Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production

Heme oxygenase-1 (HO-1) catabolizes heme into CO, biliverdin, and free iron and serves as a protective enzyme by virtue of its anti-inflammatory, antiapoptotic, and antiproliferative actions. Previously, we have demonstrated that human CD4(+) T cells express HO-1 and that HO-1-overexpressing Jurkat T cells tend to display lower proliferative response. The aim of this study is to elucidate the mechanism(s) by which HO-1 can mediate its antiproliferative effect on CD4(+) T cells. Among the three HO-1 byproducts, only CO showed suppressive effect on T cell proliferation in response to anti-CD3 plus anti-CD28 Abs, mimicking the antiproliferative action of HO-1. CO blocked the cell cycle entry of T cells, which was independent of the guanylate cyclase/cGMP pathway. CO also suppressed the secretion of IL-2, and this suppressive effect of CO on IL-2 secretion mediated the antiproliferative action of CO. CO selectively inhibited the extracellular signal-regulated kinase pathway, which could explain the suppressive effects of CO on T cell proliferation and IL-2 secretion. Based on these findings, we suggest that HO-1/CO suppresses T cell proliferation and IL-2 secretion, possibly via its inhibition of extracellular signal-regulated kinase activation.     

Lack of adverse effects in pregnant/lactating female rats and their offspring following pre- and postnatal exposure to ELF magnetic fields

We have recently reported that exposure of pregnant rats to 60 Hz at field strengths up to 0.5 mT during the entire period of pregnancy did not induce any biologically significant effects on both pregnant dams and embryo-fetal development. The present study was carried out to investigate the potential effects of gestational and lactational MF exposure on pregnancy, delivery, and lactation of dams and growth, behavior, and mating performance of their offspring in rats. Timed-pregnant female Sprague-Dawley (SD) rats (24/group) received continuous exposure to 60 Hz magnetic field (MF) at field strengths of 0 (sham control), 5 microT, 83.3 microT, or 0.5 mT. Dams received MF or sham exposures for 21 h/day from gestational day 6 through lactational day 21. Experimentally generated MF was monitored continuously throughout the study. No exposure-related changes in clinical signs, body weight, food consumption, pregnancy length, and necropsy findings were observed in dams. Parameters of growth, behavior, and reproductive performance of offspring showed no changes related to MF exposure. There were no adverse effects on embryo-fetal development of F2 offspring from dams exposed to MF. In conclusion, exposure of pregnant SD rats to 60 Hz at field strengths up to 0.5 mT from gestational day 6 to lactational day 21 did not produce biologically significant effects in dams, F1 offspring, or F2 fetuses.     

Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts.

In serum-starved mouse NIH 3T3 fibroblasts cultured in 1.8 mM Ca2+-containing medium, addition of 0.75-2 mM extra Ca2+ stimulated DNA synthesis in synergism with zinc (15-60 microM), insulin and insulin-like growth factor I. Extra Ca2+ stimulated phosphorylation/activation of p42/p44 mitogen-activated protein kinases by an initially (10 min) zinc-independent mechanism; however, insulin, and particularly zinc, significantly prolonged Ca2+-induced mitogen-activated protein kinase phosphorylation. In addition, extra Ca2+ activated p70 S6 kinase by a zinc-dependent mechanism and enhanced the stimulatory effect of zinc on choline kinase activity. Insulin and insulin-like growth factor I also commonly increased both p70 S6 kinase and choline kinase activities. In support of the role of the choline kinase product phosphocholine in the mediation of mitogenic Ca2+ effects, cotreatments with the choline kinase substrate choline (250 microM) and the choline kinase inhibitor hemicholinium-3 (2 mM) enhanced and inhibited, respectively, the combined stimulatory effect of extra Ca2+ (3.8 mM total) and zinc on DNA synthesis. In various human skin fibroblast lines, 1-2 mM extra Ca2+ also stimulated DNA synthesis in synergism with zinc and insulin. The results show that in various fibroblast cultures, high concentrations of extracellular Ca2+ can collaborate with zinc and certain growth factors to stimulate DNA synthesis. Considering the high concentration of extracellular Ca2+ in the dermal layer, Ca2+ may promote fibroblast growth during wound healing in concert with zinc, insulin growth factor-I insulin, and perhaps other growth factors.     

Silymarin Induces Insulin Resistance through an Increase of Phosphatase and Tensin Homolog in Wistar Rats

Background and aims

Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown.

Methods

Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection.

Results

Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake.

Conclusions

Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients.     

Bronchodilator effect of sodium cromoglycate and its clinical implications.

The bronchodilator effect of sodium cromoglycate (SCG) solution was investigated. Twenty asthmatic children aged 6-15 years (mean 11.3) were examined and the action of SCG compared with that of salbutamol and placebo (water). SCG produced a significantly raised peak expiratory flow rate (PEFR) before exercise, which reached a maximum immediately after exercise. The bronchodilatation was sustained for up to four hours, when the PEFR was still significantly above the resting value. This effect was comparable in degree and duration with that of salbutamol. In contrast, placebo produced insignificant bronchodilatation before exercise but significant albeit short-lived bronchodilatation after exercise, which is the characteristic response of the asthmatic to a short period of exercise. This powerful bronchodilator action of SCG and its equally potent inhibitory action on exercise-induced bronchoconstriction was achieved by administering the solution via an efficient nebuliser. In order to achieve maximum clinical effect the SCG must, therefore, be given in this form.     

High-performance data mining with intelligent SSD

An intuitive way to process the big data efficiently is to reduce the volume of data transferred over the storage interface to a host system. This is the reason that the notion of intelligent SSD (iSSD) was proposed to give processing power to SSD. There is rich literature on iSSD, however, its real implementation has not been provided to the public yet. Most prior work aims to quantify the benefits of iSSD with analytical modeling. In this paper, we first develop on iSSD simulator and present the potential of iSSD in data mining through the iSSD simulator. Our iSSD simulator performs on top of the gem 5 simulator and fully simulates all the processes of data mining algorithms running in iSSD with cycle-level accuracy. Then, we further addresse how to exploit all the computing resources for efficient processing of data mining algorithms. These days, CPU, GPU, and SSD are recently equipped together in most computing environment. If SSD is replaced with iSSD later on, we have a new computing environment where the three computing resources collaborate one another to process big data quite effectively. For this, scheduling is required to decide which computing resource is going to run for which function at which time. In our heterogeneous scheduling, types of computing resources, memory sizes in computing resources, and inter-processor communication times including IO time in SSD are considered. Our scheduling results show that processing in the collaborative environment outperforms that in the traditional one by up to about 10 times.     

Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis

Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT–TFF2 axis in the process of fibrogenesis.     

Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking

Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer’s Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKIIα and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling.