RESUMEN
We compute the optical conductivity and polarization for an out-of-plane deformation in graphene nanostructure using a theoretical approach based on Dirac equation solutions on curved2+1dimensional space-time, where the space part is considered to correspond to the Beltrami pseudosphere which belongs to the family of surfaces with negative constant Gaussian curvature. We found that different parameters of deformation along one direction translate into an enhancement of the optical conductivity peaks and polarization magnitude in the far-infrared frequencies. This allows for a very high degree of polarization with a single layer graphene and opens up a potential prospect of employing graphene layer as efficient polarizers. Therefore the experimental predictions related to the electronic configuration of the corresponding graphene-like sample may be explicitly worked out.
RESUMEN
BACKGROUND: Despite recent progressions in the treatment of melanoma, the response to conventional therapies and the long-term survival in melanoma patients still remain poor. Recently, the use of nanoparticles (NPs) has been highlighted for promoting the chemotherapeutic effects of cytotoxic drugs in melanoma. The aim of this study is to mechanistically evaluate the potential of titanium dioxide (TiO2) nanoparticles (NPs) for enhancing chemotherapy effects in in vitro and in vivo models of murine melanoma. METHODS: The F10 melanoma cells were exposed to different concentrations of TiO2 NPs and/or cisplatin, then cell growth, cell viability, and cell death were evaluated. In parallel, C57BL/6 syngeneic melanoma mice were treated by TiO2 NPs and/or cisplatin, and then drug responses, tumor size and mice's organs were studied pathologically. Autophagy was examined by evaluating the formation of autophagosomes and gene expression levels of autophagy markers (ATG5 and ATG6) by fluorescent microscopy and qPCR, respectively. RESULTS: Nontoxic concentrations of TiO2 NPs (50 µg/ml) promote anti-proliferative and cytotoxic effects of cisplatin in F10 melanoma cells, which is mediated through the induction of autophagy and necrotic cell death. Whereas TiO2 NPs have no cytotoxic or metastatic effects in melanoma mice, its combination with cisplatin enhances drug responses (up to 50%), leading to higher inhibition of tumor growth compared with each monotherapy. CONCLUSION: The combination of TiO2 NP with cisplatin enhances chemotherapy response in both in vitro and in vivo melanoma models. In addition, autophagy plays an essential role during sensitizing melanoma cells to chemotherapy.
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Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Cisplatino/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Nanopartículas/uso terapéutico , Titanio/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Autofagosomas , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Beclina-1/genética , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Combinación de Medicamentos , Sinergismo Farmacológico , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Necroptosis/efectos de los fármacos , Tamaño de la Partícula , Distribución Aleatoria , Bazo/efectos de los fármacos , Titanio/administración & dosificación , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Ameloblastoma is a common locally invasive but slow-growing neoplasm of the jaws with an odontogenic origin. Association between BRAF V600E mutation and clinicopathologic features and behavior of ameloblastoma remains controversial. This study aimed to evaluate BRAF V600E gene mutation and expression of its related proteins with clinicopathologic parameters in conventional ameloblastoma. MATERIAL AND METHODS: 50 Formalin-fixed paraffin-embedded blocks were included in this study. Immunohistochemistry was done using rabbit monoclonal BRAF V600E mutation-specific antibody VE1. Quantitative real-time polymerase chain reaction assay was used for evaluating of BRAF V600E mutation. RESULTS: Expression of BRAF V600E antibody was Positive in 42 out of 50 cases (84%). 46 (92%) out of 50 specimens showed BRAF V600E mutation. There were 13 cases of recurrence (26%). 3 out of 4 cases with negative mutations did not show recurrence. CONCLUSIONS: We report the highest frequency (92%) of BRAF V600E mutation in ameloblastomas in the Iranian population. Although there was not a significant association between BRAF V600Epositive immunoexpression and recurrence and clinicopathologic parameters, its high frequency could emphasize its role as a therapeutic marker in the future.
