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1.
Circ Res ; 134(8): e52-e71, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38497220

RESUMEN

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.


Asunto(s)
Síndrome de Andersen , Humanos , Ratones , Animales , Síndrome de Andersen/genética , Síndrome de Andersen/metabolismo , Mutación , Miocitos Cardíacos/metabolismo , Trastorno del Sistema de Conducción Cardíaco , Disulfuros , Fosfatidilinositoles/metabolismo
2.
Pediatr Allergy Immunol ; 35(7): e14204, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39016336

RESUMEN

BACKGROUND: Allergy to peanuts and tree nuts is a common cause of food allergy in Spain, with lipid transfer proteins (LTP) being the most frequently recognized panallergen. LTP sensitization often leads to multiple food group sensitivities, resulting in overly restrictive diets that hinder patient's quality of life. This study aimed to assess the tolerance of peanuts and tree nuts (hazelnuts and walnuts) in children sensitized to LTP, potentially mitigating the need for such diets. METHODS: This prospective study enrolled individuals diagnosed with allergy to peanuts, hazelnuts, or walnuts. Data were collected from medical records, including demographics and clinical history. Allergological assessment comprised skin prick tests using commercial extracts and the nuts in question, alongside measurements of total and specific IgE to nuts and their primary molecular components. Participants showing positive LTP sensitization without sensitization to seed storage proteins underwent open oral nut challenges. RESULTS: A total of 75 individuals labeled as allergic to peanuts, 44 to hazelnuts, and 51 to walnuts were included. All of them underwent an open oral provocation test with the incriminated nut, showing a high tolerance rate. Peanut was tolerated by 98.6% of patients, 97.72% tolerated hazelnut, and 84.3% tolerated walnut. CONCLUSION: The findings suggest that the majority of patients allergic to peanuts, hazelnuts, or walnuts, due to LTP sensitization and lacking IgE reactivity to seed storage proteins, can tolerate these nuts. This supports the need for personalized nut tolerance assessments to avoid unnecessary dietary restrictions.


Asunto(s)
Arachis , Proteínas Portadoras , Tolerancia Inmunológica , Inmunoglobulina E , Hipersensibilidad a la Nuez , Pruebas Cutáneas , Humanos , Masculino , Femenino , Proteínas Portadoras/inmunología , Niño , España , Estudios Prospectivos , Preescolar , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Hipersensibilidad a la Nuez/inmunología , Hipersensibilidad a la Nuez/diagnóstico , Arachis/inmunología , Hipersensibilidad al Cacahuete/inmunología , Hipersensibilidad al Cacahuete/diagnóstico , Alérgenos/inmunología , Juglans/inmunología , Nueces/inmunología , Adolescente , Corylus/inmunología , Hipersensibilidad a Nueces y Cacahuetes/inmunología , Antígenos de Plantas/inmunología
3.
Brain Behav Immun ; 108: 255-268, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36535607

RESUMEN

The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson's disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson's disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).


Asunto(s)
Síndrome Metabólico , Enfermedad de Parkinson , Animales , Humanos , Ratas , Angiotensina II/metabolismo , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Autoanticuerpos/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Células Endoteliales/metabolismo , Inflamación/metabolismo , Síndrome Metabólico/metabolismo , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo
4.
Pediatr Allergy Immunol ; 34(9): e14030, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37747756

RESUMEN

BACKGROUND: Pru p 7 has been reported as a major allergen in peach allergy, associated with severe clinical symptoms and related to IgE sensitisation to cypress pollen. The main objective of this study was to prospectively evaluate the frequency of sensitisation to Pru p 7 and its clinical relevance amongst pediatric patients with peach allergy in Madrid (Spain). METHODS: Patients with a history of IgE-mediated symptoms (oral allergy syndrome, urticaria/angioedema, rhinoconjunctivitis/asthma, gastrointestinal symptoms, or anaphylaxis) occurring within 2 h after peach intake or contact were prospectively recruited from February 2020 to September 2021. Skin tests, sIgE by ImmunoCAP® (Pru p 1, Pru p 3, Pru p 4, Pru p 7, and Cupressus arizonica) and oral food challenge (OFC) were performed. The study was approved by the local Ethics Committee (PI-4513). RESULTS: Ninety-two patients were included (53.3% male); median age, 10 (IQR 6.0-14.75) years. Seventy-four (80.4%) patients had a reaction after ingestion of fresh peach (25.0% from peel, 23.9% from pulp, and 44.6% from both). Fifteen (16.3%) patients were sensitised to Pru p 7. Upper airway symptoms, anaphylaxis, and grade 2 reactions were statistically more frequent in patients sensitised to Pru p 7. Seven (7.9%) patients presented with exercise as a cofactor, four of whom were sensitised to Pru p 7 (p = .001). Patients sensitised to Pru p 7 were significantly more likely to have a positive OFC result than patients who were not (p = .008). Four patients who reacted to peach at OFC were sensitised to Pru p 7. Specific IgE against Cupressus arizonica pollen was positive in 25 (62.5%) patients. CONCLUSIONS: Pru p 7 sensitisation was observed in 16.3% of our population and was related to severe reactions, upper airway symptoms, anaphylaxis, and the presence of an eliciting cofactor.


