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PubMed2005

Soy protein influences insulin sensitivity and cardiovascular risk in male lean SHHF rats.

Previous investigations have demonstrated a marked effect of soy protein on multiple physiological parameters associated with the metabolic syndrome (MS). This preliminary study investigated the physiological effects of soy-based diets on cardiovascular risk in a unique rodent model that reflects early stages of MS. Briefly, lean male SHHF (+/cp) rats were randomly assigned to the following treatment groups: casein (control, C); low-isoflavone (LIS) soy protein isolate; high-isoflavone (HIS) soy protein isolate; or C+ 0.01 % rosiglitazone (CR). Rats were fed for thirty-six weeks. Liver weight, heart weight, total plasma cholesterol, fasting blood glucose were lower in soy-fed animals compared to control (p < 0.01). Body weight, kidney weight, alanine aminotransferase (ALT), fasting plasma insulin, and homeostasis model assessment (HOMA) score were also lower in LIS-fed rodents (p < 0.05) compared to casein treatment. All diet groups exhibited lower urine protein (p < 0.01) and small arteriole content (p < 0.05) compared to controls. LIS feed had a slightly more profound influence on body weight, liver metabolism, and insulin sensitivity. However, both soy diets exhibited marked improvements over a casein-based diet.

Animals↗

PubMed1998

Black tea and mammary gland carcinogenesis by 7,12-dimethylbenz[a]anthracene in rats fed control or high fat diets.

Epidemiological studies suggest that tea may reduce cancer risk, and in laboratory rodents, chemopreventive effects of tea or purified extracts of tea have been demonstrated in lung, gastrointestinal tract and skin. There is some evidence of chemoprevention by tea in the mammary gland, but the data are not conclusive. In order to evaluate more fully the possible influence of black tea on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland tumors in the female S-D (Sprague-Dawley) rat, three large studies were performed: experiment 1, tumorigenesis in rats fed AIN-76A diet and given 25 mg/kg DMBA and 1.25 or 2.5% whole tea extract or water to drink; experiment 2, tumorigenesis in rats given 15 mg/kg DMBA and the same diet and fluids as in experiment 1; experiment 3, tumorigenesis in rats fed control or HF (high fat, corn oil) diet and given 15 mg/kg DMBA and 2% tea or water to drink. Tea was given throughout the experiment; DMBA was given by gastric gavage at 8 weeks of age. There was no consistent effect of tea on tumorigenesis in rats fed AIN-76A diet; there was, however, evidence in experiment 3 of a reduction of tumorigenesis by tea in rats fed the HF diet. In experiment 3, rats fed the HF diet and given water showed the expected increase in tumor burden (number and weight) compared with rats fed control diet. However, rats fed the HF diet and given 2% tea showed no increase in tumor burden; their tumor burden was significantly lower than in rats fed the HF diet and given water (P < 0.01) and was not different from rats fed control diet and given water or tea. In addition, in experiment 3, the number of malignant tumors per tumor-bearing rat was increased by the HF diet in water-drinking rats (P < 0.01) but not in tea-drinking rats. Therefore, it appears that tea partially blocked the promotion of DMBA-induced mammary tumorigenesis by the HF diet.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1995

Immunotoxicologic studies with CI-959, a novel benzothiophene cell activation inhibitor.

CI-959 is an orally effective inhibitor of cellular activation in both in vitro and animal models. To assess the effects of CI-959 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity, and reticuloendothelial system clearance of sRBC. Host resistance was measured in female B6C3F1 mice using Listeria monocytogenes, Streptococcus pneumonia, and B16F10 melanoma models. CI-959 was administered to both species of rodents at 25, 50, and 75 mg/kg/day for 14 days. A vehicle control and two positive controls (cyclophosphamide and dexamethasone) were run concurrently. CI-959 generally did not suppress immunological responses in rats at doses lower than those which also altered body weight gain and reduced spleen and thymus weights. Natural Killer cell activity was significantly reduced at 50 and 75 mg/kg CI-959. At 75 mg/kg rats also exhibited a reduction in ability to make anti-sRBC antibody. The number of T- and B-lymphocytes, proliferative response to mitogens, and macrophage activity of the reticuloendothelial system were not affected by CI-959. CI-959 also did not alter resistance of mice to Listeria monocytogenes, Streptococcus pneumoniae, or B16F10 melanoma cells. Based on these ex vivo and in vivo assays, the rodent immune system does not appear to be a sensitive or toxicologically important target for CI-959.

