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1.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209137

RESUMO

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.


Assuntos
Hipotálamo/metabolismo , Inositol/análogos & derivados , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Administração Oral , Animais , Glicemia/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Homeostase , Hipotálamo/efeitos dos fármacos , Inositol/administração & dosagem , Inositol/sangue , Inositol/química , Inositol/farmacologia , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
2.
Sci Rep ; 11(1): 15287, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315987

RESUMO

Heart failure (HF) and the development of chronic kidney disease (CKD) have a direct association. Both can be cause and consequence of the other. Many factors are known, such as diabetes or hypertension, which can lead to the appearance and/or development of these two conditions. However, it is suspected that other factors, namely genetic ones, may explain the differences in the manifestation and progression of HF and CKD among patients. One candidate factor is Rph, a gene expressed in the nervous and excretory system in mammals and Drosophila, encoding a Rab small GTPase family effector protein implicated in vesicular trafficking. We found that Rph is expressed in the Drosophila heart, and the silencing of Rph gene expression in this organ had a strong impact in the organization of fibers and functional cardiac parameters. Specifically, we observed a significant increase in diastolic and systolic diameters of the heart tube, which is a phenotype that resembles dilated cardiomyopathy in humans. Importantly, we also show that silencing of Rabphilin (Rph) expression exclusively in the pericardial nephrocytes, which are part of the flies' excretory system, brings about a non-cell-autonomous effect on the Drosophila cardiac system. In summary, in this work, we demonstrate the importance of Rph in the fly cardiac system and how silencing Rph expression in nephrocytes affects the Drosophila cardiac system.

3.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
5.
Nefrología (Madrid) ; 40(5): 552-562, sept.-oct. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-199037

RESUMO

La hipomagnesemia en hemodiálisis (HD) se asocia a mayor riesgo de mortalidad: su relación con el líquido de diálisis (LD). INTRODUCCIÓN: Concentraciones bajas de magnesio (Mg) en sangre se han relacionado con el desarrollo de diabetes, hipertensión arterial, arritmias, calcificaciones vasculares y con mayor riesgo de muerte, en población general y en hemodiálisis. La composición del LD y su concentración de Mg es uno de los principales determinantes de la magnesemia en los pacientes en HD. OBJETIVO: Estudiar las concentraciones de magnesio en los pacientes en HD, su valor predictivo de mortalidad y qué factores se asocian a la hipomagnesemia y mortalidad en HD. MÉTODOS: Estudio retrospectivo de una cohorte de pacientes prevalentes en HD seguidos 2 años. Cada 6 meses se determina el Mg sérico. En el análisis se utiliza el Mg inicial y el medio de cada paciente, comparando los pacientes con Mg por debajo de la media, 2,1mg/dl, con los que están por encima. Durante el seguimiento se han utilizado 3 tipos de LD: tipo 1, magnesio de 0,5 mmol/l y tipo 3, Mg 0,37 mmol/l ambos con acetato y tipo 2, 0,5 mmol/l de Mg con citrato. RESULTADOS: Se han incluido en el estudio 137 pacientes en hemodiálisis, 72 hombres y 65 mujeres, con una edad media de 67(15) [26-95] años. Cincuenta y siete pacientes eran diabéticos y 70 pacientes estaban en hemodiafiltración en línea (HDF-OL) y 67 en hemodiálisis de alto flujo (HD-HF). El Mg medio de los 93 pacientes con LD tipo 1 era: 2,18(0,37) mg/dl, en 27 con el tipo 3: 2,02 (0,42) mg/dl y los 17 con tipo 2: 1,84 (0,24)mg/dl (p = 0,01). El Mg se relaciona de forma directa significativa con el P y con la albúmina. Después de un seguimiento medio de 16,6(8,9)[3-24] meses, 77 seguían activos, 24 habían fallecido y 36 se habían trasplantado o trasladado. Los pacientes con un Mg superior a 2,1mg/dl tienen una supervivencia mayor, p = 0,008. La supervivencia de los pacientes con los tres tipos de LD no difería significativamente, Log-Rank, p = 0,424. Corregido por la magnesemia, los pacientes con LD con citrato tienen mejor supervivencia, p = 0,009. En el análisis de regresión de COX se observa cómo la edad, albúmina sérica, Mg, técnica de diálisis y tipo de LD tienen valor predictivo de mortalidad independiente. CONCLUSIONES: Los magnesios séricos bajos respecto a los altos se asocian a mayor riesgo de mortalidad. El tipo de LD influye en la concentración de Mg y en el riesgo de muerte


