Azaserine

We studied the eco-toxic and carcinogenic effects of a commonly used 2,4-D acid iso-octylester herbicide on rat liver and pancreas. The rats in Group 1 were fed a standard feed and the rats in Group 2 were fed with standard feed to which was added 200 mg/kg/day 2,4-D acid iso-octylester for 16 weeks. Azaserine, 30 mg/kg/body weight, was injected into rats of Groups 3 and 4 to investigate the effects of 2,4-D acid iso-octylester on the development of neoplasms. After feeding the rats with neoplasms in Group 4 with food including 200 mg/kg/day 2,4-D acid iso-octylester for 16 weeks, an autopsy was carried out on all animals. We found that 2,4-D acid iso-octylester caused the formation of atypical cell foci (ACF) in the pancreata and livers of rats. ACF that were formed experimentally by exposure to azaserine had increased diameter, volume and number of atypical cell foci/mm(2) and mm(3) after exposure to 2,4-D acid iso-octylester. Our observations indicated that this herbicide potentially is a cancer initiator.

The enzyme isocitrate dehydrogenase (ICDH; EC 1.1.1.42) catalyzes the oxidative decarboxylation of isocitrate, to produce 2-oxoglutarate. The incompleteness of the tricarboxylic acids cycle in marine cyanobacteria confers a special importance to isocitrate dehydrogenase in the C/N balance, since 2-oxoglutarate can only be metabolized through the glutamine synthetase/glutamate synthase pathway. The physiological regulation of isocitrate dehydrogenase was studied in cultures of Prochlorococcus sp. strain PCC 9511, by measuring enzyme activity and concentration using the NADPH production assay and Western blotting, respectively. The enzyme activity showed little changes under nitrogen or phosphorus starvation, or upon addition of the inhibitors DCMU, DBMIB and MSX. Azaserine, an inhibitor of glutamate synthase, induced clear increases in the isocitrate dehydrogenase activity and icd gene expression after 24 h, and also in the 2-oxoglutarate concentration.

In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine.

Hyperglycemia impairs insulin secretion as well as insulin action, being recognized as the glucotoxicity that accelerates diabetes. However, the mechanism underlying the glucotoxicity in pancreatic β-cells is not thoroughly understood. Hyperglycemia alters glucose metabolism within β-cells and interstitial conditions around β-cells, including elevated osmolarity and increased concentrations of insulin and ATP released from overstimulated β-cells. In this study, to explore direct effects of these alterations on β-cells, single β-cells isolated from rat islets were cultured for 3 days with high (22.3 mM) glucose (HG), compared with control 5.6 mM glucose, followed by their functional assessment by measuring cytosolic Ca2+ concentration ([Ca2+]i). The [Ca2+]i response to a physiological rise in glucose concentration to 8.3 mM was impaired in b-cells following culture with HG for 3 days, while it was preserved in β-cells following culture with non-metabolizable L-glucose and with elevated osmolarity, insulin and ATP.