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PubMed1996

Proliferation of pronephric lymphocytes of carp, Cyprinus carpio induced by extracts of Bothriocephalus acheilognathi.

The interaction between Bothriocephalus acheilognathi Yamaguti, 1934 (Cestoda) and pronephric lymphocytes of carp, Cyprinus carpio L. was studied by examining proliferation of lymphocytes isolated from both naïve fish and fish injected intraperitoneally with cestode extract. Lymphocytes from naïve hosts were stimulated to proliferate in the presence of the extract depending upon the extract protein concentrations; lower concentrations (0.01-0.05 microgram/ml) induced the greatest response, and immunosuppression occurred at higher concentrations. Significant differences were noted in fish that received intraperitoneal injections of parasite extracts. Five days post-injection, lymphocyte proliferation was significantly greater in these individuals compared with sham injected or untreated controls. This difference was reduced at 10 days post-injection, although the response was dependent on the concentration of the parasite extract. The possible significance of the observed stimulation/suppression of lymphocyte activity to establishment of the parasite in the wild is discussed.

Analysis of Variance↗
PubMed1994

Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis.

The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS). Puromycin aminonucleoside (PAN) was injected intraperitoneally in rats and the right kidney was removed on day 22. Nephrotic rats received successive intraperitoneal injections of PAN on days 27, 34, and 41. Control rats were subjected to a nephrectomy or a sham operation on day 22. Animals were divided into six groups. In group 1, the PAN-injected rats were fed a standard diet containing 22% protein. In group 2, the PAN-injected rats were fed a low protein diet containing 6% protein, starting on the same day as the first PAN injection. In group 3, the nephrectomized rats without PAN were fed a standard diet. In group 4, the nephrectomized rats without PAN were fed a low protein diet for the same period. In group 5, the sham operated rats were fed a standard diet. In group 6, the sham operated rats were fed a low protein diet for the same period. Rats were sacrificed on days 0, 60 or 80 after the initial PAN or saline injection. The percentage of sclerotic glomeruli in group 1 rats increased markedly with time, reaching 77% on day 80. The mRNA levels encoding for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-2, TIMP-1 and TIMP-2 increased significantly as glomerulosclerosis progressed, whereas MMP-1 and MMP-3 mRNA levels were unchanged, and no MMP-9 mRNA was detected throughout the experiments. In group 2, the low protein diet reduced the prevalence of glomerulosclerosis and attenuated the increased mRNA expression for ECM components, MMP-2, TIMP-1 and TIMP-2 in FGS glomeruli. In groups 3 through 6, mRNA levels for ECM components decreased with age, whereas those for MMPs and TIMPs changed little throughout the experiments. Immunofluorescence studies revealed the accumulation of types I, III and IV collagens, laminin, and HSPG in the sclerotic area and low protein diet attenuated the accumulation of these proteins. These data suggest that glomerulosclerosis may result from an imbalance among ECM components, MMPs and TIMPs and that a low protein diet attenuates the otherwise increased levels of mRNA for ECM components, MMP-2, TIMP-1 and TIMP-2 in glomerulosclerosis.

Animals↗
PubMed1989

Protective role of fructose 1,6-bisphosphate during CCl4 hepatotoxicity in rats.

Rats were injected intraperitoneally with CCl4 (2.5 ml/kg body wt.) and the hepatotoxicity was compared with that of rats receiving the same dose of CCl4 and an intraperitoneal injection of fructose 1,6-bisphosphate (2 g/kg body wt.). A 50-70% decrease in plasma aspartate aminotransferase and alanine aminotransferase activities was observed in the latter treatment, indicating a protective role of the sugar bisphosphate in CCl4 hepatotoxicity. The protection was accompanied by elevated hepatic activities of ornithine decarboxylase at 2, 6 and 24 h, S-adenosylmethionine decarboxylase at 6 h, and spermidine N1-acetyltransferase at 2 h. The increase in the enzymes involved in polyamine metabolism was shown in our previous work [Rao, Young & Mehendale (1989) J. Biochem. Toxicol. 4, 55-63] to correlate with increased polyamine synthesis or interconversion, which was related to the extent of hepatocellular regeneration. The hepatic contents of fructose 1,6-bisphosphate and ATP significantly decreased after CCl4 treatment, and administration of the sugar bisphosphate increased hepatic ATP. Fructose 1,6-bisphosphate, an intermediary metabolite of the glycolytic pathway, may decrease CCl4 toxicity by increasing the ATP in the hepatocytes. The ATP generated is useful for hepatocellular regeneration and tissue repair, events which enable the liver to overcome CCl4 injury.

