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F Raul

Publications and source records attributed to F Raul.

At least 37 records · Page 2Linked to original sources
PubMed2000

Blood polyamine levels after oral ornithine load, a diagnostic marker of hyperproliferative premalignant and malignant stages in a model of colon carcinogenesis.

This study was performed to determine whether a single oral dose of ornithine (Orn), the substrate of ornithine decarboxylase (ODC), increases blood concentrations of polyamines premalignant stage, and whether blood polyamine levels could be used as predictive markers of cancer development. Male Wistar rats were divided into two groups, control and 1,2-dimethylhydrazine (DMH)-treated rats. DMH (20 mg/kg body weight) was injected intraperitoneally once weekly for 10 weeks. Five, 7, and 10 weeks after the last injection when premalignant aberrant crypt foci have developed in the colon, blood levels of putrescine (PUT), spermidine (SPD), and spermine (SPM) were estimated before and after an oral load of ORN. The results showed that after a single oral load of Orn, blood PUT, but not SPD and SPM, concentrations were significantly higher in DMH-treated rats compared with control rats, indicating enhancement of ODC activity. These results support the view that the increased blood concentration of PUT after administration of Orn may be a useful marker to detect hyperproliferative premalignant and malignant stages of cancer development.

1,2-Dimethylhydrazine↗
PubMed1999

Severe dietary restriction initiated in aged rats: evidence for poor adaptation in terms of protein metabolism and intestinal functions.

BACKGROUND: Protein energy malnutrition is a common finding in elderly people, increasing morbidity and mortality in aged inpatients. Investigations need to be developed to counteract malnutrition-induced alterations early and to avoid potential irreversible lesions. The aim of this experimental study was to evaluate time-response to severe dietary restriction (DR) initiated in aged rats in terms of protein metabolism and digestive trophicity. MATERIALS AND METHODS: After the acclimatization period, 22-month-old male rats were randomized into six groups: three control groups, fed ad libitum for 3, 6 or 12 weeks with a standard diet and three corresponding dietary-restricted groups fed for the same periods with only 50% of the spontaneous intake. Intestinal mucosa, liver and skeletal muscles (soleus, extensor digitorum longus and tibialis anterior muscle) were removed when the rats were killed. RESULTS: DR induced dramatic body weight loss (up to 50% of initial body weight after 12 weeks DR). Protein metabolism was affected in terms of nitrogen balance (P < 0.01) and protein content, in particular at the splanchnic level. Morphometrically, the intestine structure was altered after 12 weeks of DR (P < 0.01), and this atrophy was correlated with malabsorption of mannitol (P < 0. 01). Ileal hydrolase activities were decreased throughout the 12 weeks of DR. CONCLUSIONS: Aged rats clearly exhibit a defect of adaptation to long-term DR initiated at an advanced age. Severe DR leads to malnutrition, which becomes of major importance after 12 weeks, in particular at the intestine level. Hence, application of these experimental results to elderly, malnourished people may contribute to a better knowledge of denutrition-induced disorders.

Aging↗
PubMed1999

Promotion of intestinal carcinogenesis by dietary methionine.

The metabolism of the polyamines spermidine and spermine is known to be enhanced in rapidly proliferating cells. Methionine is a precursor of the aminopropyl moieties of these amines. Therefore, it was of interest to study the effects of a methionine supplemented diet on polyamine metabolism and preneoplastic changes occurring in the intestinal tract of rats treated with the chemical carcinogen azoxymethane (AOM). Adult Wistar rats received 15 mg AOM/kg body wt (i.p.) once each week for 2 weeks. Thereafter, the rats were randomly divided into two groups and received controlled isoenergetic diets containing the same amount of folate, choline and vitamin B12 during 12 weeks: one group was kept on a standard diet; the other was fed the same diet, except that 1% L-methionine was added at the expense of carbohydrates. After 12 weeks, the administration of the methionine-supplemented diet stimulated the turnover rate of ileal epithelial cells, indicating enhanced crypt cell proliferation. Furthermore, in this group, a 2-fold increase in the number of aberrant hyperproliferative crypts and the appearance of tumors was observed in the colon. These effects were accompanied by the increased formation of spermidine and spermine due to the enhancement of S-adenosylmethionine decarboxylase activity and by the upregulation of Cdx-1, a homeobox gene with oncogenic potentials. The experimental data do not support the view of a chemopreventive effect of dietary methionine supplementation on intestinal carcinogenesis in rats, even at an early phase of preneoplastic development, but rather suggest that methionine promotes intestinal carcinogenesis.