Hypomagnesaemia in haemodialysis (HD) is associated with increased mortality risk: its relationship with dialysis fluid (DF). INTRODUCTION: Low concentrations of magnesium (Mg) in blood have been linked to the development of diabetes, hypertension, arrhythmias, vascular calcifications and an increased risk of death in the general population and in haemodialysis patients. The composition of the dialysis fluid in terms of its magnesium concentration is one of the main determinants of magnesium in haemodialysis patients. OBJECTIVE: To study magnesium concentrations in haemodialysis patients, their predictive mortality rate and what factors are associated with hypomagnesaemia and mortality in haemodialysis. METHODS: Retrospective study of a cohort of prevalent haemodialysis patients followed up for two years. Serum magnesium was measured every six months. The analysis used the initial and average magnesium values for each patient, comparing patients with magnesium below the mean (2.1mg/dl) with those with magnesium above the mean. During the follow-up, three types of dialysis fluid were used: type 1, magnesium 0.5 mmol/l; type 3, magnesium 0.37 mmol/l (both with acetate); and type 2, magnesium 0.5 mmol/l with citrate. RESULTS: We included 137 haemodialysis patients in the study, of which 72 were male and 65 were female, with a mean age of 67 (15) [26-95] years old. Of this group, 57 patients were diabetic, 70 were on online haemodiafiltration (OL-HDF) and 67 were on high-flow haemodialysis (HF-HD). The mean magnesium of the 93 patients with dialysis fluid type 1 was 2.18 (0.37) mg/dl. In the 27 patients with dialysis fluid type 3 it was 2.02 (0.42) mg/dl. And in the 17 with dialysis fluid type 2 it was 1.84 (0.24) mg/dl (p=.01). There was a pronounced direct relationship between Mg and P and albumin. After a mean follow-up of 16.6 (8.9) [3-24] months, 77 remained active, 24 had died and 36 had been transplanted or transferred. Patients with magnesium above than 2.1mg/dl had a longer survival (p=.008). The survival of patients with the three types of dialysis fluid did not differ significantly (Log-Rank, p=.424). Corrected for blood magnesium, patients with dialysis fluid with citrate have better survival (p=.009). The COX regression analysis shows how age, serum albumin, magnesium, dialysis technique and type of dialysis fluid have an independent predictive mortality rate. CONCLUSIONS: Low serum magnesium levels have a greater association with an increased risk of mortality compared to high levels. The type of dialysis fluid affects the magnesium concentration and the risk of death


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Deficiência de Magnésio/induzido quimicamente , Diálise Renal/métodos , Soluções para Diálise/efeitos adversos , Estudos de Coortes , Deficiência de Magnésio/mortalidade , Estudos Retrospectivos , Hemodiafiltração , Análise de Sobrevida , Magnésio/sangue
6.
Nefrologia (Engl Ed) ; 40(5): 552-562, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32651086

