Search PubMed⌕ Search

Biomedical subjects

Josef Neu

Publications and source records attributed to Josef Neu.

At least 19 recordsLinked to original sources
PubMed2007

Pathophysiology of glutamine and glutamate metabolism in premature infants.

PURPOSE OF REVIEW: The potential efficacy of glutamine and glutamate as nutritional supplements for premature infants was originally met with enthusiasm. Despite no evidence of toxicity in the clinical trials, the use of glutamine has not become routine. In certain studies, the benefits seem clear, whereas in others, benefits have not been demonstrated. Specific designs for studies have been difficult, targets based on mechanistic frameworks have been poorly defined, study populations are heterogeneous and putative mechanisms of glutamine action are multifold. Our purpose is to review recent findings pertaining to (1) the action and mechanisms of glutamine and glutamate in the gastrointestinal tract, and (2) the future directions for glutamine and glutamate research with a focus on the premature neonate. RECENT FINDINGS: Studies elucidating mechanisms of glutamine action include tissue protection, immune modulation, preservation of glutathione and antioxidant capacity, preservation of metabolism, decreased intestinal apoptosis, and enhancement of heat shock proteins. The ability to decrease gastrointestinal-derived systemic inflammation appears to have especially significant implications for premature infants. SUMMARY: We review recent studies of mechanisms of glutamine and glutamate action, pertinent clinical trials, and suggest areas for future research based on these mechanisms.

Bacterial Translocation↗
PubMed2006

Postnatal nutrition and adult health programming.

The early postnatal interplay between nutrition, growth patterns, and metabolic and epigenetic phenomena is crucial in determining subsequent health; health that extends through the lifetime of the individual and very likely even into subsequent generations. Recent research in the area of postnatal nutrition and its relationship to adult health, with an emphasis on the appropriate-for-gestational-age infant who is born prematurely and who undergoes growth delays, is presented. Select studies in animals, pertinent to understanding the mechanisms of how early postnatal under- and overnutrition might affect adult health and propagate to subsequent generations, are reviewed. Scientifically based approaches to administering postnatal nutrition designed to improve outcomes and areas where future investigations are needed are presented.

Animals↗
PubMed2006

Gastrointestinal maturation and feeding.

The intestine serves not only as a digestive absorptive organ, it is also one of the largest immune organs of the body, has a huge endocrine and exocrine role, and also encompasses neural tissue equivalent to that of the entire spinal cord. The microbial microenvironment also plays a critical role in development. This brief overview of developmental aspects of these intestinal functions will be related to clinical problems in the neonatal period and subsequent health.

Enterocolitis↗
PubMed2006

Lactobacillus rhamnosus GG decreases lipopolysaccharide-induced systemic inflammation in a gastrostomy-fed infant rat model.

OBJECTIVES: A gastrostomy-fed rat infant "pup-in-a-cup" model was used to test the hypothesis that enterally administered Lactobacillus rhamnosus GG (LGG) decreases the proinflammatory response induced by Escherichia coli lipopolysaccharide (LPS) in the developing infant rat small intestine, plasma, lung and liver. METHODS: Two groups of 6- to 7-day-old pups were fed a rat milk substitute with LPS added via the gastrostomy tube for 6 days. One of the rat milk substitute-fed groups received supplemental LGG; another group received LPS without LGG. Age-matched mother-fed rat pups were used as controls. RESULTS: LPS treatment blunted body growth, but LGG supplementation had no effect on weight increments. LGG decreased LPS-induced inflammation in intestinal tissue; CINC-1 (rodent IL-8 equivalent) production in plasma, liver, lung and distal small intestine; and tumor necrosis factor alpha (TNF-alpha) production in plasma and lung. Cytokine multiplex assay showed lung interleukin (IL)-1beta, IL-6, IL-10, IL-18, growth-related oncogene (GRO)/KC (rat CINC-1) and TNF-alpha were significantly higher in gastrostomy-fed, LPS-treated pups than in mother-reared pups, and LGG significantly blunted the LPS-induced elevation of IL-1beta, IL-10, IL-18, GRO/KC and TNF-alpha; liver GRO/KC was significantly higher in gastrostomy-fed, LPS-treated pups than in mother-reared pups, and LGG significantly blunted the LPS-induced elevation of GRO/KC. CONCLUSIONS: LGG provided by the enteral route is able to downregulate LPS-induced proinflammatory mediators. This effect is not only present in the splanchnic organs, that is, the intestine and the liver, but extends to the plasma and a distal organ, the lung.