Acetyltransferases↗
PubMed1996

Interleukin-6 is required for pristane-induced plasma cell hyperplasia in mice.

Intraperitoneal injection of pristane induces production of interleukin-6 (IL-6) and either plasmacytosis or plasmacytoma in mice, depending upon the genetic background. Pristane does not induce plasmacytoma in IL-6 knockout (IL-6-/-) mice, suggesting that IL-6 is required for this process. In the present study we determined whether IL-6 is also required for pristane-induced hyperplasia of normal plasma cells. Pristane was injected intraperitoneally into IL-6-/- and IL-6 wild-type (IL-6+/+) mice. Overall there were more deaths in IL-6+/+ mice (85%) than in IL-6-/- mice (40%), P = 0.024. Hyperplastic lymph node and spleen weight did not differ (P = 0.82 and P = 0.15, respectively) in IL-6-/- versus IL-6+/+ mice. Lymphocytosis with similar patterns of expression of B-cell (B220) and T-cell (Thy-1) antigens was noted in both IL-6-/- and IL-6+/+ mice. However, morphological studies, dual fluorescent staining for Syn-1 and B220 antigens (syn-1+ B220+ cells), and intracytoplasmic Ig staining revealed plasma cell hyperplasia in lymph node and spleen from IL-6+/+, but not IL-6-/-, mice. These plasma cells from IL-6+/+ mice were polyclonal and unable to induce tumour formation in severe combined immunodeficient mice. These data demonstrate that IL-6 is required for pristane-induced hyperplasia of polyclonal plasma cells in mice.

Animals↗
PubMed2003

Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis.

Hepatobiliary transporters are down-regulated in toxic and cholestatic liver injury. Cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) are attributed to mediate this regulation, but their particular contribution in vivo is still unknown. Thus, we studied the molecular mechanisms by which Ntcp, Oatp1, Oatp2, and Mrp2 are regulated by proinflammatory cytokines during liver injury. Rats were injected intraperitoneally with either carbon tetrachloride or endotoxin. Inactivation of TNF-alpha and IL-1 beta was achieved by repetitive intraperitoneal injection of etanercept and anakinra, respectively. Messenger RNA (mRNA) levels of transporters and binding activities as well as nuclear protein levels of Ntcp, Oatp2, and Mrp2 transactivators were determined 20 to 24 hours later. In contrast to IL-1 beta, TNF-alpha inactivation alone fully prevented down-regulation of Ntcp, Oatp1, and Oatp2 mRNA as well as reduced binding activity of hepatocyte nuclear factor 1 (HNF-1) in CCl(4)-induced toxic injury. In endotoxemia, down-regulation of Mrp2, and partially in case of Ntcp, could be prevented by IL-1 beta but not TNF-alpha blockade. However, inactivation of either cytokine led to preservation of HNF1 and partially of retinoid X receptor/retinoic acid receptor (RXR/RAR) binding activity. No effect of anticytokines was seen on pregnane X receptor (PXR) and constitutive androstane receptor (CAR) binding activity as well as nuclear protein mass. In conclusion, TNF-alpha represents the master cytokine responsible for HNF1-dependent down-regulation of Ntcp, Oatp1, and Oatp2 in CCl(4)-induced toxic liver injury. IL-1 beta predominates in a complex signaling network of Ntcp and Mrp2 regulation in cholestatic liver injury. In contrast to in vitro studies, HNF1 and RXR/RAR-independent mechanisms appear to be more important in regulation of Mrp2 and Ntcp gene expression in endotoxemia.

