RESUMEN
Ca2+ channels with a CaV1.3 pore-forming α1 subunit have been implicated in both neurodegenerative and neuropsychiatric disorders, motivating the development of selective and potent inhibitors of CaV1.3 versus CaV1.2 channels, the calcium channels implicated in hypertensive disorders. We have previously identified pyrimidine-2,4,6-triones (PYTs) that preferentially inhibit CaV1.3 channels, but the structural determinants of their interaction with the channel have not been identified, impeding their development into drugs. By a combination of biochemical, computational, and molecular biological approaches, it was found that PYTs bind to the dihydropyridine (DHP) binding pocket of the CaV1.3 subunit, establishing them as negative allosteric modulators of channel gating. Site-directed mutagenesis, based on homology models of CaV1.3 and CaV1.2 channels, revealed that a single amino acid residue within the DHP binding pocket (M1078) is responsible for the selectivity of PYTs for CaV1.3 over CaV1.2. In addition to providing direction for chemical optimization, these results suggest that, like dihydropyridines, PYTs have pharmacological features that could make them of broad clinical utility.
Asunto(s)
Bloqueadores de los Canales de Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Pirimidinonas/metabolismo , Regulación Alostérica , Sitio Alostérico , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/química , Canales de Calcio Tipo L/genética , Neuronas Dopaminérgicas/efectos de los fármacos , Células HEK293 , Humanos , Ratones , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Conejos , RatasRESUMEN
Quality of life (QoL) is a concept that is relevant for everyone, but individuals experience factors that make up QoL differently. This article considers the impact chronic oedema has on older people's QoL. There are additional challenges in this group, such as the ageing process, which interlink with QoL. The presence of appropriate support networks and psychological strategies can have a positive impact on the management of chronic oedema and the patient's perception of QoL.
Asunto(s)
Edema/complicaciones , Edema/enfermería , Calidad de Vida , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Edema/epidemiología , Alfabetización en Salud , Humanos , Autocuidado , Apoyo Social , Reino Unido/epidemiologíaRESUMEN
Lymphoedema management has evolved over many decades, but the core components of treatment remain largely unaltered, such as skin care, compression and self-lymphatic drainage. Near-infrared fluorescence lymphatic imaging (NIRFLI) offers an opportunity to enhance patient outcomes by evaluating and increasing the effectiveness of these treatment options. This is relevant when we consider the impact of this chronic condition and its endemic proportions ( Mortimer, 2014 ), while Moffatt et al (2017) suggests it is one of the biggest health risks in the Western world, due to the multiple causes, such as cancer, obesity and as a complication of an ageing population. The impact of the condition can be reduced through early identification and the risk-reduction strategies that NIRFLI can offer through greater understanding of its chronicity. The use of NIRFLI has also led to the development of a new manual lymphatic drainage technique to assist in the management of lymphoedema ( Belgrado et al, 2016 ). The aim of this article is to introduce and describe NIRFLI and its use within lymphoedema management. It will discuss use with early detection of lymphoedema and expand further, focusing on its use within the management of lymphoedema.
Asunto(s)
Linfedema/diagnóstico por imagen , Pautas de la Práctica en Enfermería , Enfermería en Salud Comunitaria , Fluoroscopía , Humanos , Linfedema/enfermería , Medicina Estatal , Reino UnidoRESUMEN
Garry Cooper, Lecturer in Adult Nursing and Lymphoedema, Birmingham City University, considers how increasing knowledge in the field needs to be translated into effective, patient-focused services.
Asunto(s)
Vendajes de Compresión , Terapia por Ejercicio , Linfedema/enfermería , Manipulaciones Musculoesqueléticas , Cuidados de la Piel , HumanosAsunto(s)
Anomalías Craneofaciales/genética , Lipedema/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Investigación Biomédica , Cadherinas/genética , Proteínas de Unión al Calcio/genética , Cromosomas Humanos X , Humanos , Canales Iónicos/genética , Mutación , Proteínas Supresoras de Tumor/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Ageing affects not only individuals but also society. It occurs throughout the western world. The ageing process may lead to the development of conditions, such as chronic oedema, as well as comorbidities such as osteoarthritis. These comorbidities can make the management of chronic oedema even more difficult. This is an especially important consideration when tailoring individualised care plans, such as exercise, as conditions such as rheumatoid arthritis can limit patients' ability to manage their oedema. Despite challenges, education can improve patient outcomes when evidence-based practice is used.
Asunto(s)
Edema/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Edema/enfermería , Edema/prevención & control , Inglaterra/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proceso de Enfermería , Educación del Paciente como Asunto , PrevalenciaRESUMEN
The aim of this research study was to estimate the potential prevalence of lymphoedema and the causes for this prevalence within two regions in England. This study is one of the first to undertake such a comparison in England and complements existing studies. The study calculates a regional prevalence figure for the Southwest (SW) of 3.59:1000 and 2.29:1000 in the West Midlands (WM). The local variation in the regions is 0.98-8.81:1000 for SW and 0.78-15.3:1000 for WM. Patient diagnosis of primary lymphoedema was 1:5129 in the SW compared with 1:2763 in the WM. These figures have relevance to patient care when considering population needs in the commissioning of services and the effect of wider determinants of health. Recommendations consider the need for national policy and the availability of education and training. Further research is required in both regions to consider age and gender set against diagnosis. Despite raising additional questions, the study has offered an opportunity to explore the effect of lymphoedema within the chosen regions.
