Orally ingested human lactoferrin is digested and secreted in the upper gastrointestinal tract in vivo in women with ileostomies

Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands. [email protected] Lactoferrin (LF), a glycoprotein present in milk and other secretions, may provide a nutritional ingredient for the treatment of intestinal disorders associated with hyperpermeability, oxidative stress and inflammation. The aim of the study was to determine the survival rate of orally administered recombinant human lactoferrin (rhLF) in the upper gastrointestinal (GI) tract and in the small intestine in vivo in humans. Female ileostomy patients [n = 8; median age 44 (43-57) y] ingested a test beverage containing 5 g rhLF and collected full ileostomy output for 24 h. The passage of the test beverage was monitored using radio-opaque markers. Intact LF in ileal effluent was quantified by ELISA. The entire test beverage passed the small bowel during the 24-h ileal effluent collection period. LF was excreted at a low but constant rate [0.35 (0.28-0.47) micro g LF/2 h]. Gastrointestinal passage of the test beverage and LF excretion over time in the ileal effluent were not correlated. In total, a median of 4 micro g LF was excreted over the 24-h collection period, whereas 5 g rhLF was ingested. Hence, dietary rhLF is digested in the upper GI tract and does not reach the colon. Intact LF appearing in ileostomy effluent is likely to originate from an endogenous source. Publication Types: Clinical Tria

Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-α (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-α and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis

Lactoferrin decreases pollen antigen-induced allergic airway inflammation in a murine model of asthma

Pollen grains contain reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidases and in contact with mucosal surfaces generate superoxide anion ([Formula: see text]). In the presence of iron, [Formula: see text] may be converted to more reactive oxygen radicals, such as to H(2)O(2) and/or (•)OH, which may augment antigen-induced airway inflammation. The aim of the study was to examine the impact of lactoferrin (LF), an iron-binding protein, on ragweed (Ambrosia artemisiifolia) pollen extract (RWE)-induced cellular oxidative stress levels in cultured bronchial epithelial cells and accumulation of inflammatory and mucin-producing cells in airways in a mouse model of allergic airway inflammation. Results show that LF lowered RWE-induced increase in cellular reactive oxygen species (ROS) levels in bronchial epithelial cells. Most importantly, LF significantly decreased accumulation of eosinophils into airways and subepithelium of intranasally challenged, sensitized mice. LF also prevented development of mucin-producing cells. Amb a 1, the major allergenic ragweed pollen antigen lacking NAD(P)H oxidase activity, induced low-grade airway inflammation. When administered along with glucose oxidase (G-ox), a superoxide-generating enzyme, Amb a 1 induced robust airway inflammation, which was significantly lowered by LF. Surprisingly, LF decreased also inflammation caused by Amb a 1 alone. Iron-saturated hololactoferrin had only a marginal effect on RWE-induced cellular ROS levels and RWE- or Amb a 1 plus G-ox-induced inflammation. We postulate that free iron in the airways chemically reduces [Formula: see text] to more reactive species which augment antigen-induced inflammation in a mouse model of asthma. Our results suggest the utility of LF in human allergic inflammatory disorders

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia.

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints