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PDF of thesis T13435 PDF of thesis T13435 - (4 M)
Title An assessment of the effects of novel anti-inflammatory compounds in cell based studies / by Fadia Mohamed Gafri.
Name Gafri, Fadia Mohamed. .
Abstract NF-(Sm(BB and AP-1 are transcription factors with an evolutionary conserved role in the triggering and coordination of both innate and adaptive immune responses. Since they regulate a large number of inflammatory genes, they are considered as potential targets for anti-inflammatory drugs. In the current study, natural SU182 and synthetic alkaloid compounds, SU331, SU432 and minor groove binder compounds AIK18/85/1 and AIK18/70 obtained from the library associated with University of Strathclyde CRUK-Small Molecule Drug Discovery (SMDD) were investigated for possible anti-inflammatory effects at (So(BM concentrations. In NCTC2544 human keratinocyte cells stably transfected with either NF-(Sm(BB- or AP-1-linked luciferase reporter plasmids, tumour necrosis factor-(Sa (B(TNF-(Sa(B) and phorbol-12-myristate- 13 acetate (PMA) well characterized stimuli for canonical NF-(Sm(BB pathway induced NF-(Sm(BB and AP-1 transcriptional activity respectively. However, all te sted compounds inhibited NF-(Sm(BB transcriptional activity; in particular AIK18/85/1 prevented the TNF-(Sa(B-induced translocation of NF-(Sm(BB (p65) to the nucleus assessed by indirect immunoflouresnce. This effect of AIK18/85/1 was also reflected in the significant reduction of nuclear extract NF-(Sm(BB-DNA binding activity as detected by Electrophoresis Mobility Shift Assay (EMSA), but without affecting the degradation of I(Sm(BB(Sa (Bprotein induced by TNF-(Sa(B. Furthermore, AIK18/70 also decreased TNF-(Sa(B- induced NF-(Sm(BB-DNA binding activity but neither affected the phosphorylation of p65 nor the degradation of I(Sm(BB(Sa(B. On the other hand, both SU331 and SU432 inhibited the I(Sm(BB(Sa (Bloss and resultant NF-(Sm(BB-DNA binding activity in a concentration dependent manner. Although none of these compounds inhibited TNF-(Sa(B-induced phosphorylation of NF-(Sm(BB (Ser536-p65), their mode of
Abstract inhibition on NF-(Sm(BB signalling wa s sufficient to prevent the expression of NF-(Sm(BB dependent proteins such as COX-2 and iNOS in LPS stimulated RAW 264.7 macrophage cells. Intriguingly, in contrast to other compounds SU182 was only effective at the level of NF-(Sm(BB and AP-1 transcriptional activities, but without affecting the expression level of iNOS and COX-2 enzymes. Taken together these data indicate the potential for tested compounds to interfere with NF-(Sm(BB signalling as IKK inhibitors or novel translocation inhibitor and thus may considered to be useful leads for the development of novel anti-inflammatory and anticancer drugs.
Publication date 2012
Name University of Strathclyde. Strathclyde Institute of Pharmacy and Biomedical Sciences.
Thesis note Thesis PhD University of Strathclyde 2012 T13435
System Number 000002351

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