Asunto(s)
Ameloblastoma , Biomarcadores de Tumor , Humanos , Irán , Mutación , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
AIMS: Mycoplasma agassizii can cause upper respiratory tract disease in the threatened desert tortoise of the Southwestern United States. Two technical challenges have impeded critical microbiological studies of this microorganism: (i) its small size limits the use of light microscopy for cell counting and (ii) its extremely slow growth in broth and agar cultures impedes colony counting. Our aim was to develop a rapid and sensitive flow cytometric method using a vital fluorescent dye to enumerate viable M. agassizii cells. METHODS AND RESULTS: Here, we demonstrate that the nonfluorescent molecule 5-carboxyfluorescein (5-CF) diacetate acetoxymethyl ester penetrates M. agassizii cell membranes and it is converted in the cytoplasm to the fluorescent molecule 5-CF by the action of intracellular esterases. Labelled mycoplasma cells can be easily detected by flow cytometry, and cultures with as few as 100 viable mycoplasma cells ml(-1) can be labelled and counted in less than 1 h. Experiments using temperature-induced cell death demonstrated that only viable M. agassizii cells are labelled with this procedure. CONCLUSIONS: A rapid and sensitive flow cytometric technique has been developed for enumerating viable M. agassizii cells. SIGNIFICANCE AND IMPACT OF THE STUDY: This technique should facilitate basic immunological, biochemical and pharmacological studies of this important pathogen which may lead to new diagnostic and therapeutic methods.
Asunto(s)
Citometría de Flujo/métodos , Infecciones por Mycoplasma/diagnóstico , Mycoplasma/aislamiento & purificación , Enfermedades Respiratorias/veterinaria , Tortugas/microbiología , Animales , Fluoresceínas , Enfermedades Respiratorias/diagnóstico , Sudoeste de Estados UnidosRESUMEN
BACKGROUND AND OBJECTIVES: Solid tumors evade the host immunologic responses they initiate by unknown mechanisms. The authors investigated patterns of cytokine content in human colon carcinomas, colon cancer cell lines in vitro, and nude mouse xenografts from those lines in order to clarify those mechanisms. METHODS: Epithelial tumor cell lines were developed from specimens of human colon adenocarcinoma. Aliquots of these cells were then xenografted into female heterozygous BALB/c nu/+ immunologically deficient mice and serially passaged. Original tumors, cell lines, and resultant xenografts were then analyzed for histology/cytology and for levels of TGF-beta and TNF-alpha by enzyme linked immunoassay. RESULTS: Cytokine levels were elevated beyond baseline mucosal levels in original tumors and xenograft mouse tumors but not detectable in extracts from epithelial cultures. CONCLUSIONS: While the precise source of cytokine production remains unclear, these data suggest tumor/host interactions not found in pure epithelial cancer cells in culture.
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Adenocarcinoma/metabolismo , Neoplasias del Colon/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adenocarcinoma/patología , Animales , Neoplasias del Colon/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patologíaRESUMEN
Techniques for creation of colon carcinoma epithelial cells lines in long-term culture have been available for years, but these techniques have involved mechanical or enzymatic methods to separate epithelial cells from surrounding tissues. While this practice has been intermittently successful, the effect of these traumatic methods on long-term cellular behavior is unknown. Samples of colon carcinoma from patient volunteers were subjected to serial nonenzymatic disruptions of carcinoma cells from surrounding fibrous tissues. Cells were collected, allowed to proliferate, and then tested for their epithelial characteristics (mucin, vimentin, cytokeratin, colon-specific antigen, carcinoembryonic antigen) by immunohistochemistry and flow cytometry. Growth characteristics were determined by phase-contrast microscopy, multiple passage, and freeze/thaw effects. Tumorigenicity was proven in nude mice. Of 11 initial attempts, three resulted in stable long-term culture lines of cells which are demonstrated to behave similarly to the original tumors from which they were derived. This technique adds another reliable in vitro tool for the study of colon carcinoma.