Animals↗
PubMed1999

Oral administration of a glutamine-enriched diet before or after endotoxin challenge in aged rats has limited effects.

Numerous studies indicate beneficial effects of glutamine (Gln) in many models of catabolic adult rats. No data were available for aged rats. The effects of oral L-Gln-enriched diet were tested in endotoxemic 24-mo old rats. First, rats received for 7 d (from d0 to d7) an oral diet supplemented with either L-Gln [1g/(kg. d)] or casein (Cas: isonitrogenous supply) prior to lipopolysaccharide (LPS) challenge. The rats were then killed after 24 h food deprivation (from d7 to d8). Endotoxemia induced a catabolic response as shown by muscle glutamine depletion, hyperphenylalaninemia, small bowel atrophy and impaired functionality and bacterial translocation. The Gln-enriched diet did not prevent muscle Gln depletion but significantly (P </= 0.05) enhanced plantaris protein content by 18% compared to the Cas-LPS rats and reduced the plasma phenylalanine-to-tyrosine ratio (1.32 +/- 0.05 vs. 1.54 +/- 0.10, respectively, P </= 0.01). Gut translocation and histomorphology were unaffected by diet. However, Gln pretreatment reduced the fall in sucrase and glucoamylase activities in the ileum, respectively, by 55 and 63% vs. Cas supplementation (P </= 0.05). In a second study, after endotoxin challenge, healthy 24-mo-old rats were then food-deprived for 2 d (from d0 to d2), received a nonpurified diet for 4 d (from d2 to d6), and then Cas or L-Gln-supplemented diet for 7 d (from d6 to d13). No beneficial effects of Gln supplementation were observed except an increase of 50 and 56% in sucrase and glucoamylase activities in the ileum of Gln-treated rats, (P </= 0.01 vs. healthy rats). In conclusion, the effects of L-Gln supplementation in aged endotoxemic rats were limited.

Aging↗
PubMed1999

Comparative study of glycine, alanine or casein as inert nitrogen sources in endotoxemic rats.

Pharmacological effects of dietary amino acids (AA) and peptides must be compared to an isonitrogenous control that is as inert as possible. To establish a rationale for the choice of such a control, potential metabolic and nutritional effects of three currently used nitrogenous controls (glycine, alanine, and casein) were evaluated in an endotoxemic rat model that has well-defined alterations in AA and protein metabolism. Five-week-old male Sprague-Dawley rats (113 +/- 1 g) were randomly assigned to four groups and received at d 0 an intraperitoneal injection of endotoxin (3 mg/kg). After withdrawal of food for 24 h, the rats were enterally refed for 48 h with a liquid diet (Osmolite((R))) supplemented with 0.19 g N. kg(-1). d(-1) in the form of glycine [lipopolysaccharide (LPS)-GLY group], alanine (LPS-ALA group) or casein (LPS-CAS group). One group (LPS group) received only Osmolite((R)). Plasma, two skeletal muscles, the liver and the intestine were then removed. Body and tissue weights and tissue protein contents did not differ among the four groups. Intestine histomorphometry showed no significant difference among groups. Jejunal hydrolase activities were significantly affected by the nitrogenous supplementations, but no effect was observed in the ileum. Only limited significant effects were observed on plasma and tissue-free AA concentrations, except for an accumulation of glycine in the plasma and tissues from the LPS-GLY group, compared to other groups. Overall, whereas glycine as a nitrogenous control should be used with care, either alanine or casein may be used as the "placebo," with the choice depending on the study to be performed.

