Pseudomonas aeruginosa, which causes serious infections in immunocompromised patients, produces numerous virulence factors, including exotoxin A and the siderophore pyoverdine. As production of these virulence factors is influenced by the host environment, we examined the effect serum has on global transcription within P. aeruginosa strain PAO1 at different phases of growth in an iron-deficient medium. At early exponential phase, serum significantly enhanced expression of 138 genes, most of which are repressed by iron, including pvdS, regA and the pyoverdine synthesis genes. However, serum did not interfere with the repression of these genes by iron. Serum enhanced regA expression in a fur mutant of PAO1 but not in a pvdS mutant. The serum iron-binding protein apotransferrin, but not ferritin, enhanced regA and pvdS expression. However, in PAO1 grown in a chemically defined medium that contains no iron, serum but not apotransferrin enhanced pvdS and regA expression. While complement inactivation failed to eliminate this effect, albumin absorption reduced the effect of serum on pvdS and regA expression in the iron-deficient medium chelexed tryptic soy broth dialysate. Additionally, albumin absorption eliminated the effect of serum on pvdS and regA expression in the chemically defined medium. These results suggest that serum enhances the expression of P. aeruginosa iron-controlled genes by two mechanisms: one through apotransferrin and another one through albumin.
While beneficial for sow reproductive efficiency and biosecurity, segregated early weaning (SEW) leads to a systemic immune response that adversely affects the digestive physiology and post-weaning growth of pigs. Two experiments were conducted to evaluate the effects of a glucocorticoid receptor agonist (GA) on growth performance, measures of immune function and intestinal integrity of SEW pigs. In both experiments, pigs were fed corn-soybean meal-based starter diets. In the first experiment, 48 pigs (initial BW 4.8 ± 0.7 kg) were weaned at 21 ± 1 days and randomly assigned to three GA treatment groups: 0, 0.2 and 0.6 mg GA/kg of BW injected intramuscularly. Treatments were administered one day before weaning. Pigs in the 0 mg GA group received sterile saline in place of GA. Body weight was measured daily from one day before to 7 days post-weaning, and then weekly until 28 days post-weaning. Piglets treated with 0.2 mg GA had a higher BW than piglets in other treatment groups during the 28-day course of the study (P <0.02). To further explore the mechanisms behind this result, a second experiment was performed in which a total of 18 gilts (BW 5.6 ± 0.85 kg) were randomly assigned into three treatment groups: suckling plus saline (UWS), weaned treated with GA (WGA; 0.2 mg GA/kg BW) and weaned plus saline (CON). Treatments were administered one day before and 3 days post-weaning. The WGA and CON groups were weaned at 23 ± 2 days, while the UWS group remained with sow for the duration of the study. Body weight was measured daily and blood plasma was collected at 0, 1, 4 and 5 days post-weaning. All gilts were euthanized 5 days after weaning and jejunum samples were collected for mucosal scrapings, histomorphological analysis and gene expression analysis. Plasma levels of interleukin-1β (IL-1β) and haptoglobin were lower in WGA pigs compared with CON (P <0.02), while plasma total antioxidant capacity was higher in WGA pigs compared with both CON and UWS groups (P <0.01). Relative to CON, GA downregulated IL-18 gene expression in the jejunum, as assessed by both tissue homogenate and mucosal scrapings, but it upregulated claudin-IV gene expression only in the tissue homogenate (P <0.01). These results suggest that GA treatment improves the growth performance of SEW pigs in part by mitigating the negative effects of systemic inflammation. However, the effect of GA on barrier integrity requires further investigation.
a-Methyl-L-tryptophan (a-MLT) is currently in use as a tracer in its 11C-labeled form to monitor the health of serotonergic neurons in humans. In the present study, we found this compound to function as an effective weight-loss agent at pharmacological doses in multiple models of obesity in mice. The drug was able to reduce the body weight when given orally in drinking water (1 mg/ml) in three different models of obesity: normal mice on high-fat diet, Slc6a14-null mice on high-fat diet, and ob/ob mice on normal diet. Only the L-enantiomer (a-MLT) was active while the D-enantiomer (a-MDT) had negligible activity. The weight-loss effect was freely reversible, with the weight gain resuming soon after the withdrawal of the drug. All three models of obesity were associated with hyperglycemia, insulin resistance, and hepatic steatosis; a-MLT reversed these features. There was a decrease in food intake in the treatment group. Mice on a high-fat diet showed decreased cholesterol and protein in the serum when treated with a-MLT; there was however no evidence of liver and kidney dysfunction. Plasma amino acid profile indicated a significant decrease in the levels of specific amino acids, including tryptophan; but the levels of arginine were increased. We conclude that a-MLT is an effective, reversible, and orally active drug for the treatment of obesity and metabolic syndrome.
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