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BMC Gastroenterol ; 19(1): 69, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064345


BACKGROUND: Irritable bowel syndrome with predominant constipation (IBS-C) is a complex disorder with gastrointestinal and nervous system components. The study aim was to assess the economic burden of moderate to severe IBS-C in six European countries (France, Germany, Italy, Spain, Sweden and the UK). METHODS: An observational, one year retrospective-prospective (6 months each) study of patients diagnosed in the last five years with IBS-C (Rome III criteria) and moderate to severe disease at inclusion (IBS Symptom Severity Scale score ≥ 175). The primary objective was to assess the direct cost to European healthcare systems. RESULTS: Five hundred twenty-five patients were included, 60% (range: 43.1-78.8%) suffered from severe IBS-C. During follow-up 11.1-24.0% of patients had a hospitalisation/emergency room (ER) visit, median stay range: 1.5-12.0 days and 41.1-90.4% took prescription drugs for IBS-C. 21.4-50.8% of employed patients took sick leave (mean: 11.6-64.1 days). The mean annual direct cost to the healthcare systems was €937.1- €2108.0. The total direct cost (combined costs to healthcare systems and patient) for IBS-C was €1421.7-€2487.1. CONCLUSIONS: IBS-C is not a life-threatening condition; however, it has large impact on healthcare systems and society. Direct and indirect costs for moderate to severe IBS-C were high with the largest direct cost driver being hospitalisations/ER visits.

Constipação Intestinal/complicações , Constipação Intestinal/economia , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/economia , Adulto , Idoso , Constipação Intestinal/diagnóstico , Custos de Medicamentos , Europa (Continente) , Utilização de Instalações e Serviços , Feminino , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Síndrome do Intestino Irritável/diagnóstico , Masculino , Pessoa de Meia-Idade , Visita a Consultório Médico/economia , Visita a Consultório Médico/estatística & dados numéricos , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença , Licença Médica/economia
Trends Biochem Sci ; 40(1): 25-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25499868


Nuclear receptors (NRs) are key players in the regulation of gene expression, coordinating protein assemblies upon their surfaces. NRs are regulated by ligand binding, which remodels the interaction surfaces and subsequently influences macromolecular complex formation. Structural biology has been instrumental in the discovery of some of these ligands, but there are still orphan NRs (ONRs) whose bona fide ligands have yet to be identified. Over the past decade, fundamental structural and functional breakthroughs have led to a deeper understanding of ONR actions and their multidomain organization. Here, we summarize the structural advances in ONRs with implications for the therapeutic treatment of diseases such as metabolic syndrome and cancer.

Proteínas de Ligação a DNA/química , Receptores Nucleares Órfãos/química , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Sítios de Ligação , Cristalografia por Raios X , Proteínas de Ligação a DNA/metabolismo , Humanos , Ligantes , Receptores Nucleares Órfãos/metabolismo , Conformação Proteica , Relação Estrutura-Atividade
Mol Cell Endocrinol ; 393(1-2): 75-82, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-24911885


The traditional structural view of allostery defines this key regulatory mechanism as the ability of one conformational event (allosteric site) to initiate another in a separate location (active site). In recent years computational simulations conducted to understand how this phenomenon occurs in nuclear receptors (NRs) has gained significant traction. These results have yield insights into allosteric changes and communication mechanisms that underpin ligand binding, coactivator binding site formation, post-translational modifications, and oncogenic mutations. Moreover, substantial efforts have been made in understanding the dynamic processes involved in ligand binding and coregulator recruitment to different NR conformations in order to predict cell/tissue-selective pharmacological outcomes of drugs. They also have improved the accuracy of in silico screening protocols so that nowadays they are becoming part of optimisation protocols for novel therapeutics. Here we summarise the important contributions that computational simulations have made towards understanding the structure/function relationships of NRs and how these can be exploited for rational drug design.

Simulação por Computador , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Sítio Alostérico , Humanos , Ligação Proteica
J Biol Chem ; 285(30): 23285-95, 2010 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-20484048


The Ca(2+)- and cAMP-responsive element-binding protein (CREB) and the related ATF-1 and CREM are stimulus-inducible transcription factors that link certain forms of cellular activity to changes in gene expression. They are attributed to complex integrative activation characteristics, but current biochemical technology does not allow dynamic imaging of CREB activation in single cells. Using fluorescence resonance energy transfer between mutants of green fluorescent protein we here develop a signal-optimized genetically encoded indicator that enables imaging activation of CREB due to phosphorylation of the critical serine 133. The indicator of CREB activation due to phosphorylation (ICAP) was used to investigate the role of the scaffold and anchoring protein AKAP79/150 in regulating signal pathways converging on CREB. We show that disruption of AKAP79/150-mediated protein kinase A anchoring or knock-down of AKAP150 dramatically reduces the ability of protein kinase A to activate CREB. In contrast, AKAP79/150 regulation of CREB via L-type channels may only have minor importance. ICAP allows dynamic and reversible imaging in living cells and may become useful in studying molecular components and cell-type specificity of activity-dependent gene expression.

Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Imagem Molecular/métodos , Proteínas de Ancoragem à Quinase A/metabolismo , Sequência de Aminoácidos , Animais , Técnicas Biossensoriais , Calcineurina/metabolismo , Sobrevivência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células HeLa , Hipocampo/citologia , Humanos , Neurônios/metabolismo , Fosforilação , Ratos , Reprodutibilidade dos Testes