Structure–activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors

Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y1 while uridine containing dinucleotides have some level of agonist response on P2Y2 and P2Y6. The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed

E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid ‘on-and-off’ signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP → ADP → AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage

The Future of Rheumatoid Arthritis and Hand Surgery - Combining Evolutionary Pharmacology and Surgical Technique

Rheumatoid arthritis is a systemic autoimmune disease of uncertain aetiology, which is characterized primarily by synovial inflammation with secondary skeletal destructions

Integration of P2Y receptor-activated signal transduction pathways in G protein-dependent signalling networks

The role of nucleotides in intracellular energy provision and nucleic acid synthesis has been known for a long time. In the past decade, evidence has been presented that, in addition to these functions, nucleotides are also autocrine and paracrine messenger molecules that initiate and regulate a large number of biological processes. The actions of extracellular nucleotides are mediated by ionotropic P2X and metabotropic P2Y receptors, while hydrolysis by ecto-enzymes modulates the initial signal. An increasing number of studies have been performed to obtain information on the signal transduction pathways activated by nucleotide receptors. The development of specific and stable purinergic receptor agonists and antagonists with therapeutical potential largely contributed to the identification of receptors responsible for nucleotide-activated pathways. This article reviews the signal transduction pathways activated by P2Y receptors, the involved second messenger systems, GTPases and protein kinases, as well as recent findings concerning P2Y receptor signalling in C6 glioma cells. Besides vertical signal transduction, lateral cross-talks with pathways activated by other G protein-coupled receptors and growth factor receptors are discussed

Participation in everyday life. Very old persons' experiences of daily occupation, occupation of interest and use of assistive devices.

The overall aim of the present thesis was to examine, extend and deepen the understanding of very old persons’ experience of participation in everyday life from an occupational perspective. The thesis consists of four empirical studies. The participants are mainly very old persons (80+) living at home and were derived from the gerontological and geriatric population studies in Göteborg (H70), Sweden. Study I (n=11) and study IV (n=10) are qualitative studies in which a phenomenographical approach was adopted. Study II is a cross-sectional study (n=205), and study III is a cross-sectional and longitudinal study (n=201), which were subjected to qualitative content- and statistical analysis. The findings in study I and II showed that very old persons used assistive devices to a high degree, and that the use of devices increased with age. Most common were devices used in hygiene- and mobility related occupations. The experiences of being a user of assistive devices varied greatly and various contradictions were found. On the one hand, the assistive devices were seen as natural or normal for the age, the devices gave support, made the person feel safe and facilitated their daily occupation. On the other hand, the assistive devices were experienced as cumbersome, gave a feeling of incapability, were a mark of old age, and made the person concerned avoid participation in everyday life. The findings in III study showed that the participants had a broad range of occupations of interest, media and individual leisure interests being the most common. Personal and environmental factors were reasons for giving up interests. Persons who regarded their health as good, or had no problems in daily activities or in mobility outdoors, had more interests than those with poor health, limited abilities in mobility and in managing daily occupations. The findings in study IV showed how 99-year old persons regarded themselves as competent and proud of their ability to participate in everyday life. Many signs of involvement in daily occupations were found; how they challenged; how occupational patterns preserve occupational abilities, and how incapability and restrictions as a result of personal, environmental and social hindrances were experienced. In conclusion these studies revealed that very old persons live a creative and varied life and appear to have a variety of management/coping ability for handling the balance between abilities, limitations and environmental demands in everyday life. Daily occupations are mainly performed with the support of assistive devices, though these may be sometimes seen in a negative light. What very old persons experience and how they experience their participation in everyday life greatly affect their self-images, and this is a challenge to everyone who works with elderly persons