RESUMO
Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (% ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1,200 µCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all nontreated controls required euthanasia because of tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen, 9.0 ± 1.5% ID/g and bone marrow, 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 µCi) of 90Y-DOTA-biotin had a survival advantage compared with untreated leukemic mice (median, 43 vs. 30 days, respectively; P < 0.0001). These data suggest bispecific antibody-mediated PRIT may be highly effective for leukemia therapy and translation to human studies.
Assuntos
Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Biotina/análogos & derivados , Antígenos Comuns de Leucócito/antagonistas & inibidores , Compostos Organometálicos/antagonistas & inibidores , Proteínas Recombinantes de Fusão/farmacologia , Animais , Anticorpos Biespecíficos/genética , Biotina/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Engenharia Genética , Humanos , Leucemia Mieloide , Camundongos , Proteínas Recombinantes de Fusão/genética , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Luteolin (LUT) is a glycosylated flavonoid compound that has multiple beneficial pharmacological and biological impacts. The current investigation was undertaken to evaluate the putative neuroprotective potency of LUT against neuronal damage induced by lead acetate (PbAc). Twenty-eight rats were placed into four equal groups. Group 1: served as the control group, group 2: rats were supplemented orally with LUT (50 mg kg-1), group 3: rats were intraperitoneally injected with PbAc (20 mg kg-1), and group 4: rats were pretreated with LUT before PbAc injection with the same doses. All animals were treated for 7 days. The exposure to PbAc increased the concentration of lead in the cortical tissue, neuronal lipid peroxidation, and nitric oxide (NO) production and decreased the antioxidant enzymes. Additionally, PbAc enhanced a neuroinflammatory response in the cortical tissue through increasing the pro-inflammatory cytokines secretion and inducible NO synthase expression. Moreover, cortical cell death was recorded following PbAc intoxication as evidenced by the enhancement of the proapoptotic and inhibiting the antiapoptotic markers. Interestingly, LUT supplementation reversed the cortical adverse reactions induced by PbAc. Taken together, these findings may suggest that LUT may be useful for attenuating neuronal damage induced by PbAc through inhibiting the oxidative damage, neuroinflammation, and the cortical cell death.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Luteolina/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Organometálicos/antagonistas & inibidores , Animais , Masculino , Compostos Organometálicos/toxicidade , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
The study of pharmacological interactions between herbal remedies and conventional drugs is important because consuming traditional herbal remedies as supplements or alternative medicine is fairly common and their concomitant administration with prescribed drugs could either have a favorable or unfavorable effect. Therefore, this work aims to determine the pharmacological interactions of a turmeric acetone extract (TAE) and its main metabolite (curcumin) with common anti-ulcer drugs (ranitidine and bismuth subsalicylate), using an ethanol-induced ulcer model in Wistar rats. The analysis of the interactions was carried out via the Combination Index-Isobologram Equation method. The combination index (CI) calculated at 0.5 of the affected fraction (fa) indicated that the TAE or curcumin in combination with ranitidine had a subadditive interaction. The results suggest that this antagonistic mechanism is associated to the mucoadhesion of curcumin and the TAE, determined by rheological measurements. Contrastingly, both the TAE and curcumin combined with bismuth subsalicylate had an additive relationship, which means that there is no pharmacological interaction. This agrees with the normalized isobolograms obtained for each combination. The results of this study suggest that mucoadhesion of curcumin and the TAE could interfere in the effectiveness of ranitidine, and even other drugs.
