Assuntos
Quelantes/administração & dosagem , Cobre/metabolismo , Sistemas de Liberação de Medicamentos , Glicoconjugados/química , Hepatócitos/metabolismo , Ácido Nitrilotriacético/administração & dosagem , Pró-Fármacos/administração & dosagem , Receptor de Asialoglicoproteína/metabolismo , Linhagem Celular , Quelantes/química , Quelantes/farmacologia , Dissulfetos/química , Glicoconjugados/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Ácido Nitrilotriacético/química , Ácido Nitrilotriacético/farmacologia , Oxirredução , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric-nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 µg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13 ± 0.01 µg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19 ± 0.01 µg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51 ± 0.08 µg/g) was determined to be approximately half the concentration in control rat brains (0.95 ± 0.11 µg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS.
Assuntos
Encéfalo/efeitos dos fármacos , Fluvoxamina/farmacocinética , Estresse Oxidativo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Férricos/administração & dosagem , Fluvoxamina/sangue , Fluvoxamina/farmacologia , Humanos , Injeções Intravenosas , Masculino , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/análogos & derivados , Ligação Proteica , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Lipid-based oil-filled nanoparticles (NPs) with a high concentration of surface-chelated nickel (Ni-NPs) were successfully prepared using a Brij 78-NTA-Ni conjugate synthesized with Brij 78 (Polyoxyethylene (20) stearyl ether) and nitrilotriacetic acid (NTA). The facile incorporation of the Brij 78-NTA-Ni conjugate into the NP formulation allowed up to 90% Ni incorporation, which was a significant improvement over the previously used standard agent DOGS-NTA-Ni which led to ~6% Ni incorporation. The Ni-NPs were targeted to the highly epidermal growth factor receptor (EGFR)-overexpressing epidermoid carcinoma cells A431. This was accomplished using a novel high affinity histidine×6-tagged EGFR-binding Z domain (heptameric Z(EGFR) domain). In vitro cell uptake studies showed enhanced internalization (up to 90%) of the targeted Ni-NPs in A431 cells with only ≤10% internalization of the untargeted Ni-NPs. ICP-MS analysis used to quantify the amount of Ni in the cells were in close agreement with flow cytometry studies, which showed a dose dependent increase in the amount of Ni with the targeted Ni-NPs. Cell uptake competition studies showed that internalization of the targeted Ni-NPs within the cells was competed off with free heptameric Z(EGFR) domain at concentrations of 8.75ng/mL or higher. In vivo studies were carried out in nude mice bearing A431 tumors to determine the biodistribution and intracellular delivery. Near Infrared (NIR) optical imaging studies using Alexa750-labeled heptameric Z(EGFR) domain showed localization of 19% of the total detected fluorescence intensity in the tumor tissue, 28% in the liver and 42% in the kidneys 16h post i.v. injection. ICP-MS analysis showed almost a two-fold increase in the amount of intracellular Ni with the targeted Ni-NPs. These new Ni-NPs could be a very useful tool for targeting and drug delivery to a wide range of EGFR positive cancers.
Assuntos
Portadores de Fármacos/administração & dosagem , Receptores ErbB/metabolismo , Nanopartículas Metálicas/administração & dosagem , Neoplasias/metabolismo , Níquel/administração & dosagem , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Receptores ErbB/química , Humanos , Nanopartículas Metálicas/química , Camundongos , Camundongos Nus , Níquel/química , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Estrutura Terciária de Proteína , Succinimidas/administração & dosagem , Succinimidas/química , Tensoativos/administração & dosagem , Tensoativos/química , Distribuição Tecidual , Triglicerídeos/administração & dosagem , Triglicerídeos/químicaRESUMO
The effect of oxidative stress (OS) on the pharmacokinetics of clomipramine (CPM), particularly addressing the change of CPM distribution to plasma components, was studied in ferric-nitrilotriacetate-induced oxidative-stress model rats (OS rats). First, CPM pharmacokinetic studies in OS rats were performed using CPM continuous infusion (17.5 µg/min/kg). Plasma concentration of CPM at a steady state in OS rats (0.20 ± 0.02 µg/mL) was significantly lower than that in control rats (0.30 ± 0.02 µg/mL). However, no difference was found in the amounts of CPM in the brains of control rats (1.67 ± 0.13 µg/g) and OS rats (1.63 ± 0.09 µg/g). Both of plasma unbound fraction and distribution to erythrocytes in OS rats were significantly higher than those of control rats. These results suggest that the lower CPM concentration in plasma in OS condition does not induce an inferior pharmacological effect.
