The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. Whether nanoparticles from plants we eat daily have a role in maintaining intestinal immune homeostasis is poorly defined. Here, we present evidence supporting our hypothesis that edible nanoparticles regulate intestinal immune homeostasis by targeting dendritic cells (DCs). Using three mouse colitis models, our data show that orally given nanoparticles isolated from broccoli extracts protect mice against colitis. Broccoli-derived nanoparticle (BDN)-mediated activation of adenosine monophosphate-activated protein kinase (AMPK) in DCs plays a role in not only prevention of DC activation but also induction of tolerant DCs. Adoptively transferring DCs pre-pulsed with total BDN lipids, but not sulforaphane (SFN)-depleted BDN lipids, prevented DSS-induced colitis in C57BL/6 (B6) mice, supporting the role of BDN SFN in the induction of DC tolerance. Adoptively transferring AMPK, but not AMPK, DCs pre-pulsed with SFN prevented DSS-induced colitis in B6 mice, further supporting the DC AMPK role in SFN-mediated prevention of DSS-induced colitis. This finding could open new preventive or therapeutic avenues to address intestinal-related inflammatory diseases via activating AMPK.

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To test the ability of nanoparticle formulations to overcome P-glycoprotein (P-gp)-mediated multidrug resistance, several different doxorubicin and paclitaxel-loaded lipid nanoparticles were prepared. Doxorubicin nanoparticles showed 6-to 8-fold lower IC 50 values in P-gp-overexpressing human cancer cells than those of free doxorubicin. The IC 50 value of paclitaxel nanoparticles was over 9-fold lower than that of Taxol in P-gp-overexpressing cells. A series of in vitro cell assays were used including quantitative studies on uptake and efflux, inhibition of calcein acetoxymethylester efflux, alteration of ATP levels, membrane integrity, mitochondrial membrane potential, apoptosis, and cytotoxicity. Enhanced uptake and prolonged retention of doxorubicin were observed with nanoparticle-based formulations in P-gp-overexpressing cells. Calcein acetoxymethylester and ATP assays confirmed that blank nanoparticles inhibited P-gp and transiently depleted ATP. I.v. injection of pegylated paclitaxel nanoparticles showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors versus all control groups. Nanoparticles may be used to target both drug and biological mechanisms to overcome multidrug resistance via P-gp inhibition and ATP depletion. [Cancer Res 2009;69(9):3918-26]

Objective-Leukotriene B 4 (LTB 4 ), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB 4 modulates atherosclerosis in cell lines expressing LTB 4 receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1 ϩ/ϩ and BLT-1 Ϫ/Ϫ mice. Methods and Results-Analysis of global changes in gene expression induced by LTB 4 in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2 , which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E Ϫ/Ϫ mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB 4 receptor, BLT-2, and exhibited chemotaxis to LTB 4 . Conclusions-The effects of LTB 4 in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB 4 promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation. A ccumulation of monocytes in vascular subendothelial spaces and their conversion into lipid-laden "foam cells" is an early and important event in atherogenesis. 1 The molecular mechanisms that regulate the recruitment of monocyte/macrophages to the vessel wall and the signaling pathways underlying their conversion to foam cells are poorly understood. Several recent studies suggest that chemokines CCL2/MCP1/JE, interleukin-8 (IL-8), and fractalkine and their receptors CCR2, CXCR2, and CX3CR1 are critical mediators of atherosclerosis. [2][3][4][5][6][7] Mice lacking macrophage colony-stimulating factor have severely reduced atherosclerosis in experimental models. 8 Thus, macrophages play a central role in the development of atherosclerotic vascular disease, which is now considered a chronic inflammatory disease. 9 LTB 4, a potent leukocyte chemoattractant, is known to promote a number of chronic inflammatory diseases. 10 G-protein coupled receptors BLT-1 and BLT-2 and the peroxisome proliferator activator receptor ␣ (PPAR␣) are the currently known LTB 4 receptors. 11-13 While BLT-1 and BLT-2 likely mediate the proinflammatory responses of LTB 4 , PPAR␣, a transcription factor, might serve as a mediator of the anti-inflammatory effects of LTB 4 . Studies on mouse models and antagonists of LTB 4 suggested a role for BLT-1 in rheumatoid arthritis, acute septic peritonitis, and atherosclerosis. 14 -16 To determine the role of BLT-1 in chronic inflammatory diseases, we ana...