Animals↗

PubMed2006

Thirteen week feeding study with transgenic maize grain containing event DAS-Ø15Ø7-1 in Sprague-Dawley rats.

Maize line 1507, containing event DAS-Ø15Ø7-1 (1507), is a genetically modified (GM) maize plant that expresses the cry1F gene from Bacillus thuringiensis (Bt) sbsp. aizawai and the phosphinothricin-N-acetyltransferase (pat) gene from Streptomyces viridochromogenes throughout the plant including in the grain expression of the Cry1F protein confers in planta resistance to the European corn borer (ECB; Ostrinia nubilalis Hübner: Crambidae) and other lepidopteran pests. Expression of the PAT protein confers tolerance to the herbicidal active ingredient glufosinate-ammonium. The current study evaluated the nutritional performance of rats fed diets containing 1507 maize grain in a subchronic rodent feeding study. The grains in this study, 1507, its near-isogenic control (33P66), and a non-GM commercial hybrid (33J56) contained similar amounts of proximates, amino acids, minerals, anti-nutrients, and secondary metabolites. The subchronic feeding study compared standard toxicology response variables in rats fed diets containing 1507 maize grain with those in rats fed diets containing non-GM maize grains. All diets were prepared according to the specifications of PMI Nutrition International, LLC Certified Rodent LabDiet 5002 (PMI) 5002). Diets were fed ad libitum to Sprague-Dawley rats for approximately 90 days. In-life response variables included indicators of dietary performance and weekly evaluations for clinical signs of toxicity. No toxicologically significant differences were observed in the nutritional performance variables, clinical and neurobehavioral signs, ophthalmology, clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis), organ weights, and gross and microscopic pathology between any pair of treatment groups. These results demonstrate that 1507 maize grain is as safe and as nutritious as non-GM maize grain.

Alkaline Phosphatase↗

PubMed1995

Impact of vitamin E supplement in standard laboratory animal diet on microvascular manifestation of ischemia/reperfusion injury.

Aimed at improving animal fertility and health, diets for farm and laboratory animals have over the last few years been supplemented with increasing amounts of the antioxidant vitamin E. We now demonstrate by intravital microscopy that feeding hamsters with a vitamin E-supplemented "standard" rodent diet (60 ppm vitamin E) significantly reduces the microvascular manifestations of ischemia/reperfusion injury when compared to animals fed a nonsupplemented diet. Postischemic leukocyte adhesion to venular endothelium was reduced from 770 +/- 204 cells/mm2 at 24 h after reperfusion in control animals on the nonsupplemented diet to 403 +/- 105 cells/mm2 in animals on the "standard" rodent diet (means +/- SD, n = 7 animals per group, p < 0.01). Animals on the nonsupplemented diet showed a dramatic loss of capillary perfusion density until 7 days after reperfusion (to 21 +/- 13% of preischemic baseline values), whereas this loss was significantly attenuated (to 71 +/- 12% of preischemic values, p < 0.01) in animals on the "standard" rodent diet. No difference in the extent of reperfusion injury was seen between animals on the "standard" rodent diet and animals on diets with substantially higher vitamin E supplements (300 ppm-30,000 ppm). Besides underscoring the benefit of vitamin E in reducing the extent of ischemia/reperfusion injury, this study raises the concern that vitamin E supplements in "standard" laboratory animal diets may have a far-reaching impact on biomedical research by jeopardizing established animal models of disease.

Animals↗

PubMed2000

Anti-sense oligonucleotides, for progestin receptors in the VMH and glutamic acid decarboxylase in the VTA, attenuate progesterone-induced lordosis in hamsters and rats.