ATP-Binding Cassette Transporters↗
PubMed1976

Copper-induced activation of aortic lysyl oxidase in vivo.

Raising day-old chicks on diets lacking copper severely depressed the activity of lysyl oxidase, a copper metalloenzyme in connective tissue. Administration of CuSO4 either through the diet or through intraperitoneal injections restored the lysyl oxidase activity in aortic tissue. Two hours after the chicks received CuSO4 (1 mg/kg) the activity of lysyl oxidase rose rapidly to attain, within 4-6 hr, a new steady-state level which was five to 20 times higher than the basal (saline-injected) activity. Twenty hours after copper administration, activity was still higher, in some experiments double that achieved at 6 hr. Very low amounts of cycloheximide injected intraperitoneally 45 min before and 3 hr after copper suppressed the activation response by two-thirds. Cycloheximide given 2 or 4 hr after the copper was only one-half as effective. Actinomycin D caused only a 10-15% inhibition of the copper-induced activation. The data suggest that copper is a key regulator of lysyl oxidase activity in aorta and may in fact be a major determinant of the steady-state levels of the enzyme in that tissue.

Amino Acid Oxidoreductases↗
PubMed2000

Anti-rat ICAM-1 antibody does not influence the course of experimental melanin-induced uveitis.

PURPOSE: Experimental melanin-induced uveitis (EMIU) is a T cell-mediated rat model of acute anterior uveitis. We investigated the possibility of preventing the inflammation with monoclonal antibody directed against rat intercellular adhesion molecule 1 (ICAM-1). METHODS: To induce EMIU, Lewis rats were immunized with bovine ocular melanin extract (250-500 microg). Each day from day 6 post-immunization, rats were injected intraperitoneally with anti-ICAM-1 monoclonal antibody (IA29) or normal mouse serum, and examined with a slit-lamp biomicroscope. On the first day of clinical inflammation, intravital microscopy of iris vasculature was performed on each animal following intraperitoneal injection of rhodamine 6G. At the peak of clinical inflammation, rats were killed, and eyes were examined histologically. Binding potency of IA29 was tested by flow cytometry using concanavalin A-stimulated rat T cells. Immunohistochemical staining was used to detect IA29 on rat uveal vascular endothelium. RESULTS: The ability of IA29 to bind T cell blasts was present to a 1:2000 dilution, and IA29 was readily detectable on uveal vascular endothelium following systemic administration. However, there was no significant difference (p > 0.05) in incidence, time of onset, or severity or histological appearance of EMIU for the rats treated with IA29 when compared with the control rats. Intravital microscopy revealed sticking of leukocytes in the iris vasculature in both groups. CONCLUSIONS: We were unable to demonstrate an inhibitory effect of anti-rat ICAM-1 antibody on the outcome of EMIU. Our observations may reflect a redundancy in the adhesion molecule profile responsible for this uveitis.

Animals↗
PubMed2002

Experimental renal failure and iron overload: a histomorphometric study in the alveolar bone of rats.

Renal failure is a serious disease of a relatively high incidence, which among other lesions, causes bone alterations. These patients frequently suffer from anemia that is generally treated with iron. Given that iron overload inhibits bone formation, our aim was to evaluate the effect of iron on the interradicular bone of animals with experimental renal failure. Acute renal failure was induced in male rats by 5/6 nephrectomy. The animals were subjected to iron overload in the form of daily intraperitoneal injections of 88 mg/kg body weight of iron-dextran over a period of 16 days. Tetracyclines were injected intraperitoneally 14 days apart to evaluate dynamic parameters of bone. Serum urea and creatinine levels were evaluated immediately before the animals were killed on day 30. Static and dynamic histomorphometric measurements were performed. The data indicate that the iron overload modified the response of the renal failure animals which showed decreased interradicular bone volume and adynamic bone disease, characterized by reduced cell activity. These results should be taken into account when renal failure patients treated with iron must undergo dental treatments that depend on bone forming activity for their success.

