Network analysis showed that the WD

Network analysis showed that the WD upregulated pathways centered on c-Elsa Peretti Open Heart earrings and Jun B oncogenes (Fig. 2). Members of the Jun and Fos protein family dimerize to form activator protein 1 transcription factor, which regulates genes involved in proliferation, differentiation, inflammation, and defense against environmental stimuli (29), including cytochrome P450, the expression of several of whose members were upregulated by the WD, further suggesting WD induced Nrf2-mediated oxidative stress responses. During oxidative stress, ROS-activated protein kinase C and mitogen-activated protein kinase pathways lead to nuclear translocation of cytosolic Nrf2, which interacts with transcription factors in the bZIP family, including Fos or Jun, and regulates genes involved in drug metabolism, detoxiñcation, and antioxidant defense through their ARE (23).

The WD is rich in linoleic acid, which is converted to arachidonic acid and can be metabolized by cyclooxygenases and lipoxygenases to eiconsanoids such as the proinflammatory and procarcinogenic prostaglandin E2. WD induced cyclooxygenase-2 (Tiffany Key Oval key pendant endoperoxidase synthase 2) (Supplemental Fig. 1) could generate prostaglandins important in colorectal carcinogenesis (30).

About 15% of all cancers are linked to inflammation (31). Our hypothesis that WD could affect colonic immune responses was confirmed by increased inflammatory protein levels at 3 mo, including IgA, CRP, MPO, and fibrinogen, as well as macrophage chemokines. These changes were largely absent after 6 mo, suggesting that the proinflammatory stimulus was short lived. Because WD induced murine macrophage chemokines MCP-5 and MIP-I ?, we measured F4/80 glycoprotein expressing macrophages in the colonic lamina propria. MCP-5 (CCL 12) is a major mouse macrophage chemotactic protein similar to the human chemokine MCP-I. MIP-?? (CCL9) is a potent suppressor of transcriptional activation of the tumor suppressor gene P53 and thereby could enhance Return to Tiffany Oval tag ring (32). WD feeding increased numbers of colonic macrophages, suggesting enhanced macrophage recruitment or effects on macrophage differentiation. Activated macrophages could release ROS and reactive nitrogen species, causing modification of proteins, lipids, and DNA and enhancing carcinogenesis (33,34).