Immunocytochemical (ICC) staining for progesterone (P) receptors (PRs) and glutamic acid decarboxylase (GAD), the enzyme responsible for GABA production, reveal that there are many PRs in the ventral medial hypothalamus (VMH) and many GAD containing neurons in the ventral tegmental area (VTA). To investigate P's action on lordosis in the VMH and VTA, anti-sense oligos specific to PRs and GAD(65&67) were intracerebrally infused into the VMH and VTA of 24 ovariectomized hamsters and 40 ovariectomized rats. Estradiol benzoate (2 microg) primed hamsters and rats were infused to the VMH and the VTA with either PR (250 ng/1.0 microl infusion) or GAD (500 ng/1.0 microl infusion) anti-sense oligos, their scramble controls, or saline vehicle at hour 0 and again at hour 24. At hr 44, rodents were subcutaneously injected with P (500 microg) and were tested for sexual receptivity with a male 4 h later. There were significant reductions in lordosis of hamsters and rats following PR anti-sense infusions to the VMH compared to scrambled or vehicle control infusions. Effects of PR anti-sense to the VMH were not different from combined VMH and VTA PR anti-sense infusions; however, VMH infusions reduced lordosis compared to VTA-only anti-sense infusions. GAD anti-sense infusions reduced lordosis when infused into the VTA, compared to scrambled or saline vehicle infusions. Lordosis responsiveness following VTA GAD anti-sense infusions was not different from combined VMH and VTA infusions, but VTA infusions of GAD anti-sense reduced lordosis compared to VMH-only anti-sense infusions. These data suggest that in the VMH, PRs are important for P-facilitated lordosis, whereas in the VTA, GABAergic neurons may be an important substrate for mediating P's actions on lordosis of rodents.

Animals↗

PubMed2005

Linkage group selection: rapid gene discovery in malaria parasites.

The identification of parasite genes controlling phenotypes such as drug resistance, virulence, immunogenicity, and transmission is vital to malaria research. Classical genetic methods have achieved these goals only rarely and with difficulty. We describe here a novel genetic method, Linkage Group Selection (LGS), which achieves rapid de novo location of genes encoding selectable phenotypes of malaria parasites. A phenotype-specific selection pressure is applied to the uncloned progeny of a genetic cross between two malaria parasites that differ in the relevant phenotype. Selected and unselected progeny are analyzed using genome-wide quantitative genetic markers. Markers of the "sensitive" parent, which are reduced after selection, are sequenced and located in genomic databases. They are expected to be closely linked to gene(s) determining the phenotype under selection. We have validated LGS with the rodent malaria parasite Plasmodium chabaudi chabaudi using a phenotype, pyrimethamine resistance, whose controlling gene, that encoding dihydrofolate reductase (dhfr), is known. We show that molecular markers closely linked to dhfr, and only those linked to this gene, were reduced or removed by pyrimethamine treatment in accordance with the expectations of LGS.

Animals↗

PubMed2000

Effects of limited access to a fat option on food intake and body composition in female rats.

OBJECTIVE: The present investigation sought to determine if limiting access to an optional fatty food would induce binge-type behavior patterns in non-energy-deprived female rats. METHOD: Four groups of rats had continuous access to a commercial rodent diet throughout the 8-week study. In addition: (1) the control group had no access to vegetable shortening; (2) the high limitation group had access to shortening for 2 hr for 3 days each week; (3) the low limitation group had access to shortening for 2 hr every day; and (4) the no limitation group had continuous access to shortening. RESULTS: As access to the shortening decreased, intake during the 2-hr access period increased. Total energy intake and body weight did not differ among groups. Body fat was greatest in the rats that ate the most cumulative shortening. DISCUSSION: These results indicate that, even under non-energy-deprived conditions, limiting access to a preferred fatty food can induce binge-type behavior in female rats.

Animals↗

PubMed2003

A hybrid 3D watershed algorithm incorporating gradient cues and object models for automatic segmentation of nuclei in confocal image stacks.

BACKGROUND: Automated segmentation of fluorescently-labeled cell nuclei in 3D confocal microscope images is essential to many studies involving morphological and functional analysis. A common source of segmentation error is tight clustering of nuclei. There is a compelling need to minimize these errors for constructing highly automated scoring systems. METHODS: A combination of two approaches is presented. First, an improved distance transform combining intensity gradients and geometric distance is used for the watershed step. Second, an explicit mathematical model for the anatomic characteristics of cell nuclei such as size and shape measures is incorporated. This model is constructed automatically from the data. Deliberate initial over-segmentation of the image data is performed, followed by statistical model-based merging. A confidence score is computed for each detected nucleus, measuring how well the nucleus fits the model. This is used in combination with the intensity gradient to control the merge decisions. RESULTS: Experimental validation on a set of rodent brain cell images showed 97% concordance with the human observer and significant improvement over prior methods. CONCLUSIONS: Combining a gradient-weighted distance transform with a richer morphometric model significantly improves the accuracy of automated segmentation and FISH analysis.

