Orazipone Inhibits Activation of Inflammatory Transcription Factors Nuclear Factor-κB and Signal Transducer and Activator of Transcription 1 and Decreases Inducible Nitric-Oxide Synthase Expression and Nitric Oxide Production in Response to Inflammatory Stimuli

Q3 · MEDICINE

Article

Author: Sareila, Outi ; Nissinen, Erkki ; Kankaanranta, Hannu ; Moilanen, Eeva ; Hamalainen, Mari

Orazipone [OR-1384; 3-[4-(methylsulfonyl)benzylidene]pentane-2,4-dione] is a novel sulfhydryl-modulating compound that has anti-inflammatory properties in experimental models of asthma and inflammatory bowel disease. In inflammation, inducible nitricoxide synthase (iNOS) generates NO, which modulates the immune response. Compounds that inhibit iNOS expression or iNOS activity possess anti-inflammatory effects. In the present study, we examined the effects of orazipone and its derivative OR-1958 [3-[3-chlorine-4-(methylsulfonyl)benzylidene]pentane-2,4-dione] on iNOS expression and NO production in J774 macrophages stimulated by bacterial lipopolysaccharide (LPS) and in human alveolar epithelial cells activated by proinflammatory cytokines. Protein expression and nuclear translocation of transcription factors were measured by Western blot. iNOS mRNA expression was determined by quantitative reverse transcription-polymerase chain reaction and iNOS mRNA stability by actinomycin D assay. iNOS promoter activity was studied in a cell line expressing luciferase under the control of iNOS promoter. Orazipone and its derivative OR-1958 but not its nonthiol-modulating analog inhibited iNOS expression and NO production in a concentration-dependent manner. Orazipone decreased LPS-induced iNOS mRNA expression, but the decay of iNOS mRNA was not affected. Orazipone extensively prevented LPS-induced activation of nuclear factor kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT) 1, which are important transcription factors for iNOS. In agreement, human iNOS promoter activity was inhibited by orazipone. In conclusion, orazipone decreased activation of inflammatory transcription factors NF-kappaB and STAT1, and expression of iNOS in cells exposed to inflammatory stimuli. The thiolmodulating property seems to be critical in mediating the antiinflammatory effects of orazipone.

01 Jun 2006·Molecular PharmacologyQ3 · MEDICINE

Antieosinophilic Activity of Orazipone

Q3 · MEDICINE

Article

Author: Zhang, Xianzhi ; Moilanen, Eeva ; Nissinen, Erkki ; Kankaanranta, Hannu ; Ilmarinen, Pinja

Orazipone is a novel sulfhydryl-reactive compound that has been previously shown to reduce lung eosinophilia in guinea pigs and rats and to inhibit degranulation in mast cells and cytokine production in monocytes and T-cells. However, the effects of orazipone on granulocyte longevity are unknown. Orazipone and its derivative 3-(4-chloro-3-nitro-benzylidene)-pentane-2,4-dione (OR-2370) reversed interleukin-5-afforded survival of human eosinophils by inducing apoptosis. In contrast, orazipone did not affect granulocyte macrophage-colony-stimulating factor-induced survival of human neutrophils. The effect of orazipone on eosinophil apoptosis is different from that of glucocorticoids in that even high con-centrations of interleukin-5 were not able to overcome the effect of orazipone. Orazipone further enhanced spontaneous apoptosis as well as that induced by CD95 ligation without inducing primary necrosis. OR-2370-induced DNA fragmentation was shown to be dependent on caspases 3 and 6 and c-jun-N-terminal kinase, whereas extracellular regulated kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase as well as caspases 4, 8, and 9 seem not to mediate its actions. Our results suggest that orazipone and its derivative OR-2370 possess strong antieosinophilic activity and thus may have anti-inflammatory efficacy in the treatment of asthma and/or allergic conditions.

01 Jan 2005·International ImmunopharmacologyQ2 · MEDICINE

Novel sulfhydryl-reactive compounds orazipone and OR-1958 inhibit cytokine production and histamine release in rat and human mast cells

Q2 · MEDICINE

Article

Author: Kari K. Eklund ; Johanna Vendelin ; Petri J. Vainio ; Erkki Nissinen ; Tiina Mäki ; Charlotta Laitinen

Orazipone (OR-1384) and OR-1958 are novel anti-inflammatory sulfhydryl reactive compounds with potential applications in the treatment of chronic obstructive lung disease and colitis. Mast cells are potent immune system cells which can be found in abundant numbers in mucosa of lung and gut. We have studied whether the anti-inflammatory effect of these compounds could be mediated through inhibition of the function of mast cells and compared their effects with the glucocorticoid budesonide. Human mast cell line (HMC-1) cells were activated using a combination of a calcium ionophore and a phorbol ester and the production of cytokines was measured using ELISA assay. Tumour necrosis factor-alpha mRNA levels were assessed using a semiquantitative reverse transcriptase polymerase chain reaction assay. Histamine release was studied in rat peritoneal mast cells. Orazipone, OR-1958 and budesonide inhibited significantly and dose dependently tumour necrosis factor-alpha production in HMC-1 cells with IC50-values of 20, 10, and 0.25 microM, respectively. Polymerase chain reaction studies showed that OR-1958 attenuated the activation-induced increase of tumour necrosis factor-alpha mRNA in HMC-1 cells. OR-1958 and, to a lesser extent, orazipone inhibited dose dependently compound 48/80-induced histamine release from rat peritoneal mast cells in a reversible manner. In contrast, budesonide did not appreciably affect the histamine release. Both orazipone and OR-1958 inhibit efficiently mast cell functions and therefore could prove useful in the treatment of diseases associated with inappropriate mast cell activation.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	FI	Orion Oyj	-
Crohn Disease	Phase 1	FI	Orion Oyj	-
Pulmonary Disease, Chronic Obstructive	Phase 1	FI	Orion Oyj	-

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