| 31. |
- Emtenäs, Hans, et al.
(författare)
-
Design and Parallel Solid Phase Synthesis of Ring Fused 2-Pyridinones that Target Pilus Biogenesis in Pathogenic Bacteria
- 2002
-
Ingår i: Journal of Combinatorial Chemistry. - : American Chemical Society (ACS). - 1520-4766 .- 1520-4774. ; 4, s. 630-639
-
Tidskriftsartikel (refereegranskat)abstract
- A new method for the solid-phase synthesis of enantiomerically enriched highly substituted ring-fused 2-pyridinones 13 has been developed. The synthesis mediates introduction of substituents at two positions in the 2-pyridinone ring in a diverse manner and is suitable for parallel synthesis. 19F NMR spectroscopy was used as a tool to monitor each of the five steps in the reaction sequence. The optimized conditions thus obtained were then used to prepare a library of 20 2-pyridinones with high yields. The library members were chosen from a statistical multivariate design to ensure diversity and reliable data for structure−activity relationships. Screening of the library against the bacterial periplasmic chaperone PapD was performed using surface plasmon resonance. Three new 2-pyridinones with a higher affinity for the chaperone PapD than the previous best 13{10,1} were found, and important structural features could be deduced.
|
|
| 32. |
- Emtenäs, Hans, et al.
(författare)
-
Stereoselective synthesis of optically active bicyclic -lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria
- 2003
-
Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 1, s. 1308-14
-
Tidskriftsartikel (refereegranskat)abstract
- Optically active bicyclic -lactams were synthesized, starting from 2-H-2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the -lactam framework were investigated. A rapid CsOH saponification of the -lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic -lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic -lactam carboxylic acids 7a–g and aldehydes 4a–d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. -Lactams substituted with large acyl substituents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic -lactams constitute a new class of potential bacterial chaperone inhibitors.
|
|
| 33. |
|
|
| 34. |
- Fredin, Maria Fritsch, 1970, et al.
(författare)
-
Dextran sulfate sodium-induced colitis generates a transient thymic involution--impact on thymocyte subsets.
- 2007
-
Ingår i: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 65:5, s. 421-9
-
Tidskriftsartikel (refereegranskat)abstract
- One of the most widely used animal models for inflammatory bowel disease (IBD) is the dextran sulfate sodium (DSS)-induced colitis. We have previously reported that 5 days administration of DSS in C57Bl/6J mice induces a colonic inflammation that progresses into chronicity after DSS removal, whereas in BALB/cJ mice the inflammation resolves within 4 weeks post-DSS. Here we show that both thymic size and thymocyte numbers dramatically decreased in the acute phase of inflammation in C57Bl/6 mice, 7 days after DSS withdrawal. Mature, CD4(+) and CD8(+) single positive (SP) CD69(lo) CD62L(hi) thymocytes were enriched in these mice, accompanied by a major decrease in the number of immature double positive (DP) thymocytes. However, the different maturation stages within the DP thymocyte subset were unchanged between healthy and inflamed C57Bl/6J mice. Interestingly, as the inflammation progressed into the chronic phase, the thymus recovered and 2 weeks after the acute inflammatory phase all the thymic parameters investigated in this study were restored to normal. In contrast, BALB/cJ mice only develop mild thymic alterations. Nevertheless, we found that within the double negative (DN) thymocytes an increased frequency and also total numbers of CD44(+) CD25(-) (DN1) cells correlated with the severity of colitis, and that the frequency of CD44(-) CD25(-) (DN4) thymocytes decreased proportionally in the acute phase in BALB/cJ mice. Our observations suggest that the thymic effects are intimately connected to the intestinal inflammatory response in colitis regardless of the inflammatory stimuli.
|
|
| 35. |
- Gjertsson, Inger, 1962, et al.
(författare)
-
Impact of transcription factors AP-1 and NF-kappaB on the outcome of experimental Staphylococcus aureus arthritis and sepsis.