Asunto(s)
Anafilaxia , Hipersensibilidad a los Alimentos , Prunus persica , Humanos , Masculino , Niño , Femenino , Alérgenos , Prunus persica/efectos adversos , Anafilaxia/diagnóstico , Anafilaxia/epidemiología , Anafilaxia/etiología , Antígenos de Plantas , Proteínas de Plantas , Inmunoglobulina E
5.
Org Biomol Chem ; 21(38): 7791-7798, 2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37706648

RESUMEN

Herein, we report the direct synthesis of a wide variety of functionalized aromatic bromides, chlorides, iodides, and fluorides from nitroarenes in a sequential one-pot operation. This protocol is based on an air- and moisture-tolerant dioxomolybdenum-catalyzed reduction of nitroaromatics, employing pinacol as a reducing agent, which enables subsequent diazotization and halogenation steps. This methodology represents a step-economical, practical, and alternative procedure for synthesizing haloaromatics directly from nitroaromatics.

6.
Org Biomol Chem ; 21(20): 4185-4190, 2023 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-37128956

RESUMEN

A new two-step procedure for the synthesis of 1,4-dicarbonyls has been developed involving an efficient and clean Mo-catalyzed oxidative cleavage of cyclobutane-1,2-diols with DMSO, which is used as solvent and oxidant. The required starting glycols were prepared by nucleophilic additions of organolithiums and Grignard reagents to easily available 2-hydroxycyclobutanones.

7.
Glia ; 70(12): 2348-2360, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35943203

RESUMEN

There are sex differences in microglia, which can maintain sex-related gene expression and functional differences in the absence of circulating sex steroids. The angiotensin type 2 (AT2) receptors mediate anti-inflammatory actions in different tissues, including brain. In mice, we performed RT-PCR analysis of microglia isolated from adult brains and RNA scope in situ hybridization from males, females, ovariectomized females, orchiectomized males and brain masculinized females. We also compared wild type and AT2 knockout mice. The expression of AT2 receptors in microglial cells showed sex differences with much higher AT2 mRNA expression in females than in males, and this was not dependent on circulating gonadal hormones, as observed using ovariectomized females, brain masculinized females and orchiectomized males. These results suggest genomic reasons, possibly related to sex chromosome complement, for sex differences in AT2 expression in microglia, as the AT2 receptor gene is located in the X chromosome. Furthermore, sex differences in expression of AT2 receptors were associated to sex differences in microglial expression of key anti-inflammatory cytokines such as interleukin-10 and pro-inflammatory cytokines such as interleukin-1ß and interleukin-6. In conclusion, sex differences in microglial AT2 receptor expression appear as a major factor contributing to sex differences in the neuroinflammatory responses beyond the effects of circulating steroids.


Asunto(s)
Microglía , Receptor de Angiotensina Tipo 2 , Angiotensinas/metabolismo , Angiotensinas/farmacología , Animales , Antiinflamatorios/farmacología , Citocinas/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Microglía/metabolismo , ARN/metabolismo , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo
8.
J Autoimmun ; 122: 102683, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34144328

RESUMEN

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19.


