title: ER stress, p66shc, and p-Akt/Akt mediate adjuvant-induced inflammation, which is blunted by argirein, a supermolecule and rhein in rats.
abstract: We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.
authors.affiliation: Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Cong
authors.forename: Ming-Jian
authors.initials: MJ
authors.lastname: Ding
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: You
authors.initials: Y
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000276:Adjuvants, Immunologic; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D007052:Ibuprofen / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D000276:Adjuvants, Immunologic; D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; C497113:Atf6 protein, rat; D008562:Membrane Glycoproteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C558481:argirhein; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D007052:Ibuprofen; C020491:rhein
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