Acute Kidney Injury↗
PubMed1984

The effects of dietary tryptophan levels on growth and metabolism of rainbow trout (Salmo gairdneri).

Groups of rainbow trout (Salmo gairdneri) (mean weight 14 g) were given diets containing 0.8, 1.3, 2, 3, 4 or 6 g tryptophan/kg diet for 12 weeks. By analysis of the growth results, the dietary requirement of tryptophan was found to be 2.5 g/kg diet (equivalent to 50 mg/kg biomass per d). Carbon dioxide expired by trout following intraperitoneal injection of [14COOH]tryptophan contained little radioactivity when dietary tryptophan level was low but, above 2.0 g/kg diet, it increased rapidly with increasing dietary tryptophan level. The break point in the dose-response curve did not, however, coincide with that from the growth results. Changes in concentrations of free tryptophan in blood and liver and activity of hepatic tryptophan pyrrolase (EC 1. 13. 11. 11) in response to changes in dietary tryptophan concentration did not provide reliable indicators for quantifying dietary requirement. Unlike the situation in mammals, blood tryptophan was not protein-bound to any appreciable extent. Tryptophan pyrrolase of trout has properties which suggest it has no apoenzyme form. In fish given adequate levels of tryptophan injected intraperitoneally with a tracer dose of [14COOH]tryptophan, 60% of the dose was incorporated into body protein within 1 d. The turnover of the label in this protein is very slow. Those trout given diets deficient in tryptophan suffered from severe scoliosis and lordosis as well as having increased liver and kidney levels of calcium, magnesium, sodium and potassium.

Animals↗
PubMed2005

Experimental renal failure and iron overload: a histomorphometric study in rat tibia.

Renal failure (RF) is a serious disease of relatively high incidence, known to cause bone alterations. RF patients frequently suffer anemia, which is usually treated with iron. Given that iron overload inhibits bone formation, the aim of the present study was to evaluate the effect of iron on the subchondral bone of rat tibiae, using a model of renal failure. Male Wistar rats were subjected to experimental nephrectomy in order to induce renal failure and to iron overload by daily intraperitoneal injections of 88 mg/kg body weight of iron-dextran for 16 days. Tetracyclines were injected intraperitoneally to evaluate dynamic parameters of bone. Undecalcified histological sections of the tibiae were obtained. Serum urea, creatinine, and paratohormone (PTH) levels were evaluated 30 days after the onset of the experiment. Static and dynamic histomorphometric measurements were performed. Iron overload modified the response of the animals with renal failure: a reduction in bone forming activity compatible with adynamic bone disease and a decrease in peritrabecular fibrosis were observed. Our results suggest that iron is yet one more factor involved in the imbalance in bone metabolism typically found in renal failure patients treated with iron, rendering diagnosis and treatment of bone disease in these patients more complex.

Animals↗
PubMed2003

Effects of laparoscopic models on anaerobic bacterial growth with bacteroides fragilis in experimentally induced peritonitis.

