Circadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily... Show moreCircadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily functions including appetite, sleep, activity and cortisol levels. The circadian clock synchronizes itself to the external world mainly by environmental light cues and can be disturbed by a variety of factors, including shift-work, jet-lag, stress, ageing and artificial light at night.Interestingly, mood has also been shown to follow a diurnal rhythm. Moreover, circadian disruption has been associated with various mood disorders and patients suffering from depression have irregular biological rhythms in sleep, appetite, activity and cortisol levels suggesting that circadian rhythmicity is crucially involved in the etiology and pathophysiology of depression.The aim of the present review is to give an overview and discuss recent findings in both humans and rodents linking a disturbed circadian rhythm to depression. Understanding the relation between a disturbed circadian rhythm and the etiology of depression may lead to novel therapeutic and preventative strategies. Show less
Work described in this thesis was aimed to further understand the role of macrophages in acute cellular rejection of transplanted kidneys, and perform a pre-clinical assessment of the localization... Show moreWork described in this thesis was aimed to further understand the role of macrophages in acute cellular rejection of transplanted kidneys, and perform a pre-clinical assessment of the localization and efficacy of liposomal prednisolone. First, we explored the role of anti-inflammatory macrophages in the onset of acute cellular rejection using human biopsy samples. Here, we discovered that the presence of high levels of CD163+ macrophages was associated with a lower risk of rejection, in a population of patients with a high rate of delayed graft function. Subsequently, we identified the ability of liposomal prednisolone to target macrophages in the kidney using in vitro models of human macrophages, and their ability to accumulate in inflamed kidney tissue in vivo rat models of ischemia reperfusion injury in the kidney. Finally, we evaluated the treatment efficacy of liposomal prednisolone in a mouse model of cellular rejection following kidney transplantation. Here, we were able to show an improved efficacy of liposomal prednisolone in treating rejection, when compared to treatment with free prednisolone. Show less
This thesis identifies specific targets, illustrates the role of these targets, and explores personalized therapeutic possibilities to inhibit tumor growth by using new treatment strategies.... Show moreThis thesis identifies specific targets, illustrates the role of these targets, and explores personalized therapeutic possibilities to inhibit tumor growth by using new treatment strategies. And the thesis describes a new animal model for CM. A proper model can mimic the human disorder and provide opportunities for studying tumor biology, and for seeking novel effective therapies to inhibit the dissemination of malignant cells. Subsequently, the potential role of immune checkpoint molecules and the presence of HLA class I antigens are studied. New animal models and therapeutic targets will broaden our understanding of CM, and help us to develop better treatments for primary and metastatic CM, thus prolonging patients’ survival. Show less
Hemodialysis is the most widely used option in chronic dialysis treatment and requires a suitable vascular access. Unfortunately, this vascular access suffers from a high number of failures... Show moreHemodialysis is the most widely used option in chronic dialysis treatment and requires a suitable vascular access. Unfortunately, this vascular access suffers from a high number of failures responsible for a high morbidity and health care costs. However, the exact pathophysiology remains unclear. In order to unravel the mechanisms of arteriovenous fistula failure we developed a novel murine model of arteriovenous fistula failure. Using this model, we studied the effects of vascular remodeling in mice that were haplodeficient for the eln gene. The role of inflammation in arteriovenous remodeling was also investigated by administrating liposomal prednisolone and by incorporating RP105 knockout mice. Show less
Stress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid... Show moreStress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid receptors as nuclear transcription factors. The lack of the p66Shc gene reduces OS and increases lifespan in mice. Main aim of the study was to elucidate whether the interactions linking OS and the neuroendocrine system represent a crucial determinant of aging in p66Shc-/- mice. Thus, the contribution of p66Shc to behaviour and neuroendocrine regulations was assessed from early post-natal life to senescence. Mutant old mice were characterized by a slow-down in physical and emotional aging; adult subjects showed increased behavioural plasticity and lower emotionality associated to increased central levels of Brain-derived neurotrophic factor, reduced oxidative stress markers and greater resilience to stress-induced changes in the internal milieu. A role has been recently described for p66Shc in regulating energetic metabolism. Intriguingly, we found metabolic and emotional aspects to be strictly related and possibly mediated by maternal behaviour in these mutants. Our results shed light on the role played by OS and metabolism in longevity and emotionality/mood disorders and point to p66Shc as a candidate gene in the trade-off between fertility and lifespan. Show less
Despite the availability of a wide range of antiepileptic drugs, in about one third of people who suffer from epilepsy, seizures cannot be adequately controlled by pharmacotherapy. The mechanisms... Show moreDespite the availability of a wide range of antiepileptic drugs, in about one third of people who suffer from epilepsy, seizures cannot be adequately controlled by pharmacotherapy. The mechanisms underlying this pharmacoresistance are still unclear. This thesis investigates the relationship between the time course of epileptogenesis, the associated changes in GABA mediated inhibition and the development of pharmacoresistance. Impairment of GABA, the brain's major inhibiting neurotransmitter, may lead to excessive activation of excitatory neuronal circuits, as is the case in epilepsy. In vivo studies using an animal model for epilepsy show that the GABA(A) receptor changes early in the epileptogenic process. Alterations include decreased expression and altered subunit composition, resulting in a receptor that is less sensitive to some ligands and more sensitive to others. Show less
