Biomedical subjects

P Pani

Publications and source records attributed to P Pani.

At least 37 records · Page 2Linked to original sources

PubMed1995

Perturbations of triglycerides but not of cholesterol metabolism are prevented by anti-tumour necrosis factor treatment in rats bearing an ascites hepatoma (Yoshida AH-130).

Rats transplanted with the ascites hepatoma Yoshida AH-130 developed a severely progressive cachexia, characterised by marked alterations in protein and lipid metabolism. In particular, high levels of serum triglycerides and free fatty acids were associated with altered levels and distribution of plasma cholesterol, with increased total and very low-density lipoprotein-low-density lipoprotein (VLDL-LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol. The tumour cells showed high rates of cholesterol synthesis and elevated content of free and esterified cholesterol, whereas total cholesterol synthesis was reduced in the host liver. To determine whether these perturbations could be related to the elevation of tumour necrosis factor alpha (TNF-alpha) previously shown in the AH-130 bearers (Tessitore L, Costelli P, Baccino FM 1993, Br J Cancer, 67, 15-23), either anti-TNF polyclonal antibodies or non-immune IgGs were injected daily after tumour transplantation. The anti-TNF treatment neither affected tumour growth nor prevented the serum cholesterol changes, while attenuating the hypertriglyceridaemia and the elevated serum free fatty acid levels. These data indicate that TNF does not appear to be directly involved in the altered cholesterol metabolism in AH-130 hosts, thus supporting the view that cholesterol metabolism and lipid metabolism are regulated differently during tumour growth.

Animals↗

PubMed1995

Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine.

Lasiocarpine (LC), a pyrrolizidine alkaloid, is able to induce a series of chronic and progressive lesions in rat liver, including a long-lasting block in the cell cycle, the appearance of enlarged hepatocytes (megalocytosis), fibrosis, cirrhosis and malignant neoplasma. In this study the effect of transplantation of normal hepatocytes on the development of LC-induced chronic lesions in rat liver was examined. Two-month-old male Fischer 344 rats were given a single dose of LC (80 mumol/kg i.p.). Four weeks later all animals were subjected to 2/3 partial hepatectomy (PH). In addition, at the time of PH one group of rats were transplanted with normal hepatocytes isolated from a syngeneic donor (10(6) cells/rats via the portal vein), while the other group received only the culture medium. All rats were killed 14 weeks after the operation. Grossly, the liver of rats exposed to LC followed by PH with no transplantation of normal hepatocytes was small in size (% liver wt/body wt 1.66 +/- 0.08) and exhibited a few whitish nodules. Histologically, approximately 88% of the liver section was occupied by enlarged hepatocytes and hepatocyte nodules composed of smaller hepatocytes developed in every animal in this group. In addition, extensive bile ductular proliferation was present. However, the liver of rats that were similarly treated but received normal hepatocytes were significantly larger in size (% liver wt/body wt 2.16 +/- 0.07) and were almost completely free of megalocytosis, bile ductular proliferation and hepatocyte nodules. These findings indicate that transplantation of normal hepatocytes is able to modulate the development of chronic liver lesions induced by LC and may be relevant to the pathogenesis of progressive liver diseases such as neoplasia and cirrhosis.

Animals↗

PubMed1995

The enhancing effect of fasting/refeeding on the growth of nodules selectable by the resistant hepatocyte model in rat liver.

