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1.
Br J Pharmacol ; 177(14): 3273-3290, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32154912

RESUMO

BACKGROUND AND PURPOSE: The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca2+ handling remodelling. EXPERIMENTAL APPROACH: We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies. KEY RESULTS: CMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca2+ mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K+ current density and the long QT, JT and TpTe intervals observed in HF animals. CONCLUSION AND IMPLICATIONS: The results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca2+ handling remodelling, attenuating the vulnerability to HF-associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HF.

2.
J Plant Physiol ; 236: 88-95, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30939333

RESUMO

Enhanced ultraviolet radiation (UV) is an important environmental factor that may cause reductions in the growth and productivity of plants. In the present work we studied the response to UV-B radiation in leaves of the model legume Lotus japonicus. After UV-B treatment, induction of phenyalanine-ammonia lyase gene expression and enzyme activity was detected. Among the ten genes encoding for PAL found in the L. japonicus genome, LjPAL1 was both the most expressed and the most induced. All the genes encoding for enzymes of the isoflavonoid pathway were also strongly induced; this was paralleled by a marked accumulation of vestitol and isoliquiritigenin. Moreover, accumulation of several other isoflavonoids was also detected. In vitro measurements of the free radical scavenging capacity of vestitol indicated that this compound can be an appropriate free radical scavenger, suggesting a possible role for this molecule in the response to abiotic stress. On the other hand, an increase of flavonol levels was not observed while the expression of the key enzymes for flavonol biosynthesis flavanone-3-hydroxylase and flavonol synthase was decreased. Taken together, these results indicate that L. japonicus follows a peculiar strategy in its response to UV radiation by accumulating isoflavonoids as an possible alternative to accumulation of flavonols as observed in other plant species.


Assuntos
Isoflavonas/biossíntese , Lotus/efeitos da radiação , Cromatografia Líquida de Alta Pressão , Indução Enzimática/efeitos da radiação , Depuradores de Radicais Livres/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Lotus/metabolismo , Espectrometria de Massas , Fenilalanina Amônia-Liase/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Reação em Cadeia da Polimerase em Tempo Real , Raios Ultravioleta
3.
Biol Psychiatry ; 85(12): 1021-1035, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987747

RESUMO

BACKGROUND: Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear. METHODS: We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs). RESULTS: Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of nonemotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory. CONCLUSIONS: Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors.


Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Locus Cerúleo/fisiopatologia , Neuralgia/fisiopatologia , Neurônios/fisiologia , Animais , Ansiedade/etiologia , Masculino , Neuralgia/complicações , Ratos Long-Evans
4.
Insuf. card ; 14(supl.1): 1-7, mar. 2019. ilus, tab
Artigo em Espanhol | LILACS-Express | ID: biblio-1002164

RESUMO

La hipertensión arterial pulmonar es una enfermedad infrecuente, caracterizada por el aumento de postcarga del ventrículo derecho. La adaptación del ventrículo derecho a esta postcarga se relaciona con el pronóstico de los pacientes. La estratificación pronóstica se basa en una valoración multiparamétrica. Los parámetros clínicos, funcionales, la valoración del ventrículo derecho y la evaluación hemodinámica van a definir la situación de riesgo de los pacientes, en función de la mortalidad a un año. La situación de bajo riesgo a un año de seguimiento se ha relacionado con mayor supervivencia. El algoritmo terapéutico actual incluye como estrategia inicial la mono, doble y triple terapia. Se debe realizar escalada terapéutica con el objetivo de mantener a los pacientes en bajo riesgo durante el seguimiento.


Pulmonary arterial hypertension is an infrequent disease, characterized by an increase in afterload of the right ventricle. The adaptation of the right ventricle to this afterload is related to the prognosis of the patients. The prognostic stratification is based on a multiparametric assessment. The clinical, functional parameters, assessment of the right ventricle and hemodynamic evaluation will define the risk situation of the patients, depending on the one-year mortality. The situation of low risk at one year of follow-up has been related to greater survival. The current therapeutic algorithm includes monotherapy, double and triple therapy as an initial strategy. Therapeutic escalation should be carried out in order to keep patients at low risk during follow-up.