BACKGROUND: Previous reports of recurrent intra-abdominal abcess formation after the laparoscopic treatment of perforated acute appendicitis led us to investigate the possible effects of gas insufflation on the spread of infection. We previously showed that Escherichia coli counts were significantly higher in a laparoscopy group that underwent carbon dioxide (CO2) insufflation than in control and laparotomy groups. The aim of this study is to investigate the effects of intra-abdominal CO2 and nitrous oxide (N2O) insufflation on anaerobic bacterial growth in a rat model. METHODS: A standard strain of Bacteroides fragilis (ATCC 25285) was injected intraperitoneally (1 x 10(6) cfu/mL per kilogram) in 40 Wistar rats under sterile conditions. Forty rats with induced peritonitis were randomly divided into five groups: control, laparotomy, CO2 insufflation, N2O insufflation, and one group without pneumoperitoneum. Eight hours after the intraperitoneal injection of B. fragilis, peritoneal aspirates were obtained and inoculated onto Brucella agar. At the sixteenth hour of induced peritoneal infection (corresponding to hour 8 in the laparoscopy groups) all animals underwent laparotomy; peritoneal aspirates were obtained and inoculated into Brucella agar for bacterial counts. The colonies of B. fragilis were counted manually, and the results were expressed as the mean number of colony-forming units per milliliter. RESULTS: No significant differences in microorganism counts were noted between the study groups before the procedure (p>.05 for all comparisons). We observed a significant increase in the number of bacteria (mean +/- SD) in the CO2 insufflation group between hour 8 and hour 16 of peritoneal contamination. CONCLUSION: The results suggest that CO2 insufflation may promote the growth of intra-abdominal anaerobic bacteria. Such bacterial growth may lead to intra-abdominal abcess formation or cause localized peritonitis to develop into generalized peritonitis. We suggest that laparoscopy without pneumoperitoneum may be preferred in patients with peritonitis.

Animals↗
PubMed1987

Conjugates of ara-AMP with lactosaminated albumin: a study on their immunogenicity in mouse and rat.

Complexes of albumin with oligosaccharides have been successfully employed in experimental chemotherapy as hepatotropic carriers of antiviral drugs or as vectors of anticancer-agents, but their clinical use is hampered by an immune response they might evoke. In the present experiments we have studied the humoral immunogenicity of conjugates of 9-beta-D-arabinofuranosyl adenine 5'-monophosphate (ara-AMP) with lactosaminated albumin (L-SA), in mice and rats. These complexes were prepared with the aim of increasing the chemotherapeutic index of ara-AMP in the treatment of chronic hepatitis B virus (HBV) infection. L-SA-ara-AMP conjugates prepared with heterologous albumin produced antibodies in mice and rats when repeatedly injected intraperitoneally. The same conjugates prepared with homologous albumin induced only low amounts of antibodies, when given by repeated intraperitoneal injection, whereas they did not evoke antibodies in mice and were tolerogenic in rats when administered repeatedly by the intravenous route. These results suggest that in a clinical use of drug conjugates prepared with oligosaccharide-albumin complexes the risk of an immune response can be reduced by employing human albumin and by injecting the conjugates by the intravenous route.

Animals↗
PubMed1998

Targeted in vivo delivery of therapeutic gene into experimental squamous cell carcinomas using anti-epidermal growth factor receptor antibody: immunogene approach.

The "Fab immunogene" is a novel gene transfer vehicle in which the Fab fragment of anti-human epidermal growth factor (EGF) receptor antibody B4G7 is conjugated with poly-L-lysine to form an affinity complex with DNA. It was developed to target delivery of therapeutic genes into EGF receptor-hyperproducing tumor cells. Various characteristic features of the immunogene have been documented (Chen et al., 1998). Here we add further evidence to prove that in vitro transfer of beta-galactosidase/Fab immunogene is exclusively to EGF receptor-positive cells and that the herpes simplex virus thymidine kinase (TK)/Fab immunogene induces substantial suicide effects on A431 tumor cells when treated together with ganciclovir. The in vivo specificity of the immunogene transfer was examined using A431 tumor-bearing nude mice. When these nude mice were injected intraperitoneally with the chloramphenicol acetyltransferase (CAT)/Fab immunogene, CAT DNA was detected in the tumors as well as in liver and kidney but not brain, whereas CAT mRNA and enzyme activity were detected only in the tumors. Local and intraperitoneal injection of the TK/Fab immunogene and subsequent administration of ganciclovir effectively suppressed the growth of A431 tumors transplanted on the backs of nude mice. These observations suggest a possible application of the Fab immunogene system in cancer gene therapy.

Animals↗
PubMed2003

Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model.

