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At least 721 records · Page 40Linked to original sources
PubMed1990

Sex differences in response to four promotion regimens in spite of common first cellular steps in the hepatocellular cancer process initiated by diethylnitrosamine.

Female adult rats were as responsive as males to initiation by diethylnitrosamine (DEN) as measured by numbers of GST-P positive hepatocytes appearing early, and do develop hepatocellular cancers. However, when females and males were exposed to four promotion regimens including orotic acid (OA), choline deficiency, deoxycholic acid (DOC), or selection for resistance (to 2-acetylaminofluorene; 2-AAF) after DEN initiation, very significant sex differences were observed with respect to oval cell proliferation and growth rates of hepatocytic foci. These results suggest that responses to promotion such as growth of foci and oval cell proliferation can accompany carcinogenesis but may not be essential to the development of hepatocellular cancer.

2-Acetylaminofluorene↗
PubMed1980

Acute hemorrhagic pancreatic necrosis in mice. Alterations of pancreatic lipase activity, pancreas lipids, and serum lipoproteins.

Acute hemorrhagic pancreatic necrosis (AHPN) with fat necrosis was induced in female mice by feeding a choline-deficient diet containing 0.5% DL-ethionine. Pancreatic lipase increases significantly prior to the onset of AHPN and is not accompanied by gross alterations in the lipid composition of the organs. In the same animals significant activities of pancreatic lipase were detected in serum and peritoneal cavity after 3 days of dietary regimen. Analysis of serum lipids and lipoproteins indicated no hyperlipemia prior to or after onset of AHPN.

Acute Disease↗
PubMed1989

Failure of a potent cholecystokinin antagonist to protect against diet-induced pancreatitis in mice.

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.

Animals↗
PubMed2006

Downregulation of miR-122 in the rodent and human hepatocellular carcinomas.

MicroRNAs (miRs) are conserved small non-coding RNAs that negatively regulate gene expression. The miR profiles are markedly altered in cancers and some of them have a causal role in tumorigenesis. Here, we report changes in miR expression profile in hepatocellular carcinomas (HCCs) developed in male Fisher rats-fed folic acid, methionine, and choline-deficient (FMD) diet. Comparison of the miR profile by microarray analysis showed altered expression of some miRs in hepatomas compared to the livers from age-matched rats on the normal diet. While let-7a, miR-21, miR-23, miR-130, miR-190, and miR-17-92 family of genes was upregulated, miR-122, an abundant liver-specific miR, was downregulated in the tumors. The decrease in hepatic miR-122 was a tumor-specific event because it did not occur in the rats switched to the folate and methyl-adequate diet after 36 weeks on deficient diet, which did not lead to hepatocarcinogenesis. miR-122 was also silent in a transplanted rat hepatoma. Extrapolation of this study to human primary HCCs revealed that miR-122 expression was significantly (P = 0.013) reduced in 10 out of 20 tumors compared to the pair-matched control tissues. These findings suggest that the downregulation of miR-122 is associated with hepatocarcinogenesis and could be a potential biomarker for liver cancers.

Animals↗
PubMed2000

Plasma concentration of urea, ammonia, glutamine around calving, and the relation of hepatic triglyceride, to plasma ammonia removal and blood acid-base balance.