Caloric restriction causes a generalized decrease in growth rate and has been shown to delay the development of both spontaneous and induced neoplasia. In contrast to chronic food restriction, the extreme condition of fasting/refeeding is associated with an overall increase in cell turnover in several organs, including liver, compared with regular feeding. The present study was therefore designed to investigate the effect of complete food withdrawal followed by refeeding on the growth of hepatocyte nodules in initiated rat liver. Male Fischer 344 rats were given a single dose of diethylnitrosamine (DEN, 200 mg/kg i.p.) and then, starting 1 wk later, they were exposed to one or three cycles of fasting (3 days) followed by refeeding (11 days). The control group was fed continuously. Seven weeks after DEN administration all rats were subjected to the resistant hepatocyte model (2-acetylaminofluorene coupled with CCl4) and 2 weeks later 2/3 partial hepatectomy (PH) was performed. All animals were killed 2 weeks after surgery. At PH rats given one cycle of fasting/refeeding had significantly larger glutathione S-transferase 7-7-positive hepatic lesions compared with controls (mean area 0.73 +/- 0.04 versus 0.50 +/- 0.05 mm2, P < 0.025; mean percent area 25.6 +/- 3.2 versus 12.4 +/- 0.9, P < 0.005), while no significant change was observed in their number. The observed differences were more pronounced with three cycles of fasting/refeeding. A similar pattern of results was obtained at the time of killing. It is concluded that fasting/refeeding can exert a positive effect on the growth of rat hepatocyte foci and nodules, in contrast to the general inhibitory effect on carcinogenesis caused by food restriction.

Animals↗

PubMed1995

[Osteoporosis and densitometry screening: preliminary results].

We have examined the bone densitometry with osteoradiometer (ORM) of 355 patients who came to the "Centre for Prevention, Diagnosis and Therapy of Osteoporosis" at the Israelitic Hospital of Rome. 144 patients, 141 females and 3 males, will be studied in the future because their densitometric values are lower than the values considered normal for age and sex. We have valued anamnestic data (age, menopause, pregnancies, excessive use of alcohol and smoke, sedentary habits), medical data hyperthyroidism, OCB, chronic diarrhoea) and surgical data (ovariectomy, thyroidectomy, gastro-duodenal resection, mastectomy) to have the correct outline of the patient situation before further researches and beginning the best medical therapy. For the prevention and screening of people "at risk" densitometry is irreplaceable both pre-clinical osteopeny, and for checking the effects of the therapy.

Adult↗

PubMed1995

Sexually differentiated response to choline in choline deficiency and ethionine intoxication.

A sex difference exists in the response of rats to a choline deficient diet and to ethionine intoxication. Female rats are less susceptible than males to the acute effects of choline deficiency, such as fatty liver and impaired secretion of triglycerides into blood plasma, while they are more susceptible to inhibition of liver protein synthesis and triglyceride accumulation by ethionine. These differences have been ascribed to sex differences in the biosynthesis of phosphatidylcholine in the liver of rats. The available data indicate that females are more dependent than males on the stepwise methylation of phosphatidylethanolamine rather than the direct incorporation of preformed choline. Continuous prefeeding with choline for three weeks was able to shift the female pattern of response to choline deficiency and ethionine intoxication towards that observed in males; thus, choline caused accumulation of hepatic triglycerides and a decrease in plasma triglycerides after choline deficiency, while it protected against ethionine induced triglyceride accumulation and protein synthesis inhibition in the liver. These results suggest that choline prefeeding in females makes them more dependent on choline availability and, thus, more susceptible to a choline deficient diet and less sensitive to ethionine intoxication, as are males. No effect of choline was observed in either choline deficient or ethionine intoxicated male rats.

Animals↗

PubMed1994

Protein kinase C isozyme pattern in liver hyperplasia.

Lead nitrate, a potent activator of protein kinase C, is able to induce reversible rat liver hyperplasia. This phenomenon shows sex-related growth differences: liver hyperplasia as well as its regression by apoptosis occurred earlier and was more pronounced in male than in female rats. Dietary choline administration to females causes a shift of growth pattern towards the male values. Analysis of protein kinase C isoenzymes with hydroxylapatite column chromatography at time points crucial for lead-induced liver proliferation in male, female and choline-treated female rats showed a significant down-regulation of beta and alpha PKC activities and a marked activation of epsilon PKC. The fluctuation of these activities could be related to the rates of DNA synthesis. These data suggest that the observed PKC isoenzymes could be involved in the signal transduction pathway leading to lead-induced liver proliferation.

Animals↗

PubMed1994

An earlier proliferative response of hepatocytes in gamma-glutamyl transferase positive foci to partial hepatectomy.