OBJECTIVES: Phage-coded lysins, i.e. murein hydrolases, are enzymes that destroy the cell wall of bacteria. A rapid killing of Streptococcus pneumoniae in the nasopharynx of mice has been described recently using a phage-coded murein hydrolase (enzybiotic). The in vivo effects of a dose-ranging treatment, using either of the phage-coded lytic enzymes Cpl-1 lysozyme or the Pal amidase, have been investigated here in a murine sepsis model. METHODS: Purified Pal amidase and/or Cpl-1 lysozyme were used alone or in combination. These enzymes were injected intraperitoneally at different times after challenge with 5 x 10(7) cfu of a type 6B, antibiotic-resistant S. pneumoniae clinical isolate. RESULTS: Animals challenged with 5 x 10(7) cfu of this strain alone died within 72 h, whereas a single intraperitoneal injection of Cpl-1 or Pal (200 microg; 1100 U) administered 1 h after the bacterial challenge was sufficient to effectively protect the mice, according to unpaired t-test (P<0.0001). Bacteraemia in unprotected mice reached colony counts >10(7) cfu/mL, whereas the mean colony count in lysin-protected animals was <10(6) cfu/mL over time and ultimately became undetectable. Interestingly, a synergic effect in vivo was observed with the combined use of 2.5 microg each of Cpl-1 and Pal. CONCLUSIONS: Our findings suggest strongly that phage lysins protect animals from bacteraemia and death. Moreover, the simultaneous attack of the pneumococcal peptidoglycan by a lysozyme and an amidase leads to a remarkable effect through enhanced destruction of the bacterial cell wall. The benefits of therapy with enzybiotics against pneumococcus reported here might warrant the examination of alternative strategies for the treatment of diseases caused by clinically relevant pathogens.

Amidohydrolases↗
PubMed1980

Zinc absorption and its relationship to intestinal metallothionein.

This study examined the relationship between zinc absorption and metallothionein. Mice injected intraperitoneally with ZnCl2 (2 mmoles) were found within 18 hours to have increased levels of intestinal metallothionein but an apparent decrease in 65Zn absorption. Induction of metallothionein with lower levels of ZnCl2 (0.2 or 0.5 mumoles) resulted in an apparent increase in 65Zn absorption. Isotope dilution experiments showed that intraperitoneal injections of 2 mumoles of ZnCl2 had resulted in a 500-fold dilution of the available 65Zn pool. Mild stress of the animals was shown to increase both 65Zn absorption and intestinal metallothionein. Actinomycin D administered 4 hours prior to ZnCl2 or stress, prevented the induction of metallothionein and obliterated the increase in 65Zn absorption. These results indicate that zinc absorption is directly proportional to intestinal metallothionein levels and imply a significant role for metallothionein in zinc absorption.

Animals↗
PubMed1996

Dietary oxidized frying oil enhances tissue alpha-tocopherol depletion and radioisotope tracer excretion in vitamin E-deficient rats.

Rats fed a diet containing 15% oxidized frying soybean oil (OFO) have been shown to have significantly lower tissue alpha-tocopherol (alpha-T) concentration than rats fed a 15% fresh soybean oil diet. To examine the turnover of alpha-tocopherol, a depletion-repletion experiment and a radioisotope tracer study were conducted. Two groups of male weanling Long-Evans rats were fed vitamin E-deficient diets containing either 15% OFO or 15% vitamin E-stripped fresh soybean oil (control). After 9 wk of depletion, rats fed the OFO diet had significantly higher plasma pyruvate kinase (PK) activity and lower concentrations of alpha-T in RBC, adrenal gland, heart, kidney, liver, spleen, testis and muscle compared with controls (P < 0.05), indicating that the vitamin E-deficient status was aggravated by feeding the OFO diet. After 12 wk, the depleted rats were intraperitoneally injected with a dose of all-rac-alpha-T (2.5 mg/rat, dissolved in Vitamin E-stripped corn oil) every other day. Three doses were administered to each rat during the 1-wk repletion period. Plasma PK activity decreased in both groups (P < 0.05) after repletion but that of the OFO rats was still significantly higher than that of the control group. The repleted OFO gorup also had significantly lower alpha-T concentration in adrenal gland, epididymal fat, liver and spleen than the repleted control group. Two rats from each group that had been vitamin E-depleted for 16 wk were injected intraperitoneally with a single dose of 5-methyl-14C-RRR-alpha-T (740 kBq/kg body weight). During the week after dosing, the radioactivity excreted in urine and feces of the OFO group was 1.3- and 1.7-fold, respectively, that of the control group. Tissue retention of radioactivity was also lower in the OFO rats than in the control rats. The results suggest that more of the alpha-T in the body was catabolized or turned over in rats fed the OFO-containing diet.

Adrenal Glands↗
PubMed1994

A study on the metabolism of spermidine in mammals: purification and identification of a newly identified metabolite, 2-oxo-1-pyrrolidinepropionic acid, in rat urine.

In order to study the metabolism of spermidine in mammals, radioactive spermidine was injected intraperitoneally into a rat and urine was collected for analysis. Incorporation of radioactivity into putreanine, isoputreanine, spermidic acid, and N-aminopropylpyrrolidin-2-one was confirmed by ion-exchange chromatography, thin layer chromatography, and paper electrophoresis, the highest radioactivity being observed in the non-polar and acidic fraction of the collected urine. A radioactive compound was purified from the non-polar and acidic fraction, and identified as 2-oxo-1-pyrrolidinepropionic acid by comparison of its behavior on ion-exchange chromatography and thin layer chromatography with that of authentic 2-oxo-1-pyrrolidinepropionic acid, and recrystallization with the authentic compound. Acid hydrolysis of the radioactive compound produced radioactive spermidic acid, confirming the identification. To examine the interconversion between isoputreanine and N-aminopropylpyrrolidin-2-one, these compounds were deuterated and then intraperitoneally injected into a rat. Analysis of 24-h urine by gas-chromatography-mass-spectrometry indicated no interconversion between the two metabolites of spermidine under these conditions. An intracerebroventricular injection of radioactive spermidine into a rat showed that radioactivity was also incorporated into the metabolites of spermidine in the brain, and oxidative deamination of the aminopropyl moiety of spermidine was thought to be dominant in the central nervous system and vice versa in peripheral organs.

Amino Acids, Diamino↗
PubMed1996

Active interleukin-1 receptor required for maximal progression of acute pancreatitis.

OBJECTIVE: The authors' aim was to determine the requirement for an active interleukin (IL)-1 receptor during the development and progression of acute pancreatitis. SUMMARY OF BACKGROUND DATA: Interleukin-1 is a pro- inflammatory cytokine that has been shown to be produced during acute pancreatitis. Earlier animal studies of moderate and severe pancreatitis have shown that blockade of this powerful mediator is associated with attenuated pancreatic destruction and dramatic increases in survival. The exact role played by IL-1 and the requirement for activation of its receptor in the initiation and progression of pancreatitis is unknown. METHODS: Conventional and IL-1 receptor "knockout" animals were used in parallel experiments of acute pancreatitis induced by intraperitoneal injection of cerulean (50 microg/kg every 1 hour X 4). The conventional mouse strain had the IL-1 receptor blocked prophylactically by means of a recombinant IL-1 receptor antagonist (10 mg/kg injected intraperitoneally every 2 hours). The second mouse strain was genetically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor (IL-1 receptor knockout). Animals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity of pancreatitis determined by serum amylase, lipase, and IL-6 levels and blind histologic grading. Strain-specific controls were used for comparison. RESULTS: The genetic absence of the IL-1 receptor or its pharmacologic blockade resulted in significantly attenuated pancreatic vacuolization, edema, necrosis, inflammation, and enzyme release. Serum IL-6, a marker of inflammation severity, was dramatically decreased in both groups. CONCLUSIONS: Activation of the IL-1 receptor is not required for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflammation.

Acute Disease↗