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Molecular basis for the action of Au(I) drugs in rheumatoid arthritis.

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Presentation on theme: "Molecular basis for the action of Au(I) drugs in rheumatoid arthritis."— Presentation transcript:

1 Molecular basis for the action of Au(I) drugs in rheumatoid arthritis

2 Rheumatoid arthritis immune system attacks joints chronic inflammatory disease Wikipedia - Joint, Rheumatoid ArthritisJointRheumatoid Arthritis

3 Anti-inflammatory and immunomodulatory effects of gold(I)-containing drugs J. Biol. Chem., Vol. 276, Issue 36, 34074-34081, September 7, 2001 Collagenase interleukin- 2 (IL-2)IL-2 proteins involved in promoting inflammation Cytokines interleukin-2 receptor genes involved in promoting inflammation down-regulated

4 Anti-inflammatory and immunomodulatory effects of gold(I)-containing drugs J. Biol. Chem., Vol. 276, Issue 36, 34074-34081, September 7, 2001 antioxidative stress proteins  - glutamylcysteine synthetase antioxidative stress genes induce heme oxygenase GO

5 Transcription factors http://en.wikipedia.org/wiki/Transcription_factor http://www.ndsu.edu/instruct/mcclean/plsc731/transcript/transcript1.htm http://www.piercenet.com/Proteomics/browse.cfm?fldID=843944B3-65F9-42A9-BF7A-6F91B4A6FBBB facilitate or inhibit gene expression Regulatory RegionGene Transcription DNA c-Junc-Fos RNA Polymerase II AP-1 transcription factor TGACTCA

6 Gold(I)-drugs inhibit AP-1

7 Electrophoresis EMSA Electrophoretic Mobility Shift Assay Lane 1 is a negative control, and contains only DNA. Lane 2 contains protein as well as a DNA fragment that, based on its sequence, does not interact. Lane 3 contains protein and a DNA fragment that does react; the resulting complex is larger, heavier, and slower-moving. Gel Electrophoresis

8 Gold(I)-drugs inhibit AP-1 binding to DNA Proc. Natl. Acad. Sci. USA Vol. 92, pp. 4497-4501, May 1995

9 Effect of Gold(I)-drugs on other transcription factors Proc. Natl. Acad. Sci. USA Vol. 92, pp. 4497-4501, May 1995

10 Gold(I) inhibition of transcription in vivo Regulatory RegionGene for CAT Transcription DNA c-Junc-Fos RNA Polymerase II AP-1 transcription factor TGACTCA (CAT) chloramphenicol acetyltransferase reporter gene

11 Interaction of Cys residues on Jun and Fos with Au(I) Proc. Natl. Acad. Sci. USA Vol. 92, pp. 4497-4501, May 1995 ~CH 2 SH~CH 2 OH

12 AP-1 : DNA interaction Nature vol. 373, pp.257-261, 1995

13 AP-1 : DNA interaction Nature vol. 373, pp.257-261, 1995

14 AP-1 : DNA interaction Nature vol. 373, pp.257-261, 1995


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