Algorithms↗

PubMed1992

A protective NOD islet-infiltrating CD8+ T cell clone, I.S. 2.15, has in vitro immunosuppressive properties.

Type 1, insulin-dependent diabetes mellitus (IDDM) appears to result from a T cell-dependent destruction of insulin-producing pancreatic beta cells. In non-obese diabetic (NOD) mice and in other rodent models of human IDDM, final expression of disease may be controlled by protective, as well as, destructive T cell influences. Previously, a CD8+ T cell clone, I.S. 2.15, was isolated directly from islets of disease-resistant male NOD mice. Upon transfer to young NOD recipients, the non-cytolytic I.S. 21.5 T cell clone, confers in vivo protection from two forms of accelerated IDDM. The present study demonstrates that I.S. 2.15 T cells induce in vitro immunosuppression. The suppressive effects of I.S. 2.15 T cells are mediated through soluble factor(s) and are independent of T cell activation, cell contact, antigen specificity or the major histocompatibility complex (MHC). By polymerase chain reaction (PCR), I.S. 2.15 T cells contain mRNA species encoding for the potentially immunosuppressive cytokines, interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). The T cell suppressive effects engendered by I.S. 2.15 T cells closely mimic those observed with TGF-beta. Moreover, I.S. 2.15-induced immunosuppression correlates with intracellular levels of TGF-beta mRNA. These results establish that immunoregulatory T cells are present within islets in IDDM-resistant NOD mice and may impact on final disease expression through the production of soluble mediator(s).

Animals↗

PubMed2004

Effect of paternal tamoxifen on the expression of insulin-like growth factor 2 and insulin-like growth factor type 1 receptor in the post-implantation rat embryos.

Nuclear transplantation studies demonstrated the importance of paternal contribution to embryogenesis. Paternal treatment with agents like cyclophosphamide and 5-azacytidine has been shown to cause an increase in pre-implantation loss (PIL) and post-implantation loss (POL). Studies from our laboratory have shown that paternal tamoxifen treatment increases PIL and POL. It was observed that the PIL occurred at day 2 of gestation (embryo at 2-4 cell stage) and the POL occurred around day 9 of gestation (mid-gestation). The insulin-like growth factor (IGF) system represents one of the major growth-controlling system expressed in the embryo. Several studies suggest that in rodents, insulin-like growth factor 2 (Igf2) signaling through the insulin-like growth factor type 1 receptor (Igf1r) modulates embryo growth at around days 9-11 of gestation (mid-gestation). The present study was undertaken to evaluate the expression of Igf2 and Igf1r transcript by RT-PCR in the post-implantation embryos obtained after paternal tamoxifen treatment. It was observed that both the genes were down regulated in resorbed embryos (POL). Since Igf2 is an imprinted gene and the imprint mark is established during spermatogenesis, the present study suggests that paternal tamoxifen treatment may have affected imprinting of the gene during spermatogenesis thereby decreasing its expression and leading to increase in POL. This is to our knowledge the first study correlating the increase in post-implantation embryo loss obtained after paternal drug treatment with the decrease in the expression of Igf2 in these embryos.

Animals↗

PubMed2003

Effect of prolonged treatment with tyramine on glucose tolerance in streptozotocin-induced diabetic rats.