Asunto(s)
Linfedema/epidemiología , Femenino , Humanos , Linfedema/etiología , Masculino , Prevalencia , Derivación y Consulta/estadística & datos numéricos , Distribución por Sexo , Encuestas y Cuestionarios , Reino Unido/epidemiologíaRESUMEN
Calcium influx elevates mitochondrial oxidant stress (mOS) in dorsal motor nucleus of the vagus (DMV) neurons that are prone to Lewy body pathologies in presymptomatic Parkinson's disease (PD) patients. In experimental PD models, treatment with isradipine, the dihydropyridine with the highest affinity to Cav1.3 channels, prevents subthreshold calcium influx via Cav1.3 channels into midbrain dopamine neurons and protects them from mOS. In DMV neurons, isradipine is also effective in reducing mOS despite overwhelming evidence that subthreshold calcium influx is negligible compared with spike-triggered influx. To solve this conundrum we combined slice electrophysiology, two-photon laser scanning microscopy, mRNA profiling, and computational modeling. We find that the unusually depolarized subthreshold voltage trajectory of DMV neurons is positioned between the relatively hyperpolarized activation curve of Cav1.3 channels and that of other high-voltage activated (HVA) calcium channels, thus creating a functional segregation between Cav1.3 and HVA calcium channels. The HVA channels flux the bulk of calcium during spikes but can only influence pacemaking through their coupling to calcium-activated potassium currents. In contrast, Cav1.3 currents, which we show to be more than an order-of-magnitude smaller than the HVA calcium currents, are able to introduce sufficient inward current to speed up firing. However, Kv4 channels that are constitutively open in the subthreshold range guarantee slow pacemaking, despite the depolarizing action of Cav1.3 and other pacemaking currents. We propose that the efficacy of isradipine in preventing mOS in DMV neurons arises from its mixed effect on Cav1.3 channels and on HVA Cav1.2 channels.
Asunto(s)
Canales de Calcio Tipo L/metabolismo , Calcio/metabolismo , Neuronas Motoras/metabolismo , Nervio Vago/metabolismo , Potenciales de Acción , Animales , Canales de Calcio Tipo L/genética , Ratones , Ratones Endogámicos C57BL , Neuronas Motoras/fisiología , Canales de Potasio Calcio-Activados/metabolismo , Nervio Vago/citología , Nervio Vago/fisiologíaRESUMEN
Lymphoedema and chronic oedema are managed through multiple interventions forming the two key stages of lymphoedema management. In the field of lymphoedema and chronic oedema research, the male perspective has received limited attention when compared with the female equivalent. Further research is needed within the UK and globally to address the present gap. Despite this limited focus, management options available to male patients do not differ significantly from female patients, with compression therapy being the main management option. The success of compression therapy and other interventions such as skin care and exercise depend on the patient's acceptance of the condition and the management options made available. This requires the development of an appropriate partnership between the health professional and the patient.
Asunto(s)
Vendajes de Compresión , Extremidad Inferior/lesiones , Linfedema/enfermería , Adulto , Enfermedad Crónica , Edema/etiología , Edema/enfermería , Femenino , Humanos , Linfedema/etiología , Masculino , Salud del Hombre , Persona de Mediana Edad , Relaciones Profesional-Paciente , Factores Sexuales , Reino Unido , Heridas no Penetrantes/complicacionesRESUMEN
Although it is known that the inflammatory response that results from disruption of epithelial barrier function after injury results in excessive scarring, the upstream signals remain unknown. It has also been observed that epithelial disruption results in reduced hydration status and that the use of occlusive dressings that prevent water loss from wounds decreases scar formation. We hypothesized that hydration status changes sodium homeostasis and induces sodium flux in keratinocytes, which result in activation of pathways responsible for keratinocyte-fibroblast signaling and ultimately lead to activation of fibroblasts. Here, we demonstrate that perturbations in epithelial barrier function lead to increased sodium flux in keratinocytes. We identified that sodium flux in keratinocytes is mediated by epithelial sodium channels (ENaCs) and causes increased secretion of proinflammatory cytokines, which activate fibroblast via the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway. Similar changes in signal transduction and sodium flux occur by increased sodium concentration, which simulates reduced hydration, in the media in epithelial cultures or human ex vivo skin cultures. Blockade of ENaC, prostaglandin synthesis, or PGE2 receptors all reduce markers of fibroblast activation and collagen synthesis. In addition, employing a validated in vivo excessive scar model in the rabbit ear, we demonstrate that utilization of either an ENaC blocker or a COX-2 inhibitor results in a marked reduction in scarring. Other experiments demonstrate that the activation of COX-2 in response to increased sodium flux is mediated through the PIK3/Akt pathway. Our results indicate that ENaC responds to small changes in sodium concentration with inflammatory mediators and suggest that the ENaC pathway is a potential target for a strategy to prevent fibrosis.
