Nutritional and Bromacological Studies of Food Factors Using In Vitro and In Vivo Disease Models  (2007's JSNFS Award for Excellence in Research)

Yagasaki Kazumi

doi:10.4327/jsnfs.62.61

Effects of food factors, including nutrients and non-nutients, on dyslipidemia associated with glomerulonephritis and hepatoma (AH109A) were studied. Cancer cells have two biological properties: unlimited proliferation and metastasis. Invasion is an important and characteristic step in the cascade of cancer metastasis. Thus, by constructing both proliferation and invasion assay systems using hepatoma cells in culture, we screened out food factors that would inhibit the proliferation and/or invasion of hepatoma cells, and tried to clarify the mechanisms involved. Supply of amino acid-fortified low-protein diets such as an 8.5% casein diet supplemented with methionine and threonine (8.5 CMT) to nephritic rats improved their proteinuria, and often hypoalbuminemia as well as dyslipidemia, without causing severe protein malnutrition. In the nephritic state, transforming growth factor-β (TGF-β), a factor that stimulates extracellular matrix production and induces glomerulosclerosis, was overproduced, while the concentration of serum erythropoietin (EPO), a glycoprotein that is produced mainly in the kidney and stimulates red blood cell production, was decreased. Dietary manipulation with 8.5 CMT succeeded in suppressing the overproduction of TGF-β and in elevating the serum EPO concentration. An 8.5% soy protein isolate diet supplemented with methionine also reduced symptoms of nephritis without causing severe protein malnutrition. These results revealed the nutritional importance of amino acids in protein restriction therapy for nephritis. Fish oil and some polyphenols were found to improve dyslipidemia in nephritis. Abnormal serum lipoprotein profiles developed with the formation of solid tumors in hepatoma-bearing rats, resulting in hypercholesterolemia and hypertriglyceridemia. The mechanisms responsible for dyslipidemia induction in the hepatoma-bearing state were clarified. A cysteine derivative, fish oil and other food factors improved the hepatoma-induced dyslipidemia, and their modes of actions were elucidated. Many kinds of food factors were found to suppress the proliferation and/or invasion of hepatoma cells in culture. Effects of several food components were examined in the hepatoma-bearing rats. Suppression of hepatoma proliferation by food components was based on apoptosis induction and/or cell cycle arrest, and on activation of macrophages that infiltrated into the solid tumors. Reactive oxygen species (ROS) were found to stimulate hepatoma invasion and the production of hepatocyte growth factor (HGF), a known cell motility factor. Resveratrol inhibited the invasion of hepatoma by scavenging ROS, leading to decreases in HGF expression and secretion by hepatoma cells and hence decreases in cell motility and invasive activity. Prostaglandin (PG), especially PGE₂, was shown to stimulate hepatoma invasion. Resveratrol is known to be an inhibitor of cyclooxygenase. Thus, another anti-invasive action of resveratrol might be attributable to inhibition of PGE₂ synthesis. Theanine, a palatable amino acid in green tea, was suggested to inhibit hepatoma invasion via NMDA-type glutamate receptors, although details of its action remain to be clarified. These findings suggest that some forms of dietary manipulation and food factors have reductive and therapeutic as well as preventive effects on some diseases.

Nutritional and Bromacological Studies of Food Factors Using In Vitro and In Vivo Disease Models (2007's JSNFS Award for Excellence in Research)

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