emissive molecular probe functionalized with a 1,10-phenanthroline moiety containing methylserotonin groups as binding sites for metal ion recognition. The synthesis, characterization, and evaluation of the in vitro imaging capability of the iridium(III) and ruthenium(II) complexes [Ir(ppy)2(N-N)](+) and [Ru(bpy)2(N-N)](2+), in which ppy is 2-phenylpyridine, bpy is 2,2'-bipyridine, and N-N is a 1,10-phenanthroline ligand functionalized with two methylserotonin groups to serve as binding sites for metal ion recognition, is reported. The uptake of these compounds by living freshwater fish (Carassius auratus) was studied by fluorescence microscopy, and the cytotoxicity of ligand N-N and [Ru(bpy)2(N-N)](2+) in this species was also investigated.


Assuntos
Irídio/química , Compostos Organometálicos/análise , Compostos Organometálicos/química , Rutênio/química , Serotonina/análogos & derivados , Animais , Corantes Fluorescentes/análise , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Carpa Dourada/metabolismo , Microscopia de Fluorescência , Modelos Biológicos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Processos Fotoquímicos , Teoria Quântica , Serotonina/química , Distribuição Tecidual
19.
Inorg Chem ; 52(1): 121-9, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23231666

RESUMO

Two novel fluorescent probes bearing a single (P) and two (a podand-like structure, L) pyrene units derived from 1,5-bis(2-aminophenoxy)-3-oxopentane have been synthesized and investigated in dioxane using UV-vis absorption, and steady-state and time-resolved (in a picosecond time scale) emission spectroscopy; in the gas phase, matrix-assisted laser desorption ionization mass spectrometry was employed. In dioxane, the absorption and emission spectra of P present a unique band with maxima at 361 and 392 nm, which have been associated with the monomer absorption and emission bands, respectively. In dioxane, for compound L, an additional band with a maximum at ∼525 nm is observed; upon the addition of water, an emissive band (with maxima varying from 405 to 490 nm) appears in both P and L spectra; this is discussed in terms of the emission of a species with charge character. Upon metal addition (Cu(2+), Zn(2+), and Ag(+)) to P, a gradual quenching effect of the monomer emission is observed and found to be more pronounced with Cu(2+). In the case of L, upon the addition of metal cations, the long emission band (∼550 nm) decreases and the monomer emission band increases (with an isoemissive point at ∼450 nm) and no evidence for the intermediate band (at ∼405-490 nm) now exists. Time-resolved data in dioxane/water mixtures showed that for P and L these two fit double- and triple-exponential decay laws, respectively. With P, this has been attributed to a two-state system, which involves the monomer and a charged species, with its emission maxima varying with the polarity of the media (here mirrored by its dielectric constant), which can potentially be addressed to an exciplex-like species, whereas with L, it has been attributed to a three-state system involving, in addition to these two species, an excimer. From absorption and fluorescence excitation and time-resolved data, evidence is given for the presence of intramolecular dimer formation in the ground state.


Assuntos
Corantes Fluorescentes/química , Pirenos/química , Dioxanos/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Ultravioleta , Fatores de Tempo
20.
Biomed Pharmacother ; 165: 115055, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37356373

RESUMO

Chromatin modification is a crucial mechanism in several important phenomena in the brain, including drug addiction. Persistence of drug craving and risk of relapse could be attributed to drug-induced epigenetic mechanisms that seem to be candidates explaining long-lasting drug-induced behaviour and molecular alterations. Histone acetylation has been proposed to regulate drug-seeking behaviours and the extinction of rewarding memory of drug taking. In this work, we studied the epigenetic regulation during conditioned place aversion and after extinction of aversive memory of opiate withdrawal. Through immunofluorescence assays, we assessed some epigenetic marks (H4K5ac and p-Brd4) in crucial areas related to memory retrieval -basolateral amygdala (BLA) and hippocampus-. Additionally, to test the degree of transcriptional activation, we evaluated the immediate early genes (IEGs) response (Arc, Bdnf, Creb, Egr-1, Fos and Nfkb) and Smarcc1 (chromatin remodeler) through RT-qPCR in these nuclei. Our results showed increased p-Brd4 and H4K5ac levels during aversive memory retrieval, suggesting a more open chromatin state. However, transcriptional activation of these IEGs was not found, therefore suggesting that other secondary response may already be happening. Additionally, Smarcc1 levels were reduced due to morphine chronic administration in BLA and dentate gyrus. The activation markers returned to control levels after the retrieval of aversive memories, revealing a more repressed chromatin state. Taken together, our results show a major role of the tandem H4K5ac/p-Brd4 during the retrieval of aversive memories. These results might be useful to elucidate new molecular targets to improve and develop pharmacological treatments to address addiction and to avoid drug relapse.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Morfina , Ratos , Animais , Morfina/farmacologia , Proteínas Nucleares , Epigênese Genética , Acetilação , Ratos Sprague-Dawley , Fatores de Transcrição , Recidiva Local de Neoplasia , Hipocampo , Cromatina
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