Lipopolysaccharide inhibits transforming growth factor-beta1-stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4–IRAK1–ERK1/2 pathway

AbstractSmad6, one of the inhibitory Smads, plays an important role in transforming growth factor-beta1 (TGF-β1)-mediated negative regulation of pro-inflammatory signaling. In this study, we found that bacterial endotoxin lipopolysaccharide (LPS) inhibits TGF-β1-induced expression of Smad6 in RAW264.7 cells. This repression was accompanied by increased Smad3 linker phosphorylation at Thr-179 and Ser-208 and was dependent on ERK1/2 activity via the TLR4–IRAK1-linked signaling cascade. The expression of a mutant Smad3, that lacks the phosphorylation sites in the linker regions, significantly reversed the inhibitory effect of LPS on TGF-β1-induced Smad6 expression and its anti-inflammatory capacity. Collectively, our findings show how LPS pro-inflammatory signal antagonizes the anti-inflammatory activity of TGF-β1

Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function

SummaryThe trace element copper (Cu) is a cofactor for biochemical functions ranging from energy generation to iron (Fe) acquisition, angiogenesis, and free radical detoxification. While Cu is essential for life, the molecules that mediate dietary Cu uptake have not been identified. Ctr1 is a homotrimeric protein, conserved from yeast to humans, that transports Cu across the plasma membrane with high affinity and specificity. Here we describe the generation of intestinal epithelial cell-specific Ctr1 knockout mice. These mice exhibit striking neonatal defects in Cu accumulation in peripheral tissues, hepatic Fe overload, cardiac hypertrophy, and severe growth and viability defects. Consistent with an intestinal Cu absorption block, the growth and viability defects can be partially rescued by a single postnatal Cu administration, indicative of a critical neonatal metabolic requirement for Cu that is provided by intestinal Ctr1. These studies identify Ctr1 as the major factor driving intestinal Cu absorption in mammals

Organ-specific regulation of ATP7A abundance is coordinated with systemic copper homeostasis

Copper (Cu) is an essential cofactor for various enzymatic activities including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Consequently, Cu dysregulation is associated with fatal neonatal disease, liver and cardiac dysfunction, and anemia. While the Cu transporter ATP7A plays a major role in both intestinal Cu mobilization to the periphery and prevention of Cu over-accumulation, it is unclear how regulation of ATP7A contributes to Cu homeostasis in response to systemic Cu fluctuation. Here we show, using Cu-deficient mouse models, that steadystate levels of ATP7A are lower in peripheral tissues (including the heart, spleen, and liver) under Cu deficiency and that subcutaneous administration of Cu to these animals restore normal ATP7A levels in these tissues. Strikingly, ATP7A in the intestine is regulated in the opposite manner - low systemic Cu increases ATP7A while subcutaneous Cu administration decreases ATP7A suggesting that intestinespecific non-autonomous regulation of ATP7A abundance may serve as a key homeostatic control for Cu export into the circulation. Our results support a systemic model for how a single transporter can be inversely regulated in a tissue-specific manner to maintain organismal Cu homeostasis

Development of Eco-VE Function for Construction

AbstractRecently accepted “Paris Agreement” has restricted the Earth temperature increase to be below 1.5 degrees Celsius contrast to previous industrialization. To follow this agreement, there should be efforts such as carbon emission reduction and eco design etc. One of these efforts is development of eco-VE function that applied eco-friendly concept on VE which is commonly used at design phase. Concept of this model includes carbon productivity concept and potential environment pollution index that reflects eco-VE function on original VE. The carbon productivity concept is a cause of production increase that offset production decrease factor depending on green-house gas reduction. The potential environment pollution index presents the possibility of environment pollution through construction phase. The carbon productivity is ‘Construction cost/Carbon emission’. The construction costs are consisted of material, equipment, labour cost and indirect expenses. Carbon emissions are calculated by emission for material production and equipment fuel consumption. The potential environment pollution index is composed of environmental pollution and conservation cost. The environmental pollution cost includes environmental damage and destruction cost. The environmental conservation cost includes environmental pollution prevention cost, waste treatment cost, environmental pollution compensation, environmental pollution test research funds and law cost

Prevalence and Genetic Structures of Streptococcus pneumoniae Serotype 6D, South Korea

To determine prevalence and genetic structures of new serotype 6D strains of pneumococci, we examined isolates from diverse clinical specimens in South Korea during 1991–2008. Fourteen serotype 6D strains accounted for 10.4% of serogroup 6 pneumococci from blood, sputum, nasopharynx, and throat samples. Serotype 6D strains consisted of 3 sequence types

Clinical implications of correlation between peripheral eosinophil count and serum levels of IL-5 and tryptase in acute eosinophilic pneumonia

SummaryBackgroundThe peripheral eosinophil count (PEC) tends to increase during the course of acute eosinophilic pneumonia (AEP), and an initially elevated PEC is associated with milder disease. However, there is a lack of data regarding these phenomena and inflammatory process of AEP.MethodsWe prospectively evaluated serial changes in serum interleukin (IL)-5 levels and the correlation between the initial level of IL-5 and the PEC to investigate whether the initial PEC indicates a resolving state of inflammation. We also evaluated serum tryptase levels to investigate the possibility of involvement of mast cell activity in AEP.ResultsTwenty-one AEP patients were included, and all patients improved within 10 days after corticosteroid treatment. The median initial serum IL-5 level among all patients was 561.0 pg/mL, which decreased to zero at 10 days of follow-up (n = 15, P < 0.001). The median initial serum tryptase level (detectable in 20 of 21 patients) was 3.7 ng/mL and decreased to a median of 1.1 ng/mL at 10 days of follow-up (n = 15, P < 0.001). The initial serum IL-5 and C-reactive protein levels were positively correlated (P = 0.009, r = 0.556), and the initial serum IL-5 level was inversely correlated with the initial PEC (P = 0.004, r = −0.603).ConclusionsOur data suggest that IL-5 is an important cytokine involved in the recruitment of eosinophils from peripheral blood into the lungs, that an initially elevated PEC is associated with a resolving state of inflammation, and that mast cells are potentially involved in the inflammatory process of AEP

Menthol Enhances an Antiproliferative Activity of 1α,25-Dihydroxyvitamin D3 in LNCaP Cells

1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], the most active form of vitamin D3, and its analogues have therapeutic benefits for prostate cancer treatment. However, the development of hypercalcemia is an obstacle to clinical applications of 1α,25(OH)2D3 for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1α,25(OH)2D3 in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1α,25(OH)2D3-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1α,25(OH)2D3 does not induce acute Ca2+ response, whereas menthol evokes an increase in [Ca2+]i, which suggests that cross-talks of menthol-induced Ca2+ signaling with 1α,25(OH)2D3-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1α,25(OH)2D3 and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1α,25(OH)2D3-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1α,25(OH)2D3