Assuntos
Clomipramina/farmacocinética , Compostos Férricos/administração & dosagem , Ácido Nitrilotriacético/análogos & derivados , Oxidantes/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Animais , Encéfalo/metabolismo , Clomipramina/administração & dosagem , Clomipramina/sangue , Eritrócitos/metabolismo , Infusões Intravenosas , Injeções Intraperitoneais , Injeções Intravenosas , Lipoproteínas/sangue , Fígado/metabolismo , Masculino , Modelos Biológicos , Ácido Nitrilotriacético/administração & dosagem , Ligação Proteica , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/sangue , Distribuição TecidualRESUMO
Iron, a source of oxidative stress, plays a major role in the pathology of neurodegenerative disease. In Alzheimer's disease, the hippocampus is vulnerable to oxidative stress, leading to impairment in memory formation. In our previous study, a brain oxidative reaction was induced after intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA). However, since only a small amount of iron reached the brain in the previous study, Fe-NTA was administered into the hippocampus using an osmotic pump in this study. After continuous injection of Fe-NTA for 2 weeks, a high level of apoptotic change was induced in the hippocampus, in accordance with the iron localization. After injection for 4 weeks, the hippocampus was totally destroyed. A small amount of iron infiltrated into the cerebral cortex and the striatum, and deposition was observed at the choroid plexus and ependymal cells. However, no apoptotic reaction or clear tissue injury was observed in these areas. In addition, muscarinic acetylcholine receptors (M1, M2, and M4) were decreased in both the cortex and hippocampus while it increased in the striatum. Thus, the hippocampus is likely vulnerable to oxidative stress from Fe-NTA, and the oxidative stress is considered to bring the disturbance in the muscarinic acetylcholine receptors.
Assuntos
Apoptose , Compostos Férricos/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Nitrilotriacético/análogos & derivados , Estresse Oxidativo , Animais , Compostos Férricos/administração & dosagem , Hipocampo/patologia , Peróxido de Hidrogênio/administração & dosagem , Peróxido de Hidrogênio/farmacologia , Masculino , Camundongos , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/farmacologia , Oxirredução , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Muscarínicos/metabolismo , Coloração e Rotulagem/métodosRESUMO
By using a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA), this study performed genome-wide analysis to identify target genes during carcinogenesis. It screened for genes with decreased expression in RCCs, with simultaneous loss of heterozygosity, eventually to focus on the fibulin-5 (fbln5) gene. Oxidative damage via Fe-NTA markedly increased Fbln5 in the proximal tubules. RCCs presented lower levels of Fbln5. However, a fraction of RCCs presenting pulmonary metastasis revealed significantly higher levels of Fbln5 than those without metastasis, accompanied by immunopositivity of RCC cells and myofibroblast proliferation. Experiments revealed that RCC cell lines showed lower expression of fbln5 than its non-transformed counterpart NRK52E, but that fbln5 transfection to RCC cell lines changed neither proliferation nor migration/invasion. The data suggest that Fbln5 plays a role not only in the tissue repair and remodelling after renal tubular oxidative damage but also in RCC metastasis, presumably as a cytokine.
Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proteínas da Matriz Extracelular , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Túbulos Renais Proximais/patologia , Neoplasias Pulmonares/secundário , Proteínas Recombinantes , Animais , Sequência de Bases , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Compostos Férricos/administração & dosagem , Compostos Férricos/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Imuno-Histoquímica , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/genética , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Perda de Heterozigosidade/genética , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/efeitos adversos , Ácido Nitrilotriacético/análogos & derivados , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Butyrate, formed by bacterial fermentation of plant foods, has been shown to protect human colon cells from selected genotoxic substances. The mechanism for this effect could be the enhancement of toxicological defence leading to an increased detoxification of genotoxic risk factors and thus to a reduction of DNA and chromosome damage. Previous protective properties of butyrate against DNA damage induction in colon cells were demonstrated using the comet assay. In the present study the effect of butyrate on chromosome damage induced by ferric nitrilotriacetate (Fe-NTA) and hydrogen peroxide (H(2)O(2)) (suggested to be putative risk factors of colorectal carcinogenesis) was investigated using the cytokinesis-block micronucleus (CBMN) test. It was possible to reveal that pre-treatment of HT29 colon carcinoma cells with butyrate (2 and 4mM) for 15 min caused a reduction of micronuclei induced with H(2)O(2) (75 microM; p<0.01) and Fe-NTA (500 and 1000 microM; p<0.05). The decrease in the level of Fe-NTA- and H(2)O(2)-induced micronuclei was also confirmed in most of the corresponding variants of 24h pre-treatment of cells with butyrate. The results obtained demonstrate for the first time protective properties of butyrate against chromosome damage induced by H(2)O(2) and Fe-NTA in human colon carcinoma cells.
