L-Glutamine or L-alanyl-L-glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes.

This study tested the hypothesis that L-glutamine (Gln) or L-alanyl-L-glutamine (Ala-Gln) prevents oxidant- or endotoxin-induced death of neonatal enterocytes. Enterocytes of neonatal pigs rapidly hydrolyzed Ala-Gln and utilized Gln. To determine whether Gln or Ala-Gln has a cytoprotective effect, IPEC-1 cells were cultured for 24 h in Gln-free Dulbecco's modified Eagle's-F12 Ham medium containing 0, 0.5, 2.0 or 5.0 mM Gln or Ala-Gln, and 0, 0.5 mM H(2)O(2) or 30 ng/ml lipopolysaccharide (LPS). Without Gln or Ala-Gln, H(2)O(2)- or LPS-treated cells exhibited almost complete death. Gln or Ala-Gln at 0.5, 2 and 5 mM dose-dependently reduced H(2)O(2)- or LPS-induced cell death by 14, 54 and 95%, respectively, whereas D: -glutamine, alanine, glutamate, ornithine, proline, glucosamine or nucleosides had no effect. To evaluate the effectiveness of Gln or Ala-Gln in vivo, 7-day-old piglets received one-week oral administration of Gln or Ala-Gln (3.42 mmol/kg body weight) twice daily and then a single intraperitoneal injection of LPS (0.1 mg/kg body weight); piglets were euthanized in 24 and 48 h to analyze intestinal apoptotic proteins and morphology. Administration of Gln or Ala-Gln to LPS-challenged piglets increased Gln concentrations in small-intestinal lumen and plasma, reduced intestinal expression of Toll-like receptor-4, active caspase-3 and NFkB, ameliorated intestinal injury, decreased rectal temperature, and enhanced growth performance. These results demonstrate a protective effect of Gln or Ala-Gln against H(2)O(2)- or LPS-induced enterocyte death. The findings support addition of Gln or Ala-Gln to current Gln-free pediatric amino acid solutions to prevent intestinal oxidative injury and inflammatory disease in neonates.

Synthesis of nearly monodisperse embedded nanoparticles by separating nucleation and growth in ion implantation.

We investigate the formation of nanoparticles of Au in SiO(2) by multiple ion implantation steps and intermediate anneals to isolate nucleation and growth, thereby producing a narrow particle size distribution. We discuss the effects of varying the initial nucleation dose and the growth temperature and establish guidelines for synthesizing nanoparticles with improved size uniformity. By this method, we have obtained a standard deviation of 16% on an average diameter of 1.68 nm, compared to 28% when no attempt is made to isolate nucleation and growth.

Photoinduced phase transition in VO2 nanocrystals: ultrafast control of surface-plasmon resonance.

We study the ultrafast insulator-to-metal transition in nanoparticles of VO2, obtained by ion implantation and self-assembly in silica. The nonmagnetic, strongly correlated compound VO2 undergoes a reversible phase transition, which can be photoinduced on an ultrafast time scale. In the nanoparticles, prompt formation of the metallic state results in the appearance of surface-plasmon resonance. We achieve large, ultrafast enhancement of optical absorption in the near-infrared spectral region that encompasses the wavelength range for optical-fiber communications. One can further tailor the response of the nanoparticles by controlling their shape.

Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats.

This study was conducted to test the hypothesis that dietary supplementation of arginine, the physiologic precursor of nitric oxide (NO), reduces fat mass in the Zucker diabetic fatty (ZDF) rat, a genetically obese animal model of type-II diabetes mellitus. Male ZDF rats, 9 wk old, were pair-fed Purina 5008 diet and received drinking water containing arginine-HCl (1.51%) or alanine (2.55%, isonitrogenous control) for 10 wk. Serum concentrations of arginine and NO(x) (oxidation products of NO) were 261 and 70% higher, respectively, in arginine-supplemented rats than in control rats. The body weights of arginine-treated rats were 6, 10, and 16% lower at wk 4, 7, and 10 after the treatment initiation, respectively, compared with control rats. Arginine supplementation reduced the weight of abdominal (retroperitoneal) and epididymal adipose tissues (45 and 25%, respectively) as well as serum concentrations of glucose (25%), triglycerides (23%), FFA (27%), homocysteine (26%), dimethylarginines (18-21%), and leptin (32%). The arginine treatment enhanced NO production (71-85%), lipolysis (22-24%), and the oxidation of glucose (34-36%) and octanoate (40-43%) in abdominal and epididymal adipose tissues. Results of the microarray analysis indicated that arginine supplementation increased adipose tissue expression of key genes responsible for fatty acid and glucose oxidation: NO synthase-1 (145%), heme oxygenase-3 (789%), AMP-activated protein kinase (123%), and peroxisome proliferator-activated receptor gamma coactivator-1alpha (500%). The induction of these genes was verified by real-time RT-PCR analysis. In sum, arginine treatment may provide a potentially novel and useful means to enhance NO synthesis and reduce fat mass in obese subjects with type-II diabetes mellitus.

Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells.

Tetrahydrobiopterin (BH4) is a member of the pterin family that has a core structure of pyrazino-2,3-d-pyrimidine rings. Because BH4 is an essential cofactor for the biosynthesis of nitric oxide (a major vasodilator), there is growing interest in BH4 biochemistry in endothelial cells (the cells that line blood vessels). BH4 is synthesized via de novo and salvage pathways from guanosine 5'-triphosphate (GTP) and 7,8-dihydrobiopterin, respectively, in animal cells. GTP cyclohydrolase-I (GTP-CH) is the first and rate-controlling enzyme in the de novo pathway. Available evidence shows that endothelial GTP-CH expression and BH4 synthesis are stimulated by a wide array of nutritional (phenylalanine and arginine), hormonal (insulin and estrogen), immunological (inflammatory cytokines including interleukin [IL]-1, interferon-gamma, and tumor necrosis factor-alpha), therapeutic (statins and cyclosporin A), and endothelium-derived (basic fibroblast growth factor and H2O2) factors. In contrast, glucocorticoids and anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor [TGF]-beta) inhibit endothelial BH4 synthesis. Because BH4 is oxidized to 7,8-dihydrobiopterin and 7,8-dihydropterin at physiological pH, endothelial BH4 homeostasis is regulated by both BH4 synthesis and its oxidation. Vitamin C, folate, and other antioxidants enhance endothelial BH4 bioavailability through chemical stabilization or scavenging of reactive oxygen species, thereby contributing to the maintenance of physiological homeostasis in the endothelium. New knowledge about the cellular and molecular mechanisms for the regulation of endothelial BH4 synthesis and bioavailability is beneficial for developing effective means to prevent and treat cardiovascular disorders, the leading cause of death in developed nations.

Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats.

This study tested the hypothesis that dietary arginine supplementation increases endothelial tetrahydrobiopterin (BH(4)) availability for nitric oxide (NO) synthesis in diabetic rats. Streptozotocin-induced diabetic rats either were given unrestricted access to a casein-based diet (Expt. 1) or were pair-fed the diet on the basis of the food intake per kg of body weight of nondiabetic rats (Expt. 2). Beginning 1 d after vehicle or streptozotocin injection, arginine-HCl (1.51%) or alanine (isonitrogenous control, 2.55%) was added daily to the drinking water for nondiabetic rats, whereas concentrations were adjusted (0.43% arginine-HCl and 0.73% alanine) in the drinking water for diabetic rats (which consumed more water) to ensure isonitrogenous provision. At 2 wk after the initiation of arginine supplementation, coronary endothelial cells and plasma were obtained for the measurement of NO synthesis and metabolites. In both experiments, plasma and endothelial concentrations of N(G)-monomethylarginine, asymmetric dimethylarginine, and symmetric dimethylarginine increased, but those of arginine as well as endothelial BH(4) availability and NO synthesis decreased in diabetic rats, compared with nondiabetic rats. In both diabetic and nondiabetic rats, arginine supplementation increased plasma concentrations of arginine and insulin, endothelial concentrations of arginine and BH(4), and endothelial NO synthesis, but did not affect plasma and endothelial concentrations of methylarginines or plasma concentrations of homocysteine. Dietary arginine supplementation or provision of a BH(4) precursor normalized endothelial NO synthesis in diabetic rats. Arginine supplementation did not affect plasma glucose levels in nondiabetic rats, but reduced body weight loss and plasma glucose levels in diabetic rats. Thus, dietary L-arginine supplementation stimulates endothelial NO synthesis by increasing BH(4) provision, which is beneficial for vascular function and glucose homeostasis in diabetic subjects.