Alanine↗
PubMed1998

Concomitant changes in polyamine pools and DNA methylation during growth inhibition of human colonic cancer cells.

The effects of CGP 48664 and DFMO, selective inhibitors of the key enzymes of polyamine biosynthesis, namely, of S-adenosylmethionine decarboxylase (AdoMetDC) and ornithine decarboxylase (ODC), were investigated on growth, polyamine metabolism, and DNA methylation in the Caco-2 cell line. Both inhibitors caused growth inhibition and affected similarly the initial expression of the differentiation marker sucrase. In the presence of the AdoMetDC inhibitor, ODC activity and the intracellular pool of putrescine were enhanced, whereas the spermidine and spermine pools were decreased. In the presence of the ODC inhibitor, the AdoMetDC activity was enhanced and the intracellular pools of putrescine and spermidine were decreased. With both compounds, the degree of global DNA methylation was increased. Spermine and spermidine (but not putrescine) selectively inhibited cytosine-DNA methyltransferase activity. Our observations suggest that spermidine (and to a lesser extent spermine) controls DNA methylation and may represent a crucial step in the regulation of Caco-2 cell growth and differentiation.

Adenosylmethionine Decarboxylase↗
PubMed1998

A pancreatic extract-enriched diet corrects ileal mucosa atrophy in endotoxemic aged rats.

An altered adaptive response of the pancreas and small intestine to nutritional stress has an adverse impact upon nutritional status in elderly humans or senescent rats. We evaluated the effects of a pancreatic extract nutritional supplement on intestinal mucosa adaptation in LPS-treated aged rats. Endotoxemic rats were starved for 48 hr and then refed ad libitum for four days with a standard diet. Afterwards they received, over one week, the standard diet enriched with either pancreatic extract (PE) (2.4 g/day) or casein (isonitrogenous to PE supplement). Healthy aged rats fed ad libitum with a standard diet were studied in parallel. Whereas no changes occurred in the jejunal segment, an adaptive villus hyperplasia was observed in the proximal ileum of rats receiving PE without an increase in the brush border hydrolase activities. Our results indicate that oral PE supplementation exerts a trophic effect on the ileal mucosa of aged rats in response to nutritional stress.

Aging↗
PubMed1998

Preventive administration of ornithine alpha-ketoglutarate improves intestinal mucosal repair after transient ischemia in rats.

OBJECTIVES: To investigate whether the preventive enteral administration of a polyamine precursor, such as ornithine alpha-ketoglutaiate (OKG), has a beneficial effect on the repair process of the intestinal mucosa after transient mesenteric vascular occlusion. DESIGN: A controlled laboratory study. SETTING: A research laboratory facility at the Research Institute for Digestive Cancer. SUBJECTS: Male Wistar rats, weighing 330 to 350 g, housed individually in plastic cages under standardized conditions (23 degrees C, 73 degrees F, 60% relative humidity, 12-hr light and 12-hr dark cycles). INTERVENTIONS: Intragastrically, 1.5 or 17 hrs before surgery, animals received either distilled water (water group), or an amino acid solution of either OKG (1 g/kg) or L-lysine (0.68 g/kg) in distilled water under isonitrogenous conditions. Intestinal ischemia was produced in anesthetized rats by occluding the superior mesenteric artery for 90 mins with a microbulldog clamp. At the end of the ischemic period, the clamp was removed, allowing reperfusion, and the abdomen was closed. MEASUREMENTS AND MAIN RESULTS: At 0, 4, and 24 hrs after ischemia/reperfusion, the midjejuno-ileum was resected. Intestinal morphology, polyamine content, and hydrolase activities were determined. In all groups at the end of the ischemic period, the villi were dismantled with preservation of the crypts. Rats treated with OKG exhibited a restoration of short villi by 4 hrs after ischemia/reperfusion. In other groups, the villi remained extensively denuded. By 24 hrs, only rats treated with OKG showed a complete recovery of normal mucosal architecture. The amount of the polyamines, putrescine, and spermidine were significantly enhanced by 4 hrs after ischemia/reperfusion in the mucosa of rats treated with OKG, as compared with the two other groups. At a functional level, sucrase and aminopeptidase activities remained significantly higher by 4 hrs of ischemia/reperfusion in rats treated with OKG as compared with rats receiving water or lysine. By 24 hrs, hydrolase activities were normalized in rats treated with OKG, whereas an important deficit in hydrolase activities remained in rats receiving either water or lysine. CONCLUSIONS: OKG administration to rats did not prevent ischemic damage of the intestinal mucosa, but it accelerated the repair of the mucosa during reperfusion. OKG favored the restitution of normal villus architecture and the functional recovery of the intestinal mucosa. We hypothesized that OKG-triggered metabolites might mediate the restitution process and contribute to the healing of the intestinal mucosa by minimizing cell injury and by promoting the replacement of injured cells.