Assuntos
Antiulcerosos/uso terapêutico , Bismuto/uso terapêutico , Curcumina/farmacologia , Etanol/efeitos adversos , Compostos Organometálicos/uso terapêutico , Extratos Vegetais/farmacologia , Ranitidina/uso terapêutico , Salicilatos/uso terapêutico , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/antagonistas & inibidores , Curcuma , Modelos Animais de Doenças , Interações Medicamentosas , Mucosa Gástrica/efeitos dos fármacos , Interações Ervas-Drogas , Masculino , Compostos Organometálicos/antagonistas & inibidores , Ranitidina/antagonistas & inibidores , Ratos , Ratos Wistar , Salicilatos/antagonistas & inibidores , Úlcera Gástrica/induzido quimicamenteRESUMO
Lead (Pb) is a toxic, environmental heavy metal that induces serious clinical defects in all organs, with the nervous system being its primary target. Curcumin is the main active constituent of turmeric rhizome (Curcuma longa) with strong antioxidant and anti-inflammatory properties. This study is aimed at evaluating the therapeutic potentials of curcumin on Pb-induced neurotoxicity. Thirty-six male Sprague Dawley rats were randomly assigned into five groups with 12 rats in the control (normal saline) and 6 rats in each of groups, i.e., the lead-treated group (LTG) (50 mg/kg lead acetate for four weeks), recovery group (RC) (50 mg/kg lead acetate for four weeks), treatment group 1 (Cur100) (50 mg/kg lead acetate for four weeks, followed by 100 mg/kg curcumin for four weeks) and treatment group 2 (Cur200) (50 mg/kg lead acetate for four weeks, followed by 200 mg/kg curcumin for four weeks). All experimental groups received oral treatment via orogastric tube on alternate days. Motor function was assessed using a horizontal bar method. The cerebellar concentration of Pb was evaluated using ICP-MS technique. Pb-administered rats showed a significant decrease in motor scores and Superoxide Dismutase (SOD) activity with increased Malondialdehyde (MDA) levels. In addition, a marked increase in cerebellar Pb concentration and alterations in the histological architecture of the cerebellar cortex layers were recorded. However, treatment with curcumin improved the motor score, reduced Pb concentration in the cerebellum, and ameliorated the markers of oxidative stress, as well as restored the histological architecture of the cerebellum. The results of this study suggest that curcumin attenuates Pb-induced neurotoxicity via inhibition of oxidative stress and chelating activity.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Doenças Cerebelares/tratamento farmacológico , Quelantes/farmacologia , Curcumina/farmacologia , Compostos Organometálicos/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antioxidantes/administração & dosagem , Doenças Cerebelares/induzido quimicamente , Doenças Cerebelares/patologia , Quelantes/administração & dosagem , Curcumina/administração & dosagem , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Lead without nutritional value is a widely studied occupational and environmental toxicant. Leads' toxic effects on female reproduction are decreased fertility, inability to sustain pregnancy and reduced pregnancy. OBJECTIVE: This study aimed at examining the effect of oral administration of lead acetate (1.5 mg/kg) on the histology of female albino Wistar rats' ovary and Uterus and the extracts' protective role against toxicity. METHODS: The experiment took 28 days involving 25 female Wistar rats divided into 5 groups A, B, C, D and E. A is an untreated group that received normal saline, D lead acetate group that received lead acetate solution, E received aqueous extract, B and C low and high dose of aqueous extract respectively and lead acetate solution. RESULTS: The positive control group showed a significant increase in SOD at P ≤ 0.01 compared to the negative control. Group E showed significant decrease ovarian SOD. The organs weights were significantly reduced in group D. The changes seen in the organs include oedema, necrosis, optical empty spaces, denudations and fatty changes. Administrating the extract protected the organs against the lead acetate. These alterations are shown to cause infertility in female rats. CONCLUSION: The results suggested that the extract has protective role against lead reproductive toxicity.
Assuntos
Ficus/química , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/toxicidade , Ovário/diagnóstico por imagem , Extratos Vegetais/farmacologia , Útero/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Compostos Organometálicos/administração & dosagem , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Gravidez , Ratos , Ratos WistarRESUMO
Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a gasoline antiknock additive. However, the toxic effect of MMT is currently not well understood. In this study, we investigated the toxic effect of MMT on rat thymocytes using a flow cytometer and fluorescent probes. MMT at 100-300 µM significantly increased the population of cells exhibiting propidium fluorescence, i.e., the population of dead cells. The intensity of BES-So-AM fluorescence significantly increased when using 100 µM MMT. In addition, the intensity of oxonol fluorescence in rat thymocytes increased with the treatment with MMT in a concentration-dependent manner (10-100 µM). The toxic effect of MMT was inhibited by quercetin, antioxidant flavonoid. Moreover, co-treatment with 30-100 µM MMT and 100 µM H2O2 increased the cell lethality further. These results indicate that MMT increases cell vulnerability to oxidative stress on rat thymocytes. This study provides insight into the toxic effect of MMT on the immune system.
Assuntos
Compostos Organometálicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Timócitos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Citometria de Fluxo , Corantes Fluorescentes , Peróxido de Hidrogênio/farmacologia , Masculino , Compostos Organometálicos/antagonistas & inibidores , Quercetina/farmacologia , Ratos , Ratos WistarRESUMO
Lead (Pb)-induced reproductive toxicity is a well-characterized adverse effect associated with this heavy metal. It has been found that Pb exposure is associated with altered spermatogenesis, increased testicular degeneration, and pathological sperm alterations. On the other hand, it has been reported that Pb-induced reproductive toxicity is associated with increased reactive oxygen species (ROS) formation and diminished antioxidant capacity in the reproductive system. Hence, administration of antioxidants as protective agents might be of value against Pb-induced reproductive toxicity. This study was designed to investigate whether carnosine (CAR) and histidine (HIS) supplementation would mitigate the Pb-induced reproductive toxicity in male rats. Animals received Pb (20 mg/kg/day, oral, 14 consecutive days) alone or in combination with CAR (250 and 500 mg/kg/day, oral, 14 consecutive days) or HIS (250 and 500 mg/kg/day, oral, 14 consecutive days). Pb toxicity was evident in the reproductive system by a significant increase in tissue markers of oxidative stress along with severe histopathological changes, seminal tubule damage, tubular desquamation, low spermatogenesis index, poor sperm parameters, and impaired sperm mitochondrial function. It was found that CAR and HIS supplementation blunted the Pb-induced oxidative stress and mitochondrial dysfunction in the rat reproductive system. Thereby, antioxidative and mitochondria-protective properties serve as primary mechanisms for CAR and HIS against Pb-induced reproductive toxicity.
Assuntos
Carnosina/farmacologia , Histidina/farmacologia , Mitocôndrias/efeitos dos fármacos , Compostos Organometálicos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Espermatozoides/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Carnosina/administração & dosagem , Suplementos Nutricionais , Histidina/administração & dosagem , Masculino , Mitocôndrias/metabolismo , Compostos Organometálicos/toxicidade , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Lead acetate (Led) and mercury chloride (Mer) represent important ecological and public health concerns due to their hazardous toxicities. Naturally found products play a vital role in chemopreventive agent innovation. The current study aimed to assess the modifying effect of garlic (Gar) and/or vitamin E (Vit E) against the half-maximal inhibitory concentration (IC50) Led and/or Mer-induced cytotoxic, genotoxic and apoptotic effects. METHODS: Human lung cells (WI-38) were pretreated with Gar and/or Vit E for 24h and then treated with Led and/or Mer either alone or with their combination for 24h. Cytotoxicity of Led and Mer and the viability of Gar and Vit E were assessed using MTT assay. The alkaline comet assay was used to assess DNA damage, whereas QRT-PCR was performed to evaluate p53, Bax, and Bcl2 mRNA-expression. RESULTS: The results of this study showed that IC50 of Led was (732.72µg/mL) and for Mer was (885.83µg/mL), while cell viability effective dose for Gar was (300µg/mL) and for Vit E was (26,800µg/mL). Treating cells with the IC50-concentration of Led or Mer or their combination using half IC50 of both of them induced severe DNA-damage. Bax-expression was increased, while p53 and Bcl2-expressions were decreased. Pretreatment of cells with Gar and/or Vit E ameliorated the previous alternations. CONCLUSIONS: Led and Mer can induce oxidative stress and change the expressions of apoptosis-related proteins in WI-38 cells. Gar and Vit E may be promising protective candidate agent against the toxic effect of heavy metals.
Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Alho/química , Cloreto de Mercúrio/antagonistas & inibidores , Compostos Organometálicos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Vitamina E/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Interações Ervas-Drogas , Humanos , Cloreto de Mercúrio/toxicidade , Compostos Organometálicos/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Proteína X Associada a bcl-2/biossínteseRESUMO
Flavonoids are agents with strong antioxidant properties and ameliorate many diseases associated with oxidative stress. Leaves of Casimiroa sapota were investigated for components and antioxidant/anti-inflammatory activities against lead acetate ((AcO)2 Pb) induced hepatotoxicity in rats. Three groups of male albino rats were administrated orally with vehicle or C. sapota (100 and 200 mg/kg b.w/day) for 28 days; other group was injected with sub-acute dose (100 mg/kg b.w/day) of (AcO)2 Pb. Three protective groups were injected with (AcO)2 Pb (100 mg/kg b.w/day) for 7 days at day 22 after treatment with either C. sapota (100 or 200 mg/kg b.w/day) or silymarin (SILY) for 28 days. We isolated and identified, from C. sapota, a new compound for the 1st time in nature; 5,6,2',3'-tetramethoxyflavone in addition to the rare compound 5,6,3'-trimethoxyflavone (second report of isolation from nature) and the known compound 5,6,2',3',4'-pentamethoxyflavone. There is an improvement in all hemato-biochemical parameters, antioxidant defense system and anti-inflammatory cytokines of protective groups, which received C. sapota in dose dependent manner. The percentage of changes in all parameters measured in (AcO)2 Pb groups that received vehicle, CS100, CS200 or SILY were 109.2, 37.3, 12.5%, and 1.2% compared with the healthy control group. The C. sapota groups confer a better antioxidant activity by preventing oxidative stress and inflammation in (AcO)2 Pb treated rats. The compounds isolated are responsible at least in part for the observed protective effects.
Assuntos
Casimiroa/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavonas/farmacologia , Compostos Organometálicos/antagonistas & inibidores , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Relação Dose-Resposta a Droga , Flavonas/química , Flavonas/isolamento & purificação , Masculino , Estrutura Molecular , Compostos Organometálicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Relação Estrutura-AtividadeRESUMO
In this study, the effect of geraniol (50 mg/kg for 30 d), a natural antioxidant and repellent/antifeedant monoterpene, in a rat model of lead acetate-induced (500 ppm for 30 d) liver damage was evaluated. Hepatic malondialdehyde increased in the lead acetate group. Reduced glutathione unchanged, but glutathione S-transferase, glutathione reductase, as well as carboxylesterase activities decreased in geraniol, lead acetate and geraniol + lead acetate groups. 8-OhDG immunoreactivity, mononuclear cell infiltrations and hepatic lead concentration were lower in the geraniol + lead acetate group than the lead acetate group. Serum aspartate aminotransferase and alanine aminotransferase activities increased in the Pb acetate group. In conclusion, lead acetate causes oxidative and toxic damage in the liver and this effect can reduce with geraniol treatment. However, we first observed that lead acetate, as well as geraniol, can affect liver carboxylesterase activity.