Two experiments were conducted to test the following two hypotheses: 1) fatty liver could hamper hepatic conversion of ammonia to urea and increase circulating ammonia or Gln% [Gln% = Gln x 100/(Gln + Glu)] in cows around parturition; 2) decreased ureagenesis might cause alkalosis and in turn reduce blood Ca. In the first experiment, 14 Holstein cows were monitored from 27 d prepartum to 35 d postpartum. There was a rise in circulating ammonia and Gln% at calving, suggesting an increase in ammonia passing to and through the liver. Stepwise regression analysis revealed the following relationship for plasma samples at 22 h and liver triglyceride at 2 d postpartum: ammonia (microM) = 32.1+/-0.89 triglyceride (% DM), Gln% = 71.2 + 0.23 triglyceride (% DM) + 1.31 urea (mM). The positive correlation between liver triglyceride and plasma ammonia and Gln% suggests that hepatic triglyceride accumulation might inhibit ureagenesis, thereby increasing ammonia concentration at the perivenous hepatocytes where Gln synthesis occurs and increasing ammonia concentration in blood leaving the liver. In the second experiment, 28 rats were used to determine whether hepatic triglyceride accumulation, induced by choline deficiency, affects urinary ammonia N and blood pH homeostasis. There was a trend for a positive correlation between urinary ammonia N and liver triglyceride. No correlation between liver triglyceride and blood pH, bicarbonate, pCO2 or plasma Ca was found. In conclusion, hepatic triglyceride accumulation may inhibit ureagenesis and result in increased circulating ammonia, Gln% and urinary ammonia N in vivo. Hepatic triglyceride accumulation did not affect blood pH homeostasis.

Acid-Base Equilibrium↗
PubMed1989

Selective proliferation of chemically altered rat liver epithelial cells following hepatic transplantation.

Although proliferation of oval cells is often observed during the early stages of chemical hepatocarcinogenesis, the role of these putative hepatic stem cells during the neoplastic process is unknown. In earlier studies our laboratory showed that feeding a choline-deficient (CD) diet containing 0.05% 2-acetylaminofluorene (CD-AAF) to rats produced three subpopulations of oval cells that antigenically resemble biliary duct cells, fetal liver cells, and transitional cells. In the present investigation we have employed a semiallogeneic transplantation protocol in order to study the fate of these nonparenchymal epithelial cells (NPEC) beyond the 4-week endpoint imposed by the lethality of CD-AAF diet. An enriched NPEC suspension containing gamma-glutamyl-transpeptidase (GGT)-positive oval cells (greater than 75%) was isolated from ACI rats maintained on CD-AAF diet for 3 weeks. The donor cells were transplanted via the portal vein into livers of male F1 progeny (LExACI) that had been fed a CD diet for 7 days prior to receiving a partial hepatectomy and the cell suspension. Host rats were then fed either a CD or choline-supplemented (CS) diet for 12 weeks and killed. Colonies of donor-derived cells identified in frozen sections by their lack of reactivity with ACI anti-LE alloantiserum in indirect immunofluorescence (IF) assays were only observed in rats continuously fed the CD diet. Histochemical analysis indicated that the donor-derived colonies expressed GGT, a preneoplastic marker for liver cancer. IF assays using MAbs previously shown to be capable of distinguishing between oval cells and mature hepatocytes indicated that the donor-derived colonies consisted of a mixture of cells with phenotypes resembling those of mature and immature hepatocytes rather than those of oval or ductal cells. Although the cellular origin of the GGT+ donor-derived colonies has not been unequivocally resolved, our results demonstrate that the livers of rats fed a CD-AAF diet contain a chemically altered call population that can be induced to proliferate by a CD diet. In contrast, a CD diet did not promote colonization when normal hepatocytes were employed as the donor cell population, suggesting that the GGT+ oval cells and not the few contaminating GGT- hepatocytes (1%) in the CD-AAF donor cell suspension were the preneoplastic precursors that gave rise to donor-derived colonies. This transplantation protocol will be useful to define the biological potential of chemically altered liver cells during carcinogenesis.

2-Acetylaminofluorene↗
PubMed1987

The role of necrosis in hepatocellular proliferation and liver tumors.

