SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis

Suppressor of Cytokine Signaling (SOCS) proteins are recently identified inhibitors/regulators of cytokine/growth factor signaling pathways. We have previously shown that SOCS-3 is upregulated in mice after sepsis induced by cecal ligation and puncture; however, the contribution of SOCS-1 to septic morbidity and mortality is unclear. In the present study, we characterized SOCS-1 expression in different tissues and delineated putative mechanisms effecting SOCS-1 expression in thymus from septic mice. We observed no difference in SOCS-1 expression in blood, peritoneal leukocytes, lung, and spleen taken from sham or septic animals at 24 h after surgery. In contrast, SOCS-1 expression in thymus declined significantly after sepsis and this down-regulation of SOCS-1 was associated with increased thymocyte apoptosis as well as augmented Bax recruitment to the mitochondria. Administration of RU-38486, a steroid receptor antagonist, reversed the above effects in the septic thymus. Furthermore, SOCS-1+/− mice showed a significant higher mortality when compared to SOCS-1+/+ mice after sepsis. Together, these results show that sepsis increases steroid-induced thymic lymphoid cell apoptosis, which is associated with reduced SOCS-1 expression and increased Bax translocation to mitochondria. Survival data suggests that SOCS-1 protein may play an important role in sepsis.     

Molecular basis of the differences between normal and tumor tissues of gastric cancer

To be able to describe the differences between the normal and tumor tissues of gastric cancer at a molecular level would be essential in the study of the disease. We investigated the gene expression pattern in the two types of tissues from gastric cancer by performing expression profiling of 86 tissues on 17K complementary DNA microarrays. To select for the differentially expressed genes, class prediction algorithm was employed. For predictor selection, samples were first divided into a training (n=58), and a test set (n=28). A group of 894 genes was selected by a t-test in a training set, which was used for cross-validation in the training set and class (normal or tumor) prediction in the test set. Smaller groups of 894 genes were individually tested for their ability to correctly predict the normal or tumor samples based on gene expression pattern. The expression ratios of the 5 genes chosen from microarray data can be validated by real time RT-PCR over 6 tissue samples, resulting in a high level of correlation, individually or combined. When a representative predictor set of 92 genes was examined, pathways of 'focal adhesion' (with gene components of THBS2, PDGFD, MAPK1, COL1A2, COL6A3), 'ECM-receptor interaction' pathway (THBS2, COL1A2, COL6A3, FN1) and 'TGF-beta signaling' (THBS2, MAPK1, INHBA) represent some of the main differences between normal and tumor of gastric cancer at a molecular level.     

Effects of tert-butyl acetate on maternal toxicity and embryo-fetal development in Sprague-Dawley rats

This study investigated the potential adverse effects of tert-butyl acetate (TBAc) on maternal toxicity and embryo-fetal development after maternal exposure of pregnant rats from gestational days 6 through 19. TBAc was administered to pregnant rats by gavage at 0, 400, 800, and 1,600 mg/kg/day. All dams were subjected to a Caesarean section on day 20 of gestation, and their fetuses were examined for any morphological abnormalities. At 1,600 mg/kg, maternal toxicity manifested as increases in the incidence of clinical signs and death, lower body weight gain and food intake, increases in the weights of adrenal glands and liver, and a decrease in thymus weight. Developmental toxicity included a decrease in fetal weight, an increase in the incidence of skeletal variation, and a delay in fetal ossification. At 800 mg/kg, only a minimal developmental toxicity, including an increase in the incidence of skeletal variation and a delay in fetal ossification, were observed. In contrast, no adverse maternal or developmental effects were observed at 400 mg/kg. These results show that a 14-day repeated oral dose of TBAc is embryotoxic at a maternally toxic dose (i.e., 1,600 mg/kg/day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 800 mg/kg/day) in rats. However, no evidence for the teratogenicity of TBAc was noted in rats. It is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of TBAc is considered to be 800 mg/kg/day for dams and 400 mg/kg/day for embryo-fetal development.     

Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2

Ubiquitin-fold modifier 1 (Ufm1) is a recently identified new ubiquitin-like protein, whose tertiary structure displays a striking resemblance to ubiquitin. Similar to ubiquitin, it has a Gly residue conserved across species at the C-terminal region with extensions of various amino acid sequences that need to be processed in vivo prior to conjugation to target proteins. Here we report the isolation, cloning, and characterization of two novel mouse Ufm1-specific proteases, named UfSP1 and UfSP2. UfSP1 and UfSP2 are composed of 217 and 461 amino acids, respectively, and they have no sequence homology with previously known proteases. UfSP2 is present in most, if not all, of multicellular organisms including plant, nematode, fly, and mammal, whereas UfSP1 could not be found in plant and nematode upon data base search. UfSP1 and UfSP2 cleaved the C-terminal extension of Ufm1 but not that of ubiquitin or other ubiquitin-like proteins, such as SUMO-1 and ISG15. Both were also capable of releasing Ufm1 from Ufm1-conjugated cellular proteins. They were sensitive to inhibition by sulfhydryl-blocking agents, such as N-ethylmaleimide, and their active site Cys could be labeled with Ufm1-vinylmethylester. Moreover, replacement of the conserved Cys residue by Ser resulted in a complete loss of the UfSP1 and UfSP2 activities. These results indicate that UfSP1 and UfSP2 are novel thiol proteases that specifically process the C terminus of Ufm1.     

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.