Search

Colon cancer is the third most malignant neoplasm in the world and it remains today an important cause of death, especially in western countries. In this study, we have evaluated the chemopreventive efficacy of morin on tissue lipid peroxidation and antioxidant status, which are used as biomarkers in 1,2-dimethylhydrazine-induced colon carcinogenesis in a rat model. Male Wistar rats were divided into four groups and received high fat diet. Group 1 served as control, groups 2 and 4 were given a daily treatment of morin (50 mg/kg body weight) orally, everyday for a total period of 30 weeks. Groups 3 and 4 were given weekly subcutaneous injections of DMH at a dose of 20 mg/kg body weight in the groin for 15 weeks. Animals were sacrificed at the end of 30 weeks. The liver, intestine, colon and caecum from different groups were subjected to histopathological studies, determination of lipid peroxidation and antioxidant status. Our results showed decreased levels of liver enzymic and non-enzymic antioxidants and increased levels of lipid peroxidation (LPO) products such as tissue thiobarbituricacid substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD) in DMH treated rats, which were significantly (P < 0.05) reversed on morin supplementation. Moreover, intestinal, colonic and caecal TBARS, LOOH, CD and also the antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and reduced glutathione (GSH) were significantly diminished in DMH treated rats, which were significantly (P < 0.05) elevated on simultaneous morin supplementation. Moreover, enhanced activity of intestinal, colonic and caecal ascorbic acid and alpha-tocopherol levels were also observed in DMH alone treated rats, which were significantly (P < 0.05) reduced on morin supplementation. These results indicate that morin could exert a significant chemopreventive effect on colon carcinogenesis induced by DMH.

UTP, CTP, and RNA synthesis were studied in the renal cortex of diabetic and control rats in vivo. The incorporation of UTP into RNA (nmol/h DNA) was used as estimate of RNA synthesis rate. Two to three days after streptozotocin injection, UTP and CTP ppol size and orotate incorporation into UTP and RNA were greater in diabetic animals than in controls. In addition, RNA content and RNA synthesis rate were increased. These changes were corrected by insulin infusion. In diabetic animals, additional increases in UTP pool, RNA content, and RNA synthesis rate followed contralateral nephrectomy. This increase in RNA content was greater than in uninephrectomized controls. The changes in the diabetic renal cortex were not accompanied by increased plasma concentrations of growth hormone. The increase in RNA content in the diabetic renal cortex is probably due to increased RNA synthesis. Increased synthesis of pyrimidines and expansion of the UTP pool may make this substrate more readily available for the synthesis of UDP sugars and may facilitate the synthesis of basement membrane in diabetes.

Glomerular uracil nucleotide metabolism was studied in vivo in control and diabetic rats 48 h after the injection of streptozotocin. The animals were infused for 2 h with 3H-orotate and the fraction of infused dpm incorporated into glomerular uracil nucleotides and RNA/mg of glomerular DNA was calculated. Diabetic glomeruli showed an increase in RNA/DNA compared to controls (p less than 0.05) and a greater incorporation of 3H-orotate into uracil nucleotides and RNA. These changes were reversed by insulin therapy. In separate experiments the renal cortical uracil nucleotide pool was expanded by feeding chow supplemented with 0.5% orotate to rats for 6 months. Normal animals fed orotate developed significant glomerular basement membrane thickening (p less than 0.01) when compared to age-matched controls, which was morphologically indistinguishable from that of diabetics. Orotate feeding also produced further basement membrane thickening in diabetic rats. These results suggest that early diabetes is characterized by an increase in glomerular uracil nucleotides, and that chronic expansion of the uracil nucleotide pool is associated with glomerular basement membrane thickening.