One of the hallmarks of initiated hepatocytes is their resistance to several hepatotoxins. This property forms the basis for their selective growth under conditions which are inhibitory to the non-initiated hepatocytes. Selective growth of initiated hepatocytes also occurs, albeit at a low level, in initiated rat liver without exposure to any known promoting regimen and/or in the absence of any known selective pressure to which initiated hepatocytes can possibly be resistant. This latter phenotypic property of initiated hepatocytes was further characterized by comparing the kinetics of response of hepatocytes in gamma-glutamyl transferase positive foci and in the surrounding liver to 2/3 partial hepatectomy both in the presence and in the absence of a promoting regimen. Male Fischer 344 rats (130-150 g) were initiated with a single dose of diethylnitrosamine and 1 week later they were placed on either a semi-synthetic basal diet or a promoting diet containing 1% orotic acid. Partial hepatectomy was performed 15 weeks after initiation and animals from both groups were killed at 12, 16, 20, 24, 30, 36, 48, 72 or 96 h after operation. Each animal received a pulse of 3H-labelled thymidine 1 h prior to killing. Autoradiographic studies revealed that hepatocytes in gamma-glutamyl transferase positive foci in the livers of rats fed the basal diet were significantly labelled at 16 h post-partial hepatectomy while surrounding hepatocytes were still virtually quiescent (LI 12.7 +/- 4.7 versus 1.2 +/- 0.5%, respectively). Higher labelling index in foci compared to the surrounding liver was also seen at 20 h post-PH (36.9 +/- 2.6 versus 21.5 +/- 2.4). Similar earlier response of hepatocytes in gamma-glutamyl transferase positive foci was also seen in initiated rats exposed to dietary orotic acid. In addition, orotic acid treatment appears to have imposed a slight delay on the entry of hepatocytes in the surrounding liver into 'S' phase and thereby enhancing the differential of growth response between these two populations.

Animals↗

PubMed1994

Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer.

BACKGROUND: The authors have previously demonstrated in different experimental models that sustained processes of cellular growth are characterized by alterations of cholesterol metabolism not only in the proliferating tissues but also in the plasma compartment. METHODS: To evaluate whether alterations of cholesterol metabolism similar to those observed in experimental models are also associated with human cancer, in the present study cholesterol distribution in tumor tissues and lipid composition in the plasma compartment were determined in patients with different types of gastrointestinal cancer. RESULTS: The results showed that tumor tissues contain increased amounts of cholesterol when compared with the corresponding normal tissues. Intracellular alterations of cholesterol were accompanied by specific changes of cholesterol in the plasma compartment: high-density lipoprotein (HDL) cholesterol was markedly reduced in the serum of patients with gastrointestinal cancer and the lipoprotein profiles showed a decrease in HDL3 fraction, the main HDL subfraction in human serum. The decrease of HDL cholesterol was negatively associated with the clinical stage of the disease. No changes in either total or low-density lipoprotein cholesterol levels were observed. CONCLUSIONS: A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it is possible to hypothesize that low HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in proliferating tissues.

Adult↗

PubMed1993

The development of hepatocellular carcinoma in initiated rat liver after a brief exposure to orotic acid coupled with partial hepatectomy.

Previous work from this laboratory has revealed that a minimum of 10-20 weeks of continuous exposure to 1% dietary orotic acid (OA) is necessary for this regimen to exert a significant promoting effect on the carcinogenic process in rat liver. The present study investigates the effect of partial hepatectomy (PH), given during a short-term exposure (4 weeks) to OA, on the development of hepatocyte nodules (HN) and hepatocellular carcinoma (HCC) initiated by diethylnitrosamine (DEN). Male Fischer 344 rats (130-150 g) were given a single dose of DEN (200 mg/kg body wt i.p.). Starting a week later they were fed either a semisynthetic basal diet (BD) or the same diet containing 1% OA for 2 weeks; two-thirds PH was then performed followed by another 2 weeks of BD or OA diet respectively. At the end of this treatment some animals from both groups were killed while the rest were continued on BD and killed at 20 or 56 weeks thereafter. The results showed no difference between the two groups in the incidence of gamma-glutamyltransferase-positive foci when rats were killed at 2 weeks after PH. However, 4 week exposure to OA coupled with PH significantly enhanced the incidence of HN and HCC when this protocol was followed by 20 or 56 weeks of BD feeding respectively, leading to 63% incidence of HCC in the OA-fed group, while no HCC was observed in control animals. It is concluded that a type of stable or permanent change(s) ('imprinting' or 'memory effect') is induced in the initiated rat liver by this treatment, which imposes a promoting environment in the liver even after withdrawal of the promoter.