The biogenic amine tyramine has been reported to stimulate in vitro glucose transport in adipocytes, cardiomyocytes and skeletal muscle, and to improve in vivo glucose utilization in rats. These effects were dependent on amine oxidation, since they were blocked by inhibitors of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO). We thus tested in this work whether a prolonged treatment with tyramine could improve glucose tolerance in streptozotocin-induced diabetic rats. First, tyramine content of standard rodent chow was determined by HPLC and daily tyramine intake of control rats was estimated to be around 26 micromol/kg body weight. Then, tyramine was administred during 3 weeks in streptozotocin-induced diabetic rats at 29 micromol/kg by daily i.p. injection alone or together with vanadate 0.02 micromol/kg. In another group of diabetic rats, tyramine was subcutaneously delivered at 116 micromol/kg/day by osmotic minipumps. All tyramine treatments resulted in a decrease of the hyperglycemic responses to an i.p. glucose load. Adipocytes isolated from either untreated or treated diabetic rats were sensitive to the stimulation of glucose uptake by tyramine. However, diabetic animals receiving tyramine for three weeks did not recover from their hyperglycemia, hypoinsulinemia and glucosuria. These results show that the improvement of glucose tolerance induced by prolonged tyramine administration occurs in an insulin-depleted model and probably results from peripheral insulin-like actions of the oxidation of MAO/SSAO substrates, such as the stimulation of glucose uptake into adipocytes.

Adipocytes↗

PubMed2005

Cajal-like cells in the upper urinary tract: comparative study in various species.

The interstitial cells of Cajal (ICC) play an important role in the control of gut motility. The recognition that the ICC cell membrane harbors the c-kit receptor (CD117) sparked rapid advancement in ICC research on the gut and certain pathologies using immunochemical and molecular methods. The question arises whether ICC exist in the upper urinary tract (UUT) and trigger motility. The present study analyzed the distribution of the c-kit receptor in the normal human UUT compared with various species. Immunohistochemistry (alkaline-phosphatase-anti-alkaline-phosphatase technique, immunofluorescence) was applied on serial sections using monoclonal and polyclonal antibodies recognizing the c-kit receptor. C-kit staining was compared with standard endothelial, epithelial, neurogenic, histiocytic, mast cell, and smooth muscle markers, as well as a negative control. Normal proximal, middle, and distal ureter segments were analyzed in rodents, carnivores, porcines, cow, and humans. In all species the c-kit receptor was detected in either round or spindle-shaped cells. Because of their antigenic profile, the round cells were identified as mast cells occurring in all layers of the ureteral wall except the urothelium and were more frequent in humans. In contrast, the population of spindle-shaped cells was marked only by anti-c-kit receptor antibodies, thus resembling ICC. These ICC-like cells were found among the inner and outer smooth muscle layers and in the lamina propria of all species. In humans, spindle-shaped cells were also found vertically oriented within the urothelium. Our morphological data present for the first time the distribution of ICC in the UUT of various species. The ubiquitous distribution in the entire pyeloureteral complex provides strong evidence that ICC generate electrical pacemaker activity within the UUT as an intrinsic system. Animal studies may help to understand the physiological importance of these ICC-like cells. The significance of these findings needs to be evaluated by functional studies and investigations of certain congenital pathologies with disturbance of the urinary outflow.

Animals↗

PubMed2005

Gene expression in human skeletal muscle: alternative normalization method and effect of repeated biopsies.

The reverse transcriptase-polymerase chain reaction (RT-PCR) method has lately become widely used to determine transcription and mRNA content in rodent and human muscle samples. However, the common use of endogenous controls for correcting for variance in cDNA between samples is not optimal. Specifically, we investigated (1) a new normalization method based on determining the cDNA content by the flourophores PicoGreen and OliGreen, (2) effect of repeated muscle biopsies on mRNA gene expression, and (3) the spatial heterogeneity in mRNA expression across the muscle. Standard curves using oligo standards revealed a high degree of sensitivity and linearity (2.5-45 ng; R2>0.99) with OliGreen reagent, as was the case for OliGreen analyses with standard curves constructed from serial dilutions of representative RT samples (R2 >0.99 for a ten times dilution range of a representative reversed transcribed (RT) sample). Likewise, PicoGreen reagent detected the RNA:DNA hybrid content in RT samples with great sensitivity. Standard curves constructed from both double-stranded lambda DNA (1-10 ng) and from serial dilutions of representative RT samples consistently resulted in linearity with R2 >0.99. The present determination of cDNA content in reversed transcribed human skeletal muscle RNA samples by both PicoGreen and OliGreen analyses suggests that these fluorophores provide a potential alternative normalization procedure for human gene expression studies. In addition, the present study shows that multiple muscle biopsies obtained from the same muscle do not influence the mRNA response induced by an acute exercise bout for any of the genes examined.