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Adenocarcinoma/patología , Neoplasias del Colon/patología , Técnicas Citológicas , Células Tumorales Cultivadas , Animales , División Celular , Células Epiteliales/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Factores de TiempoRESUMEN
Glutamine is the major fuel for enterocytes and prevents mucosal atrophy in certain animal models. Previous studies in our laboratory have failed to show a trophic effect of glutamine on the small-bowel mucosa following massive resection when added to a chow diet. However, the complexity of the chow diet might potentially interfere with the adequate evaluation of the trophic effect of a single agent such as glutamine. This study was therefore designed to determine whether the addition of glutamine to an elemental diet would augment mucosal adaptation following massive small intestinal resection in a rat model. Male Sprague-Dawley rats were divided into two dietary groups, one receiving an amino acid-based pediatric elemental diet supplemented with 2% glutamine, and the other receiving the diet supplemented with 2% glucose. One half of the animals in each dietary group received 80% jejunoileal resection, and the remainder were sham operated. Fifteen days postsurgery, mucosal weight, DNA, protein, and sucrase activities were determined in both the proximal and the distal small intestine. While both groups of resected animals developed marked increases in all parameters of adaptation, the glutamine-supplemented group did not differ from the control diet group in any parameter. The addition of glutamine to an elemental diet had no enhancing effect on intestinal adaptation after bowel resection. These results are similar to those previously observed in our laboratory when glutamine was added to chow diet. The addition of glutamine to an elemental diet cannot be justified on the basis of its trophic effect in animals.
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Alimentos Formulados , Glutamina/administración & dosificación , Mucosa Intestinal/fisiología , Intestino Delgado/cirugía , Adaptación Fisiológica , Animales , ADN/metabolismo , Duodeno/metabolismo , Glucosa/administración & dosificación , Íleon/metabolismo , Íleon/cirugía , Mucosa Intestinal/anatomía & histología , Yeyuno/cirugía , Masculino , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Sacarasa , Aumento de PesoRESUMEN
The present study examined the effects of dexamethasone on mucosal adaptation after massive small bowel resection. Rats underwent 80% jejunoileal resection or a sham operation and received either vehicle or 128 micrograms.kg-1.day-1 sc dexamethasone for 7 days. Dexamethasone infusion resulted in decreased weight, DNA content, and protein content in the duodenojejunal and ileal mucosa in both sham and resected rats. Sucrase, lactase, and maltase activities (all in mumol.g protein-1.min-1) in the duodenojejunal mucosa were elevated by dexamethasone infusion. By contrast, enzyme activities were elevated only in the ileal mucosa of dexamethasone-infused sham-operated rats compared with sham-operated control rats, and dexamethasone did not elevate enzyme activities in resected rats. We further examined whether the inhibitory effects of dexamethasone on mucosal adaptation may be related to changes in either insulin-like growth factor (IGF) or IGF binding protein (BP) serum levels. Serum IGF-I and IGF-II levels were markedly decreased in dexamethasone-infused resected and sham-operated rats. IGF BP-1 serum levels were elevated by dexamethasone treatment with a concomitant depression in serum IGF BP-2 levels. IGF BP-3 levels were lowered by dexamethasone treatment in sham-operated rats and by gut resection, and serum IGF BP-4 levels did not change. These results suggest that the growth-inhibiting effects of dexamethasone in small intestinal mucosa may be partially mediated by decreased serum IGF levels or by alterations in IGF activity associated with changes in serum levels of IGF BPs.
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Adaptación Fisiológica/efectos de los fármacos , Dexametasona/farmacología , Mucosa Intestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/cirugía , Animales , Proteínas Portadoras/sangre , ADN/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina/análisis , Factor II del Crecimiento Similar a la Insulina/análisis , Mucosa Intestinal/fisiología , Intestino Delgado/metabolismo , Masculino , Periodo Posoperatorio , Proteínas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The biodistribution of 111In-labeled stabilized fragments of monoclonal antiferritin was studied in nude mice bearing a human hepatoma tumor xenograft. Pharmacokinetics and tumor targeting of fragment Fab'-linker-Fab' fragment molecules (stabilized F(ab')2) were compared to unmodified F(ab')2 fragment molecules and immunoglobulin G (IgG). Significant differences were observed in tumor and normal organ uptake at 12, 24, 48 and 72 hr. Tumor retention of stabilized F(ab')2 fragments was approximately 2.5-fold higher than of unmodified F(ab')2 at 48 hr. Blood clearance for stabilized F(ab')2 was relatively faster than intact IgG, while unmodified F(ab')2 cleared more rapidly from the circulation. Kidney radioactivity of unmodified F(ab')2 was at least two times higher than kidney radioactivity of stabilized F(ab')2 at all time points. Stabilized F(ab')2 demonstrated 40% less liver uptake than intact IgG. In these studies with nude mice, substantial retention of stabilized F(ab')2 in tumor and significant reduction in liver and kidney uptake of these fragments indicated that they could also have a higher therapeutic ratio than IgG or unmodified F(ab')2 in human patients.