Animals↗

PubMed1993

Increasing the interval between initiation and the onset of exposure to orotic acid decreases its promoting effect on rat liver carcinogenesis.

The present study was designed to determine whether a delay in the start of the promoting regimen after the administration of a carcinogen would influence the promoting efficacy of orotic acid on the development of hepatocellular carcinoma in rats. Male Fischer 344 rats weighing 130-150 g were injected with a single dose of diethylnitrosamine (200 mg/kg body wt i.p.) then divided into 3 groups: groups 1 and 2 were given semi-synthetic basal diet or the same diet containing 1% orotic acid (OA) respectively starting 1 week after the carcinogen; group 3 received the OA diet starting 5 weeks after the administration of diethylnitrosamine. Animals from these 3 groups were sacrificed after 25, 32, 42 and 60 weeks of being fed their respective diets. The results indicated that delaying the start of the OA diet after the carcinogen resulted in about a 50% decrease in the incidence of hepatic nodules and/or hepatocellular carcinomas at various time points during the experiment. This decrease in promoting efficacy of OA was not apparently explainable by lack of metabolic effects of OA, at least in terms of induction of nucleotide pool imbalance, a condition that appears to be important for OA to exert its tumor promoting effects.

Animals↗

PubMed1993

Studies on liver tumor promotion in the rat by orotic acid: dose and minimum exposure time required for dietary orotic acid to promote hepatocarcinogenesis.

Our earlier studies indicated that orotic acid, a precursor for pyrimidine nucleotide biosynthesis, exerts a promoting effect on rat hepatocarcinogenesis. The present study was designed to determine the optimum conditions of exposure to orotic acid required for promotion of hepatocarcinogenesis in the initiated rats. The first series of experiments was designed to determine the optimum dose of orotic acid needed to exert its liver tumor promoting effect. Accordingly male Fischer rats were given diethylnitrosamine (200 mg/kg, i.p.) or 0.9% NaCl. One week later carcinogen-injected rats were divided into six groups and fed either basal diet or the same diet containing 0.1, 0.5, 1, 2 or 4% orotic acid. Rats given 0.9% NaCl were fed 4% orotic acid. Two-thirds partial hepatectomy was performed on all animals 10 weeks after starting on their respective diets, and all groups were killed 3 weeks thereafter. Analysis of gamma-glutamyltransferase-positive foci and nodules revealed that 0.5-1% orotic acid in the diet is sufficient to exert a significant promoting effect on the selective growth of initiated hepatocytes, while higher concentrations of orotic acid were only marginally more effective. No gamma-glutamyltransferase-positive foci were observed in animals given 4% orotic acid diet following saline injection. Using 1% orotic acid as the promoting regimen, in the next series, the minimum exposure time required for dietary orotic acid to promote liver carcinogenesis was determined. Male Fischer 344 rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or 0.9% NaCl 18 h after 2/3 partial hepatectomy. After 1 week of recovery one group of rats was continued on a semisynthetic basal diet, while others were transferred to the same basal diet containing 1% orotic acid. Rats that were on the 1% orotic acid diet were progressively transferred to the basal diet after 5, 10, 20, 29 and 40 weeks of exposure. All rats were sacrificed 54 weeks after the beginning of the experiment. The results indicate that 100% of the initiated rats developed hepatic nodules whether or not they were exposed to an orotic acid-containing diet. However, the incidence of hepatocellular carcinoma was greatly increased in animals exposed to the orotic acid diet, with 42% incidence in initiated rats given orotic acid diet for 10 weeks and up to 75% in those exposed to this diet for 40 weeks. Further, promotion by orotic acid exhibited a high metastatic potential with 33-60% metastasis to the lungs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

The effect of long-term feeding of orotic acid on the incidence of foci of enzyme-altered hepatocytes and hepatic nodules in Fischer 344 rats.