Assuntos
Butiratos/farmacologia , Neoplasias do Colo/metabolismo , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Adenocarcinoma/metabolismo , Butiratos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/toxicidade , Células HT29 , Humanos , Peróxido de Hidrogênio/administração & dosagem , Peróxido de Hidrogênio/toxicidade , Testes para Micronúcleos , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidadeRESUMO
Iron is known to be involved in neuronal diseases such as neurodegenerative diseases, brain ischemia and epilepsy. However, it is unclear if a high level of peripheral iron induces these pathological conditions. Since ferric nitrilotriacetate (Fe-NTA), a low molecule iron chelate, causes kidney carcinoma and diabetes in animals due to its strong and unique oxidative stress, it is also considered to cause pathological conditions in the brain. Therefore, we studied brain changes after intraperitoneal (i.p.) injection of Fe-NTA. We investigated iron distribution in the brain and evaluated heme oxygenase (HO)-1 mRNA, IL-6 mRNA and 4-hydroxy-2-nonenal (4-HNE) quantitatively. In addition, changes in muscarinic acetylcholine receptor mRNAs were measured. It was found that iron was localized in the cortex and the hypothalamus, but not in other areas of the brain. HO-1 was induced in both the cortex and hypothalamus, and the levels of IL-6 and 4-HNE were raised in the hypothalamus, but not in the cortex. In the cortex, expression in M1 and M2 mAChRs were suppressed. In conclusion, iron reached the brain parenchyma after i.p. injection of Fe-NTA, and Fe-NTA caused oxidative reactions and suppression of mAChRs in the brain.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Férricos/farmacologia , Quelantes de Ferro/farmacologia , Ácido Nitrilotriacético/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Aldeídos/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Compostos Férricos/administração & dosagem , Heme Oxigenase (Desciclizante)/genética , Histocitoquímica , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Immunoblotting , Injeções Intraperitoneais , Interleucina-6/genética , Ferro/metabolismo , Quelantes de Ferro/administração & dosagem , Masculino , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/farmacologia , Reação em Cadeia da Polimerase , Ratos , Ratos Sprague-DawleyRESUMO
Curcumin (diferuloylmethane), a biologically active ingredient derived from rhizome of the plant Curcuma longa, has potent anticancer properties as demonstrated in a plethora of human cancer cell lines/animal carcinogenesis model and also acts as a biological response modifier in various disorders. We have reported previously that dietary supplementation of curcumin suppresses renal ornithine decarboxylase (Okazaki et al. Biochim Biophys Acta 1740:357-366, 2005) and enhances activities of antioxidant and phase II metabolizing enzymes in mice (Iqbal et al. Pharmacol Toxicol 92:33-38, 2003) and also inhibits Fe-NTA-induced oxidative injury of lipids and DNA in vitro (Iqbal et al. Teratog Carcinog Mutagen 1:151-160, 2003). This study was designed to examine whether curcumin possess the potential to suppress the oxidative damage caused by kidney-specific carcinogen, Fe-NTA, in animals. In accord with previous report, at 1 h after Fe-NTA treatment (9.0 mg Fe/kg body weight intraperitoneally), a substantial increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts in renal proximal tubules of animals was observed. Likewise, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and protein reactive carbonyl, an indicator of protein oxidation, were also increased at 1 h after Fe-NTA treatment in the kidneys of animals. The prophylactic feeding of animals with 1.0% curcumin in diet for 4 weeks completely abolished the formation of (i) HNE-modified protein adducts, (ii) 8-OHdG, and (iii) protein reactive carbonyl in the kidneys of Fe-NTA-treated animals. Taken together, our results suggest that curcumin may afford substantial protection against oxidative damage caused by Fe-NTA, and these protective effects may be mediated via its antioxidant properties. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.