A sequence of events which appear to be common in the development of cancer in all mammalian species includes atrophy, hyperplasia, and neoplasia. Evidence to date suggests that cell death (necrosis) is an integral, perhaps essential, factor in the initiation and maintenance of the process but the extent to which necrosis is involved, and the nature of that participation is unclear. Choline deficient B6C3F1 mice have been used to accentuate and investigate necrosis and the development of liver neoplasia following exposure to aflatoxin B1. The binding of AFB1 to DNA correlates with the level of acute necrosis and the early appearance of foci of alteration and later, tumor development. Adducts of GSH-DNA varied as do other parameters including products of peroxidation, but the relation of these variables to necrosis and cancer are unclear at present. These parameters are currently under study.

Aflatoxin B1↗
PubMed1989

Role of zinc in treatment of experimental acute pancreatitis in mice.

A study on the effect of zinc feeding on the survival rate as well as the levels of trypsinogen, alpha 2-macroglobulin, zinc, calcium, and magnesium in the plasma, pancreata, and livers of BALB/c mice fed a choline-deficient diet supplemented with 0.5% DL-ethionine (CDE diet) was undertaken. Feeding them a zinc-excess diet significantly increased the survival rate of mice with pancreatitis induced by CDE diet feeding. Trypsinogen concentrations in plasma and pancreas increased in mice fed a CDE diet and further increased in mice fed a zinc-deficient diet. The plasma alpha 2-macroglobulin levels in mice fed a zinc-deficient diet decreased compared to those fed a zinc-adequate or a zinc-excess diet. In mice with pancreatitis, zinc and calcium concentrations of pancreata increased and magnesium concentrations decreased compared to those of normal controls. The calcium concentrations in both livers and pancreata increased, but magnesium concentrations in these tissues decreased. These results suggest that altered mineral metabolism in the pancreas may have contributed to the pathophysiology of the mice with acute pancreatitis and that zinc supplementation in the diet may be therapeutic for pancreatitis.

Acute Disease↗
PubMed1990

Usefulness of rapid production model for pancreatic carcinoma in male hamsters.

The rapid production model of pancreatic duct adenocarcinoma established previously in female Syrian hamsters was applied to male hamsters to confirm the efficacy of the "augmentation pressure" procedure and to reveal sex difference in response to this procedure. Hamsters received 70 mg/kg N-nitrosobis (2-oxopropyl) amine (BOP) as an initiation and two cycles of "augmentation pressure" consisting of ethionine on a choline-deficient diet, methionine and BOP and an additional 20 mg/kg BOP and were killed 10 weeks after the beginning of the experiment. During the experimental period, 28% of the hamsters died and severe body weight loss was observed, however, incidence of pancreatic carcinomas reached 50% which is a significantly higher level than that in hamsters which received BOP without "augmentation pressure". A 66.7% yield of cholangiocellular tumors was also observed. The present result indicates that the "augmentation pressure" effected rapid production of pancreatic carcinoma in male hamsters in spite of sex difference in response.

Animals↗
PubMed1982

Acute hemorrhagic pancreatic necrosis in mice. Induction in male mice treated with estradiol.

Acute hemorrhagic pancreatic necrosis (AHPN) is induced in young female mice fed fo 4 days a choline-deficient diet containing diet 0.5% DL-ethionine (CDE). Contrary to females, male mice do not develop AHPN when fed the same diet. For determination of whether estrogens are involved in the induction of AHPN, estradiol-treated male mice were fed the CDE diet. In such estrogen-treated male mice, the mortality rate, incidence of AHPN, and alterations in biochemical parameters of the pancreas and of serum were similar to those induced by the CDE diet in females.

Acute Disease↗
PubMed1989

The role of sinusoidal stenoses in portal hypertension of liver cirrhosis.

To investigate the significance of sinusoidal stenoses in portal hypertension, liver cirrhosis was produced by feeding a choline-deficient diet for 6 months in rats, and hepatic haemodynamics were examined in the cirrhotic rats before and after feeding ordinary rat pellets for another 2 months. Feeding ordinary rat pellets led to the disappearance of fat droplets accumulated in the hepatocytes, normalization of the size of the swollen hepatocytes, and recovery from sinusoidal stenoses. As a result, increased sinusoidal vascular resistance and elevated portal vein pressure were reduced markedly, and clinical signs of portal hypertension, ascites and collateral blood circulation around the liver improved prominently. These facts suggest that sinusoidal stenoses lead to an increase in hepatic vascular resistance and portal hypertension.