Asunto(s)
Enzima Convertidora de Angiotensina 2/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , COVID-19/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Anciano , Autoanticuerpos/inmunología , COVID-19/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/inmunología , SARS-CoV-2
9.
Chemistry ; 27(54): 13613-13623, 2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34288167

RESUMEN

A catalytic domino reduction-imine formation-intramolecular cyclization-oxidation for the general synthesis of a wide variety of biologically relevant N-polyheterocycles, such as quinoxaline- and quinoline-fused derivatives, and phenanthridines, is reported. A simple, easily available, and environmentally friendly dioxomolybdenum(VI) complex has proven to be a highly efficient and versatile catalyst for transforming a broad range of starting nitroarenes involving several redox processes. Not only is this a sustainable, step-economical as well as air- and moisture-tolerant method, but also it is worth highlighting that the waste byproduct generated in the first step of the sequence is recycled and incorporated in the final target molecule, improving the overall synthetic efficiency. Moreover, selected indoloquinoxalines have been photophysically characterized in cyclohexane and toluene with exceptional fluorescence quantum yields above 0.7 for the alkyl derivatives.


Asunto(s)
Glicoles , Compuestos Orgánicos , Catálisis , Ciclización , Oxidación-Reducción
10.
Clin Sci (Lond) ; 135(3): 465-481, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33479758

RESUMEN

The key link between renin-angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.


Asunto(s)
Bencimidazoles/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Captopril/administración & dosificación , Tetrazoles/administración & dosificación , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , COVID-19/genética , COVID-19/metabolismo , COVID-19/virología , Femenino , Humanos , Pulmón/metabolismo , Pulmón/virología , Masculino , Ratas , Sistema Renina-Angiotensina/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología
11.
Parasitol Res ; 120(11): 3795-3803, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34561748

RESUMEN

Rapid diagnostics provide actionable information for patient care at the time and site of an encounter with the health care system. The mainstay of infectious diseases care is early detection (case finding) and treatment completion, but for many, it is hard to identify positive individuals, as is the case of infection with low burden in schistosomiasis, a parasitic disease common in the tropics and subtropics. We developed a new, accurate, and fast Dot blot methodology (iDot) to indirectly detect Schistosoma mansoni in individuals with very low parasite burden using urine samples. Accuracy of 0.74 was obtained with a significant difference between negative and positive patients and a substantial agreement was found when iDot was compared with five available methods. Our analysis also revealed the superiority of iDot in detecting negative individuals from non-endemic sites, thus, presenting the lowest rate of false positives. This new method called iDot is convenient and suitable for qualitative and quantitative detection of schistosomiasis in individuals with low parasite burden.


Asunto(s)
Esquistosomiasis mansoni , Esquistosomiasis , Animales , Antígenos Helmínticos , Heces , Humanos , Schistosoma mansoni , Esquistosomiasis mansoni/diagnóstico , Sensibilidad y Especificidad
12.
J Appl Biomed ; 19(4): 210-219, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34907740

RESUMEN

This study investigated whether a 30-day co-treatment with 1 g/kg glutamine dipeptide (GdiP) and 1 U/kg regular (rapid acting) or 5 U/kg degludec (long acting) insulins modifies glucose homeostasis and liver metabolism of alloxan-induced type 1 diabetic (T1D) male Swiss mice undergoing insulin-induced hypoglycemia (IIH). Glycemic curves were measured in fasted mice after IIH with 1 U/kg regular insulin. One hour after IIH, the lipid profile and AST and ALT activities were assayed in the serum. Morphometric analysis was assessed in the liver sections stained with hematoxylin-eosin and glycolysis, glycogenolysis, gluconeogenesis and ureagenesis were evaluated in perfused livers. T1D mice receiving GdiP or the insulins had a smaller blood glucose drop at 60 minutes after IIH, which was not sustained during the subsequent period up to 300 minutes. The 30-day treatment of T1D mice with insulin degludec, but not with regular insulin, improved fasting glycemia, body weight gain and serum activity of AST and ALT. Treatments with insulin degludec, GdiP and insulin degludec + GdiP decreased the liver capacity in synthesizing glucose from alanine. GdiP, in combination with both insulins, was associated with increases in the serum triglycerides and, in addition, regular insulin and GdiP increased AST and ALT activities, which could be the consequence of hepatic glycogen overload. GdiP and the insulins improved the IIH, although to a small extent. Caution is recommended, however, with respect to the use of GdiP because of its increasing effects on serum triglycerides and AST plus ALT activities.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Dipéptidos , Glutamina , Hipoglucemia , Insulina de Acción Prolongada , Insulinas , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Dipéptidos/efectos adversos , Glucosa/metabolismo , Glutamina/farmacología , Homeostasis , Hipoglucemia/inducido químicamente , Insulina/efectos adversos , Insulina de Acción Prolongada/farmacología , Hígado/química , Hígado/metabolismo , Masculino , Ratones , Triglicéridos/efectos adversos
13.
Clin Exp Allergy ; 50(7): 815-823, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32511782