Assuntos
Carboxilesterase/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Repelentes de Insetos/uso terapêutico , Intoxicação por Chumbo/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Terpenos/uso terapêutico , Monoterpenos Acíclicos , Animais , Antioxidantes/efeitos adversos , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Carboxilesterase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Glutationa/química , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Repelentes de Insetos/efeitos adversos , Intoxicação por Chumbo/metabolismo , Intoxicação por Chumbo/patologia , Intoxicação por Chumbo/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Masculino , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/toxicidade , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/efeitos adversos , Distribuição Aleatória , Ratos Wistar , Terpenos/efeitos adversosRESUMO
Lead, one of the most harmful heavy metals, can cause various hazardous effects on living organisms. This study was undertaken to evaluate the antagonistic and protective effects of two economically important laver species, Pyropia yezoensis and P. haitanensis, against subchronic lead poisoning in rats by a 30-day feeding test. Sixty-four healthy Wistar rats were randomly divided into eight groups with eight rats (4â + 4â) per group, among which, one group was served as the control, the others were respectively treated with lead acetate (5 mg/kg b w), and a combination of lead acetate and P. yezoensis or P. haitanensis at different dosages. Weight gain of rats was observed and recorded. Changes in antioxidant indexes, and liver and renal function markers were determined to evaluate the antagonistic effect. Lead content in rats was determined to investigate lead excretion effect of laver. The results showed that exposure to lead caused lead accumulation in kidney and liver, thus leading to significant oxidative damage and impaired liver and renal function compared to the control group. The co-treatment of laver slightly increased body weight compared to the lead-treated group. The co-administration of laver restored liver and renal function of rats by preventing the increment in the activities of alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate transaminase (AST), and the levels of blood urea nitrogen (BUN) and creatinine (Cr). The increasing of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and lowering of the enhanced malondialdehyde (MDA) contents of rats were observed in the laver co-treated groups, which indicated that laver enhanced the antioxidative capacity of rats. The laver also enhanced lead content in feces and reduced it in liver and kidney. The results indicated that P. yezoensis and P. haitanensis could maintain or promote the normal physiological and biochemical function of lead-induced subchronic poisoning of rats, probably owing to their enhancements of antioxidant capacity and lead excretion.
Assuntos
Antioxidantes/farmacologia , Intoxicação por Chumbo/tratamento farmacológico , Compostos Organometálicos/antagonistas & inibidores , Extratos Vegetais/farmacologia , Rodófitas/química , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Rim/efeitos dos fármacos , Rim/metabolismo , Intoxicação por Chumbo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
The aim of this study was to investigate the beneficial effects of zinc (Zn) in preventing lead (Pb)-induced reproductive toxicity in Wistar rats. The rats were divided into four groups, namely, control group, Pb group, Zn group, and Pb + Zn group. Animals were exposed to Pb (819 mg of Pb/L) or Zn (71 mg of Zn/L) or both through drinking water for 65 days. Rats exposed to Pb showed decreased weights of testes and accessory sex organs. Significant decrease in the testicular daily sperm production, epididymal sperm count, motility, viability, and number of hypoosmotic tail coiled sperm was observed in Pb-exposed rats. Testicular 3ß- and 17ß-hydroxysteroid dehydrogenase activity levels and circulatory testosterone levels were also decreased significantly in Pb-exposed rats. A significant increase in the lipid peroxidation products with a significant decrease in the activities of catalase and superoxide dismutase were observed in the testes and epididymis of Pb-exposed rats. Moreover, the testicular architecture showed lumens devoid of sperm in Pb-exposed rats. Supplementation of Zn mitigated Pb-induced oxidative stress and restored the spermatogenesis and steroidogenesis in Pb-exposed rats. In conclusion, cotreatment of Zn is effective for recovering suppressed spermatogenesis, steroidogenesis, elevated oxidative status, and histological damage in the testis of rats treated with Pb.