Aminopeptidases↗
PubMed1998

Premature stimulation of rat sucrase-isomaltase (SI) by exogenous insulin and the analog B-Asp10 is regulated by a receptor-mediated signal triggering SI gene transcription.

The mechanism(s) by which insulin enhance prematurely the activity of brush border membrane (BBM) hydrolases in rat immature intestine is unknown. Therefore, we have compared the responses of four BBM enzymes [sucrase-isomaltase (SI), maltase, lactase-phloridzine hydrolase (LPH), and aminopeptidase] with exogenous insulin, the analog B-Asp10, IGF-I, and antireceptor MAb [insulin-receptor (IR) MAb] given to preweaning pups. Low doses of insulin caused a precocious induction of SI and of SI mRNA and stimulated maltase activity without effect on LPH nor on aminopeptidase activities. IGF-I given at the same dose as that of insulin had no detectable effect on these enzymes. Administration to sucklings of IR MAb prevented the effect of endogenous insulin by inhibiting the expression of SI and maltase without effect on LPH activity. B-Asp10, an insulin analogue that exhibits in vitro a 3.5-fold increase in receptor affinity with sustained signaling of the receptor tyrosine kinase, caused an overexpression of SI by 3.5-fold and of maltase by 1.5-fold compared with equivalent doses of normal insulin. The premature increases in SI activity, SI mRNA, and maltase activity in response to insulin were dose-dependent and were associated with dose-dependent increases in intracellular spermine and spermidine concentrations. In conclusion, these data suggest that the premature induction of SI by insulin is mediated by a dose-dependent signal initiated by binding of the hormone to its intestinal receptor, which after transduction into the cell indirectly triggers the transcription of the SI gene, possibly by changes in intracellular polyamine concentrations.

Aging↗
PubMed1998

Polyamine metabolism as target for cancer chemoprevention (review).

The natural polyamines putrescine, spermidine and spermine are intimately involved in growth-related processes. More and more evidence indicates that the excessive accumulation of putrescine and spermidine favors malignant transformation of cells. Selective depletion of putrescine has been shown to restore in some transformed cells the normal phenotype. Inhibition of polyamine formation appears, therefore, a rational target in chemoprevention. Clinical trials with 2-(difluoromethyl)ornithine, a selective inactivator of ornithine decarboxylase, a key enzyme of polyamine biosynthesis, are promising. Structural analogs of the polyamines with polyamine-mimetic or antagonist properties, and calmodulin antagonists are other types of drugs which affect several key reactions of polyamine metabolism, and appear to be candidates for the prevention of carcinogenesis especially of the gastrointestinal tract.

Antineoplastic Agents↗
PubMed1997

Suppression of preneoplastic changes in the intestine of rats fed low levels of polyamines.