A hipertensão arterial pulmonar é uma doença infreqüente, caracterizada por aumento da pós-carga do ventrículo direito. A adaptação do ventrículo direito a essa pós-carga está relacionada ao prognóstico dos pacientes. A estratificação prognóstica é baseada em uma avaliação multiparamétrica. Os parâmetros clínicos, funcionais, avaliação do ventrículo direito e avaliação hemodinâmica definirão a situação de risco dos pacientes, dependendo da mortalidade em um ano. A situação de baixo risco em um ano de seguimento tem sido relacionada à maior sobrevida. O algoritmo terapêutico atual inclui como estratégia inicial a monoterapia e a terapia dupla e tripla. O escalonamento terapêutico deve ser realizado a fim de manter os pacientes em baixo risco durante o acompanhamento.

5.
Front Physiol ; 10: 40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792662

RESUMO

Cardiovascular complications are the primary death cause in type 2 diabetes, where inflammation can play a role. We, and others, have previously shown that, in diabetic cardiomyopathy, cardiac dysfunction is associated with Ca2+ mishandling. It is possible that diabetic cardiomyopathy differently affects men and women, as the latter present higher risk to develop heart failure and a higher plasmatic level of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), than men. However, the gender-dependent regulation of Ca2+ signaling in diabetes and its relationship with TNFα signaling are still unclear. Here, we analyzed TNFα signaling pathway and its role in Ca2+ signaling dysfunction in male and female rodent models of type 2 diabetes linked to obesity (db/db mice) using confocal microscopy in freshly isolated cardiomyocytes. TNFα increased [Ca2+]i transient amplitude and accelerated its decay without affecting SR Ca2+ load or Ca2+ spark frequency in cells from control mice. All TNFα effects on Ca2+ handling were prevented by the inhibition of the ceramidase and the phospholipase A2 (PLA2). While the plasmatic level of TNFα was similar in male and female db/db mice, only male db/db hearts over-expressed both TNFα converting enzyme (TACE) and the protective TNFα receptors 2 (TNF-R2). TNFα receptor 1 (TNF-R1) expression, involved in negative inotropic response of TNFα, was unchanged in both male and female db/db mice compared to controls. We found that male db/db mice cardiomyocytes presented a decrease in [Ca2+]i transient amplitude associated to a drop of sarcoplasmic reticulum Ca2+ load, not seen in female db/db mice. Interestingly, sustained incubation with TNFα did not restored Ca2+ signaling alteration observed in male db/db mice but still induces an increase in Ca2+ spark frequency as seen in control littermates. In cardiomyocytes from female db/db mice, TNFα had no visible effects on Ca2+ handling. In conclusion, our study shows that the alteration of Ca2+ signaling and TNFα, seen in db/db mice, is gender specific presenting an increase in TNFα cardio-protective pathway in male mice.

6.
Nephrol Dial Transplant ; 34(11): 1864-1875, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629224

RESUMO

BACKGROUND: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation-contraction (EC) coupling. METHODS: We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram. RESULTS: Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho). CONCLUSIONS: Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD.


Assuntos
Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Ventrículos do Coração/fisiopatologia , Contração Muscular , Miócitos Cardíacos/fisiologia , Disfunção Ventricular/fisiopatologia , Animais , Arritmias Cardíacas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Acoplamento Excitação-Contração , Glucuronidase/metabolismo , Masculino , Miócitos Cardíacos/citologia , Ratos , Ratos Wistar , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
7.
Crit Care Med ; 47(3): 377-385, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30624279

RESUMO

OBJECTIVES: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials. DESIGN: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated different thresholds for patient's age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age (< 50, 50-70, > 70 yr), PaO2/FIO2 (≤ 100, 101-150, > 150 mm Hg), plateau pressure (< 29, 29-30, > 30 cm H2O), and number of extrapulmonary organ failure (< 2, 2, > 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84-0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model. CONCLUSIONS: Combined thresholds for patient's age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials.