RESUMEN

BACKGROUND: Pollen food allergy syndrome (PFAS) related to PR10 from vegetables is common in northern Europe, whereas in Mediterranean countries PFAS has been preferentially associated with profilins. However, there are pollen-allergic patients reactive to Bet v 1 in birch-free regions. Since it cannot be the primary sensitizer, there has to be another culprit. Quercus ilex is a good candidate as it belongs to the order Fagales. This order includes trees with highly sensitizing pollen such as alder, hazel, hornbeam, oak and chestnut because of the presence of PR10 allergens. PR10 allergens have indeed been described in other Quercus species. OBJECTIVE: Our goals were to determine the rate of sensitization to Q. ilex in central Spain and the associated frequency of PFAS; secondly to identify and clone the Q. ilex allergen PR10. METHODS: We included 224 allergic patients with respiratory symptoms to estimate the rate of sensitization. A skin prick test (SPT) and ImmunoCAP were performed. A total of 38 Q. ilex-sensitized patients were tested using Western blotting to determine the rate of Que i 1. Peptides from Que i 1 were analysed by MALDI-TOF/TOF and Orbitrap LC-MSMS. The Que i 1 sequence was first obtained from the Holm oak transcriptome then cloned and expressed in bacteria. RESULTS: 59.8% of pollen-allergic children were sensitized to Q. ilex. We described and cloned the Q. ilex PR10, Que i 1, which has a sensitization rate of 60.5% and was recognized by 65.4% patients reporting PFAS. CONCLUSION AND CLINICAL RELEVANCE: Sensitization to Q. ilex pollen has increased significantly since 1995. This sensitization could be important, as the presence of PFAS in this population is higher than in patients not sensitized to Q. ilex. The first Q. ilex allergen has been described and is related to PFAS in Spanish patients sensitized to PR10 but not exposed to birch pollen.


Asunto(s)
Alérgenos , Hipersensibilidad a los Alimentos/epidemiología , Quercus , Rinitis Alérgica Estacional/epidemiología , Adolescente , Alérgenos/genética , Alérgenos/inmunología , Niño , Femenino , Hipersensibilidad a los Alimentos/inmunología , Humanos , Masculino , Quercus/genética , Quercus/inmunología , Rinitis Alérgica Estacional/inmunología , España/epidemiología , Síndrome
14.
Brain Behav Immun ; 87: 256-271, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31863823

RESUMEN

Overactivity of the angiotensin-type-1 receptor (AT1)/NADPH-oxidase axis enhances aging processes, neuroinflammation and neurodegeneration. The role of AT2 receptors in the above-mentioned AT1-related effects in the aged brain, particularly substantia nigra, was investigated in this study. In the nigra, we observed a progressive decrease in AT2 mRNA expression with aging, and AT2 deletion led to changes in spontaneous motor behavior, dopamine receptors, renin-angiotensin system, and pro-oxidative and pro-inflammatory markers similar to those observed in aged wild type (WT) mice. Both aged WT mice and young AT2 KO mice showed an increased AT1, decreased MAS receptor and increased angiotensinogen mRNA and/or protein expression, as well as upregulation of pro-oxidative and pro-inflammatory markers. In cultures of microglial cells, activation of AT2 receptors inhibited the LPS-induced increase in AT1 mRNA and protein expression and neuroinflammatory markers. Both in AT2 KO microglial cultures and microglia obtained from adult AT2 KO mice, an increase in AT1 mRNA expression was observed. In cultured dopaminergic neurons, AT2 activation down-regulated AT1 mRNA and protein, and dopaminergic neurons from adult AT2 KO mice showed upregulation of AT1 mRNA expression. Both in microglia and dopaminergic neurons the pathway AT2/nitric oxide/cyclic guanosine monophosphate mediates the regulation of the AT1 mRNA and protein expression through downregulation of the Sp1 transcription factor. MAS receptors are also involved in the regulation of AT1 mRNA and protein expression by AT2. The results suggest that an aging-related decrease in AT2 expression plays a major role in the aging-related AT1 overexpression and AT1-related pro-inflammatory pro-oxidative effects.