Animals↗
PubMed2006

The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy.

PURPOSE: Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS: The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS: Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82%+/-7% (P<0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64%+/-9% (P<0.001). CONCLUSIONS: Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.

Angiogenesis Inhibitors↗
PubMed2005

Intestinal innate immunity: how does it relate to the pathogenesis of necrotizing enterocolitis.

The pathogenesis of necrotizing enterocolitis (NEC) is poorly understood, but appears to be multifactorial and highly associated with immaturity of the gastrointestinal tract, colonization of the intestinal microbiota, and immature innate immune system. The goal of this review is to provide an overview of some of these risk factors and how they might lead to the genesis of NEC. A better understanding of these factors should help us prevent and treat this devastating disease.

Enterocolitis, Necrotizing↗
PubMed2005

Glutamine modulates LPS-induced IL-8 production through IkappaB/NF-kappaB in human fetal and adult intestinal epithelium.

The intestinal epithelium may serve as a nidus for inflammation that can cause local and systemic organ dysfunction. Relative to the adult, the immature intestine is exquisitely sensitive to inflammatory agents. Glutamine (Gln), an amino acid that is rapidly depleted during critical illness, modulates intestinal inflammation in vitro and in vivo. Here we relate Gln status to activation of the inhibitor of kappaB (IkappaB)/nuclear factor (NF)-kappaB signaling pathway in fetal-derived (H4) and adult (Caco-2) enterocytes. In the absence of Gln with or without LPS, H4 cells expressed more interleukin (IL)-8) than Caco-2 cells. Gln supplementation partially prevented the LPS-induced elevation of IL-8 in both cell types. IkappaBalpha was significantly decreased in both H4 and Caco-2 cells with Gln deprivation, and this was followed by an increase in NF-kappaB p65 in the nucleus. DNA binding of NF-kappaB was increased in both H4 and Caco-2 cells with Gln deprivation. IkappaBalpha phosphorylation was not altered by Gln status in either H4 or Caco-2 cells. Proteasomal inhibition after Gln depletion in Caco-2 cells was associated with an increase in the IkappaB-ubiquitin complex, but a decrease in complex formation in H4 cells, indicating that Gln deprivation alters IkappaBalpha through a pathway that differs from Caco-2 cells. We speculate that a reduced capacity of the immature enterocyte (H4) to respond to Gln deprivation with increased synthesis of IkappaBalpha rather than increased proteolysis as seen in the Caco-2 cells is the underlying mechanism.

Adult↗
PubMed2005

Alive and dead Lactobacillus rhamnosus GG decrease tumor necrosis factor-alpha-induced interleukin-8 production in Caco-2 cells.

Certain probiotic bacteria show anti-inflammatory activity after being heat killed, whereas others do not, suggesting that the gastrointestinal environment may alter the activity of probiotic bacteria. Occasionally, probiotics are provided when a patient is also being treated with oral antibiotics; this may have an effect on the probiotic activity. We hypothesized that Lactobacillus rhamnosus GG (LGG) are capable of downregulating tumor necrosis factor-alpha (TNFalpha)-induced interleukin (IL)-8 production under all 3 of these conditions, and that LGG act through the nuclear factor kappaB (NFkappaB)/inhibitor of kappaB (IkappaB) pathway. Caco-2 cells were treated with live or heat-killed LGG in doses ranging from 10(4) to 10(10) cfu/L, in the presence or absence of antibiotics and TNFalpha in the media. TNFalpha-induced production of IL-8 by Caco-2 cells was modulated by LGG under all 3 conditions. However, higher doses of live LGG without TNFalpha in the presence or absence of antibiotics in vitro induced the production of IL-8 (P = 0.001). Heat-killed LGG also blunted the TNFalpha-induced IL-8 production (P < 0.01), but by itself did not increase IL-8 production at higher doses as markedly as live LGG (P < 0.05). LGG reduced the TNFalpha-induced NFkappaB translocation to the nucleus and lessened the decrease in IkappaB in the cytoplasm (P < 0.05). LGG reduced TNFalpha-induced IL-8 production by affecting the NFkappaB/IkappaB pathway in Caco-2 cells. High doses of live LGG markedly increased IL-8 production, but heat-killed LGG caused only a slight increase in IL-8. Thus, heat-killed LGG may effectively ameliorate inflammation with a lower potential than live LGG at high doses to cause inflammation.