Assuntos
Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia
8.
Pediatr Crit Care Med ; 20(3): e130-e136, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664037

RESUMO

OBJECTIVES: Increasing evidence supports the association of fluid overload with adverse outcomes in different diseases. To our knowledge, few studies have examined the impact of fluid balance on clinical outcome in severe bronchiolitis. Our aim was to determine whether fluid overload was associated with adverse clinical outcomes in critically ill children with severe bronchiolitis. DESIGN: Descriptive, prospective, multicenter study. SETTING: Sixteen Spanish PICUs. PATIENTS: Severe acute bronchiolitis who required admission from October 2014 to May 2015 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total fluid intake and output were prospectively recorded during PICU assistance. Fluid balance was measured at 24, 48, and 72 hours after PICU admission. A total of 262 patients were enrolled; 54.6% were male. Median age was 1 month (interquartile range, 1-3 mo). Patients had a positive fluid balance during the first 4 days of PICU admission, reaching a neutral balance on day 4. A positive balance at 24 hours in patients admitted to the PICU with severe bronchiolitis was related with longer stay in PICU (p < 0.001), longer hospital stay (p < 0.001), longer duration of mechanical ventilation (p = 0.016), and longer duration of noninvasive ventilation (p = 0.0029). CONCLUSIONS: Critically ill patients with severe acute bronchiolitis who present a positive balance in the first 24 hours of PICU admission have poorer clinical outcomes with longer PICU and hospital length of stay and duration of invasive and noninvasive mechanical ventilation.


Assuntos
Bronquiolite/terapia , Estado Terminal/terapia , Hidratação/efeitos adversos , Feminino , Hidratação/métodos , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Tempo de Internação , Masculino , Estudos Prospectivos , Respiração Artificial , Fatores de Risco , Índice de Gravidade de Doença , Espanha , Fatores de Tempo
9.
Front Physiol ; 9: 1186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30197603

RESUMO

Calcitriol, the bioactive metabolite of vitamin D, interacts with the ubiquitously expressed nuclear vitamin D receptor (VDR) to induce genomic effects, but it can also elicit rapid responses via membrane-associated VDR through mechanisms that are poorly understood. The down-regulation of K+ currents is the main origin of electrophysiological remodeling in pathological hypertrophy and heart failure (HF), which can contribute to action potential prolongation and subsequently increase the risk of triggered arrhythmias. Adult mouse ventricular myocytes were isolated and treated with 10 nM calcitriol or vehicle for 15-30 min. In some experiments, cardiomyocytes were pretreated with the Akt inhibitor triciribine. In the adult mouse ventricle, outward K+ currents involved in cardiac repolarization are comprised of three components: the fast transient outward current (Itof), the ultrarapid delayed rectifier K+ current (Ikur), and the non-inactivating steady-state outward current (Iss). K+ currents were investigated using the whole-cell or the perforated patch-clamp technique and normalized to cell capacitance to obtain current densities. Calcitriol treatment of cardiomyocytes induced an increase in the density of Itof and Ikur, which was lost in myocytes isolated from VDR-knockout mice. In addition, calcitriol activated Akt in cardiomyocytes and pretreatment with triciribine prevented the calcitriol-induced increase of outward K+ currents. In conclusion, we demonstrate that calcitriol via VDR and Akt increases both Itof and Ikur densities in mouse ventricular cardiomyocytes. Our findings may provide new mechanistics clues for the cardioprotective role of this hormone in the heart.

10.
J Cardiovasc Dev Dis ; 5(3)2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096870

RESUMO

BACKGROUND: According to the ventricular myocardial band model, the diastolic isovolumetric period is a contraction phenomenon. Our objective was to employ speckle-tracking echocardiography (STE) to analyze myocardial deformation of the left ventricle (LV) and to confirm if it supports the myocardial band model. METHODS: This was a prospective observational study in which 90 healthy volunteers were recruited. We evaluated different types of postsystolic shortening (PSS) from an LV longitudinal strain study. Duration of latest deformation (LD) was calculated as the time from the start of the QRS complex of the ECG to the latest longitudinal deformation peak in the 18 segments of the LV. RESULTS: The mean age of our subjects was 50.3 ± 11.1 years. PSS was observed in 48.4% of the 1620 LV segments studied (19.8%, 13.5%, and 15.1% in the basal, medial, and apical regions, respectively). PSS was more frequent in the basal, medial septal, and apical anteroseptal segments (>50%). LD peaked in the interventricular septum and in the basal segments of the LV. CONCLUSIONS: The pattern of PSS and LD revealed by STE suggests there is contraction in the postsystolic phase of the cardiac cycle. The anatomical location of the segments in which this contraction is most frequently observed corresponds to the main path of the ascending component of the myocardial band. This contraction can be attributed to the protodiastolic untwisting of the LV.