Angiography↗
PubMed2000

Retrospective evaluation of serum ornithine carbamyltransferase activity as an index of hepatotoxicity in toxicological studies with rats.

The sensitivity of elevated serum ornithine carbamyltransferase (OCT) as an index of hepatotoxicity in rats was assessed in different studies conducted over a number of years and originally designed to examine the toxicity or carcinogenicity of a variety of test chemicals and diets. Changes in serum OCT activities were compared with the more widely used clinical endpoints, alanine aminotranserase (ALT) and aspartate aminotransferase (AST). In the first study, rats received a single oral dose of the hepatotoxic and hepatocarcinogenic fungal toxin aflatoxin B(1) (AFB(1)). The increase in enzyme levels between control and AFB(1)-treated rats was greater for serum OCT than for ALT or AST. This response was similar to the changes in serum enzyme levels in studies where rats ingested a hepatotoxic and hepatocarcinogenic choline deficient (CD) diet. When rats were exposed to the hepatotoxic and nephrotoxic fungal toxin fumonisin B(1) (FB(1)) by intraperitoneal injection for 6 days, serum AST and ALT were significantly elevated above control levels while OCT was unaffected. The peroxisome proliferator ciprofibrate caused elevated ALT and AST but not OCT at week 52 of dietary exposure, after the development of liver nodules and tumours. Of the two liver-specific enzymes examined in all of the studies, ALT was more consistently predictive of hepatotoxicity than OCT.

Administration, Oral↗
PubMed1987

Protective effect of glucan-enhanced macrophage function in experimental pancreatitis.

In an effort to assess the impact of enhanced macrophage function in acute pancreatitis, mice were subjected to a choline-deficient diet supplemented by ethionine to induce necrotizing pancreatitis. Treatment with the macrophage stimulant glucan resulted in improved survival rates (58 percent versus 14 percent) and maintenance of pancreatic architecture. Glucan treatment also resulted in decreased plasma and peritoneal trypsin activity, as well as increased trypsin-binding activity in the blood and peritoneal cavity. Plasma interleukin-1, as well as macrophage production of interleukin-1, were increased in the glucan-treated mice, which indicated enhanced macrophage function. These composite findings suggest that by enhancing diverse aspects of reticuloendothelial function, clinical use of immunomodulators may have significant impact on the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed1995

Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis.

In an effort to elucidate factors that determine the severity of an attack of acute pancreatitis, we have quantitated the extent of necrosis and of apoptosis in five different models of experimental acute pancreatitis. Severe pancreatitis was induced by obstructing the opossum common bile-pancreatic duct, by administering to mice 12 hourly injections of a supramaximally stimulating dose of caerulein, and by feeding young female mice a choline-deficient, ethionine-supplemented diet. In each of these models of severe pancreatitis, marked necrosis but very little apoptosis was found. Mild pancreatitis was induced by obstructing the rat common bile-pancreatic duct and by infusing rats with a supramaximally stimulating dose of caerulein. In contrast to our findings in severe pancreatitis, mild pancreatitis was characterized by very little necrosis but a high degree of apoptosis. Our finding that the severity of acute pancreatitis is inversely related to the degree of apoptosis suggests that apoptosis may be a teleologically beneficial response to acinar cell injury in general and especially in acute pancreatitis.

Acute Disease↗
PubMed1987

Enhancement of low-dose N-2-fluorenylacetamide-induced hyperplastic liver nodules by pre-existing cirrhosis.