Asunto(s)
Envejecimiento , Estrés Oxidativo , Receptor de Angiotensina Tipo 2 , Animales , Ratones , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Sustancia Negra/metabolismo
15.
Molecules ; 25(7)2020 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-32290123

RESUMEN

Pistachio and cashew contain allergenic proteins, which causes them to be removed from the diet of allergic people. Previous studies have demonstrated that food processing (thermal and non-thermal) can produce structural and/or conformational changes in proteins by altering their allergenic capacity. In this study, the influence of instant controlled pressure drop (DIC) on pistachio and cashew allergenic capacity has been studied. Western blot was carried out using IgG anti-11S and anti-2S and IgE antibodies from sera of patients sensitized to pistachio and cashew. DIC processing causes changes in the electrophoretic pattern, reducing the number and intensity of protein bands, as the pressure and temperature treatment increment, which results in a remarkable decrease in detection of potentially allergenic proteins. The harshest conditions of DIC (7 bar, 120 s) markedly reduce the immunodetection of allergenic proteins, not only by using IgG (anti 11S and anti 2S) but also when IgE sera from sensitized patients were used for Western blots. Such immunodetection is more affected in pistachio than in cashew nuts, but is not completely removed. Therefore, cashew proteins are possibly more resistant than pistachio proteins. According these findings, instant controlled pressure drop (DIC) can be considered a suitable technique in order to obtain hypoallergenic tree nut flour to be used in the food industry.


Asunto(s)
Alérgenos/inmunología , Hipersensibilidad a la Nuez/inmunología , Nueces/efectos adversos , Alérgenos/química , Anacardium/efectos adversos , Antígenos de Plantas/inmunología , Cromatografía Liquida , Femenino , Manipulación de Alimentos , Humanos , Inmunoglobulina E/inmunología , Masculino , Hipersensibilidad a la Nuez/diagnóstico , Nueces/química , Pistacia/efectos adversos , Proteínas de Plantas/efectos adversos , Proteínas de Plantas/química , Espectrometría de Masas en Tándem
16.
Int J Clin Pract ; 73(6): e13317, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30694579

RESUMEN

AIMS: There is currently no consensus on the effect of treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), on the prognosis of patients with heart failure and preserved ejection fraction (HFpEF). Therefore, we have analysed the relationship of commencing treatment with ACEIs or ARBs and the prognosis of patients with incident HFpEF. METHODS: Retrospective study over 15 years on 3864 patients with HFpEF (GAMIC cohort). Main outcomes were mortality (all-cause and cardiovascular) and hospitalisations for HF. The independent relationship between CT-RASIs and the prognosis, stratifying patients for cardiovascular comorbidity after propensity score-matching was analysed. RESULTS: During a median follow-up of 7.94 years, 2960 died (76.6%) and 3138 were hospitalised (81.2%). Therapy with RASIs was associated with a lower mortality, all-cause (RR [95% CI] for ACEIs: 0.76 [0.66-0.86], and RR for ARBs: 0.88 [0.80-0.96]; P < 0.001 in both cases), and cardiovascular (RR for ACEIs: 0.72 [0.66-0.78], and RR for ARBs: 0.87 [0.80-0.94]; P < 0.001), a lower hospitalisation rate (RR for ACEIs: 0.82 [0.74-0.90], and RR for ARBs: 0.90 [0.82-0.98]; P < 0.001), and a lower 30-day readmission rate (RR for ACEIs: 0.66 [0.60-0.73], and RR for ARBs: 0.86 [0.75-0.97]; P < 0.001), after adjustment for the propensity to take RASIs or other medications, comorbidities and other potential confounders. Results on the effect of ARBs are compromised by the small number of patients. Analyses of recurrent hospitalisations gave larger treatment benefits than time-to-first-event analyses. CONCLUSION: In this propensity-matched study, commencing treatment with ACEIs is associated with an improved prognosis of patients newly diagnosed with incident HFpEF.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Puntaje de Propensión , Estudios Retrospectivos , Volumen Sistólico , Resultado del Tratamiento , Adulto Joven
17.
Angew Chem Int Ed Engl ; 58(7): 2129-2133, 2019 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-30576054

RESUMEN

The synthesis of aromatic amines is of utmost importance in a wide range of chemical contexts. We report a direct amination of boronic acids with nitro compounds to yield (hetero)aryl amines. The novel combination of a dioxomolybdenum(VI) catalyst and triphenylphosphine as inexpensive reductant has revealed to be decisive to achieve this new C-N coupling. Our methodology has proven to be scalable, air and moisture tolerant, highly chemoselective and engages both aliphatic and aromatic nitro compounds. Moreover, this general and step-economical synthesis of aromatic secondary amines showcases orthogonality to other aromatic amine syntheses as it tolerates aryl halides and carbonyl compounds.

