Edited by Tamas Dalmay Keywords:MicroRNA-29a Oxidized low density lipoprotein Dendritic cell Lipoprotein lipase Immuno-inflammation a b s t r a c t There is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with DC immuno-inflammatory responses with oxidized low density lipoprotein (oxLDL) stimulation is not yet known. Our study aims to explore the link of miRNAs with lipidoverload and immuno-inflammatory mechanism for atherosclerosis. In DCs transfected with microRNA-29a mimics or inhibitors, we showed that microRNA-29a plays an important role in proinflammatory cytokine secretion and scavenger receptor expression upon oxLDL-treatment. Furthermore, we suggest an additional explanation for the mechanism of microRNA-29a regulation of its functional target, lipoprotein lipase. We conclude that microRNA-29a could regulate proinflammatory cytokine secretion and scavenger receptor expression by targeting lipoprotein lipase in oxLDL-stimulated dendritic cells.

Curcumin has high potential in suppressing many types of cancer and overcoming multidrug resistance in a multifaceted manner by targeting diverse molecular targets. However, the rather low systemic bioavailability resulted from its poor solubility in water and fast metabolism/excretion in vivo has hampered its applications in cancer therapy. To increase the aqueous solubility of curcumin while retaining the stability in blood circulation, here we report curcumin-loaded copolymer micelles with excellent in vitro and in vivo stability and antitumor efficacy. The two copolymers used for comparison were methoxy-poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-PCL) and N-(tert-butoxycarbonyl)-l-phenylalanine end-capped mPEG-PCL (mPEG-PCL-Phe(Boc)). In vitro cytotoxicity evaluation against human pancreatic SW1990 cell line showed that the delivery of curcumin in mPEG-PCL-Phe(Boc) micelles to cancer cells was efficient and dosage-dependent. The pharmacokinetics in ICR mice indicated that intravenous (i.v.) administration of curcumin/mPEG-PCL-Phe(Boc) micelles could retain curcumin in plasma much better than curcumin/mPEG-PCL micelles. Biodistribution results in Sprague-Dawley rats also showed higher uptake and slower elimination of curcumin into liver, lung, kidney, and brain, and lower uptake into heart and spleen of mPEG-PCL-Phe(Boc) micelles, as compared with mPEG-PCL micelles. Further in vivo efficacy evaluation in multidrug-resistant human erythroleukemia K562/ADR xenograft model revealed that i.v. administration of curcumin-loaded mPEG-PCL-Phe(Boc) micelles significantly delayed tumor growth, which was attributed to the improved stability of curcumin in the bloodstream and increased systemic bioavailability. The mPEG-PCL-Phe(Boc) micellar system is promising in overcoming the key challenge of curcumin's to promote its applications in cancer therapy.

a b s t r a c tThere is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether miRNAs are associated with dendritic cell (DC) immuno-inflammatory responses to oxidized low density lipoprotein (oxLDL) stimulation is yet unknown. Our study aims to explore the link of miRNA to lipid-overload and the immuno-inflammatory mechanism for atherosclerosis. Human primary monocyte-derived DCs were transfected with miR-146a mimics and inhibitor, and then stimulated by oxLDL. For the flow cytometric analysis of the DC immunophenotype, supernatants were collected to determine inflammatory chemokine markers. Our study clearly revealed that miRNA146a regulates the maturation process and pro-inflammatory cytokine secretion in DCs by targeting CD40L in ox-LDL-stimulated DCs.

Background/Aims: Tanshinone IIA (Tan IIA) is effective in the treatment of inflammation and atherosclerosis. The adhesion of inflammatory cells to vascular endothelium plays important role in atherogenic processes. This study examined the effects of Tan IIA on expression of adhesion molecules in tumor necrosis factor-α (TNF-α)-induced endothelial progenitor cells (EPCs). Methods: EPCs were pretreated with Tan IIA and stimulated with TNF-α. Mononuclear cell (MNC) adhesion assay was performed to assess the effects of Tan IIA on TNF-α-induced MNC adhesion. Expression of vascular cell adhesion molecule-1 (VCAM-1)/intracellular adhesion molecule-1 (ICAM-1) and activation of Nuclear factor κB (NF-κB) signaling pathway were measured. Results: The results showed that the adhesion of MNCs to TNF-α-induced EPCs and expression of VCAM-1/ICAM-1 in EPCs were promoted by TNF-α, which were reduced by Tan IIA. TNF-α increased the amount of phosphorylation of NF-κB, IκB-α and IKKα/β in cytosolic fractions and NF-κB p65 in nucleus, while Tan IIA reduced its amount. Conclusion: This study demonstrated a novel mechanism for the anti-inflammatory/anti-atherosclerotic activity of Tan IIA, which may involve down-regulation of VCAM-1 and ICAM-1 through partial blockage of TNF-α-induced NF-κB activation and IκB-α phosphorylation by the inhibition of IKKα/β pathway in EPCs.

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