The potentiating effect of pre-existing cirrhosis on the formation of hyperplastic liver nodules and/or foci was investigated by feeding a low dose (0.008%) of 2-N-fluorenylacetamide (FAA) in a choline-deficient (CD) diet for 32 weeks to cirrhotic and non-cirrhotic rats. Liver cirrhosis was induced by feeding the rats a CD diet for the preceding 36 weeks. The number and area of gamma-glutamyltranspeptidase-positive hyperplastic liver nodules and/or foci were significantly larger in cirrhotic rats exposed to low-dose FAA than in non-cirrhotic rats similarly treated. Hyperplastic liver nodules and/or foci were not observed in rats continuously fed a CD diet alone for 68 weeks (control cirrhotic rats). The results suggest that cirrhotic liver might alter the metabolic response to FAA, even at low doses, and lead to enhanced induction of hyperplastic liver nodules and/or foci.

2-Acetylaminofluorene↗
PubMed1992

Effect of protease inhibitor FUT-175 on acute hemorrhagic pancreatitis in mice.

The effect of FUT-175, a new synthetic trypsin inhibitor, was evaluated in a lethal model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented diet (CDE diet). When FUT-175 was given prophylactically at doses of 20 mg/kg body wt, the survival rate was significantly improved (p less than 0.05). The serum amylase concentration and trypsin activity in serum were also significantly diminished (p less than 0.05). Prophylactic administration of 5 mg/kg body wt of FUT-175 showed a statistically significant decrease in the serum trypsin activity, but it did not improve the survival rate. Therapeutic administration of FUT-175 showed no favorable effect. FUT-175 showed protective effects on the course of severe acute pancreatitis only when given prophylactically at the beginning of the pancreatitis induced by the CDE diet.

Acute Disease↗
PubMed1981

On the existence of variant forms of gamma-glutamyl transferase in regenerating and neoplastic liver.

We attempted to identify variants of gamma-glutamyl transferase (GGT) which may differ in their affinity for Concanavalin A (Con A) in extracts of fetal, regenerating, neoplastic and normal adult rat liver. GGT activity was low in normal liver and did not increase after partial hepatectomy. Feeding a choline-deficient diet containing 0.05% ethionine caused a large increase in hepatic GGT activity which persisted throughout the feeding period of 23 weeks. Practically all of the GGT contained in extracts prepared with Triton X-100 from fetal, regenerating, pre-neoplastic and neoplastic rat liver as well as that from normal adult liver bound to Con A-Sepharose and was eluted from the columns with methyl-alpha-D-mannopyranoside. In contrast, GGT from bovine kidney extracts prepared in an identical way did not bind to Con A-Sepharose. We conclude that if variants of rat liver GGT exist, they cannot be reliable separated by simple affinity chromatography on Con A-Sepharose of Agarose columns.

Animals↗
PubMed1984

Accelerated regression of carcinogen-induced preneoplastic hepatocyte foci by peroxisome proliferators, BR931, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio (N-B-hydroxyethyl)acetamide, and di-(2-ethylhexyl)phthalate.

Enzyme altered preneoplastic hepatocyte foci were induced in male Sprague Dawley rats by a single injection of diethylnitrosamine (DEN) followed by dietary promotion of a choline-deficient (CD) diet for 4 weeks or by feeding a diet containing 0.02% 2-acetylaminofluorene for 4 weeks. BR931, a hypolipidemic agent, administered to rats bearing preneoplastic foci caused a rapid regression of the foci within 4-6 weeks. Di(2-ethylhexyl)phthalate (DEHP), a plasticiser, exerted the similar effect when tested on rats bearing preneoplastic foci induced by DEN + CD diet. Since BR931 and DEHP have been shown to be carcinogenic after long term feeding, the results suggest that the short-term effects of the class of agents known as hypolipidemic peroxisome proliferators are different from the chronic effects. Alternatively, the precursor lesions of hepatocellular carcinomas induced by hypolipidemic, peroxisome proliferators may differ from enzyme altered hepatocytic foci.

Animals↗