The possibility of compartmentation of UTP in vivo was investigated in the renal cortex of unanaesthetized rats. In addition, liver and spleen were studied in order to compare tissues with different utilization of precursors for pyrimidine nucleotide synthesis. After continuous 2h infusions of [(3)H]uridine or [(3)H]orotate, their incorporation into UTP, UDP-sugars and RNA was quantified. Rates of RNA synthesis were calculated by dividing the incorporation of precursor into RNA by the average specific radioactivity of the UTP pool. Although similar RNA-synthesis rates might have been expected with the two precursors, higher rates were found with uridine than with orotate. The relative incorporation into UDP-sugars of these precursors was also different. Similar results were obtained in the liver. In the spleen, equal amounts of both precursors were incorporated into UTP, but [(3)H]orotate incorporation did not lead to labelling of RNA. To evaluate the heterogeneity of cells with respect to the metabolism of pyrimidines, precursor incorporation was studied in isolated glomeruli and by radioautography. Incorporation into glomeruli was qualitatively similar to but quantitatively different from results in the renal cortex. Although there is obvious tissue heterogeneity, compartmentation of UTP pools is the most credible explanation for the results obtained with the renal cortex and liver. Consequently RNA and UDP-sugars may originate from two different UTP pools. Tissue heterogeneity is the likely explanation for the results obtained in the spleen. Studies of synthesis of pyrimidine and RNA, particularly in relation to growth and regeneration, must take into consideration the precursor used, the apparent existence of UTP compartmentation and the degree of cellular heterogeneity.

The association between renal transplantation and malignancy, particularly histiocytic lymphoma, is well known. Hodgkin's disease also occurs in renal transplant recipients. We report such a case and also review three other reports in the literatures. The Hodgkin's disease was insensitive to conventional MOPP chemotherapy in two of two, and was sensitive to combined MOPP-Bleomycin in one patient. The disease was rapidly fatal in three of four cases.

Experimental diabetes induces increased content of RNA and UTP in the renal cortex. Studies were designed to assess the bioavailability of 5-phosphoribosyl-1-pyrophosphate (PRPP) in the diabetic renal cortex because PRPP is an important determinant of the de novo synthesis of nucleotides. The tissue bioavailability of PRPP determines the effects of orotate or adenine administration on UTP, ATP, and GTP content and on the incorporation of labeled precursors into UTP and ATP. Diabetic and control rats with chronic intravenous cannulas were infused over 2.5-24 h with orotate or adenine. Orotate administration induced greater decreases in ATP and GTP and in labeled adenine incorporation into ATP concomitant with smaller increases in UTP in controls than in diabetic animals. Adenine administration induced a greater decrease of labeled orotate incorporation into UTP and a smaller increase in ATP in controls than in diabetic animals. Prolonging the adenine infusion resulted in disappearance of these differences. The results are compatible with greater initial bioavailability of PRPP in the diabetic renal cortex than in controls but with a rate of maximal PRPP generation that is the same in both tissues.

Incorporation in vivo of labeled orotate into RNA and total nucleotides was measured in isolated glomeruli and whole renal cortex. In 2-day diabetic animals, glomerular RNA was increased, and there was greater incorporation of orotate into total nucleotides and RNA as compared with controls. Insulin reversed the exaggerated incorporation at infusion rates that corrected hyperglucagonemia without reducing plasma glucose and with only minimal changes in insulin concentrations. The addition of glucagon to insulin infusions reproduced the increased incorporation observed in untreated diabetics. Similar changes occurred in renal cortex, where differences in orotate incorporation into nucleotide precursors seemed to be the main cause for alterations in RNA labeling. Isotope incorporation in glomeruli correlated positively with plasma glucagon, but not with insulin or glucose concentrations. Although in 7-month diabetic animals orotate incorporation into RNA was less than in controls, probably as a consequence of renal disease, 24-hour insulin infusion decreased it further. Our results confirm that in the diabetic kidney, abnormal uracil nucleotide metabolism and increased cellular content of RNA are demonstrable in glomeruli as in the renal cortex. These changes appear to be related directly to hyperglucagonemia.

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3-7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1-33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2-68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P less than 0.05) and patient survival (93% vs. 81%, P less than 0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P less than 0.05) and the number of rejection episodes per patient was also lower in this group (1.0 +/- 15 vs. 1.6 +/- 49, P less than 0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.