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Anticuerpos Monoclonales , Ferritinas/inmunología , Radioisótopos de Indio , Animales , Anticuerpos Monoclonales/metabolismo , Cromatografía Líquida de Alta Presión , Reactivos de Enlaces Cruzados , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos de Inmunoglobulinas , Radioisótopos de Indio/farmacocinética , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/radioterapia , Ratones , Ratones Desnudos , Radioinmunoterapia , Distribución TisularRESUMEN
To identify the factors regulating the proliferation of intestinal epithelium, we examined the effects of various growth factors on [3H] thymidine incorporation into the DNA of IEC-6 cells, an intestinal epithelial cell line derived from rat jejunal crypts. Insulin-like growth factor-I (IGF-I), IGF-II, and insulin stimulated the DNA and protein synthesis of IEC-6 cells in serum-free medium supplemented with transferrin, dexamethasone, and BSA (basal medium). Concentration-response experiments demonstrated that IGF-I is approximately 10 times more potent than IGF-II or insulin in producing 2- to 3-fold stimulations of DNA and protein synthesis by IEC-6 cells. In addition, IEC-6 cells proliferated slowly in the basal medium without any added growth factors. Analysis of medium conditioned by IEC-6 cells by gel filtration chromatography, RIA, HPLC, and N-terminal sequencing revealed that IEC-6 cells synthesize and secrete mature, 7,500 mo wt (M(r)) IGF-II as well as high M(r) forms of IGF-II. In addition, ligand blot, immunoblot, and N-terminal sequence analyses showed that IEC-6 cells produce the 34,000 M(r) IGF-binding protein-2 (IGFBP-2). To determine if IGFBP-2 modulates IGF responses in IEC-6 cells, the IGF-I analogs, Des-(1-3)-IGF-I and [Gln3,Ala4,Tyr15,Leu16]IGF-I, both of which have a reduced affinity for IGFBPs, were tested for their effects on IEC-6 cell proliferation. Both analogs exhibited 10-fold greater potency than IGF-I, presumably because endogenously secreted IGFBPs depress IGF-I binding to cell surface receptors. Finally, purified IGFBP-2 attenuated the DNA synthesis of IEC-6 cells in a dose-dependent manner. We conclude that IGFBP-2 secreted by intestinal epithelial cells is capable of limiting the mitogenic activity of both exogenous and endogenous IGFs by blocking the association of the growth factors with cell surface binding sites. These results further suggest that the growth of IEC-6 cells is modulated by autocrine mechanisms involving IGF-II and IGFBP-2.