The present study was designed to determine the long-term effects of orotic acid (OA), a multi-organ tumor promoter, in rats not exposed to any carcinogen. Male Fischer 344 rats (130-150 g) were divided into two groups and given either a semisynthetic basal diet (BD) or the same diet containing 1% OA. Animals from both groups were killed after 1 or 2 years of treatment. Foci of placental glutathione-S-transferase (GST 7-7) positive hepatocytes were observed in the livers of both BD and OA fed rats killed after 1 year. However, they were more in number in animals receiving OA (156 +/- 21 versus 51 +/- 11/cm3). After 2 years, hepatic nodules were seen in almost all the animals given OA and in approximately 30% of the rats given BD. The nodules were of two main types: (i) a reddish-brown type, present in 85% of rats exposed to OA and in 27% of rats given BD, and (ii) a greyish-white type, found in 50% of animals fed OA and in none of the animals fed BD. These two types of lesions were also histologically different. Reddish-brown nodules were composed of slightly enlarged hepatocytes resembling normal surrounding tissue, while greyish-white nodules were similar in structure and are indistinguishable from hepatic nodules induced by genotoxic chemical carcinogens. The results are interpreted to suggest that the foci/nodules seen in OA-fed rats are due to a promoting effect of OA on spontaneously arising and/or diet-induced altered cells.

Animals↗

PubMed1992

Serum lipoprotein profile in the Mediterranean variant of glucose-6-phosphate dehydrogenase deficiency.

Sardinian males with erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency have lower serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), compared to normals. Since the enzyme deficiency is expressed also in nucleated cells, we studied cholesterol (C) and DNA synthesis and LDL-receptor expression in freshly isolated circulating mononuclear cells from normal and G-6-PD-deficient Sardinians. Synthesis of C (as 14C-acetate incorporation) and of DNA (as 3H-thymidine incorporation) was clearly reduced, both in basal state and after PHA stimulation, in G-6-PD-deficient cells compared to normal cells. On the other hand, no clear influence of G-6-PD deficiency on LDL-receptor expression could be demonstrated. The Mediterranean variant of G-6-PD deficiency is characterized, whatever the metabolic mechanism may be, by a serum lipoprotein pattern of reduced atherogenicity.

Adult↗

PubMed1992

Cholesterol metabolism during the growth of a rat ascites hepatoma (Yoshida AH-130).

The metabolism of cholesterol has been investigated in tumour cells, ascitic fluid and blood serum during the growth of an ascites hepatoma (Yoshida AH-130) in the rat. High rates of cholesterol synthesis and elevated free and esterified cholesterol content were observed in tumour cells. During tumour growth, the host animals progressively developed marked changes in the level and distribution of serum cholesterol consisting in an increase of total cholesterol and of a marked reduction of HDL cholesterol (HDL2 subfraction in particular). In agreement with previous observations, these findings indicate that a consistent pattern of altered cholesterol homeostasis develops in relation to normal or neoplastic tissue growth. High synthetic rates and intracellular accumulation of cholesterol are observed in the proliferating cells. Moreover, blood serum cholesterol decreases in the HDL fraction while it increases in LDLs, suggesting that during proliferative processes cholesterol fluxes between tissues and serum lipoproteins are markedly perturbed.

Animals↗

PubMed1992

Mechanisms of the enhanced liver carcinogenesis by choline in female rats: delay in liver growth after partial hepatectomy and stimulation of 2-AAF mitoinhibition.

