Large amounts of choline are required in neonates for rapid organ growth and membrane biosynthesis. Human infants derive much of their choline from milk. In our study, mature human milk contained more phosphocholine and glycerophosphocholine than choline, phosphatidylcholine, or sphingomyelin (P < 0.01). Previous studies have not recognized that phosphocholine and glycerophosphocholine exist in human milk. Concentrations of choline compounds in mature milk of mothers giving birth to preterm or full-term infants were not significantly different. Infant formulas also contained choline and choline-containing compounds. In infant formulas derived from soy or bovine milk, unesterified choline, phosphocholine, glycerophosphocholine, phosphatidylcholine, and sphingomyelin concentrations varied greatly. All infant formulas contained significantly less phosphocholine than did human milk. Soy-derived formulas contained significantly less glycerophosphocholine (P < 0.01) and phosphocholine (P < 0.01) and more phosphatidylcholine (P < 0.01) than did human or bovine milk or bovine milk-derived infant formulas. Rat milk contained greater amounts of glycerophosphocholine (almost 75% of the total choline moiety in milk) and phosphocholine than did human milk. When dams were provided with either a control, choline-deficient, or choline-supplemented diet, milk composition reflected the choline content of the diet. Because there are competing demands for choline in neonates, it is important to ensure adequate availability through proper infant nutrition. Although the free choline moiety is adequately provided by infant formulas and bovine milk, reevaluation of the concentrations of other choline esters, in particular glycerophosphocholine and phosphocholine, may be warranted.

We have previously shown that fetal rat brain cells, preneuronal (PC12), and hepatocyte (CWSV-1) cells undergo apoptosis during choline deficiency (CD). The PC12 and epithelial cell culture models were used to determine the molecular mechanism by which CD induces apoptosis. Our data indicate that CD leads to both growth arrest and apoptosis in a subpopulation of cells, which correlate with the up-regulation of the tumor suppressor protein p53 and concurrent up-regulation of the cyclin-dependent kinase-inhibitor p21 WAF1/CIP1. Additionally, CD induced both a G 1 /S and a G 2 /M arrest. Transient transfection of a dominant negative p53 (p53DN) construct into PC12 cells, which inhibited endogenous p53 activation, significantly reduced the induction of apoptosis associated with CD. Interestingly, CD also induced the persistent activation of the transcription factor NF-B. Activation of NF-B has been shown to promote cell survival and proposed to antagonize p53. Consistent with this, expression of a superrepressor form of IB␣ (SR-IB␣) that functions to strongly inhibit NF-B activation, profoundly enhanced cell death during CD. In summary, these results suggest that the effects of CD on apoptosis and subsequent cell survival are mediated through two different signaling pathways, p53 and NF-B, respectively. Taken together, our data demonstrates the induction of opposing mechanisms associated with nutrient deficiency that may provide a molecular mechanism by which CD promotes carcinogenesis.

No abstract

The nuclear factor kappa B family of inducible transcription factors regulates the expression of many genes. Nuclear factor kappa B has been implicated in autoimmune and inflammatory diseases, infection, cell survival, and cell transformation with subsequent promotion of cancer. In this review, we summarize features of nuclear factor kappa B regulation in several catabolic disorders, and describe its role in normal cellular function as well as provide an important link to the role of scaffold proteins, cellular receptors, and other cell signaling pathway kinases that converge on the nuclear factor kappa B signaling cascade. Subsequently, we focus on the role of nuclear factor kappa B in cell survival and oxidative stress. Finally, potential therapeutic strategies are discussed that may modify nuclear factor kappa B activity including endogenous antioxidant systems and the Fas/FasL system. However, challenges still remain in developing new therapeutic strategies that not only include identifying novel agents, but also by improving clinical endpoint definitions and by defining biological efficacy.