| 1. |
- Bjermer, Leif, et al.
(författare)
-
Experimental granulomatous alveolitis in rat. Effect of antigen manipulation, smoke exposure and route of administration
- 1994
-
Ingår i: Sarcoidosis. - 0393-1447. ; 11:1, s. 52-57
-
Tidskriftsartikel (refereegranskat)abstract
- When Sephadex beads (0.45mg/kg b.w) are instilled intratracheally into rats, a granulomatous alveolitis with giant cell formation and fibrosis occurs. Moreover, the events in the alveolar region are paralleled by an eosinophil-dominated peribronchitis/bronchiolitis and perivasculitis. Bronchoalveolar lavage (BAL) shows a very distinct feature with an early pronounced neutrophil increase, followed by an increase of eosinophils and lymphocytes. BAL findings returned to normal after 1-2 weeks, but tissue morphology showed persistent inflammation with large numbers of eosinophils and to a lesser degree mononuclear cells, peribronchially and perivascularly several weeks after the instillation. Fragmentation of the Sephadex beads by ultrasonication dramatically diminished the response, giving a transient neutrophil alveolitis, without eosinophils and with no granuloma formation. On the other hand, when the Sephadex dose was divided into three, given 10 days apart, a more pronounced fibrosing activity occurred, with mast cells appearing in the collagen rich granulomas. Finally, smoke exposure had a significant suppressive effect upon the response. The numbers of cells in the interstitium as well as in the peribronchial and perivascular tissue were markedly decreased in the smoke exposed group compared to the controls. This decrease was mainly due to decreased numbers of mononuclear cells, while the numbers of eosinophils remained unchanged.
|
|
| 2. |
- Chen, Xingchen, et al.
(författare)
-
A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa
- 2019
-
Ingår i: Marine Drugs. - : MDPI. - 1660-3397. ; 17:12
-
Tidskriftsartikel (refereegranskat)abstract
- Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.
|
|
| 3. |
- Graffner-Nordberg, Malin, et al.
(författare)
-
Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model
- 2003
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:16, s. 3455-3462
-
Tidskriftsartikel (refereegranskat)abstract
- Crohn's disease is a chronic inflammatory bowel disease characterized by inflammation of both the small and large intestines. Methotrexate (MTX), a classical dihydrofolate reductase (DHFR) inhibitor, has been used as a therapeutic agent in the treatment of patients with Crohn's disease in recent years. We sought to develop antifolates similar in structure to MTX that would be effective in reducing inflammation in a mouse disease model of colitis. Four classical DHFR inhibitors encompassing ester bridges in the central parts of the molecules were synthesized. These antifolates were efficient inhibitors of the DHFR enzyme derived from rat. They were also tested in vitro for their ability to inhibit induced proliferation of lymphocytes from mouse spleen. Inhibition of cell proliferation was achieved only in the micromolar range, whereas MTX was effective at low nanomolar concentrations. One of the DHFR inhibitors (1), with an IC50 value for rlDHFR approximately 8 times higher than that of methotrexate, was selected for in vivo experiments in an experimental colitis model in mice. This compound demonstrated a clear antiinflammatory effect after topical administration, comparable to the effect achieved with the glucocorticoid budesonide. Three parameters were evaluated in this model: myeloperoxidase activity, colon weight, and inflammation scoring. A favorable in vivo effect of compound 1 (15 mg/(kg(.)day)) was observed in all three inflammatory parameters. However, the results cannot be explained fully by DHFR inhibition or by inhibition of lymphocyte cell proliferation, suggesting that other yet unidentified mechanisms enable reduction of inflammation in the colitis model. The mechanism of action of methotrexate analogues encompassing a bridging ester group is not well understood in vivo but seems to lend itself well to further development of similar compounds.
|
|
| 4. |
|
|
| 5. |
- Linden, M, et al.
(författare)
-
Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis
- 1993
-
Ingår i: The American Review of Respiratory Disease. - 0003-0805. ; 148:5, s. 1226-1232
-
Tidskriftsartikel (refereegranskat)abstract
- To assess the manifestation and location of airway inflammation in smokers with chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD), we lavaged the airways of 12 smokers with CB and 11 smokers with COPD and coexisting CB (OCB). For comparison, the airways of 5 asymptomatic smokers (AS) and 10 healthy nonsmokers (HNS) were lavaged. In all cases, the first lavage aliquot, labeled "bronchial lavage" (BL), was processed separately from the four subsequent aliquots, which were combined and labeled "bronchoalveolar lavage" (BAL). The composition of BL and BAL fluids indicate an ongoing inflammatory process in the airways of all three groups of smokers. CB patients with obstruction had significantly lower concentrations of inflammatory cells in the BL and BAL fluids compared with subjects with nonobstructed CB. Furthermore, airway obstruction, indicated by a reduced FEV1, was significantly correlated with the concentrations of glutathione (p < 0.001), myeloperoxidase (MPO; p < 0.01), and eosinophil cationic protein (ECP; p < 0.01) in BAL fluids. Taken together, these findings suggest that the manifestations of inflammation present in the airways of smokers with CB are different in those who have developed obstruction compared with those who have not.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Wieslander, E, et al.
(författare)
-
Antioxidative properties of organotellurium compounds in cell systems
- 1998
-
Ingår i: BIOCHEMICAL PHARMACOLOGY. - : PERGAMON-ELSEVIER SCIENCE LTD. ; 55:5
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The protective/antioxidative properties of diaryl tellurides were demonstrated in cellular systems of increasing complexity. In the presence of glutathione, bis(4-hydroxyphenyl) celluride (1a), bis(4-aminophenyl) telluride (1d) and bis(2-carboxyphenyl) t
|
|
