154 research outputs found

    Splenic nerve bundle stimulation in acute and chronic inflammation

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    Splenic neurovascular bundle stimulation holds potential to treat acute and chronic inflammatory conditions. In the first part of the thesis, the available literature on the interactions between the immune system and nervous system in the intestine is summarized. Then, it is shown that a specialized T-cell, that can produce the neurotransmitter acetylcholine, resides in the gut an plays a dual role in the development of experimental colitis in mice. Furthermore, electrical splenic neurovascular bundle stimulation ameliorated the outcomes of colitis in mice and reversed transcriptomic changes in the gut that were induced by colitis. The second part of the thesis focused on the translation of splenic neurovascular bundle stimulation to the human situation. It is shown that there are significant changes between murine and human innervation of the spleen. Using computed tomography (CT) images the course and the characteristics of the splenic artery were described. These data were used to develop a cuff electrode that could be used for electrical stimulation of the splenic neurovascular bundle in humans. Finally, it was demonstrated that splenic neurovascular bundle stimulation in humans was safe and feasible in a pilot study with patients that underwent esophagectomy

    Stem Cells in Domestic Animals

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    Stem cells are an attractive tool for cell-based therapies in regenerative medicine, both for humans and animals. The research and review articles published in this first book of the Collection “Stem Cells in Domestic Animals: Applications in Health and Production” are excellent examples of the recent advances made in the field of stem/stromal cell research in veterinary medicine. In this field, sophisticated and new treatments are now required for improving patients’ quality of life; in livestock animals, the goal of regenerative medicine is to improve not only animal welfare but also the quality of production, aiming to preserve human health. The contributions collected in this book concern both laboratory research and clinical applications of mesenchymal stem/stromal cells. The increasing knowledge of cell-based therapies may constitute an opportunity for researchers, veterinary practitioners, and animal owners to contribute to animal and human health and well-being

    Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction

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    In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1F77A/F77A mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation

    MicroRNAs and GRK2 as modulators of Kiss1/GPR54 system: Physiopathological role in pubertal alterations and obesity induced hypogonadism

