D-dopachrome tautomerase in adipose tissue inflammation and wound repair

D-dopachrome tautomerase (D-DT/MIF-2) is a member of the macrophage migration inhibitory factor (MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D-DT have been reported to be involved in obesity, but there is little known about the regulation of D-DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D-DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D-DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D-DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF-CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D-DT to MIF in inflamed adipose tissue, and indicate that D-DT may be beneficial in wound repair by improving fibroblast survival and proliferation

Tools and techniques for solvent selection: green solvent selection guides

Driven by legislation and evolving attitudes towards environmental issues, establishing green solvents for extractions, separations, formulations and reaction chemistry has become an increasingly important area of research. Several general purpose solvent selection guides have now been published with the aim to reduce use of the most hazardous solvents. This review serves the purpose of explaining the role of these guides, highlighting their similarities and differences. How they can be used most effectively to enhance the greenness of chemical processes, particularly in laboratory organic synthesis and the pharmaceutical industry, is addressed in detail

The Role of the IKKα Kinase in Atherosclerosis

Most fatal cardio- and cerebrovascular incidents are caused by atherosclerosis, a chronic inflammatory disease of the vessel wall in which the transcription factor NF-κB has been shown to be involved. Two main pathways activate NF-κB: whereas inflammatory signals induce “canonical” NF-κB activation through the IKKβ/IKKγ kinase complex, “alternative” NF-κB activation, triggered by e.g. RANKL, CD40L and LT-β depends on the IKKα kinase. In addition, IKKα was reported to terminate the canonical NF-κB activation in macrophages, thereby contributing to the resolution of inflammation. Furthermore, IKKα exerts multiple NF-κB-independent functions, e.g. modulating gene expression by phosphorylating histone H3. Despite these known functions of IKKα, the contribution of IKKα to atherogenesis remained unexplored. Thus, the aim of this study was to identify the role of haematopoietic IKKα activation versus the global function of IKKα activation in atherosclerosis. For both approaches an activation-resistant Ikkα (IkkαAA/AA) mouse model was used, with a hyperlipidemic Apolipoprotein E-deficient (Apoe-/-) background.To study the bone marrow-specific function of Ikkα kinase activity, IkkαAA/AA Apoe-/- or Apoe-/- bone marrow was transplanted in lethally-irradiated Apoe-/- mice, followed by high-fat diet for 8 or 13 weeks. Haematopoietic profiling revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in IkkαAA/AAApoe-/- bone marrow chimeras, whereas the naive T-cell population was increased. However, an overall zero effect on atherosclerosis, canonical NF-κB activation in macrophages and gene expression was observed. Taken together, the data indicate that diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveal that targeting haematopoietic Ikkα kinase activity alone does not represent a suitable therapeutic approach. Furthermore, the global role of Ikkα in atherosclerosis was studied in IkkαAA/AA Apoe-/- mice after 13 weeks of high-fat diet. IkkαAA/AA Apoe-/- mice showed significantly increased plaque formation in the aorta compared to wildtype controls, but surprisingly the lesions in aortic root were significantly reduced compared to the control group. These site-specific effects could not be attributed to differences in leukocyte infiltration as lesion phenotypes were comparable between the groups. Also, NF-κB p65 activation showed similar levels between IkkαAA/AA Apoe-/- and Ikkα+/+Apoe-/- mice. However, IkkαAA/AA knock-in reduced histone H3 phosphorylation in aortic arch. Furthermore, the aortic root showed increased amounts of total endogenous Ikkα compared to aortic arch and aorta, whereas levels of activated, phosphorylated Ikkα were significantly higher in arch and thoracic aorta. Also, gene expression studies in IkkαAA/AA Apoe-/- vs Ikkα+/+ Apoe-/- mice revealed site-specific gene expression variations when comparing aortic root to arch and aorta, with Ccr7 and Ccl19 to be significantly reduced in IkkαAA/AA Apoe-/- mice only in arch and aorta but not in aortic root. The combination of the Ikkα activation profile and the gene studies point to regional differences of Ikkα kinase function, which might cause the site-specific atherosclerotic effects, although the exact mechanisms remain to be further examined.Thus, my data illustrate the functional diversity of the Ikkα kinase and indicate that an exploration of site-specific effects of Ikkα-targeting drugs and of drugs in general on atherosclerosis is required before potential therapeutic application can be considered

The Role of the IKKα Kinase in Atherosclerosis

Most fatal cardio- and cerebrovascular incidents are caused by atherosclerosis, a chronic inflammatory disease of the vessel wall in which the transcription factor NF-κB has been shown to be involved. Two main pathways activate NF-κB: whereas inflammatory signals induce “canonical” NF-κB activation through the IKKβ/IKKγ kinase complex, “alternative” NF-κB activation, triggered by e.g. RANKL, CD40L and LT-β depends on the IKKα kinase. In addition, IKKα was reported to terminate the canonical NF-κB activation in macrophages, thereby contributing to the resolution of inflammation. Furthermore, IKKα exerts multiple NF-κB-independent functions, e.g. modulating gene expression by phosphorylating histone H3. Despite these known functions of IKKα, the contribution of IKKα to atherogenesis remained unexplored. Thus, the aim of this study was to identify the role of haematopoietic IKKα activation versus the global function of IKKα activation in atherosclerosis. For both approaches an activation-resistant Ikkα (IkkαAA/AA) mouse model was used, with a hyperlipidemic Apolipoprotein E-deficient (Apoe-/-) background.To study the bone marrow-specific function of Ikkα kinase activity, IkkαAA/AA Apoe-/- or Apoe-/- bone marrow was transplanted in lethally-irradiated Apoe-/- mice, followed by high-fat diet for 8 or 13 weeks. Haematopoietic profiling revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in IkkαAA/AAApoe-/- bone marrow chimeras, whereas the naive T-cell population was increased. However, an overall zero effect on atherosclerosis, canonical NF-κB activation in macrophages and gene expression was observed. Taken together, the data indicate that diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveal that targeting haematopoietic Ikkα kinase activity alone does not represent a suitable therapeutic approach. Furthermore, the global role of Ikkα in atherosclerosis was studied in IkkαAA/AA Apoe-/- mice after 13 weeks of high-fat diet. IkkαAA/AA Apoe-/- mice showed significantly increased plaque formation in the aorta compared to wildtype controls, but surprisingly the lesions in aortic root were significantly reduced compared to the control group. These site-specific effects could not be attributed to differences in leukocyte infiltration as lesion phenotypes were comparable between the groups. Also, NF-κB p65 activation showed similar levels between IkkαAA/AA Apoe-/- and Ikkα+/+Apoe-/- mice. However, IkkαAA/AA knock-in reduced histone H3 phosphorylation in aortic arch. Furthermore, the aortic root showed increased amounts of total endogenous Ikkα compared to aortic arch and aorta, whereas levels of activated, phosphorylated Ikkα were significantly higher in arch and thoracic aorta. Also, gene expression studies in IkkαAA/AA Apoe-/- vs Ikkα+/+ Apoe-/- mice revealed site-specific gene expression variations when comparing aortic root to arch and aorta, with Ccr7 and Ccl19 to be significantly reduced in IkkαAA/AA Apoe-/- mice only in arch and aorta but not in aortic root. The combination of the Ikkα activation profile and the gene studies point to regional differences of Ikkα kinase function, which might cause the site-specific atherosclerotic effects, although the exact mechanisms remain to be further examined.Thus, my data illustrate the functional diversity of the Ikkα kinase and indicate that an exploration of site-specific effects of Ikkα-targeting drugs and of drugs in general on atherosclerosis is required before potential therapeutic application can be considered

Spelar föräldrarna någon roll? : En kvalitativ studie om de professionellas upplevelser och erfarenheter av föräldrarollen för ungdomar i vård

Föreliggande studie handlar om professionellas syn på föräldrars roll och betydelse vid arbete med ungdomar som befinner sig i någon form av vård i samhällets regi. Varje år får tusentals barn och ungdomar vård i samhällets regi och forskning visar att föräldrarnas delaktighet är en av faktorerna som avgör vårdresultatet. Kvalitén på ungdomarnas relationer med sin familj kan vara antingen en risk- eller en skyddsfaktor. Då föräldrars bristande förmåga är en av de vanligaste orsakerna till att ungdomar är i behov av vård anses studien viktig. Syftet med studien är att belysa socialarbetarens erfarenheter och upplevelser av föräldrarnas roll för ungdomen i vård. För att kunna svara på detta har arbetet utgått från följande frågeställningar:   1.     Hur arbetar de professionella för att inkludera föräldrarna i ungdomens vård?   2.     Hur upplever de professionella föräldrarnas förmåga att vara en resurs för sin ungdom i vård?   För att svara på ovanstående frågor så har fem kvalitativa intervjuer genomförts med yrkesverksamma inom området. Den vetenskapsteoretiska utgångspunkten i studien har varit hermeneutik och studiens resultat har analyserats utifrån Urie Bronfenbrenners ekologiska utvecklingsteori. Studiens resultat överensstämmer med tidigare forskning i avseendet att de professionella är av uppfattningen att föräldrar är oerhört viktiga för sina barn. Som delar i barnets mikrosystem är föräldrarna del av en grund till huruvida barnet utvecklas gynnsamt. De kommer att påverka ungdomen senare i ungdomens liv oavsett kvalitén på deras relation. En viktig del i de professionellas arbete är därför att få en fungerande allians och relation med föräldrarna till ungdomen i vård, samt mellan ungdomen och föräldrarna. Det finns dock tillfällen när detta är problematiskt och de professionella kan tvingas till beslut om att minska en förälders delaktighet, exempelvis när denne är en förövare och på något sätt begår övergrepp mot sitt barn. Studien visar på ett fortsatt behov av forskning inom området och då med fokus på ungdomars bild av sina föräldrars betydelse när de är i behandling och även få föräldrarnas perspektiv.