Caco-2 Cells↗
PubMed2005

Changes in intestinal morphology and permeability in the biobreeding rat before the onset of type 1 diabetes.

OBJECTIVE: Type 1 diabetes is an autoimmune disorder that occurs in genetically susceptible individuals. It has been hypothesized that the disease could be triggered by environmental agents that gain entry into the body through small intestinal absorption. Increased intestinal permeability has been reported both in spontaneous animal models of type 1 diabetes and human type 1 diabetes. In these studies, we examined both the physical and functional permeability characteristics of the small intestine in diabetes-prone and control rats. METHODS: In a series of studies, BioBreeding diabetes-prone(n = 31), BioBreeding diabetes-resistant (n = 20) and control Wistar (n = 25) rats were examined at intervals from 21 to 125 days of age. RESULTS: The percentage of goblet cells and the mucosal crypt depth were significantly greater in BioBreeding diabetes-prone than BioBreeding diabetes-resistant rats (P < 0.001 and P = 0.01, respectively). BioBreeding diabetes-prone and BioBreeding diabetes-resistant rats expressed less of the tight junction protein claudin (P < 0.05) and exhibited greater intestinal permeability (P < 0.001) than did Wistar rats. Intestinal permeability measured both in vivo and ex vivo decreased in all rat strains as age increased (P < 0.001). CONCLUSIONS: In a genetically susceptible rodent model of diabetes, early increased intestinal permeability might allow unregulated passage of environmental antigens that could potentially trigger the autoimmune response leading to type 1 diabetes.

Animals↗
PubMed2005

Feeding intolerance in very-low-birthweight infants: what is it and what can we do about it?

The increased survival of very-low-birth-weight infants has resulted in the need to better understand the immaturities that challenge optimal nutrition for these infants and how to surmount them. This is critical if we are to prevent short and long term morbidity associated with poor nutrition. Here we describe several of these immaturities including those related to digestion and absorption, suck-swallow incoordination, delayed gastric emptying, and intestinal motility and how they lead to the common problem of feeding intolerance. Scientifically based strategies for introducing, stopping and continuing enteral feedings in association with parenteral nutrition are presented.

Child Development↗
PubMed2005

Neonatal necrotizing enterocolitis: an update.

Necrotizing enterocolitis (NEC) is a leading cause of mortality and morbidity in neonatal intensive care units. Here we review selected manifestations of NEC, risk factors involved in its pathophysiology as well as putative mechanisms associated with how an immature gut might be more susceptible to NEC. Treatment and potential preventive strategies are discussed.

Diagnosis, Differential↗
PubMed2005

The developing intestinal ecosystem: implications for the neonate.

Interactions of resident intestinal microbes with the luminal contents and the mucosal surface play important roles in normal intestinal development, nutrition, and innate and adaptive immunity. The neonate, especially the premature, who possesses a highly immunoreactive intestinal submucosa underlying a single layer of epithelial cells that are continuously exposed to the luminal environment, is highly susceptible to perturbations of the luminal environment. Understanding the interactions of the intestinal ecosystem with the host and luminal nutritional environment, especially in regard to human milk and pre- and probiotics, has major implications for the pathogenesis of diseases that affect not only the intestine but distal organs such as the lung and brain.

Animals↗
PubMed2004

Artificial rearing of mouse pups: development of a mouse pup in a cup model.