Assuntos
Carcinógenos/administração & dosagem , Quimioprevenção/métodos , Curcumina/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Aldeídos/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Compostos Férricos/administração & dosagem , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Neoplasias/prevenção & controle , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/análogos & derivados , Proteínas/metabolismoRESUMO
Didymocarpus pedicellata R. Br. (Gesneriaceae) is widely used in traditional Indian medicines against renal afflictions. In the present study, we have revealed ethanolic extract of aerial parts of D. pedicellata to possess significant antioxidant activity and protect against ferric nitrilotriacetate (Fe-NTA) mediated renal oxidative stress, nephrotoxicity and tumor promotion response. D. pedicellata extract was found to possess a high content of total polyphenolics, exhibit potent reducing power and significantly scavenge free radicals including several reactive oxygen species (ROS) and reactive nitrogen species (RNS). The extract also significantly and dose-dependently protected against Fe-NTA plus H(2)O(2)-mediated damage to lipids and DNA. Protective efficacy of the extract was also tested in vivo against Fe-NTA mediated nephrotoxicity and tumor promotion response. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to Swiss albino mice depleted renal glutathione content and activities of antioxidant and phase II metabolizing enzymes with concomitant induction of oxidative damage. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Elevation in serum creatinine (SCr) and blood urea nitrogen (BUN), and histopathological changes were also evident and suggested Fe-NTA to afflict damage to kidney. Pretreatment of mice with D. pedicellata extract (100-200 mg/kg body weight) for 7 days not only restored antioxidant armory near normal values but also significantly protected against renal oxidative stress and damage restoring normal renal architecture and levels of renal damage markers, viz., BUN and SCr. The results of the present study indicate D. pedicellata to possess potent antioxidant and free radical scavenging activities and preclude oxidative damage and hyperproliferation in renal tissues.
Assuntos
Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Nefropatias/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Magnoliopsida/química , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal , Creatinina/sangue , DNA/metabolismo , Compostos Férricos/administração & dosagem , Sequestradores de Radicais Livres/metabolismo , Glutationa/metabolismo , Medicina Herbária , Nefropatias/patologia , Camundongos , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/análogos & derivados , Ornitina Descarboxilase/metabolismo , Timidina/metabolismo , Fatores de TempoRESUMO
Metallothionein (MT) demonstrates strong antioxidant properties, yet the physiological relevance of its antioxidant action is not clear. Injection of mice with ferric nitrilotriacetate (Fe-NTA) caused a dose-dependent increase in hepatic and renal MT. Fe-NTA caused a greater increase in hepatic and renal MT concentration (2.5- and 4-fold) compared with FeCl(3) at the same dose of ferric ion. MT mRNA levels were markedly elevated in both of tissues. Thiobarbituric acid (TBA) values in both tissues reached a maximum after 2-4 h. The MT concentrations were significantly increased after 2-4 h in liver and after 8-16 h in kidneys. Plasma concentrations of cytokines such as IL-6 and TNFalpha were elevated by 4 h; IL-6 levels were 24 times higher after Fe-NTA than that after injection of FeCl(3). Pretreatment of mice with ZnSO(4) attenuated nephrotoxicity induced by Fe-NTA after 2 h, but was not effective 4 h after injection. After a Fe-NTA injection, a loss of Cd-binding properties of preinduced MT was observed only in kidneys of Zn-pretreated mice but not in liver. Treatment with BSO, glutathione (GSH) depletor, intensified a loss of its Cd-binding properties after a Fe-NTA injection. These results indicate that induction of MT synthesis may result from reactive oxygen species (ROS) generated by Fe-NTA, and MT may act in vivo as a complementary antioxidant.
Assuntos
Antioxidantes/metabolismo , Compostos Férricos/toxicidade , Rim/metabolismo , Fígado/metabolismo , Metalotioneína/metabolismo , Mutagênicos/toxicidade , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidade , Animais , Bismuto , Nitrogênio da Ureia Sanguínea , Bromatos/toxicidade , Cádmio/metabolismo , Cloretos , Compostos Férricos/administração & dosagem , Interleucina-6/biossíntese , Interleucina-6/sangue , Rim/efeitos dos fármacos , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Masculino , Metalotioneína/biossíntese , Camundongos , Camundongos Endogâmicos , Ácido Nitrilotriacético/administração & dosagem , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossíntese , ZincoRESUMO
In an earlier communication we reported that Nigella sativa suppresses potassium bromate-induced renal oxidative damage. In the present study, we report the chemopreventive effect of Nigella sativa against ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, hyperproliferative response and renal carcinogenesis. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally) enhances renal lipid peroxidation, xanthine oxidase, gamma-glutamyl transpeptidase and hydrogen peroxide (H2O2) generation with reduction in renal glutathione content, antioxidant enzymes and phase II metabolizing enzymes. It also caused increase in blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and thymidine [H] incorporation into renal DNA. It also enhanced DEN (N-diethylnitrosamine)-initiated renal carcinogenesis by increasing the percentage incidence of tumours. Treatment of rats orally with Nigella sativa (50 and 100 mg/kg body weight) resulted in significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal ODC activity, DNA synthesis (P<0.001) and incidence of tumours. Renal glutathione content (P<0.01), glutathione-metabolizing enzymes (P<0.001) and antioxidant enzymes were also recovered to significant levels (P<0.001). Thus, our data suggest that Nigella sativa is a potent chemopreventive agent and suppresses Fe-NTA-induced oxidative stress, hyperproliferative response and renal carcinogenesis in Wistar rats.
Assuntos
Carcinoma de Células Renais/prevenção & controle , Neoplasias Renais/prevenção & controle , Nigella sativa/química , Ácido Nitrilotriacético/análogos & derivados , Estresse Oxidativo , Animais , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Carcinoma de Células Renais/fisiopatologia , Proliferação de Células , Quimioprevenção , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/toxicidade , Neoplasias Renais/fisiopatologia , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/toxicidade , Extratos Vegetais/farmacologia , Ratos , Ratos WistarRESUMO
Ferric nitrilotriacetate (Fe-NTA) is a known potent nephrotoxic agent. In this communication, we report the chemopreventive effect of soy isoflavones on renal oxidative stress, toxicity and cell proliferation response in Wistar rats. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H2O2) generation with reduction in renal glutathione content, antioxidant enzymes, viz., glutathione peroxidase, glutathione reductase, catalase, glucose-6-phosphate dehydrogenase and phase-II metabolising enzymes such as glutathione-S-transferase and quinone reductase. Fe-NTA treatment also induced tumor promotion markers, viz., ornithine decarboxylase (ODC) activity and thymidine [3H] incorporation into renal DNA. A sharp elevation in the levels of blood urea nitrogen and serum creatinine has also been observed. Treatment of rats orally with soy isoflavones (5 mg/kg body weight and 10 mg/kg body weight) resulted in significant decreases in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01), glutathione metabolizing enzymes (P < 0.001) and antioxidant enzymes were also returned to normal levels (P < 0.001). Thus, our data suggest that soy isoflavones may be used as an effective chemopreventive agent against Fe-NTA-mediated renal oxidative stress, toxicity and cell proliferation response in Wistar rats.
Assuntos
Carcinógenos/toxicidade , Compostos Férricos/toxicidade , Isoflavonas/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Administração Oral , Animais , Carcinógenos/administração & dosagem , Divisão Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/antagonistas & inibidores , Glutationa/metabolismo , Injeções Intraperitoneais , Isoflavonas/administração & dosagem , Rim/enzimologia , Nefropatias/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/antagonistas & inibidores , Ratos , Ratos Wistar , Glycine max/químicaRESUMO
Dendritic cells (DCs) are potent stimulators of immunity, and DCs pulsed with tumor antigen ex vivo have applications in tumor immunotherapy. However, DCs are a small population of cells, and their isolation and pulsing with antigen can be impractical. Here we show that a crude preparation of plasma membrane vesicles (PMV) from the highly metastatic murine melanoma (B16-OVA) and a surrogate tumor antigen (OVA) can be targeted directly to DCs in vivo to elicit functional effects. A novel metal-chelating lipid, 3(nitrilotriacetic acid)-ditetradecylamine, was incorporated into B16-OVA-derived PMV, allowing recombinant hexahistidine-tagged forms of single chain antibody fragments to the DC surface molecules CD11c and DEC-205, to be conveniently "engrafted" onto the vesicle surface by metal-chelating linkage. The modified PMV, or similarly engrafted synthetic stealth liposomes containing OVA or OVA peptide antigen, were found to target DCs in vitro and in vivo, in experiments using flow cytometry and fluorescence confocal microscopy. When used as vaccines in syngeneic mice, the preparations stimulated strong B16-OVA-specific CTL responses in splenic T cells and a marked protection against tumor growth. Protection was dependent on the simultaneous delivery of both antigen and a DC maturation or "danger signal" signal (IFN-gamma or lipopolysaccharide). Administration of the DC-targeting vaccine to mice challenged with B16-OVA cells induced a dramatic immunotherapeutic effect and prolonged disease-free survival. The results show that the targeting of antigen to DCs in this way is highly effective at inducing immunity and protection against the tumor, with protection being at least partially dependent on the eosinophil chemokine eotaxin.
