The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose-and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochrome c and second mitochondria-derived activator of caspase/ direct IAP binding protein with low pH of isoelectric point (pI) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription-polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this IntroductionMcl-1 was first cloned from ML-1 cells, a human myeloid leukemia cell line, as an early-induction gene. 1,2 Structurally and functionally, Mcl-1 belongs to the prosurvival Bcl-2 family. 3 Mice transgenic for Mcl-1 demonstrated the enhanced viability of a wide range of hematopoietic cell types, including B and T lymphocytes, and CD 11b-positive myeloid cells including monocytes, macrophages, and polymorphonuclear leukocytes (PMNs) at both immature and mature stages of differentiation. 4 Mcl-1 is essential for the survival of certain hematopoietic cells because apoptosis is rapidly triggered by antisense (AS) depletion of Mcl-1 in primary human macrophages, in differentiating U937 cells, a human monocytic cell line, and in human polymorphonuclear cells (PMNs). [5][6][7] The cell type-specific mechanisms that contribute to the regulation of Mcl-1 are controversial. PI3K/Akt signaling pathway mediated Mcl-1 expression in interleukin-3 (IL-3)-induced TF-1 leukemia cells 8 and IL-6-stimulated human hepatoma cell line Hep3B. 9 In contrast, in human myeloma cells, the IL-6-induced expression of Mcl-1 was mediated through the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. 10 Recent observations employing human PMNs and leukemic large granular lymphocytes (LGLs) demonstrated that the JAK/STAT3 pathway was responsible for the regulation of Mcl-1 expression. 11,12 Our recently published observations demonstrated that the PI3K/Akt-1 pathway was critical for the expression of Mcl-1 in primary human macrophages. 7 Functional analysis of the murine Mcl-1 promoter revealed a STAT binding SIE (serum inducible element) at position Ϫ86 to Ϫ93 and a CRE (cAMP response element) at Ϫ70 to Ϫ76, which contributed to IL-3 stimulation of Mcl-1 gene expression. 8 Putative SIE and CRE sites have also been identified in human Mcl-1 promoter region, 13 however, the mechanisms by which they may contribute to the regulation of Mcl-1 expression remain to be ...

Nanoparticles represent an attractive option for systemic delivery of therapeutic compounds to the heart following myocardial infarction. However, it is well known that physicochemical properties of nanoparticles such as size, shape and surface modifications can vastly alter the distribution and uptake of injected nanoparticles. Therefore, we aimed to provide an examination of the rapid size-dependent uptake of fluorescent PEG-modified polystyrene nanoparticles administered immediately following cardiac ischaemia-reperfusion injury in mice. By assessing the biodistribution of nanoparticles with core diameters between 20 nm and 2 μm 30 minutes after their administration, we conclude that 20–200 nm diameter nanoparticles are optimal for passive targeting of the injured left ventricle.

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The flow characteristics and the heat transfer properties of the rectangular channels with staggered transverse ribs on two opposite walls are experimentally studied. The rib height to channel height ratio ranges from 0.15 to 0.61 (rib height to channel hydraulic diameter ratio from 0.09 to 0.38). The pitch to rib height ratio covers from 2.5 to 26. The aspect ratio of the rectangular channel is 4. The flow characteristics are studied in a water channel, while the heat transfer experiments are performed in a wind tunnel. Particle image velocimetry (PIV) is employed to obtain the quantitative flow field characteristics. Fine-wire thermocouples imbedded near the inner surface of the bottom channel wall are used to measure the temperature distributions of the wall and to calculate the local and average Nusselt numbers. Using the PIV measured streamline patterns, various characteristic flow modes, thru flow, oscillating flow, and cell flow, are identified in different regimes of the domain of the rib height to channel height ratio and pitch to rib height ratio. The vorticity, turbulence intensity, and wall shear stress of the cell flow are found to be particularly larger than those of other characteristic flow modes. The measured local and average Nusselt numbers of the cell flow are also particularly higher than those of other characteristic flow modes. The distinctive flow properties are responsible for the drastic increase of the heat transfer due to the enhancement of the momentum, heat, and mass exchanges within the flow field induced by the large values of the vorticity and turbulence intensity. Although the thru flow mode is conventionally used in the ribbed channel for industrial application, the cell flow could become the choice if the heat transfer rate, instead of the pressure loss, is the primary concern.