Asunto(s)
Canales Epiteliales de Sodio/metabolismo , Homeostasis/fisiología , Inflamación/metabolismo , Transducción de Señal/fisiología , Piel/metabolismo , Sodio/metabolismo , Agua/metabolismo , Animales , Comunicación Celular/fisiología , Células Cultivadas , Cicatriz/prevención & control , Técnicas de Cocultivo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/antagonistas & inhibidores , Dinoprostona/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Modelos Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Conejos , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a CaV1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and CaV1.2 LTCCs are very similar.
Asunto(s)
Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo L/química , Dihidropiridinas/síntesis química , Imitación Molecular , Piranos/síntesis química , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/química , Dihidropiridinas/farmacología , Células HEK293 , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica/efectos de los fármacos , Piranos/química , Piranos/farmacologíaRESUMEN
CaV1.3 L-type calcium channels (LTCCs) have been a potential target for Parkinson's disease since calcium ion influx through the channel was implicated in the generation of mitochondrial oxidative stress, causing cell death in the dopaminergic neurons. Selective inhibition of CaV1.3 over other LTCC isoforms, especially CaV1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a CaV1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both CaV1.3 and CaV1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the CaV1.3 and CaV1.2 LTCCs binding sites. The SAR also identified four important moieties that either retain selectivity or enhance binding affinity. Our study represents a significant enhancement of the SAR of PYTs at CaV1.3 and CaV1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.
Asunto(s)
Antiparkinsonianos/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio/metabolismo , Pirimidinonas/síntesis química , Antiparkinsonianos/química , Antiparkinsonianos/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/genética , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Pirimidinonas/química , Pirimidinonas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , TransfecciónRESUMEN
L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca(V)1.2 pore-forming subunit. L-type calcium channels with a Ca(V)1.3 pore-forming subunit are much less abundant, but have been implicated in the generation of mitochondrial oxidant stress underlying pathogenesis in Parkinson's disease. Thus, selectively antagonizing Ca(V)1.3 L-type calcium channels could provide a means of diminishing cell loss in Parkinson's disease without producing side effects accompanying general antagonism of L-type calcium channels. However, there are no known selective antagonists of Ca(V)1.3 L-type calcium channel. Here we report high-throughput screening of commercial and 'in-house' chemical libraries and modification of promising hits. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (8), a potent and highly selective Ca(V)1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca(V)1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease.
Asunto(s)
Barbitúricos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Barbitúricos/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Cristalografía , Evaluación Preclínica de Medicamentos/métodos , Células HEK293/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Técnicas de Placa-Clamp , Conejos , Ratas , Bibliotecas de Moléculas Pequeñas , Relación Estructura-ActividadRESUMEN
This article will focus on the evidence to support the treatment of a palliative patient who was diagnosed with cancer-related secondary lymphoedema. A case study approach has been adopted, which focuses on the anatomy and physiology of lymphoedema and how this is treated through an analysis of the treatment regimens. To establish the effectiveness of these treatment regimes, the use of objective and subjective tools will also be analysed to ascertain their importance within care. The findings of this case study and the supporting evidence indicate a positive correlation between the use of lymphoedema treatment methods in both limb volume reduction and quality-of-life outcomes. However, robust evidence is required to expand the importance of each treatment used in the area of lymphoedema management.
Asunto(s)
Neoplasias de la Mama/complicaciones , Linfedema/terapia , Cuidados Paliativos , Vendajes , Drenaje , Ejercicio Físico , Humanos , Linfedema/diagnóstico , Linfedema/etiología , Masculino , Persona de Mediana EdadRESUMEN
Lymphoedema is often unrecognised by both health professionals and patients. In addition, its impact is often underestimated. This article discusses how to recognise the condition, the consequences of misdiagnosis, reducing or preventing complications and various treatment options.
Asunto(s)
Adaptación Psicológica , Linfedema/diagnóstico , Linfedema/psicología , Adulto , Imagen Corporal , Diagnóstico Precoz , Humanos , Linfedema/terapia , MasculinoRESUMEN
The factor p8 is a high mobility group (HMG) A family member that is upregulated during the cellular stress response in numerous tissues. Because expression of this protein encourages cellular transformation, our goal is to characterize the mechanism by which the p8 gene is regulated. Using LbetaT2 cells as a model of a transformed cell in which p8 plays a role in tumor formation, we dissected the p8 promoter into its minimal functional units and found that activating transcription factor 4 (ATF4), a factor also upregulated during cellular stress responses, enhances p8 promoter activity in a dose-dependent manner. In addition, ATF4 binds in the highly conserved major activation domain of the p8 proximal promoter between -130 and -100 bp. Furthermore, we show that six of the nine base pairs that encompass the putative element are essential for ATF4 binding. These findings increase our knowledge of the mechanisms regulating the p8 gene in a genetically defined tumor model.