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Proteínas Portadoras/metabolismo , Sustancias de Crecimiento/farmacología , Factor II del Crecimiento Similar a la Insulina/metabolismo , Secuencia de Aminoácidos , Análisis de Varianza , Animales , Proteínas Portadoras/farmacología , División Celular/efectos de los fármacos , Línea Celular , Medio de Cultivo Libre de Suero , ADN/biosíntesis , Replicación del ADN/efectos de los fármacos , Epitelio , Insulina/farmacología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina/análogos & derivados , Factor I del Crecimiento Similar a la Insulina/farmacología , Yeyuno , Cinética , Datos de Secuencia Molecular , Biosíntesis de Proteínas , Ratas , Proteínas Recombinantes/farmacología , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
It has been shown previously that insulinlike growth factors (IGFs) stimulate the proliferation of intestinal crypt cells in vitro. To examine the in vivo effects of IGF-I on mucosal adaptation, three groups of Sprague-Dawley rats underwent 80% jejunoileal resection. Miniosmotic pumps were then inserted under the skin immediately after resection to deliver vehicle (resected control), 1.5 mg/kg per day of IGF-I, or 1.5 mg/kg per day of des-(1-3)-IGF-I (des-IGF-I). Des-IGF-I is a truncated form of IGF-I that binds as well to type I IGF receptors but less tightly to several forms of IGF-binding proteins (IGFBPs) than IGF-I. Ad libitum food intake did not differ among the three resected groups. Body weight gains were greater in animals receiving des-IGF-I than in those receiving IGF-I, which were greater than resected controls. All animals were killed 7 days postoperatively, and the remaining small intestine was removed and divided at the anastomotic site. Both IGF-I and des-IGF-I induced hyperplasia (increased DNA and protein content) in the duodenojejunum but not in the ileum. IGF-I and des-IGF-I were equally active. In contrast, sucrase, maltase, and leucine aminopeptidase activities were greater only in the ileum of animals receiving IGF-I and des-IGF-I than in resected controls. Although more potent in stimulating overall body weight gain, des-IGF-I was not more potent than IGF-I when duodenal and ileal responses were determined. IGF infusion (IGF-I greater than des-IGF-I) increased the levels of circulating IGFBP-3 and IGFBP-2, which may act to modulate the biological effectiveness of the infused peptides. These results suggest that both IGF-I and des-IGF-I may have potential as therapeutic agents for short bowel patients.
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Adaptación Fisiológica/efectos de los fármacos , Íleon/cirugía , Factor I del Crecimiento Similar a la Insulina/farmacología , Mucosa Intestinal/fisiología , Yeyuno/cirugía , Animales , Proteínas Portadoras/sangre , ADN/análisis , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina/análisis , Mucosa Intestinal/química , Masculino , Fragmentos de Péptidos/farmacología , Proteínas/análisis , Ratas , Ratas EndogámicasRESUMEN
Following massive small bowel resection, the remaining small bowel increases in mucosal weight, protein, deoxyribonucleic acid (DNA) content and absorptive function. Enteral nutrients are known to be important in stimulating this response. Recently, glutamine has been described as an essential fuel for the small intestinal mucosa and is thought to be trophic to the small bowel. We investigated if glutamine, when added to the diet in large quantities, might stimulate mucosal adaptation beyond that which normally occurs following physiologic feedings. Male Sprague-Dawley rats were placed on powdered rat chow supplemented with either 5% glutamine, 5% glycine or 5% glucose. After 4 days rats underwent 70% jejunoileal resection. Fourteen days after resection, protein, DNA and sucrase activity in the duodenum of the glutaminefed animals were all significantly lower than results from both the glycine and glucose groups. Duodenal mucosal weight was lower in the glutamine group than in the glycine group. In the ileum, DNA content was significantly lower for the glutamine group than the glycine group. These results suggest that high concentrations of glutamine in the diet can have negative effects on intestinal adaptation.
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Duodeno/crecimiento & desarrollo , Glutamina/administración & dosificación , Íleon/crecimiento & desarrollo , Intestino Delgado/cirugía , Adaptación Fisiológica , Administración Oral , Animales , ADN/análisis , Duodeno/química , Duodeno/enzimología , Glucosa/administración & dosificación , Glicina/administración & dosificación , Íleon/química , Íleon/enzimología , Absorción Intestinal , Mucosa Intestinal/crecimiento & desarrollo , Masculino , Proteínas/análisis , Distribución Aleatoria , Ratas , Ratas Endogámicas , Sacarasa/análisis , Aumento de PesoRESUMEN
We evaluated the effects of menhaden oil on growth and development of the small intestinal mucosa in growing rats and on the progression and resolution of methotrexate-induced mucosal injury in the rats. One study compared effects of diets containing 10% safflower oil(SO), 9% SO and 1% menhaden oil (MO), 10% MO, or 9% MO and 1% SO on mucosal growth and development for 125 d. In another study, animals fed the 10% MO or the 10% SO diet for 5 wk were subjected to subcutaneous methotrexate injections for 3 consecutive days. Feeding rats a diet containing large amounts of menhaden oil resulted in lower prostaglandin E2 and leukotriene B4 synthesis and lower sucrase activities. Indicators of mucosal mass after methotrexate-induced injury were significantly improved in both the jejunum and ileum at 3 and 10 d after methotrexate administration. Our data suggest that dietary menhaden oil stimulates mucosal regeneration after methotrexate-induced injury.