Assuntos
Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Imunoterapia/métodos , Melanoma Experimental/imunologia , Ácido Nitrilotriacético/análogos & derivados , Aminas/administração & dosagem , Aminas/química , Animais , Feminino , Fragmentos de Imunoglobulinas/administração & dosagem , Fragmentos de Imunoglobulinas/química , Lipossomos , Masculino , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/química , Ovalbumina/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
BACKGROUND & AIMS: L-ergothioneine is a fungal metabolite exhibiting antioxidant functions in cells. The aim of this study was to assess the effect of oral administration of L-ergothioneine on the oxidative damage in vivo caused by the Fenton reagent ferric-nitrilotriacetate. METHODS: Rats were supplemented with L-ergo prior to the administration of acute dose of ferric-nitrilotriacetate. Kidney and liver levels of L-ergothioneine, glutathione, alpha-tocopherol, polyunsaturated fatty acids and conjugated dienes were assessed. RESULTS: Oral administration of 70 mg L-ergo/kg body weight of rats for 7 days prior to the injection of ferric-nitrilotriacetate protected the fatty acids against oxidation, with notable protections directed to: 20:5 (eicosapentaenoic acid) (23%), 22:6 (docosahexaenoinic acid) (30%), 20:3 n6 (eicosatrienoic acid) (22%), 20:4 (arachidonic acid) (25%), 18:2 linoleic acid (25%) and 18:1 oleic acid (14%) in the kidney. The protection of 20:5, 20:3 n6 and 18:1 in the liver by 32%, 20% and 11%, respectively, were statistically significant. L-ergothioneine significantly reduced kidney and liver levels of conjugated dienes and conserved the concentrations of alpha-tocopherol and glutathione in the kidney and liver in the ferric-nitrilotriacetate/L-ergothioneine treated rats. CONCLUSION: Supplementation with L-ergothioneine not only protects the organs against the lipid peroxidation but conserves the consumption of endogenous glutathione and alpha-tocopherol. However consumption of mushrooms may have better promise as dietary sources of L-ergothioneine to humans.
Assuntos
Antioxidantes/farmacologia , Ergotioneína/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ácido Nitrilotriacético/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Ergotioneína/análise , Ácidos Graxos Insaturados/análise , Compostos Férricos/administração & dosagem , Glutationa/análise , Rim/química , Lipídeos/análise , Fígado/química , Masculino , Ácido Nitrilotriacético/administração & dosagem , Oxirredução , Ratos , Ratos Wistar , alfa-Tocoferol/análiseAssuntos
Anticorpos/efeitos da radiação , Especificidade de Anticorpos/efeitos da radiação , Western Blotting/métodos , Micro-Ondas , Ácido Nitrilotriacético/análogos & derivados , Proteínas/efeitos da radiação , Animais , Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacologia , Injeções Intraperitoneais , Rim/química , Rim/efeitos dos fármacos , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/farmacologia , Proteínas/imunologia , Ratos , Ratos Wistar , Organismos Livres de Patógenos EspecíficosRESUMO
Differential patterns in terms of nephropathology and 8-hydroxyguanine formation in the course of oral 28-day studies were observed with nitrilotriacetic acid (NTA) and FeNTA. FeNTA, but not NTA, caused enhanced 8-hydroxyguanine formation in kidney DNA after oral and intraperitoneal administration. Enhanced lipid peroxidation in the kidney homogenate was observed with FeNTA as well as with NTA. For NTA, the low dose (9 mg/kg per day) was without adverse effect. The kidney toxicity of oral FeNTA (50, 200, and 1000 mg/kg per day) was only mild, 50 mg/kg per day; however, it still led to an increased 8-hydroxyguanine content. The relevance of Iron(III) (Fe(III)) or Fe(III)NTA formation as a relevant mediator of NTA-related toxicity was excluded on the basis of these data. Also, a thermodynamic consideration presented here, supports the view that zinc (Zn), and not Fe, is likely to mediate the tubular cell cytotoxicity of NTA.