Choline given to female rats resulted in an enhanced growth of focal lesions induced by the Solt-Farber model [diethylnitrosamine (DEN) as initiator and 2-acetylaminofluorene (2-AAF) associated with partial hepatectomy (PH) as promoter] when it was administered during promotion, but not during DEN treatment. Based on these data, the mechanisms by which choline might interfere with 2-AAF-PH promotion have been investigated. Compensatory liver growth after PH was faster in females than in males as shown by the restoration of both liver weight and protein content in rats fed a basal diet or a 2-AAF diet. The [3H]thymidine incorporation into DNA occurred a few hours earlier in females than in males. Choline administered to normal females delayed the peak of liver regeneration, by inhibiting [3H]thymidine incorporation into DNA and the mitotic index, resulting in later restoration of liver mass. 2-AAF feeding for 1 week markedly depressed the incorporation of precursor into DNA following PH in both sexes but at greater extent in males. Choline enhanced the mitoinhibition of 2-AAF only in females. No effect of choline was observed in male rats either with or without 2-AAF. The differential effect of choline between sexes in the development of focal lesions appeared to be related to the sexual dimorphism in the 2-AAF mitoinhibition and in the liver proliferation after PH.

2-Acetylaminofluorene↗

PubMed1992

Rat hepatocyte nodules are resistant to the necrogenic effect of D-galactosamine.

D-Galactosamine is a known hepatotoxin which induces liver cell necrosis via depletion of UTP and other uridine nucleotides. Our previous work indicated that nodular hepatocytes have higher levels of total uridine nucleotides compared to normal liver, and in the present study we investigate the effect of galactosamine treatment on hepatocyte nodules and surrounding liver. Hepatic nodules were generated in male Wistar rats according to the Solt and Farber protocol. Six months after initiation animals received a single injection of D-galactosamine (500 mg/kg i.p.) and were then killed 1, 2, 4 or 7 days later. Histological analysis of liver revealed the presence of extensive liver cell necrosis in normal tissue 1 and 2 days after galactosamine treatment. However, very little or no necrosis was detectable inside hepatic nodules at any time point, indicating that these focal areas are resistant to the cytotoxic effect of galactosamine. This type of resistance could be the expression of a new component in the resistant phenotype of hepatic nodules.

Animals↗

PubMed1992

Choline enhances acetylaminofluorene promotion of liver carcinogenesis in female but not in male rats.

The growth of focal lesions during chemical carcinogenesis has been analyzed after promotion in the liver of female and male rats receiving choline for 4 or 5 weeks. The number and size of foci of altered hepatocytes were first evaluated after methylnitrosourea was used as initiator and 2-acetylaminofluorene (2-AAF) associated with carbon tetrachloride as promoter. The development of enzyme-altered foci was lower in female rats than in males. Choline given intragastrically stimulated the growth of focal lesions in female rats by increasing both the enzyme-positive area of the single focus and the total area of positive foci per cm2 of liver section up to levels close to those of males. No effect of choline was observed in males. In a second set of experiments, focal proliferative lesions induced with the Solt-Farber model were larger in females fed a choline-enriched diet during the promotion phase, as a result of the area of the focus and the total area of foci per cm2 of liver being higher than that in females not receiving choline, with no significant change in the number of foci. When cell proliferation was selected during promotion by 2-AAF and carbon tetrachloride instead of partial hepatectomy, the effect of the choline-enriched diet was even more pronounced. This difference might be accounted for by the greater hepatotoxicity of xenobiotics after choline administration. The hypothesis that choline may enhanced hepatocyte susceptibility towards 2-AAF action by an increase in drug toxicity is discussed.

2-Acetylaminofluorene↗

PubMed1992

Serum lipoprotein pattern as modified in G6PD-deficient children during haemolytic anaemia induced by fava bean ingestion.

In the present study, plasma lipid concentrations were determined at different times after admission in sera from G6PD-deficient children during haemolytic crisis induced by fava bean ingestion. Reductions in total, LDL and HDL cholesterol were found in association with the maximum of bone marrow hyperplasia. A return towards normal values occurred with regression of the disease. No changes in other lipid parameters were observed. These data suggest that alterations of lipoprotein pattern, other than in experimental animals, are also present in humans with non-malignant proliferative processes. These changes appear to be a consequence of the disease, probably due to an increased utilization of cholesterol by proliferating cells.

Anemia, Hemolytic↗