11.
Front Physiol ; 9: 702, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962957

RESUMO

Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during ß-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the ß-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of ß1 and ß2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under ß-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the ß-adrenergic modulation of Ca2+ handling in failing hearts.

12.
Eur J Clin Invest ; 48(4)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29394451

RESUMO

BACKGROUND: Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart. AIM: The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting. RESULTS: Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF-23-klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF-23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation. CONCLUSIONS: Among all mineral components, an increase in systemic FGF-23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF-23, especially those related to cardiomyocyte function, remain to be discovered.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Cardiopatias/etiologia , Hormônio Paratireóideo/metabolismo , Vitamina D/metabolismo , Animais , Modelos Animais de Doenças , Glucuronidase/deficiência , Humanos , Rim/metabolismo , Camundongos , Minerais/metabolismo , Deficiência de Vitamina D/complicações
13.
JMIR Ment Health ; 5(1): e7, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29367183

RESUMO

BACKGROUND: This study provides an analysis on the use of emerging technologies for the prevention of suicide in 8 different European countries. OBJECTIVE: The objective of this study was to analyze the potentiality of using emerging technologies in the area of suicide prevention based on the opinion of different professionals involved in suicide prevention. METHODS: Opinions of 3 groups of stakeholders (ie, relevant professionals in suicide field) were gathered using a specifically designed questionnaire to explore dimensions underlying perceptions of facilitating factors and barriers in relation to the use of emerging technologies for suicide prevention. RESULTS: Goal 1 involved facilitating factors for the use of emerging technologies in suicide prevention. Northern European countries, except for Belgium, attach greater relevance to those that optimize implementation and benefits. On the other hand, Southern European countries attach greater importance to professionally oriented and user-centered facilitating factors. According to different stakeholders, the analysis of these facilitating factors suggest that professionals in the field of social work attach greater relevance to those that optimize implementation and benefits. However, professionals involved in the area of mental health, policy makers, and political decision makers give greater importance to professionally oriented and user-centered facilitating factors. Goal 2 was related to barriers to the usability of emerging technologies for suicide prevention. Both countries and stakeholders attach greater importance to barriers associated with resource constraints than to those centered on personal limitations. There are no differences between countries or between stakeholders. Nevertheless, there is a certain stakeholders-countries interaction that indicates that the opinions on resource constraints expressed by different stakeholders do not follow a uniform pattern in different countries, but they differ depending on the country. CONCLUSIONS: Although all countries and stakeholders agree in identifying resource constraints as the main barrier to the use of emerging technologies, factors facilitating their use in suicide prevention differ among countries and among stakeholders.

14.
Plant Cell Physiol ; 58(12): 2112-2125, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29059445

RESUMO

An adequate carbon supply is fundamental for plants to thrive under ammonium stress. In this work, we studied the mechanisms involved in tomato (Solanum lycopersicum L.) response to ammonium toxicity when grown under ambient or elevated CO2 conditions (400 or 800 p.p.m. CO2). Tomato roots were observed to be the primary organ dealing with ammonium nutrition. We therefore analyzed nitrogen (N) and carbon (C) metabolism in the roots, integrating the physiological response with transcriptomic regulation. Elevated levels of CO2 preferentially stimulated root growth despite the high ammonium content. The induction of anaplerotic enzymes from the tricarboxylic acid (TCA) cycle led to enhanced amino acid synthesis under ammonium nutrition. Furthermore, the root transcriptional response to ammonium toxicity was improved by CO2-enriched conditions, leading to higher expression of stress-related genes, as well as enhanced modulation of genes related to signaling, transcription, transport and hormone metabolism. Tomato roots exposed to ammonium stress also showed a defense-like transcriptional response according to the modulation of genes related to detoxification and secondary metabolism, involving principally terpenoid and phenolic compounds. These results indicate that increasing C supply allowed the co-ordinated regulation of root defense mechanisms when dealing with ammonium toxicity.


