Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged,... Show moreAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD. Show less
Messchendorp, A.L.; Spithoven, E.M.; Casteleijn, N.F.; Dam, W.A.; Born, J. van den; Tonnis, W.F.; ... ; DIPAK Consortium 2018
The work described in this thesis focussed on the modes of action of maggot therapy in chronic wounds, especially related to the inflammatory phase of wound healing. For this purpose, the effect of... Show moreThe work described in this thesis focussed on the modes of action of maggot therapy in chronic wounds, especially related to the inflammatory phase of wound healing. For this purpose, the effect of maggot excretions and/or secretions on microbiological, haematological and immunological processes was investigated. The results showed that maggot excretions/secretions breakdown biofilms of both Gram-positive and Gram-negative bacteria, exposing them to the immune system, antibiotics, and ingestion and subsequent degradation by the maggots. Furthermore, proteases in maggot secretions enhance debridement by increasing the fibrinolytic activity of wound components and by degrading matrix components directly. Additionally, maggot secretions inhibit the pro-inflammatory responses of phagocytes but do not affect their ability to ingest and intracellularly kill micro-organisms. Finally, secretions induce the production of growth factors essential for angiogenesis. In conclusion, the results described in this thesis provide new insights into the modes of action of maggot therapy in chronic wounds. The success of maggot therapy may be explained by the broad spectrum of processes that are modulated by maggot secretions. Show less
Through evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation... Show moreThrough evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation of developmental decisions in the model organism Dictyostelium discoideum. It also shows the first molecular-based phylogeny of the Dictyostelids. Development in Dictyostelium is characterized by the formation of a multicellular structure, the fruiting body, with a well-defined temporal and spatial pattern. cAMP, normally used as intracellular second messenger, in Dictyostelium is used also as an extracellular signal (chemoattractant) to mediate cell movement and cell differentiation. The study of the different components that control the formation of a multicellular fruiting body at a molecular level and from an evolutionary perspective shows that extracellular cAMP signalling was originally developed to control fruiting body morphogenesis. Furthermore it reinforces the idea that Dictyostelium is a simple but yet robust model to study the origins of multicellularity. Do to cAMP being so prevalent in Dictyostelium development I have studied the regulation of cAMP production during particular developmental stages showing in this thesis novel roles for the adenylyl cyclases that produce cAMP and their specific patters of expression during development. A thorough pharmacological analysis of these enzymes is also present in this work. Show less
