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Title: Oral administration of curcumin and salsalate attenuates high fat diet-induced up-regulation of pro-inflammatory colonic cytokines via suppression of Akt/NFkappaB in azoxymethane-treated mice

Author
item WU, XIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item PFALZER, ANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item TANG, SANYUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item THOMAS, MICHAEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MEYDANI, MOHSEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 4/1/2017
Publication Date: 4/1/2017
Citation: Wu, X., Pfalzer, A.C., Koh, G., Crott, J.W., Tang, S., Thomas, M.J., Meydani, M., Mason, J.B. 2017. Oral administration of curcumin and salsalate attenuates high fat diet-induced up-regulation of pro-inflammatory colonic cytokines via suppression of Akt/NFkappaB in azoxymethane-treated mice [abstract]. Federation of American Societies for Experimental Biology Conference. 31(1):46.6.

Interpretive Summary:

Technical Abstract: Background: Obesity, a robust risk factor for colorectal cancer (CRC), is known to elevate the concentrations of proinflammatory cytokines in the murine colon. Also, signaling through the Akt pathway, which is known to be activated by proinflammatory cytokines, is thought to play a role in colorectal carcinogenesis, in part by enhancing NFkappaB signaling. Further, we have previously demonstrated that high fat diets (HFD) and excess adiposity each alter the expression of the regulators of colonic Akt signaling in a pattern suggestive of Akt activation. Objective: We sought to determine whether the combination of a pharmacologic agent and a dietary component that each possesses anti-inflammatory properties might suppress obesity-induced elevations in colonic cytokines and Akt/NFkappaB signaling, with the ultimate intent of mitigating the cancer-promoting effect of obesity. Methods: Curcumin (CUR), a natural polyphenol in turmeric, and salsalate (SAL) a non-steroidal anti-inflammatory drug (NSAID) that lacks the gastrointestinal toxicity of other NSAIDs, were tested alone and in combination in the azoxymethane (AOM) model of colonic carcinogenesis in 110 A/J mice, randomized to five groups including a control group receiving a lowfat diet. AOM (7 mg/kg body weight, 4 weekly injections) in combination with a HFD that contained 60% kcals as fat was used induce a pro-tumorigenic milieu in the colons of mice. Results: The results showed that HFD-mice had 30.4% greater fat mass and a lower lean mass than did low-fat diet (10% kcal fat, LFD, p<0.005) mice. In the colonic mucosa of the obese mice addition of CUR and SAL (0.2% and 0.15% w/w, respectively) to the diet significantly diminished concentrations of IL1beta and IL6 (p<0.015). Moreover, CUR/SAL co-treatments also profoundly suppressed phosphorylation of Akt (p<0.044) and concurrently suppressed NFkappaB p65 signaling (p<0.042). Conclusions: Our results demonstrate, for the first time, that co-administration of CUR and SAL present in very low, well-tolerated, concentrations attenuates inflammatory cytokines levels, Akt activation, and NFkappaB signaling in the colons of AOM/HFD mice, providing a scientific rationale for using this combination as a chemopreventive regimen to mitigate the risk of obesity associated colon cancer.