Assuntos
Compostos de Amônio/toxicidade , Dióxido de Carbono/metabolismo , Lycopersicon esculentum/fisiologia , Raízes de Plantas/metabolismo , Compostos de Amônio/metabolismo , Biomassa , Carbono/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Lycopersicon esculentum/efeitos dos fármacos , Nitratos/metabolismo , Nitratos/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Estresse Fisiológico
15.
BMC Genomics ; 18(1): 781, 2017 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-29025409

RESUMO

BACKGROUND: Asparagine is a very important nitrogen transport and storage compound in plants due to its high nitrogen/carbon ratio and stability. Asparagine intracellular concentration depends on a balance between asparagine biosynthesis and degradation. The main enzymes involved in asparagine metabolism are asparagine synthetase (ASN), asparaginase (NSE) and serine-glyoxylate aminotransferase (SGAT). The study of the genes encoding for these enzymes in the model legume Lotus japonicus is of particular interest since it has been proposed that asparagine is the principal molecule used to transport reduced nitrogen within the plant in most temperate legumes. RESULTS: A differential expression of genes encoding for several enzymes involved in asparagine metabolism was detected in L. japonicus. ASN is encoded by three genes, LjASN1 was the most highly expressed in mature leaves while LjASN2 expression was negligible and LjASN3 showed a low expression in this organ, suggesting that LjASN1 is the main gene responsible for asparagine synthesis in mature leaves. In young leaves, LjASN3 was the only ASN gene expressed although at low levels, while all the three genes encoding for NSE were highly expressed, especially LjNSE1. In nodules, LjASN2 and LjNSE2 were the most highly expressed genes, suggesting an important role for these genes in this organ. Several lines of evidence support the connection between asparagine metabolic genes and photorespiration in L. japonicus: a) a mutant plant deficient in LjNSE1 showed a dramatic decrease in the expression of the two genes encoding for SGAT; b) expression of the genes involved in asparagine metabolism is altered in a photorespiratory mutant lacking plastidic glutamine synthetase; c) a clustering analysis indicated a similar pattern of expression among several genes involved in photorespiratory and asparagine metabolism, indicating a clear link between LjASN1 and LjSGAT genes and photorespiration. CONCLUSIONS: The results obtained in this paper indicate the existence of a differential expression of asparagine metabolic genes in L. japonicus and point out the crucial relevance of particular genes in different organs. Moreover, the data presented establish clear links between asparagine and photorespiratory metabolic genes in this plant.


Assuntos
Asparagina/metabolismo , Respiração Celular/efeitos da radiação , Perfilação da Expressão Gênica , Luz , Lotus/genética , Lotus/metabolismo , Respiração Celular/genética , Lotus/efeitos da radiação , Mutação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos da radiação
16.
JMIR Ment Health ; 4(2): e23, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28655705

RESUMO

BACKGROUND: New technologies are an integral component of today's society and can complement existing suicide prevention programs. Here, we analyzed the use of new technologies in the prevention of suicide in 8 different European countries. OBJECTIVE: The aim of this paper was to assess the opinions of professionals in incorporating such resources into the design of a suicide prevention program for the region of Zamora in Spain. This investigation, encompassed within the European project entitled European Regions Enforcing Actions against Suicide (EUREGENAS), includes 11 regions from 8 different countries and attempts to advance the field of suicide prevention in Europe. METHODS: Using a specifically designed questionnaire, we assessed the opinions of 3 different groups of stakeholders regarding the use, frequency of use, facilitators, content, and format of new technologies for the prevention of suicide. The stakeholders were comprised of policy and public management professionals, professionals working in the area of mental health, and professionals related to the social area and non-governmental organizations (NGOs). A total of 416 participants were recruited in 11 regions from 8 different European countries. RESULTS: The utility of the new technologies was valued positively in all 8 countries, despite these resources being seldom used in those countries. In all the countries, the factors that contributed most to facilitating the use of new technologies were accessibility and free of charge. Regarding the format of new technologies, the most widely preferred formats for use as a tool for the prevention of suicide were websites and email. The availability of information about signs of alarm and risk factors was the most relevant content for the prevention of suicide through the use of new technologies. The presence of a reference mental health professional (MHP) was also considered to be a key aspect. The countries differed in the evaluations given to the different formats suggesting that the cultural characteristics of the country should be taken into account. CONCLUSIONS: New technologies are much appreciated resources; however they are not often underused in the field of suicide prevention. The results of this exploratory study show that new technologies are indeed useful resources and should be incorporated into suicide prevention programs.