Administration for 7 days of an enteral diet that is naturally deficient in polyamines strikingly reduces the preneoplastic changes observed in the intestines of adult Wistar rats previously treated with the carcinogen 1,2-dimethylhydrazine. On the contrary, supplementing the enteral diet with spermidine favors preneoplastic development. The effects of the low-polyamine diet included a 40% decline in the putrescine content of the intestinal mucosa, a significant decrease in the turnover rate of the epithelial cells from the crypts to villus tip in the ileum, and a 2-fold reduction in the number of abnormal colonic crypts. The experimental data support the view that it might be of interest to control the dietary intake of polyamines in the clinical management of cancer patients.

1,2-Dimethylhydrazine↗
PubMed1997

Enteral supplementation with ornithine alpha ketoglutarate improves the early adaptive response to resection.

BACKGROUND: Polyamine synthesis or uptake, or both, might be an important event that initiates the adaptive hyperplasia seen in the intestinal remnant after partial small bowel resection. AIM: The ability of an enteral diet supplemented with the ornithine salt: ornithine alpha ketoglutarate (OKG), a precursor for polyamine synthesis, to modulate the adaptive response of the remnant ileum after jejunectomy was evaluated. METHODS: Adult Wistar rats underwent a resection of the proximal 50% of the small intestine. Controls underwent a single transection. The rats were fed intragastrically with a nutritive mixture supplemented either with casein hydrolysate or with OKG (1 g/kg). The isoenergetic and isonitrogeneous diets was given continuously for seven days. RESULTS: Villus and crypt hyperplasia was observed in the remnant ileum compared with transfected controls. OKG supplementation started after resection a further increase in villus height. After resection, OKG supplementation increased significantly the putrescine content and the amount of ornithine decarboxylase mRNA. A twofold to threefold increase of sucrase activity was measured in the resected animals compared with the transected rats. In contrast, the amount of sucrase mRNA was significantly lower in the ileum of the resected rats and OKG supplementation initiated a further drop in the amount of sucrase mRNA without pronounced changes in enzyme activity. CONCLUSIONS: The adaptive hypertrophy seen after resection can be accelerated by supplementing the diet with ornithine (OKG) a precursor of polyamine synthesis. In the remnant ileum, the reduced amount of sucrase mRNA, despite the increased level of sucrase activity, suggests a post-translational control of sucrase expression.

Adaptation, Biological↗
PubMed1996

Sucrase-isomaltase gene expression in suckling rat intestine: hormonal, dietary, and growth factor control.

The effect of hydrocortisone, sucrose, and epidermal growth factor (EGF), alone or in combination, was investigated on the precocious expression of sucrase activity and sucrase-isomaltase (SI) mRNA in normal and adrenalectomized (ADX) suckling rats. In normal rats, each regulatory factor administered separately from 12 to 13 days of age induced a parallel expression of sucrase activity and SI mRNA. A potentiation of both sucrase activity and SI mRNA was observed after administration of hydrocortisone plus sucrose. Only SI mRNA was potentiated after EGF-sucrose administration or EGF-hydrocortisone administration. However, the potentiation of the activity was obtained after a prolonged treatment period of 4 days. In adrenalectomized rats, sucrose and EGF were still able to induce precocious induction of SI mRNA and sucrase activity, but sucrase activity was lowered by 75% by sucrose and by 30% by EGF. The combined treatments gave results similar to those obtained in normal rats. The results obtained in ADX rats indicate that the effects of sucrose and EGF on the precocious expression of sucrase and the potentiation of SI mRNA are independent of endogenous glucocorticoids. The rate of [3H]thymidine incorporation into mucosal DNA of normal sucklings was similar after single or combined treatments. From this study, we conclude that the precocious induction of intestinal sucrase by various regulatory factors, alone or in combination, is primarily regulated at the level of mRNA and is independent of increases in cellular proliferation and circulating glucocorticoids.

Adrenalectomy↗
PubMed1996

Prophylactic administration of L-arginine improves the intestinal barrier function after mesenteric ischaemia.

