The sensitivity of Coxs (cyclo-oxygenases) to inhibition is known to be highly dependent on assay conditions. In the present study, the inhibitor sensitivities of purified Cox-1 and -2 were determined in a colorimetric assay using the reducing agent N,N,N´,N´-tetramethyl-p-phenylenediamine. With the detergent genapol X-100 (2 mM) present, the potencies of nimesulide, ibuprofen, flufenamic acid, niflumic acid and naproxen were increased over 100-fold against Cox-2 and titration curve shapes changed, so that maximal inhibition now approached 100%. Indomethacin, diclofenac and flosulide were not changed in potency. Similar effects of genapol were observed with inhibitors of Cox-1. DuP-697 and two analogues became more than 10-fold less potent against Cox-2 with genapol present. Tween-20, Triton X-100 and phosphatidylcholine, but not octylglucoside, gave qualitatively similar effects as genapol. Similar detergent-dependent changes in inhibitor potency were also observed using a [14C]arachidonic acid HPLC assay. The increases in potency of ibuprofen, flufenamic acid, isoxicam and niflumic acid towards Cox-2 and ibuprofen towards Cox-1 were accompanied by a change from time-independent to time-dependent inhibition. The interactions of Cox inhibitors has been described in terms of multiple binding step mechanisms. The genapol-dependent increase in inhibitor potency for ketoprofen was associated with an increase in the rate constant for the conversion of the initial enzyme–inhibitor complex to a second, more tightly bound form. The loss of potency for some inhibitors is probably due to inhibitor partitioning into detergent micelles. The present study identifies detergents as another factor that must be considered when determining inhibitor potencies against both Cox isoforms.

01 May 2003·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Inflammatory cytokines upregulate nephrin expression in human embryonic kidney epithelial cells and podocytes

Q3 · BIOLOGY

Article

Author: Andrea Huwiler ; Hermann Pavenstädt ; Harry Holthöfer ; Josef Pfeilschifter ; Shuyu Ren

Nephrin is an important regulator of the glomerular filtration barrier and its malfunction is associated with severe proteinuria. In this study we show that exposure of human embryonic kidney epithelial A293 cells to the proinflammatory cytokine interleukin-1beta (IL-1beta) causes a dose-dependent upregulation of nephrin mRNA level. Time-course analyses reveal first significant increases in nephrin mRNA levels after 4h of stimulation. Furthermore, nephrin protein is also elevated by IL-1beta treatment. Tumor necrosis factor-alpha (TNFalpha) exerted a comparable effect on nephrin mRNA and protein expression. The IL-1beta-induced upregulation of nephrin expression occurs independently of nitric oxide (NO) generation, since the NO-synthase inhibitor N(G)-monomethyl-L-arginine does not block the IL-1beta effect. Mechanistically, we found that the IL-1beta-induced response does not involve protein kinase C, protein kinase A, the classical mitogen-activated protein kinase (MAPK), the stress-activated p38-MAPK, or the NF-kappaB cascade, since selective inhibitors of these pathways were unable to alter the IL-1beta response. Moreover, neither unselective cyclooxygenase (COX) inhibitors, like indomethacin, nor COX-2-selective inhibitors, like flosulide and NS 398, nor the anti-inflammatory glucocorticoid dexamethasone were able to alter IL-1beta-induced nephrin expression. The only inhibitor that was able to block IL-1beta- and TNFalpha-induced nephrin upregulation was rottlerin, which has been suggested to act as a selective PKCdelta inhibitor. However, concerning cytokine-triggered nephrin expression, rottlerin action involved inhibition of another still to be identified protein kinase. Importantly, cytokine-induced upregulation of nephrin expression was also confirmed in primary human podocytes. In summary, these data show for the first time that inflammatory cytokines like IL-1beta or TNFalpha can upregulate nephrin expression and this mechanistically involves a rottlerin-sensitive protein kinase.

01 Aug 2001·Prostaglandins & Other Lipid MediatorsQ3 · BIOLOGY

Changes in prostaglandin E2 (PGE2) levels in paw exudate, stomach and kidney of arthritic rats: effects of flosulide

Q3 · BIOLOGY

Article

Author: Queralt, J. ; Turull, A.

To further examine the organ-specific toxic effects of selective and non-selective COX-2 inhibitors in adjuvant arthritis (CAA), we assessed the PGE2 concentration in various organs. AA was induced by intradermal injection of Mycobacterium butyricum. Fourteen days after inoculation, AA rats were selected and treated orally every day for two weeks with the selective COX-2 inhibitor, flosulide, or the COX-1-COX-2 inhibitor, indomethacin. The time-course of paw swelling was determined. At the end of treatments, PGE2 was extracted from paw, stomach (wall and mucosa) and kidney and its concentration was determined by ELISA. Paw edema increase was accompanied by a rise in PGE2 concentration. PGE2 also increased in stomach (mucosa and wall) and kidney. The anti-inflammatory treatment with flosulide (5 mg/kg x day), and indomethacin (1 mg/kg x day), reduced plantar edema by 98.0% and 74.4% respectively. Both drugs greatly decreased PGE2 levels in paw (73.7-53.2%), stomach wall (84.5-80.3%), stomach mucosa (109.9-110.9%) and kidney (92.9-97.5% respectively). However, PGE2 reductions in AA rats did not fall significantly below control values.

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Phase 2	GB	Innovations	-
Rheumatoid Arthritis	Phase 2	-	Bayer AG	-
Rheumatoid Arthritis	Preclinical	-	Novartis Pharma AG	-

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