17.
J Physiol ; 595(13): 4227-4243, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28374413

RESUMO

KEY POINTS: Leptin, is a 16 kDa pleiotropic peptide not only primarily secreted by adipocytes, but also produced by other tissues, including the heart. Controversy exists regarding the adverse and beneficial effects of leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca2+ ]i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction. We find that leptin activates mechanisms that contribute to cardiac dysfunction under physiological conditions. However, after the establishment of pressure overload, an increase in leptin levels has protective cardiac effects with respect to rescuing the cellular heart failure phenotype. These beneficial effects of leptin involve restoration of action potential duration via normalization of transient outward potassium current and sarcoplasmic reticulum Ca2+ content via rescue of control sarcoplasmic/endoplasmic reticulum Ca2+ ATPase levels and ryanodine receptor function modulation, leading to normalization of Ca2+ handling parameters. ABSTRACT: Leptin, is a 16 kDa pleiotropic peptide not only primary secreted by adipocytes, but also produced by other tissues, including the heart. Evidence indicates that leptin may have either adverse or beneficial effects on the heart. To obtain further insights, in the present study, we analysed the effect of leptin treatment on cardiac function, [Ca2+ ]i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction (TAC). Three weeks after surgery, animals received either leptin (0.36 mg kg-1  day-1 ) or vehicle via osmotic minipumps for 3 weeks. Echocardiographic measurements showed that, although leptin treatment was deleterious on cardiac function in sham, leptin had a cardioprotective effect following TAC. [Ca2+ ]i transient in cardiomyocytes followed similar pattern. Patch clamp experiments showed prolongation of action potential duration (APD) in TAC and leptin-treated sham animals, whereas, following TAC, leptin reduced the APD towards control values. APD variations were associated with decreased transient outward potassium current and Kv4.2 and KChIP2 protein expression. TAC myocytes showed a higher incidence of triggered activities and spontaneous Ca2+ waves. These proarrhythmic manifestations, related to Ca2+ /calmodulin-dependent protein kinase II and ryanodine receptor phosphorylation, were reduced by leptin. The results of the present study demonstrate that, although leptin treatment was deleterious on cardiac function in control animals, leptin had a cardioprotective effect following TAC, normalizing cardiac function and reducing arrhythmogeneity at the cellular level.


Assuntos
Estenose da Valva Aórtica/tratamento farmacológico , Cardiotônicos/farmacologia , Leptina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação , Animais , Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotônicos/uso terapêutico , Células Cultivadas , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Leptina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo
18.
J Am Coll Cardiol ; 69(4): 423-433, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28126160

RESUMO

BACKGROUND: Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases. OBJECTIVES: This study evaluated the role of NOD1 in HF progression. METHODS: NOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1-/- mice (Nod1-/--PMI). RESULTS: The NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1-/--PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1-/--PMI mice was associated with prevention of Ca2+ dynamic impairment linked to HF, including smaller and longer intracellular Ca2+ concentration transients and a lesser sarcoplasmic reticulum Ca2+ load due to a down-regulation of the sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump and by augmented levels of the Na+/Ca2+ exchanger. Increased diastolic Ca2+ release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1-/--PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca2+ mishandling in wt-PMI mice. Nod1-/--PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca2+ release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-/--PMI mice. CONCLUSIONS: NOD1 modulated intracellular Ca2+ mishandling in HF, emerging as a new target for HF therapy.