18.
Br J Nutr ; 120(7): 732-739, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30079843

RESUMEN

Keto analogues and amino acids (KAAA) supplementation can reduce blood ammonia concentrations in athletes undergoing high-intensity exercise under both ketogenic and thermoneutral conditions. This study evaluated the acute effects of KAAA supplementation on ammonia metabolism during extenuating endurance exercise in rats fed a ketogenic diet. In all, eighty male Fischer rats at 90 d of age were divided into eight groups, and some were trained using a swimming endurance protocol. A ketogenic diet supplemented with keto analogues was administered for 10 d. Administration of the ketogenic diet ended 3 d before the exhaustion test (extenuating endurance exercise). A ketogenic diet plus KAAA supplementation and extenuating endurance exercise (trained ketogenic diet supplemented with KAAA (TKKa)) increased blood ammonia concentrations by approximately 50 % compared with the control diet (trained control diet supplemented with KAAA (TCKa)) and similar training (effect size=1·33; statistical power=0·50). The KAAA supplementation reduced blood urea concentrations by 4 and 18 % in the control and ketogenic diet groups, respectively, compared with the groups fed the same diets without supplementation. The trained groups had 60 % lower blood urate concentrations after TCKa treatment than after TKKa treatment. Our results suggest that KAAA supplementation can reduce blood ammonia concentrations after extenuating endurance exercise in rats fed a balanced diet but not in rats fed a ketogenic diet.


Asunto(s)
Aminoácidos/uso terapéutico , Amoníaco/sangre , Dieta , Suplementos Dietéticos , Hiperamonemia/prevención & control , Cetoácidos/uso terapéutico , Resistencia Física/fisiología , Aminoácidos/farmacología , Animales , Dieta Cetogénica , Hiperamonemia/sangre , Hiperamonemia/etiología , Cetoácidos/farmacología , Masculino , Condicionamiento Físico Animal/fisiología , Ratas Endogámicas F344
19.
Int J Clin Pract ; 72(11): e13217, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30248211

RESUMEN

BACKGROUND: Resting heart rate (HR) reduction with ivabradine (IVA) improves outcomes of patients with heart failure and reduced ejection fraction (HFrEF). Nevertheless, the best option to slow HR in patients with HFrEF treated with beta-blockers and a HR >70 bpm is unsettled. AIMS: To evaluate whether, in patients with HFrEF, commencing therapy with digoxin (CT-DIG) is associated to a worse prognosis than commencing treatment with ivabradine (CT-IVA). METHODS: Observational study over 10 years on 2364 patients with HFrEF in sinus rhythm and a HR >70 bpm. Main outcomes were mortality, hospitalisations and visits. We analyse the independent relationship of CT-DIG or CT-IVA with the prognosis, stratifying patients for cardiovascular comorbidity, and for other potential confounders (378 patients who CT-DIG vs another 355 patients who CT-IVA vs another 1631 patients non-exposed to IVA or DIG). RESULTS: During a median follow-up of 57.5 months, 1751 patients (74.1%) died, and 2151 (91.0%) were hospitalised for HF. CT-DIG or CT-IVA was associated with a lower all-cause mortality (DIG: HR = 0.86 [95% CI, 0.82-0.90], and IVA: HR = 0.88 [0.83-0.93]), cardiovascular mortality (DIG: HR = 0.84 [0.80-0.89] and IVA: HR = 0.83 [0.78-0.89]), hospitalisation (DIG: HR = 0.86 [0.83-0.89] and IVA: HR = 0.87 [0.83-0.91]) and 30-day readmission (DIG: HR = 0.84 [0.79-0.90] and IVA: HR = 0.88 [0.79-0.95]), after adjustment for cardiovascular comorbidity, and other potential confounders. These associations with the prognosis of HFrEF did not differ between patients who CT-DIG and those who CT-IVA. CONCLUSION: Commencing therapy with digoxin or with ivabradine is associated with an improved prognosis of patients with HFrEF.


Asunto(s)
Cardiotónicos/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Digoxina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Ivabradina/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Estudios de Cohortes , Comorbilidad , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Readmisión del Paciente , Pronóstico , Volumen Sistólico , Resultado del Tratamiento
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