| 11. |
- Janke, J, et al.
(author)
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Angiotensin type 1 receptor antagonists induce human in-vitro adipogenesis through peroxisome prolifertor-activated receptor-gamma activation
- 2006
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In: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352 .- 1473-5598. ; 24:9, s. 1809-1816
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In clonal animal cells, certain angiotensin receptor blockers (ARB) activate the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of this work was to validate that observation in human cells and humans. METHODS: We investigated the induction of in-vitro adipogenesis and the activation of PPARgamma-target genes, adiponectin and lipoprotein lipase, by ARB in human preadipocytes. We also studied PPARgamma response-element-driven luciferase reporter gene activation in human adipocytes. Finally, we treated 14 obese men for 10 days with placebo crossed over with 150 mg/day irbesartan. Subcutaneous fat was analyzed for mRNA expression of adiponectin and lipoprotein lipase. RESULTS: Telmisartan and irbesartan, and to a lesser degree losartan, induced adipogenesis and activated PPARgamma-target genes. This stimulation of PPARgamma-target genes was prevented by the PPARgamma antagonist GW9662. Eprosartan had no effect. Paradoxically, all ARB activated the luciferase reporter gene. PPARgamma activity increased approximately two-fold with pioglitazone and 1.5-fold with the ARB in all assays. In the cross-over clinical study, irbesartan lowered blood pressure but had no effect on adiponectin or lipoprotein lipase mRNA expression. CONCLUSIONS: Our data are the first to show that ARB induce adipogenesis and PPARgamma-target gene expression in human adipocytes. Pharmacokinetic differences may contribute to the heterogeneous effects on metabolism and preadipocyte differentiation. In humans, larger doses of ARB, longer treatments, or both may be required to activate PPARgamma in adipose cells.
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| 12. |
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| 13. |
- Jordan, J, et al.
(author)
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Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients.
- 2008
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In: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 83:2, s. 281-7
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Journal article (peer-reviewed)abstract
- Cholecystokinin (CCK) decreases meal size through activation of CCK-A receptors on vagal afferents. We tested the hypothesis that the selective CCK-A agonist GI181771X induces weight loss in obese patients. Patients with body mass index > or = 30 or > or = 27 kg/m2 with concomitant risk factors were randomized to 24-week, double-blind treatment with different GI181771X doses or matching placebo together with a hypocaloric diet. The primary efficacy end point was the absolute change in body weight. To monitor pancreatic and gallbladder effects, patients underwent abdominal ultrasound and magnetic resonance imaging before and after treatment. We randomized 701 patients to double-blind treatment. GI181771X did not reduce body weight and had no effect on waist circumference or other cardiometabolic risk markers. Gastrointestinal side effects were more common with GI181771X than with placebo treatment, whereas hepatobiliary or pancreatic abnormalities did not occur. CCK-A by itself does not have a central role in long-term energy balance.
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| 14. |
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| 15. |
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| 16. |
- McLoughlin, Stephen, 1964-, et al.
(author)
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Seed ferns survived the end-Cretaceous mass extinction in Tasmania.
- 2008
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In: American Journal of Botany. - : Wiley. - 0002-9122 .- 1537-2197. ; 95:4, s. 465-71
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Journal article (peer-reviewed)abstract
- Seed ferns, dominant elements of the vegetation in many parts of the world from the Triassic to Cretaceous, were considered to have disappeared at the end of the Cretaceous together with several other groups that had occupied key positions in terrestrial and marine ecosystems such as dinosaurs, plesiosaurs, and ammonoids. Seed-fern demise is generally correlated with competition from diversifying flowering plants through the Cretaceous and the global environmental crisis related to the Chicxulub impact event in the paleotropics at the end of the period. New fossils from Tasmania show that one seed-fern lineage survived into the Cenozoic by at least 13 million years. These fossils are described here as a new species, Komlopteris cenozoicus. Komlopteris is a genus of seed ferns attributed to Corystospermaceae and until now was not known from sediments younger than the Early Cretaceous. Discovery of this "Lazarus taxon," together with the presence of a range of other relictual fossil and extant organisms in Tasmania, other southern Gondwanan provinces, and some regions of northern North America and Asia, underscores high-latitude regions as biodiversity refugia during global environmental crises and highlights their importance as sources of postextinction radiations.
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| 17. |
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| 18. |
- Perruccio, A V, et al.
(author)
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The development of a short measure of physical function for knee OA KOOS-Physical Function Shortform (KOOS-PS) - an OARSI/OMERACT initiative
- 2008
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 16:5, s. 542-550
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Journal article (peer-reviewed)abstract
- Objective: To develop a short measure of physical function for knee osteoarthritis (OA) using multi-national data from. individuals with varying degrees of severity of knee OA. Methods: Rasch analysis, based on the partial credit model, was conducted on Knee injury and Osteoarthritis Outcome Score and Western Ontario McMaster Universities' Osteoarthritis Index data from individuals with knee OA, ranging from community to pre-total knee replacement samples from five countries. Fit of the data to the Rasch model was evaluated by overall model fit and item-level fit statistics (chi(2), size of residual, F-test). Invariance across age, gender and country was evaluated. Unidimensionality was evaluated by factor analysis of residuals. The derived short measure was further tested for fit through re-analyses in individual sub-samples. A nomogram converting raw summed scores to Rasch-derived interval scores was developed. Results: Thirteen data sets were included (n = 2145), with an age range of 26-95 years, and a male/female ratio of 1:1.4. The final model included seven of the original 22 items. From easiest to most difficult, the items (logit) were as follows: rising from bed (1.366), putting on socks/stockings (1.109), rising from sitting (0.537), bending to the floor (0.433), twisting/pivoting on injured knee (-0.861), kneeling (-1.292) and squatting (-1.292). Sub-sample analyses confirmed findings. Conclusion: Based on the use of accepted Rasch-based measurement methods and the compliment of countries, languages and OA severity represented in this study, our seven item short measure of physical function for knee OA is likely generalizable and widely applicable. This measure has potential for use as the function component in an OA severity scoring system.
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| 19. |
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| 20. |
- Wang, Stephanie X., et al.
(author)
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The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family
- 2007
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In: Structure. - : Elsevier BV. - 0969-2126. ; 15:5, s. 535-543
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Journal article (peer-reviewed)abstract
- Protein inhibitors of proteolytic enzymes regulate proteolysis and prevent the pathological effects of excess endogenous or exogenous proteases. Cysteine proteases are a large family of enzymes found throughout the plant and animal kingdoms. Disturbance of the equilibrium between cysteine proteases and natural inhibitors is a key event in the pathogenesis of cancer, rheumatoid arthritis, osteoporosis, and emphysema. A family (142) of cysteine protease inhibitors (http://merops.sanger.ac.uk) was discovered in protozoan parasites and recently found widely distributed in prokaryotes and eukaryotes. We report the 2.2 A crystal structure of the signature member of the 142 family, chagasin, in complex with a cysteine protease. Chagasin has a unique variant of the immunoglobulin fold with homology to human CD8 alpha. Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds.
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