Assuntos
Cálcio/metabolismo , Insuficiência Cardíaca/metabolismo , Proteína Adaptadora de Sinalização NOD1/fisiologia , Animais , Arritmias Cardíacas/metabolismo , Cálcio/fisiologia , Progressão da Doença , Humanos , Camundongos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Regulação para Cima
19.
Heart Rhythm ; 14(3): 432-439, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27989685

RESUMO

BACKGROUND: Calcitriol, the bioactive metabolite of vitamin D, exerts its effects through interaction with the nuclear vitamin D receptor (VDR) to induce genomic responses. Calcitriol may also induce rapid responses via plasma membrane-associated VDR, involving the activation of second messengers and modulation of voltage-dependent channels. VDR is expressed in cardiomyocytes, but the molecular and cellular mechanisms involved in the rapid responses of calcitriol in the heart are poorly understood. OBJECTIVE: The aim of the present study was to analyze the rapid nongenomic effect of calcitriol on L-type calcium channels, intracellular Ca2+ ([Ca2+]i) transients, and cell contractility in ventricular myocytes. METHODS: We used the whole-cell patch-clamp technique to record L-type calcium current (ICaL) and confocal microscopy to study global [Ca2+]i transients evoked by electrical stimulation and cell shortening in adult mouse ventricular myocytes treated with vehicle or with calcitriol. In some experiments, ICaL was recorded using the perforated patch-clamp technique. RESULTS: Calcitriol treatment of cardiomyocytes induced a concentration-dependent increase in ICaL density (Half maximal effective concentration (EC50) = 0.23 nM) and a significant increase in peak [Ca2+]i transients and cell contraction. The effect of calcitriol on ICaL was prevented by pretreatment of cardiomyocytes with the protein kinase A (PKA) inhibitor KT-5720 but not with the ß-adrenergic blocker propranolol. The effect of calcitriol on ICaL was absent in myocytes isolated from VDR knockout mice. CONCLUSION: Calcitriol induces a rapid response in mouse ventricular myocytes that involves a VDR-PKA-dependent increase in ICaL density, enhancing [Ca2+]i transients and contraction.


Assuntos
Calcitriol/farmacologia , Canais de Cálcio Tipo L/fisiologia , Sinalização do Cálcio/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos , Animais , Carbazóis/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico , Inibidores Enzimáticos/farmacologia , Acoplamento Excitação-Contração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Pirróis/farmacologia , Receptores de Calcitriol/metabolismo
20.
Biochem J ; 474(3): 399-410, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27803247

RESUMO

Cardiac fibrosis and chronic inflammation are common complications in type 2 diabetes mellitus (T2D). Since nucleotide oligomerization-binding domain 1 (NOD1), an innate immune receptor, is involved in the pathogenesis of insulin resistance and diabetes outcomes, we sought to investigate its involvement in cardiac fibrosis. Here, we show that selective staining of cardiac fibroblasts from T2D (db/db;db) mice exhibits up-regulation and activation of the NOD1 pathway, resulting in enhanced NF-κB and TGF-ß signalling. Activation of the TGF-ß pathway in cardiac fibroblasts from db mice was prevented after inhibition of NF-κB with BAY-11-7082 (BAY). Moreover, fibrosis progression in db mice was also prevented by BAY treatment. Enhanced TGF-ß signalling and cardiac fibrosis of db mice was dependent, at least in part, on the sequential activation of NOD1 and NF-κB since treatment of db mice with a selective NOD1 agonist induced activation of the TGF-ß pathway, but co-administration of a NOD1 agonist plus BAY, or a NOD1 inhibitor prevented the NOD1-induced fibrosis. Therefore, NOD1 is involved in cardiac fibrosis associated with diabetes, and establishes a new mechanism for the development of heart fibrosis linked to T2D.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Fibrose Endomiocárdica/metabolismo , Miocárdio/metabolismo , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Ácido Diaminopimélico/análogos & derivados , Ácido Diaminopimélico/farmacologia , Fibrose Endomiocárdica/genética , Fibrose Endomiocárdica/patologia , Fibrose Endomiocárdica/prevenção & controle , Regulação da Expressão Gênica , Humanos , Insulina/sangue , Resistência à Insulina , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Células NIH 3T3 , Nitrilos/farmacologia , Proteína Adaptadora de Sinalização NOD1/agonistas , Proteína Adaptadora de Sinalização NOD1/genética , Transdução de Sinais , Sulfonas/farmacologia , Fator de Crescimento Transformador beta/agonistas , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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