Assuntos
Quelantes/toxicidade , Compostos Férricos/toxicidade , Guanina/análogos & derivados , Rim/patologia , Peroxidação de Lipídeos , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidade , Administração Oral , Animais , Quelantes/administração & dosagem , DNA/química , Compostos Férricos/administração & dosagem , Guanina/análise , Infusões Parenterais , Masculino , Ácido Nitrilotriacético/administração & dosagem , Ratos , Ratos Wistar , Termodinâmica , Zinco/farmacologiaRESUMO
This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogenic nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplastic and neoplastic renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxic nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).
Assuntos
Carcinógenos/toxicidade , Neoplasias Renais/induzido quimicamente , Mutagênicos/toxicidade , Lesões Pré-Cancerosas/induzido quimicamente , Propano/análogos & derivados , Administração Oral , Animais , Animais Geneticamente Modificados , Testes de Carcinogenicidade , Carcinógenos/administração & dosagem , Ciclosporina/administração & dosagem , Ciclosporina/toxicidade , Furanos/administração & dosagem , Furanos/toxicidade , Injeções Intraperitoneais , Neoplasias Renais/patologia , Masculino , Mutagênicos/administração & dosagem , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/toxicidade , Nitroparafinas/administração & dosagem , Nitroparafinas/toxicidade , Fenilenodiaminas/administração & dosagem , Fenilenodiaminas/toxicidade , Lesões Pré-Cancerosas/patologia , Propano/administração & dosagem , Propano/toxicidade , Ratos , Ratos EndogâmicosRESUMO
The antioxidant cocktail EM-X derived from ferment of unpolished rice, papaya and sea weeds with effective microorganisms (EM) of lactic acid bacteria, yeast, and photosynthetic bacteria is widely available in South-East Asia. Oral administration of a EM-X to rats for 7 days inhibited the ferric-nitrilotriacetic acid (Fe-NTA)-dependent oxidation of fatty acids with protections directed towards docosahexanoic, arachidonic, docosapentanenoic acids, oleic, linoleic and eicosadieonoic acids in the liver and kidney. But only the protections of oxidation to docosahexanoic, arachidonic acid in the kidney were statistically significant. Treatment of rats with EM-X prior to the intraperitoneal administration of Fe-NTA led to a reduction in the overall levels of conjugated dienes (CD) measured in the kidney by 27% and in the liver by 19% suggesting inhibition of lipid peroxidation in these organs. The levels of glutathione and alpha-tocopherol were largely unaffected suggesting that the protection by the regular strength of EM-X was confined to the inhibition of lipid peroxidation in vivo, a point dependent on the concentrations of bioactive flavonoids.
Assuntos
Antioxidantes/farmacologia , Ácidos Graxos Insaturados/metabolismo , Compostos Férricos/antagonistas & inibidores , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Plantas/química , Animais , Antioxidantes/química , Carica/química , Carica/microbiologia , Fermentação , Compostos Férricos/administração & dosagem , Compostos Férricos/toxicidade , Injeções Intraperitoneais , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ácido Nitrilotriacético/administração & dosagem , Ácido Nitrilotriacético/toxicidade , Oryza/química , Oryza/microbiologia , Oxirredução/efeitos dos fármacos , Fitoterapia , Plantas/microbiologia , Ratos , Ratos Wistar , Alga Marinha/química , Alga Marinha/microbiologiaRESUMO
Intraperitoneal injection of the iron-complex, ferric-nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage associated with oxidative damage in vivo. Fe-NTA induced a time-dependent decrease of several polyunsaturated fatty acids (PUFA), together with increased conjugated diene values and decreased cellular levels of alpha-tocopherol and glutathione. At the time of maximum detectable oxidation (3 h), after the injection of a sublethal dose of Fe-NTA there were clear reductions in the peak values over the controls for several fatty acids notably, 20:5 (eicosapentaenoic acid) (36%), 22:6 (docosahexanoic acid) (30%), 20:3 n6 (eicosatrienoic acid) (30%) and 20:4 (arachidonic acid) (28%) in the kidney. Fewer fatty acids showed a reduction in their residual values in the liver. 20:5 was reduced by 45% and for the 18:3 n3 and 18:3 n6, reductions of 35%, respectively. The profile of PUFAs is sensitive to the oxidative damage due to Fe-NTA and this may find applications as oxidative biomarker model.