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Grasas Insaturadas en la Dieta/farmacología , Aceites de Pescado/farmacología , Enfermedades Intestinales/dietoterapia , Mucosa Intestinal/crecimiento & desarrollo , Animales , Dinoprostona/biosíntesis , Aceites de Pescado/administración & dosificación , Íleon/crecimiento & desarrollo , Íleon/patología , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Yeyuno/crecimiento & desarrollo , Yeyuno/patología , Leucotrieno B4/biosíntesis , Masculino , Metotrexato , Tamaño de los Órganos , Ratas , Ratas Endogámicas , Aceite de Cártamo/administración & dosificación , Aceite de Cártamo/farmacología , Sacarasa/metabolismoRESUMEN
The present studies were conducted to determine if diets containing a large amount of fat stimulate the regeneration of damaged intestinal mucosa in the presence or absence of essential fatty acid deficiency. To simulate injury, male Sprague-Dawley rats were given methotrexate, 2.5 mg/kg body wt, subcutaneously for 3 consecutive days. Twenty-four hours after the last methotrexate injection, rats were placed on diets containing either 0%, 1%, or 10% safflower oil. Mucosal weight, protein, deoxyribonucleic acid, maltase, sucrase, lactase, alkaline phosphatase, leucine aminopeptidase, and fatty acids were all determined 3 and 12 days after methotrexate. Crypt-cell production rates were also determined. Essential fatty acid deficiency was confirmed in the 0% safflower oil group, in which triene-tetraene ratios were greater than 0.4. Mucosal weight, deoxyribonucleic acid, protein content, and villus height were all greater in the 1% safflower oil group than in the 0% group at 12 days. In the ileum, 1-h thymidine incorporation was greater in the 0% safflower oil group than in the other two groups. No differences in any of the parameters studied were observed between the 1% and 10% groups. These results suggest that diets deficient in essential fatty acids may impair the recovery of intestinal mucosa from injury.
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Grasas de la Dieta/farmacología , Mucosa Intestinal/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Ácidos Grasos Esenciales/deficiencia , Íleon/efectos de los fármacos , Íleon/fisiología , Mucosa Intestinal/fisiología , Yeyuno/efectos de los fármacos , Yeyuno/fisiología , Masculino , Metotrexato/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Ratas , Ratas Endogámicas , Regeneración/efectos de los fármacos , Regeneración/fisiología , Aceite de Cártamo/farmacologíaRESUMEN
The effects of various levels of dietary iron on hepatic lipid peroxidation (malondialdehyde [MDA] content), reduced glutathione (GSH) and GSH peroxidase (GSH-PX) activity as well as liver and body weights of female rats following TCDD administration were examined. Rats were fed diets containing deficient (6 ppm), normal (35 ppm) and supplemented (120 ppm) iron for 17, 24 and 31 days. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 40 micrograms/kg/day P.O.) in corn oil or the vehicle was given on days 9, 8 and 7 prior to sacrifice. TCDD treatment produced a 3-fold increase in hepatic MDA content in animals on normal iron diet. TCDD administration failed to increased MDA content in iron deficient animals. In the iron supplemented groups, TCDD resulted in 2.5 fold increases in lipid peroxidation. Dietary iron had no effect on hepatic GSH-PX activity. Animals on the iron deficient diet had 12-21% decreases in hepatic GSH content. TCDD administration resulted in 15-22% decreases in GSH content in animals on the control and iron supplemented diets. TCDD treatment resulted in significant decreases in body weights of animals on all 3 diets. TCDD induced lipid peroxidation appears to be iron dependent. However, the loss in body weight due to TCDD toxicity may not be dependent on lipid peroxidation.
