New insights into the mode of action of anti-inflammatory drugs

Vane, John R.; Botting, Regina M.

doi:10.1007/bf01630479

Cited by 810 publications

(486 citation statements)

References 79 publications

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“…The anti-inflammatory agent sodium salicylate is also known as an antioxidant (Sagone and Husney, 1987) and inhibitor of cyclooxygenases (Vane and Botting, 1995). This compound caused a weak, but highly reproducible suppression of TNFR1-and TNF-mediated CMV promoter-enhancer activation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Thommesen¹,

Lægreid²

2005

BMB Reports

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Tumor necrosis factor (TNF) signaling is mediated via two distinct receptors, TNFR2 and TNFR1, which shows partially overlapping signaling mechanisms and biological roles. In the present study, TNFR2 and TNFR1 signal transduction mechanisms involved in activation of NFκB and CMV promoter-enhancer were compared with respect to their susceptibility towards inhibitors of intracellular signaling. For this, we used SW480 cells, where we have shown that TNF-signaling can occur independently through each of the two receptors. The TNFR1 response was inhibited by D609, bromophenacyl bromide (BPB), nordihydroguararetic acid (NDGA), and by sodium salicylate, while TNFR2-mediated activation of NFκB and CMV promoter-enhancer was resistant to these compounds. The signaling mechanisms known to be affected by these inhibitors include phospholipases as well as redox-and pH-sensitive intracellular components. Our results imply that TNFR2 signaling involved in NFκB activation proceeds independently of these inhibitor-sensitive signaling components, indicating distinct signaling pathways not shared with TNFR1.

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Section: Resultsmentioning

confidence: 99%

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Thommesen¹,

Lægreid²

2005

BMB Reports

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“…This panel of genes was selected for analysis based on their high levels of expression in normal macrophages in response to LPS and for the capacity of their products to mediate diverse macrophage effector functions in the host that contribute to septic shock. For example, COX-2 is an enzyme that regulates the production of prostaglandins, mainly PGE 2 , by macrophages and is responsible for the generation of fever and pain during inflammation (29,30). COX-2 enzymatic activity also results in the generation of PGI 2 , which induces vasodilatation and contributes to hypotension during septic shock (31).…”

mentioning

confidence: 99%

CD11b/CD18 Acts in Concert with CD14 and Toll-Like Receptor (TLR) 4 to Elicit Full Lipopolysaccharide and Taxol-Inducible Gene Expression

Perera

Mayadas

Takeuchi

et al. 2001

The Journal of Immunology

369

285

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Overproduction of inflammatory mediators by macrophages in response to Gram-negative LPS has been implicated in septic shock. Recent reports indicate that three membrane-associated proteins, CD14, CD11b/CD18, and Toll-like receptor (TLR) 4, may serve as LPS recognition and/or signaling receptors in murine macrophages. Therefore, the relative contribution of these proteins in the induction of cyclooxygenase 2 (COX-2), IL-12 p35, IL-12 p40, TNF-α, IFN-inducible protein (IP)-10, and IFN consensus sequence binding protein (ICSBP) genes in response to LPS or the LPS-mimetic, Taxol, was examined using macrophages derived from mice deficient for these membrane-associated proteins. The panel of genes selected reflects diverse macrophage effector functions that contribute to the pathogenesis of septic shock. Induction of the entire panel of genes in response to low concentrations of LPS or Taxol requires the participation of both CD14 and TLR4, whereas high concentrations of LPS or Taxol elicit the expression of a subset of LPS-inducible genes in the absence of CD14. In contrast, for optimal induction of COX-2, IL-12 p35, and IL-12 p40 genes by low concentrations of LPS or by all concentrations of Taxol, CD11b/CD18 was also required. Mitigated induction of COX-2, IL-12 p35, and IL-12 p40 gene expression by CD11b/CD18-deficient macrophages correlated with a marked inhibition of NF-κB nuclear translocation and mitogen-activated protein kinase (MAPK) activation in response to Taxol and of NF-κB nuclear translocation in response to LPS. These findings suggest that for expression of a full repertoire of LPS-/Taxol-inducible genes, CD14, TLR4, and CD11b/CD18 must be coordinately engaged to deliver optimal signaling to the macrophage.

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“…The discovery of novel, potent and safer nonsteroidal anti-inflammatory drugs (NSAIDs) represents a challenging goal (Van, Botting, 1995) because resistance to NSAIDs is widespread. Therefore, there is an increasing need for identification of lead structures that may be of use in designing new, potent drugs with less toxic effects (Takaya et al, 1979;Heinisch et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

Analgesic and anti-inflammatory activities of several 4-substituted-6-(3'-nitrophenyl)pyridazin-(2H)-3-one derivatives

Singh¹,

Lakshmayya

Asif

2013

Braz. J. Pharm. Sci.

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Several 6-aryl-4-substituted benzylidene/furfurylidene pyridazin(2H)-3-one derivatives (4a-f) were synthesized and evaluated as analgesic and anti-inflammatory agents in mice and rats, respectively. All compounds were tested by using Eddy's hot plate and the carrageenan-induced hind paw oedema method for the evaluation of analgesic and anti-inflammatory activities, respectively. Results showed that compounds 4f, 4b, 4d, and 4e exhibited higher analgesic and anti-inflammatory activities than other remaining compounds. All title compounds (4a-f) were characterized by IR, NMR and Mass spectroscopy.

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New insights into the mode of action of anti-inflammatory drugs

Cited by 810 publications

References 79 publications

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

Distinct Differences between TNF Receptor 1- and TNF Receptor 2- mediated Activation of NFκB

CD11b/CD18 Acts in Concert with CD14 and Toll-Like Receptor (TLR) 4 to Elicit Full Lipopolysaccharide and Taxol-Inducible Gene Expression

Analgesic and anti-inflammatory activities of several 4-substituted-6-(3'-nitrophenyl)pyridazin-(2H)-3-one derivatives

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