Artificial rearing of rat pups has been used in the investigation of the neonatal gut. We propose to adapt the model of artificially rearing rat pups for use in mouse pups, thereby allowing the use of transgenic animals for our research. We hypothesized that gastrostomy catheters may be placed successfully into neonatal mouse pups and that the pups may be artificially reared without significant alterations in their growth or intestinal development. Gastrostomy tubes are placed into 5-d-old mouse pups [artificially reared (AR); n = 32], and the mice are fed rodent milk substitute. Littermate pups [maternally reared (MR); n = 22] are used as controls. After 5 d, pups are killed and their organs are harvested. Intestinal villus measurements, protein content, and DNA content are determined. Data are reported as mean +/- SEM, compared with appropriate statistical methods, and significance is determined at P < 0.05. Initial weights and lengths are not different between the two groups, but after 5 d, MR pups weigh more than their AR counterparts (5.0 +/- 0.13 versus 4.1 +/- 0.14 g, MR versus AR; P < 0.01). However, the pups' length and the intestinal villus height-to-width ratios, protein, and DNA content are not different between the MR and AR pups. To our knowledge, this is the first report of artificially rearing mouse pups. Development of this technique will permit nutritional manipulation in neonatal mice, a mammalian model wherein the genome is sequenced and transgenic mutants are available.

Animals↗
PubMed2004

Glutamine regulates Caco-2 cell tight junction proteins.

Intestinal epithelial tight junction (TJ) barrier dysfunction may lead to inflammation and mucosal injury. Glutamine (GLN) plays a role in maintenance of intestinal barrier function in various animal models and critically ill humans. Recent evidence from intestinal cell monolayers indicates that GLN maintains transepithelial resistance and decreases permeability. The mechanisms of these effects remain undefined. We hypothesized that GLN affects proteins involved in the intercellular junctional complex. GLN availability was controlled in Caco-2 monolayers by addition to the medium and treatment with methionine sulfoximine (MSO) to inhibit glutamine synthetase (GS). Expression of TJ proteins, claudin-1, occludin, and zonula occluden (ZO)-1 was measured by immunoblotting. Localization of TJ proteins was evaluated by immunofluorescence light microscopy. Structure of TJ was determined by transmission electron microscopy (TEM). Deprivation of GLN decreased claudin-1, occludin, and ZO-1 protein expression and caused a disappearance of perijunctional claudin-1 and a reduction of occludin but had no effect on ZO-1. TEM revealed that MSO-treated cells in the absence of GLN formed irregular junctional complexes between the apical lateral margins of adjoining cells. These findings indicate that TJ protein expression and cellular localization in Caco-2 cell monolayers rely on GLN. This mechanism may similarly relate to GLN-mediated modulation of intestinal barrier function in stressed animals and humans.

Blotting, Western↗
PubMed2004

Mechanism of glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells.

The mechanism of glutamine (Gln)-mediated down-regulation of inflammation in the intestine is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated IL-8 production in intestinal epithelial cells via transcription factors that counteract the effect of LPS-mediated increase in IL-8. Caco-2 cells were incubated with different doses of Gln with or without methionine sulfoximine (MS), an inhibitor of glutamine synthetase for 24 h before stimulation by LPS (100 microg/ml for 24 h). Inhibitors of the mitogen activated protein kinase (MAPK) family were added to cells for 1.5 h following stimulation by LPS. The p38 inhibitor SB 203580 resulted in a significant decrease in IL-8 peptide production (p < 0.01). However, p38 MAPK activity increased with Gln (p < 0.05), suggesting that this was not involved with Gln-mediated down-regulation of IL-8. Screening of 54 transcription factors demonstrated that STAT-4 was the only inflammation-related transcription factor that was up-regulated by Gln depletion and down-regulated with Gln supplementation (2-fold increase), paralleling IL-8 production. EMSA analysis confirmed these findings (3.5-fold increase). These results indicate that Gln deprivation enhances IL-8 production by Caco-2 cells after LPS stimulation and that down-regulation of IL-8 production with Gln is associated with alterations in STAT-4 transcription factor binding.

Caco-2 Cells↗