- 2001
-
Ingår i: Microbes and infection. - 1286-4579. ; 3:7, s. 527-34
-
Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus infection is, despite adequate antibiotic treatment, a disease characterized by high mortality. The bacterium triggers an exaggerated immune response in the host, which on the one hand acts as an efficient defense, but on the other hand gives rise to tissue damage. In this study we have modulated the hosts response to S. aureus by inhibition of nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1)-triggered release of pro-inflammatory cytokines and tissue-destructive proteins, respectively. Mice were administered with antisense oligonucleotides (ODN) to the p65 subunit of NF-kappaB and/or a double-stranded oligonucleotide (mCoAP-1) with homology to the murine AP-1 binding site of collagenase IV gene (metalloproteinase-9; MMP-9), solely or in combination with antibiotics. In mice systemically treated with antisense ODN to NF-kappaB p65 alone, the bacterial burden in the kidneys was significantly increased (P = 0.04) The same tendency was seen when mCoAP-1 was administered either alone or in combination with antibiotics. We also found significantly (P = 0.04) elevated levels of IL-6 in p65 antisense treated mice. Surprisingly, this p65 antisense therapy approach, which has turned out to be highly efficient in amelioration of aseptic arthritis and colitis, failed to change the clinical course of either septic arthritis or sepsis. We suggest that interaction with transcription factors leads to increased bacterial burden in vivo, abrogating the potential benefits of the anti-inflammatory properties exerted by these compounds.
|
|
| 36. |
|
|
| 37. |
- Göranzon, C., et al.
(författare)
-
Immunohistochemical characterization of lymphocytes in microscopic colitis
- 2013
-
Ingår i: Journal of Crohn's and Colitis. - : Elsevier. - 1197-4982 .- 1873-9946. ; 7:10, s. e434-e442
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry.Methods Paraffin-embedded biopsies from 23 untreated patients with MC (CC = 13, LC = 10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP.Results In CC and LC, an increase of predominantly CD8+ lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4+ lymphocytes was found in the lamina propria. CD45RO+ and Foxp3+ cells were more abundant in all areas in both patient groups compared to controls, as were CD20+ areas, although more scarce. Ki67+ areas were only more abundant in the epithelium, whereas CD30+ areas were more abundant in the lamina propria of both patient groups compared to controls.Conclusions This study confirms an increased amount of CD8+ lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4+ lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).
|
|
| 38. |
- Hedenström, Mattias, et al.
(författare)
-
NMR studies of interactions between periplasmic chaperones from uropathogenic E-coli and pilicides that interfere with chaperone function and pilus assembly
- 2005
-
Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 3:23, s. 4193-4200
-
Tidskriftsartikel (refereegranskat)abstract
- Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane of the bacterium. The chaperones FimC and PapD are key components in pilus assembly since they catalyse folding of subunits that are incorporated in type 1 and P pili, respectively, and also transport the subunits across the periplasmic space. Recently, compounds that inhibit pilus biogenesis and interfere with chaperone-subunit interactions have been discovered and termed pilicides. In this paper NMR spectroscopy was used to study the interaction of different pilicides with PapD and FimC in order to gain structural knowledge that would explain the effect that some pilicides have on pilus assembly. First relaxation-edited NMR experiments revealed that the pilicides bound to the PapD chaperone with mM affinity. Then the pilicide-chaperone interaction surface was investigated through chemical shift mapping using N-15-labelled FimC. Principal component analysis performed on the chemical shift perturbation data revealed the presence of three binding sites on the surface of FimC, which interacted with three different classes of pilicides. Analysis of structure-activity relationships suggested that pilicides reduce pilus assembly in E. coli either by binding in the cleft of the chaperone, or by influencing the orientation of the flexible F1-G1 loop, both of which are part of the surface by which the chaperone forms complexes with pilus subunits. It is suggested that binding to either of these sites interferes with folding of the pilus subunits, which occurs during formation of the chaperone-subunit complexes. In addition, pilicides that influence the F1-G1 loop also appear to reduce pilus formation by their ability to dissociate chaperone-subunit complexes.
|
|
| 39. |
|
|
| 40. |
|
|