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Dioxinas/toxicidad , Glutatión/metabolismo , Hierro/administración & dosificación , Peróxidos Lipídicos/biosíntesis , Hígado/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Dieta , Femenino , Glutatión Peroxidasa/metabolismo , Hígado/enzimología , Hígado/metabolismo , Malondialdehído/metabolismo , Ratas , Ratas EndogámicasRESUMEN
1. The abilities of BHA and ascorbic acid to prevent the toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined in female Sprague-Dawley rats. 2. Rats treated with BHA were partially protected from TCDD-induced lipid peroxidation, inhibition of glutathione peroxidase activity, and losses in liver, thymus and body weights. 3. Ascorbic acid had no effect on TCDD-induced alterations in glutathione peroxidase and aryl hydrocarbon hydroxylase activities, or body, liver and thymus weight changes. Ascorbic acid was unable to protect against the lethality of TCDD. 4. Some of the toxic manifestations of TCDD may be mediated by reactive oxygen species and free radical processes.
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Ácido Ascórbico/farmacología , Hidroxianisol Butilado/farmacología , Dioxinas/antagonistas & inhibidores , Peróxidos Lipídicos/metabolismo , Hígado/metabolismo , Dibenzodioxinas Policloradas/antagonistas & inhibidores , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Femenino , Glutatión Peroxidasa/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Tamaño de los Órganos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Ratas , Ratas EndogámicasRESUMEN
Thyroid hormones have been implicated in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, the effects of methimazole (MMI) and propylthiouracil (PTU) induced hypothyroidism and surgical thyroidectomy on several toxic manifestations of TCDD were investigated. Female rats were treated with MMI (0.50 mg/kg) for 10 or 28 days, or PTU (5.0 mg/kg) for 10 days. Other animals were surgically thyroidectomized. The animals received TCDD (100 micrograms/kg) orally or the corn oil vehicle 6 days prior to sacrifice. MMI and PTU decreased serum thyroxine (T4) levels by 27-33% while surgical thyroidectomy decreased T4 levels by 66%. TCDD alone decreased T4 levels by 67%, and similar effects occurred in MMI and PTU treated animals. TCDD produced a 9% increase in serum triiodothyronine (T3) concentrations, and neither MMI or PTU treatment for 10 days modified this effect. Neither antithyroid drug prevented TCDD induced weight loss. TCDD administration resulted in over a 300% increase in hepatic malondialdehyde (MDA) content and a 60% decrease in glutathione peroxidase activity. Neither antithyroid compound affected TCDD-induced alterations in these two parameters. TCDD enhanced MDA content by 220% and inhibited glutathione peroxidase activity by 39% in surgically thyroidectomized rats. Thus, only severe hypothyroidism produced by surgical thyroidectomy was able to partially prevent the effects of TCDD on hepatic MDA content and glutathione peroxidase activity.
Asunto(s)
Dioxinas/farmacología , Peróxidos Lipídicos/metabolismo , Dibenzodioxinas Policloradas/farmacología , Tiroidectomía , Animales , Femenino , Glutatión Peroxidasa/metabolismo , Metimazol/farmacología , Propiltiouracilo/farmacología , Ratas , Ratas EndogámicasRESUMEN
Previous studies have shown that high doses of TCDD induce hepatic lipid peroxidation and inhibit selenium dependent glutathione peroxidase (GSH-Px) activity. The dose dependent effects of TCDD on hepatic lipid peroxidation (malondialdehyde content) and GSH-Px activity were determined. A dose as low as 1 microgram/kg induced hepatic lipid peroxidation and inhibited GSH-Px. Based on the use of scavengers of reactive oxygen species, lipid peroxidation (malondialdehyde formation) by hepatic microsomes from both control and TCDD-treated rats appears to be due primarily to H2O2. The results indicate that superoxide, hydroxyl radical and singlet oxygen are also involved. The differences in the reactive oxygen species involved in microsomal lipid peroxidation between control and TCDD treated animals appear to be quantitative rather than qualitative. A 5.9-fold greater rate of malondialdehyde (MDA) formation by microsomes from TCDD treated animals occurred as compared to controls, while livers of TCDD rats had an MDA content that was 5.0-fold greater than the controls. These differences may be due in part to an enhanced production of H2O2 as well as a decrease in the activity of selenium dependent glutathione peroxidase which metabolizes H2O2.