Adaptation, Physiological↗

PubMed2001

Plasticity of skeletal myosin in endurance-trained rats (I). A quantitative study.

The aim of this study was to quantify modifications in the expression of skeletal myosin light chain (MLC) and myosin heavy chain (MHC) isoforms of five muscles, according to their fiber composition and function, following endurance training in rats. Rodents were assigned randomly to one of two groups: caged sedentary controls (C) or endurance-trained rats (T). In T rats, three out of the four fast and mixed muscles studied exhibited a significant increase in the expression of MLC1s, 1f and 2s and a significant decrease in MLC2f and 3f, the exception being the plantaris muscle. In two out of the four muscles we observed a significant increase in MHCI and IIa, the exception being both gastrocnemii, where the expression of MHCI did not change. In the soleus of T rats, the expression of MLC1s, 2f and 3f decreased significantly, while that of MLC2s increased significantly, compared with those of C rats. The expression of MHCIIa in T rats decreased significantly compared with that of C rats, while the expression of MHCI increased significantly. In all muscles studied, a significant slowing of myosin isoforms was observed after endurance training.

Animals↗

PubMed2004

Non-invasive analysis of myoblast transplants in rodent cardiac muscle.

BACKGROUND: Magnetic resonance imaging (MRI) of magnetically labeled stem cells is a non-invasive approach that can provide images with high spatial resolution. We evaluated the ability of a commercially available, Food and Drug Administration (FDA) approved contrast agent to allow the monitoring of myoblast transplants in the rodent heart. METHODS AND RESULTS: Primary rat myoblasts were efficiently labeled by incubation with ferumoxide-polycation complexes and labeled cells retained their normal capacity to generate mature myotubes. Intra-cellular iron-oxide accumulation resulted in MRI contrast changes, allowing for three-dimensional, non-invasive detection of labeled cells in the rodent myocardium. Histological analysis of hearts injected with labeled myoblasts or control, non-viable myoblasts revealed that areas of MRI contrast changes corresponded to iron contained within engrafted myotubes and scavenger cells up to two months post-injection. CONCLUSIONS: The high sensitivity of MR imaging will allow for non-invasive studies of cardiac stem cell migration and homing. Additional techniques are in development to non-invasively determine stem cell engraftment rates, viability and differentiation.

Animals↗

PubMed1996

N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.

Amides↗

PubMed1987

Application of microencapsulation for toxicology studies. II. Toxicity of microencapsulated trichloroethylene in Fischer 344 rats.

Gelatin-sorbitol microcapsules containing 44.1% trichloroethylene (TCE) were prepared and mixed in NIH-07 rodent meal diet and provided at microcapsule concentrations of 0 (untreated control group), 1.25, 2.5, 5.0, or 10% (equivalent to 0, 0.55, 1.10, 2.21, or 4.41% TCE, respectively) to groups of 10 male F344 rats for 14 days. An additional control group received diets containing 5% empty capsules. For comparisons, TCE dissolved in corn oil was administered by gavage to different groups of 10 male rats for 14 consecutive days at dose levels adjusted to correspond to those in the feed study. Treatment-related deaths occurred only in the highest dose group of the gavage study. Body weight gain and feed consumption were reduced in high-dose groups of both the feed and gavage studies. There was no measurable loss of TCE in feed sampled from the cages during the study. Dose-related increases in organ (liver and kidney) weight/body weight ratios, individual cell necrosis in the liver, and hepatic microsomal NADPH cytochrome c reductase and peroxisomal palmitoyl-CoA oxidase and catalase activities were found in both the dosed-fed and gavage groups. Induction of cytochrome P-450 occurred only in the dosed-feed study. There were no significant compound-related pathologic lesions observed in the kidneys, the only other organ examined microscopically. Differences in lethality, cytochrome P-450 levels, and induction of microsomal or peroxisomal enzyme activities were attributed to differences in the method of dosing (gavage versus dosed-feed). The demonstration of no significant loss of TCE from the feed and of similar toxic effects produced by microencapsulated TCE via feed and TCE in corn oil via gavage indicate that microencapsulation can provide an excellent alternative exposure route for studying the oral toxicological properties of volatile chemicals, such as TCE, in rats.

Animal Feed↗