RESUMO

Hypomagnesaemia in haemodialysis (HD) is associated with increased mortality risk: its relationship with dialysis fluid (DF). INTRODUCTION: Low concentrations of magnesium (Mg) in blood have been linked to the development of diabetes, hypertension, arrhythmias, vascular calcifications and an increased risk of death in the general population and in haemodialysis patients. The composition of the dialysis fluid in terms of its magnesium concentration is one of the main determinants of magnesium in haemodialysis patients. OBJECTIVE: To study magnesium concentrations in haemodialysis patients, their predictive mortality rate and what factors are associated with hypomagnesaemia and mortality in haemodialysis. METHODS: Retrospective study of a cohort of prevalent haemodialysis patients followed up for two years. Serum magnesium was measured every six months. The analysis used the initial and average magnesium values for each patient, comparing patients with magnesium below the mean (2.1mg/dl) with those with magnesium above the mean. During the follow-up, three types of dialysis fluid were used: type 1, magnesium 0.5 mmol/l; type 3, magnesium 0.37 mmol/l (both with acetate); and type 2, magnesium 0.5 mmol/l with citrate. RESULTS: We included 137 haemodialysis patients in the study, of which 72 were male and 65 were female, with a mean age of 67 (15) [26-95] years old. Of this group, 57 patients were diabetic, 70 were on online haemodiafiltration (OL-HDF) and 67 were on high-flow haemodialysis (HF-HD). The mean magnesium of the 93 patients with dialysis fluid type 1 was 2.18 (0.37) mg/dl. In the 27 patients with dialysis fluid type 3 it was 2.02 (0.42) mg/dl. And in the 17 with dialysis fluid type 2 it was 1.84 (0.24) mg/dl (p=.01). There was a pronounced direct relationship between Mg and P and albumin. After a mean follow-up of 16.6 (8.9) [3-24] months, 77 remained active, 24 had died and 36 had been transplanted or transferred. Patients with magnesium above than 2.1mg/dl had a longer survival (p=.008). The survival of patients with the three types of dialysis fluid did not differ significantly (Log-Rank, p=.424). Corrected for blood magnesium, patients with dialysis fluid with citrate have better survival (p=.009). The COX regression analysis shows how age, serum albumin, magnesium, dialysis technique and type of dialysis fluid have an independent predictive mortality rate. CONCLUSIONS: Low serum magnesium levels have a greater association with an increased risk of mortality compared to high levels. The type of dialysis fluid affects the magnesium concentration and the risk of death.

7.
Nutrients ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575416

RESUMO

Both maternal and early life malnutrition can cause long-term behavioral changes in the offspring, which depends on the caloric availability and the timing of the exposure. Here we investigated in a rat model whether a high-caloric palatable diet given to the mother and/or to the offspring during the perinatal and/or postnatal period might dysregulate emotional behavior and prefrontal cortex function in the offspring at adult age. To this end, we examined both anxiety responses and the mRNA/protein expression of glutamatergic, GABAergic and endocannabinoid signaling pathways in the prefrontal cortex of adult offspring. Male animals born from mothers fed the palatable diet, and who continued with this diet after weaning, exhibited anxiety associated with an overexpression of the mRNA of Grin1, Gria1 and Grm5 glutamate receptors in the prefrontal cortex. In addition, these animals had a reduced expression of the endocannabinoid system, the main inhibitory retrograde input to glutamate synapses, reflected in a decrease of the Cnr1 receptor and the Nape-pld enzyme. In conclusion, a hypercaloric maternal diet induces sex-dependent anxiety, associated with alterations in both glutamatergic and cannabinoid signaling in the prefrontal cortex, which are accentuated with the continuation of the palatable diet during the life of the offspring.


Assuntos
Ansiedade/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Fatores Sexuais , Tempo
8.
Int J Mol Sci ; 19(7)2018 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-29986523

RESUMO

Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich's ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.


Assuntos
Modelos Animais de Doenças , Drosophila melanogaster/fisiologia , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/patologia , Animais , Drosophila melanogaster/genética , Avaliação Pré-Clínica de Medicamentos , Ataxia de Friedreich/genética , Inativação Gênica , Predisposição Genética para Doença , Humanos , Proteínas de Ligação ao Ferro/genética , Metabolismo dos Lipídeos , Estresse Oxidativo , Fenótipo
9.
Am Surg ; 83(5): 512-514, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28541864

RESUMO

Wound site infections increase costs, hospital stay, morbidity, and mortality. Techniques used for wounds management after laparotomy are primary, delayed primary, and vacuum-assisted closures. The objective of this study is to compare infection rates between those techniques in contaminated and dirty/infected wounds. Eighty-one laparotomized patients with Class III or IV surgical wounds were enrolled in a three-arm randomized prospective study. Patients were allocated to each group with the software Research Randomizer® (Urbaniak, G. C., & Plous, S., Version 4.0). Presence of infection was determined by a certified board physician according to Centers for Disease Control's Criteria for Defining a Surgical Site Infection. Twenty-seven patients received primary closure, 29 delayed primary closure, and 25 vacuum-assisted closure, with no exclusions for analysis. Surgical site infection was present in 10 (37%) patients treated with primary closure, 5 (17%) with primary delayed closure, and 0 (0%) patients receiving vacuum-assisted closure. Statistical significance was found between infection rates of the vacuum-assisted group and the other two groups. No significant difference was found between the primary and primary delayed closure groups. The infection rate in contaminated/dirty-infected laparotomy wounds decreases from 37 and 17 per cent with a primary and delayed primary closures, respectively, to 0 per cent with vacuum-assisted systems.


