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.

Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

“…In the primary evaluation of severity of CP, less inflammatory infiltrates were observed in the pancreatic tissues of CP mice that were prophylactically and therapeutically fed with rhein; meanwhile, the cerulein-elevated systemic pro-inflammatory cytokines namely TNF-α and IL-1β were accordingly reduced in those rhein-treated animals. Our results here are in agreement to the findings of other research groups that the anthraquinone compound exerts pharmacological activities against inflammatory diseases majorly inhibiting the production of TNF-α and IL-1β and hence resulted in a suppressed recruitment of immune cells [31,43]. In terms of pancreatic architecture, the degree of atrophy was significantly attenuated in those rhein-treated CP mice as implicated by the substantial restoration of their pancreatic wet weights.…”

“…In fact, rhein, the active metabolite of acetylrhein, is the predominant form found in bloodstream that possesses potent bioactivities in mammals including rodents, rabbits and human [39]. The pharmacological actions of this anthraquinone derivative have been lately evidenced in various inflammatory diseases such as arthritis [31,40] and dermatological disorders [41]. A recent study by He et al demonstrated that rhein could effectively inhibit the activation of renal interstitial fibroblasts in mice [35] implicating its potential in targeting fibrogenesis.…”

“…In recent decades, administration of rhein in the range of 25 to 100 mg/kg/day has been demonstrated to exert diverse pharmacological actions including anti-microbial [27], anti-angiogenic [28] and anti-cancer activities [29,30]. In some latest reports, Cong et al showed that the anti-inflammatory effect of rhein was actually comparable to the accredited pain-killer ibuprofen in adjuvant-induced inflammation via a significant amelioration of oxidative stress [31] whereas Fernand and colleagues claimed that rhein provided anti-angiogenic effect against breast cancer cell proliferation and migration by inactivating the phosphatidylinositol 3-kinase pathway [32]. The underlying mechanisms for anthraquinone derivatives have yet been relatively delineated; at least involve the partial inhibition of cyclooxygenase 2 [33] and the negative modulation the p38 MAPK cascade [34].…”

Activation of AQP4, p66Shc and endoplasmic reticulum stress is involved in inflammation by carrageenan and is suppressed by argirein, a derivative of rhein

“…l ‐arginine alone had no definite benefit in relieving acute inflammation and biomarkers in rat paw oedema, in comparison with either rhein or argirein; argirein was more prominent in suppressing the inflammatory oedema than rhein at 1 h. Rhein released from argirein acts as an active metabolite, suppressing inflammatory responses, and the content of rhein in argirein, calculated based on weight to weight ratio, is about 65% compared with unchanged rhein. The efficacy of argirein encountering inflammatory reactions is at least the same as rhein, as found in the present study and in studies of adjuvant arthritis in rats [32] . Based on these findings, we may conclude that this is because of synergistic action of l ‐arginine with rhein in improving vascular endothelium in the inflamed regions, beneficial to anti‐inflammatory activity of argirein.…”

A Novel Combination of Methotrexate and Epigallocatechin Attenuates the Overexpression of Pro-inflammatory Cartilage Cytokines and Modulates Antioxidant Status in Adjuvant Arthritic Rats

“…The inflammatory edema was accompanied by upregulation of cytokines [51]. The spontaneous production of IL-1 by rheumatoid synoviocytes can be inhibited by anti-TNF antibodies, suggesting that the activity of TNF occurs earlier in the cascade than that of IL-1, whereas IL-6 occupies a position later in the cascade being produced in response to either TNF or IL-1 [52].…”