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    The reproductive function is governed by the so-called hypothalamic-pituitary-gonadal (HPG) axis, where an intricated network of central, peripheral and external factors determine hormonal balance and proper functioning of the reproductive system and the gonadal function, guaranteeing the perpetuation of the species 1–3. In recent years, it has been documented that a plethora of central (glutamate, GABA, NKB, NPY) 4–7, peripheral (insulin, leptin, ghrelin) 8,9 and external (nutritional availability, endocrine disruptors, circadian rhythms) 10–13 cues converge (either acting directly or indirectly) onto Kiss1 neurons in the hypothalamus, as major signaling hub of the HPG axis 14, whose products, kisspeptins, act on the GnRH neurons, via its canonical receptor, GPR5415, activating puberty onset and reproductive function. In addition, it is well recognized that reproductive function is altered under conditions of metabolic distress, ranging from subnutrition to obesity, type 2 diabetes and metabolic syndrome, which are bound to numerous perturbations, including disordered puberty, central hypogonadism (mainly in males) and cardiometabolic impairment16,17. MicroRNAs have been recently pointed out as essential players in the control of normal pubertal development18–21, although no study has addressed the specific regulation of Kiss1, at central levels, exerted by miRNAs 21,22. Further, the effects of miRNAs in the pathogenesis of central hypogonadism are completely unexplored. In parallel, the Kiss1/GPR54 system is a key element for the integration of the energetic status and reproductive capacity 23, where GPR54 inactivating mutations were described decades ago as underlying origin of hypogonadotropic hypogonadism 24,25. The G-protein coupled receptor kinase 2 (GRK2) 26, which is largely recognized as pleiotropic regulator of cellular signaling 27–29, has been suggested in vitro as a modulator of GPR5426. Nevertheless, no studies had addressed to date its potential roles in proper pubertal development and maintenance of reproductive capacity. In the above context, this Doctoral Thesis has addressed, as main aims, (i) the putative role of specific miRNAs in the physiological control of puberty via regulation of the Kiss1 system; (ii) the pathophysiological role of miRNAs in obesity-induced hypogonadism (OIH), their interplay with Kiss1 and their potential therapeutic implications; (iii) the role of GRK2 in the control of puberty and the HPG axis through regulation of GPR54 in normal conditions and under nutritional stress; and (iv) the implication of GRK2 in OIH through GPR54 regulation.La función reproductora está determinada por el correcto funcionamiento del eje hipotálamohipofiso-gonadal (HHG), donde una compleja red de factores centrales, periféricos y externos determinan el balance hormonal necesario para la adquisición de la capacidad reproductora y, en consecuencia, para el mantenimiento de las especies 1–3. De este modo, se ha documentado que una multitud de factores centrales (GABA, glutamato, NKB, NPY) 4–7, periféricos (leptina, insulina o ghrelina) 8,9 y externos (disruptores endocrinos, aporte energético, ritmos circadianos) 10–13 convergen (actuando directa o indirectamente) en las neuronas Kiss1 hipotalámicas como principal núcleo del eje HHG 14 y cuyo producto, las kisspeptinas, transmitirán información a la neurona GnRH, por medio de su receptor canónico, GPR5415 , activando la pubertad y la función reproductora. Al mismo tiempo, existen evidencias sobre la afectación de la función reproductora como consecuencia del desequilibrio homeostático presente en situaciones como la subnutrición o la obesidad, diabetes mellitus tipo 2 o síndrome metabólico, que se encuentran vinculadas a numerosos desórdenes, incluyendo alteraciones de la edad de pubertad, el hipogonadismo central (principalmente masculino) y la enfermedad cardiovascular 16,17. Datos recientes señalan que los microRNAs (miRNAs) son elementos implicados en la correcta transición puberal 18–21, aunque existen pocos estudios dirigidos a evaluar al papel de los miRNAs en la regulación específica de la expresión de Kiss1, a nivel central19,22. Además, la desregulación de determinados miRNAs en condiciones de hipogonadismo central, su impacto sobre el sistema Kiss1 y su implicación fisiopatológica en esta condición, permanecen inexplorados. En paralelo, el sistema Kiss1/GPR54 es un elemento clave en la integración del estado energético y la capacidad reproductora23, estando descrito que mutaciones inactivantes en GPR54 son una causa subyacente en determinados casos de hipogonadismo hipogonadotropo 24,25. La quinasa de receptor acoplado a proteína G (GRK2) 26 está reconocida como un regulador pleiotrópico de la señalización celular 27–29 y ha sido demostrada su capacidad para regular GPR54, in vitro 26. En cualquier caso, no existen estudios relacionados con su potencial implicación en la correcta maduración puberal y en el mantenimiento de la capacidad reproductora in vivo. En base a lo anterior, esta Tesis Doctoral ha abordado, como objetivos principales, (i) el estudio del papel específico de microRNAs en la regulación puberal a través de la regulación del sistema Kiss1; (ii) el papel fisiopatológico de los microRNAs en el hipogonadismo central inducido por obesidad (HIO) y sus potenciales implicaciones terapéuticas; (iii) el papel de GRK2 en el control de la puberal y el eje HHG mediante la regulación de GPR54 en condiciones control y de estrés nutricional; y (iv) la implicación de GRK2 en HIO a través de la regulación de GPR54

    Role of the G protein-coupled receptor 55 in the pathogenesis of atherosclerosis

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    Prevention of varicella zoster and SARS-CoV-2 disease in kidney transplant recipients

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    Immunocompromised patients are at higher risk of severe disease from viral infections but are less able to mount an adequate immune response to vaccination.This thesis focusses on the immunogenic effects of vaccination against two viruses, varicella zoster (VZV) and SARSCoV-2, in patients with chronic kidney disease, patients on dialysis and recipients of a kidney transplant.<br/

    Prevention of varicella zoster and SARS-CoV-2 disease in kidney transplant recipients

    Get PDF
    Immunocompromised patients are at higher risk of severe disease from viral infections but are less able to mount an adequate immune response to vaccination.This thesis focusses on the immunogenic effects of vaccination against two viruses, varicella zoster (VZV) and SARSCoV-2, in patients with chronic kidney disease, patients on dialysis and recipients of a kidney transplant.<br/

    Stem Cells in Domestic Animals: Applications in Health and Production

    Get PDF
    Stem cells are an attractive tool for cell-based therapies in regenerative medicine, both for humans and animals. The research and review articles published in this first book of the Collection “Stem Cells in Domestic Animals: Applications in Health and Production” are excellent examples of the recent advances made in the field of stem/stromal cell research in veterinary medicine. In this field, sophisticated and new treatments are now required for improving patients’ quality of life; in livestock animals, the goal of regenerative medicine is to improve not only animal welfare but also the quality of production, aiming to preserve human health. The contributions collected in this book concern both laboratory research and clinical applications of mesenchymal stem/stromal cells. The increasing knowledge of cell-based therapies may constitute an opportunity for researchers, veterinary practitioners, and animal owners to contribute to animal and human health and well-being
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