Assuntos
Laparotomia/efeitos adversos , Tratamento de Ferimentos com Pressão Negativa , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Técnicas de Fechamento de Ferimentos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
13.
Rev. Soc. Esp. Enferm. Nefrol ; 13(2): 105-111, abr.-jun. 2010. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-79448

RESUMO

Es imprescindible un acceso vascular adecuado para obtener una hemodiálisis óptima. El daño causado por la punción de la aguja convencional o complicaciones intradiálisis derivadas del movimiento del brazo pueden comprometer la supervivencia del acceso. Otro factor esencial en la calidad de la hemodiálisis, íntimamente relacionado con el calibre de la aguja, es conseguir un mayor flujo sanguíneo eficaz. El catéter-fístula, una nueva cánula de punción de fluoruroplástico, disminuye el daño en la pared interna del acceso y presenta un menor calibre de punción con un mayor calibre interior, lo que le permite alcanzar mayores flujos con una máxima eficacia depuradora y menores complicaciones vasculares. El objetivo de este estudio prospectivo fue comparar el uso del catéter-fístula con el uso de la aguja convencional. Se realizaron 18 sesiones de hemodiálisis con cada uno de los dispositivos en pacientes estables y con buen acceso vascular, recogiéndose en todos los casos el flujo obtenido, las presiones y otros parámetros del monitor, analíticas e incidencias. Los resultados han demostrado que la utilización del catéter-fístula disminuyó la presión arterial y la presión venosa, sin disminuir la eficacia dialítica, en consecuencia, mejoró el perfil hemodinámico. Mejoró significativamente el flujo de sangre real, el número de litros dializados y el Kt. El menor trauma mecánico producido en el acceso vascular permitió disminuir la dosis de heparina, el tiempo de hemostasia y hubo una reducción de las complicaciones vasculares: extravasación y resangrado. Siendo bien tolerada la punción, hay un leve empeoramiento en la sensación dolorosa, justificada por la inexperiencia del manejo. La mejoría en los parámetros dinámicos abren las posibilidades de conseguir mayor eficacia dialítica al hacer factible la utilización de mayores flujos sanguíneos con presiones más adecuadas (AU)


Adequate vascular access is essential in order toobtain optimal haemodialysis. The damage caused by conventional needle puncture or intradialytic complications deriving from the movement of the arm can compromise the survival of the access. Another essential factor in the quality of the haemodialysis, closely related to the calibre of the needle, is obtaining a greater efficient blood flow. The fistula catheter, a new puncture cannula made of fluoroplastic, reduces the damage to the internal wall of the access and presents a lower puncture calibre with a higher interior calibre, which allows it to reach better flows with maximum efficiency and fewer vascular complications. The aim of this prospective study was to compare the use of the fistula catheter with the use of the needle. Eighteen haemodialysis sessions were carried out with each of the devices in stable patients with good vascular access, recording in all cases the flow obtained, pressures and other monitor parameters, test results and incidents. The results have shown that the use of the fistula catheter reduced the arterial pressure and venous pressure, without reducing the dialytic efficiency, and consequently the haemodynamic profile improved. The actual blood flow, number of litres dialysed and Kt improved significantly. The lesser mechanical trauma caused in the vascular access made it possible to reduce the dose of heparin, the haemostasis time and there was a reduction in vascular complications: extravasation and rebleeding. While the puncture is well tolerated, there is a slight worsening in the feeling of pain, explained by the lack of experience in handling. The improvement in dynamic parameters opens up the possibilities of achieving greater dialytic efficiency by making it feasible to use greater blood flows with more adequate pressures (AU)


Assuntos
Humanos , Masculino , Feminino , Cateterismo/métodos , Cateterismo Cardíaco , Fístula/diagnóstico , Fístula/fisiopatologia , Pressão Venosa/fisiologia , Biópsia/instrumentação , Biópsia/métodos , Biópsia/tendências , Estudos Prospectivos , Comorbidade , Doenças Vasculares/complicações , Doenças Vasculares/diagnóstico , Doenças Vasculares/terapia
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