BACKGROUND: Ischaemia/reperfusion (I/R) of the intestine causes mucosal injury associated with a high death rate in rats. AIM: To investigate whether nitric oxide (NO) might be implicated in the recovery of the intestinal mucosa after ischaemic insult. METHODS: Wistar rats were subjected to mesenteric artery occlusion for 90 minutes. The animals were given either L-arginine, the substrate of NO synthase, or molsidomine, a NO donor. The controls received casein hydrolysate. The compounds were administered by gavage 19, 16, and 1.5 hours before ischaemia. Mucosal barrier permeability and cGMP content were determined 24 hours after ischaemia. RESULTS: Survival after I/R was 50% in the control group. Animals treated with L-arginine or molsidomine exhibited a higher survival rate (70% and 83% respectively). Mucosal barrier permeability was decreased in rats receiving L-arginine or molsidomine compared with controls (4.0 (0.9) and 2.6 (0.6) v 11.2 (1.6) 14C-PEG pmol/segment, p < 0.05). Increased cGMP content was seen in the mucosa of the L-arginine group. CONCLUSION: The findings suggest that pretreatment with L-arginine or molsidomine ameliorates survival after intestinal I/R and improves mucosal barrier function.

Amino Acids, Essential↗
PubMed1996

Premature expression of sucrase-isomaltase triggered by corticoid-dependent changes in polyamine metabolism.

A possible link between the corticoid-elicited premature expression of intestinal sucrase-isomaltase (SI) and endogenous changes in polyamine metabolism was investigated in preweaned rats. Starvation at postnatal day 12 caused a precocious expression of SI mRNA and activity. A rapid upsurge of serum corticosterone was observed during the first hour of isolation, occurring in parallel with a transient enhancement of ornithine decarboxylase (ODC) expression and followed by an increase in mucosal polyamine content. Administration of the antiglucocorticoid RU-38486 completely prevented the starvation-evoked stimulation of ODC. The treatment of the sucklings with RU-38486 or with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, dramatically reduced the amount of SI mRNA. When exogenous hydrocortisone (HC) was administered to 12-day-old sucklings nourished by their dam, an important accumulation of ODC mRNA was observed in the intestinal mucosa 4 h after treatment. Sucklings receiving HC and treated concomitantly with either RU-38486 or DFMO exhibited a reduced amount of ODC mRNA and a dramatic decline in both SI mRNA and activity. Altogether these data support the view that the premature induction of SI expression is dependent on changes in ODC expression and polyamine metabolism that can be elicited either by endogenous changes or by exogenously administered glucocorticoids.

Animals↗
PubMed1995

Beneficial effects of L-arginine on intestinal epithelial restitution after ischemic damage in rats.

The polyamines are involved in repair processes after intestinal ischemia. Arginine and ornithine, both precursors of polyamines were therefore expected to exert beneficial effects on mucosal barrier dysfunction. Arginine may also generate NO and there is support for the view that NO may be beneficial after an ischemic insult. Male Wistar rats were given, by gavage, isonitrogenous solutions of L-arginine (0.5 g/kg) or L-ornithine (0.7 g/kg) 17 and 2 h before ischemia. Controls received an isonitrogenous solution of casein hydrolysate (1 g/kg). Transient intestinal ischemia was produced in anesthetized rats by occluding the superior mesenteric artery for 90 min. Intestinal morphology, hydrolase activities, polyamine and cGMP contents, and cell proliferation rates were determined 4 h after reperfusion. Administration of arginine or ornithine did not prevent ischemic damage but accelerated morphological repair, enhanced cell proliferation, and polyamine content was observed. Arginine was significantly more effective than ornithine. Formation of cGMP was enhanced after arginine administration. NG-nitroarginine methylester, an inhibitor of NO synthase, prevented the arginine effects on mucosal repair. We conclude that arginine-derived NO is an important mediator in the restitution of intestinal mucosa by minimizing cell injury during reperfusion.

Aminopeptidases↗