Assuntos
Suplementos Nutricionais , Epididimo/efeitos dos fármacos , Infertilidade Masculina/prevenção & controle , Intoxicação por Chumbo/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Zinco/uso terapêutico , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/química , 17-Hidroxiesteroide Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 3-Hidroxiesteroide Desidrogenases/química , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Suplementos Nutricionais/efeitos adversos , Epididimo/metabolismo , Epididimo/patologia , Infertilidade Masculina/etiologia , Intoxicação por Chumbo/metabolismo , Intoxicação por Chumbo/patologia , Intoxicação por Chumbo/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/toxicidade , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Doenças Transmitidas pela Água/metabolismo , Doenças Transmitidas pela Água/patologia , Doenças Transmitidas pela Água/fisiopatologia , Doenças Transmitidas pela Água/prevenção & controle , Zinco/efeitos adversosRESUMO
OBJECTIVE: Lead (Pb) is a long-known poison of environment and industrial origin. Its prolonged exposure affects cellular material and alters cellular genetics and produces oxidative damages. In this study, we investigated the exposure of chronic sustained hypoxia or lead acetate alone or in combination with or without supplementation of α-tocopherol on hepatic oxidative and nitrosative stress in rats. MATERIALS AND METHODS: The rats weighing 165 ± 5 g were exposed to chronic sustained hypoxia (10% oxygen) or lead acetate (25 mg/kg of body weight, intraperitoneally) alone or in combination with or without supplementation of α-tocopherol (10 mg/100 g b.wt, intramuscularly). The body weight of all the rats was recorded on the day 1 of the treatment and the day of sacrifice. Serum lipid profile was estimated by using a biochemical analyzer. Oxidant and enzymatic antioxidants status was evaluated by using spectrophotometer. Serum levels of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by using ELISA technique. Histopathological assessments of hepatic tissue were also done. RESULTS: Exposure of both lead and hypoxia showed decreased body weight, altered serum lipid profile, oxidant and enzymatic antioxidants status, serum HIF-1α and VEGF concentrations. Simultaneous α-tocopherol supplementation showed beneficial effects to all these alterations. Histopathological observations also showed hepatic degenerative changes after lead or hypoxia exposure either alone or in combination, but remarkable improvement has been noticed after α-tocopherol supplementation. CONCLUSION: Supplementation of α-tocopherol is beneficial to counter both lead acetate and hypoxia induced hepatic cytotoxicities possibly by reducing oxidative and nitrosative stress.
Assuntos
Antioxidantes/farmacologia , Hipóxia/prevenção & controle , Hepatopatias/prevenção & controle , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/toxicidade , alfa-Tocoferol/farmacologia , Animais , Antioxidantes/administração & dosagem , Peso Corporal/efeitos dos fármacos , Interações Medicamentosas , Hipóxia/sangue , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Lipídeos/sangue , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Fator A de Crescimento do Endotélio Vascular/sangue , alfa-Tocoferol/administração & dosagemRESUMO
The effect of four trichlorotelluro-dypnones, named compounds 1, 2, 3, and 4, on the bioenergetics of isolated rat liver mitochondria (RLM) and cells was investigated. In a dose-dependent manner, the studied organotelluranes promoted Ca(2+)-dependent mitochondrial swelling inhibited by cyclosporine A and were associated with a decrease of the total mitochondrial protein thiol content. These effects characterize the opening of the classical mitochondrial permeability transition pore. Despite the reactivity with mitochondrial protein thiol groups, these compounds did not promote significant glutathione depletion. In the absence of Ca(2+), the organotelluranes promoted mitochondrial loss of ΔΨ in RLM concomitant with respiratory control decrease due to an increase of the state 4 respiration rate. In these conditions, mitochondrial swelling was absent, and thiol content was higher than that in the presence of Ca(2+). The differentiated effects observed in the presence and absence of Ca(2+) are probably related to the effects of that ion on membrane structure, with repercussions for the exposure of specific reactive protein thiol groups. In smooth muscle cells, these compounds promoted the loss of mitochondrial ΔΨ and apoptosis. The loss of ΔΨ was not preceded by a decrease of cell viability that is consistent with mitochondria as the primary targets for the action of these organotelluranes.
Assuntos
Chalconas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Compostos Organometálicos/farmacologia , Compostos de Sulfidrila/metabolismo , Animais , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Chalconas/antagonistas & inibidores , Chalconas/química , Ciclosporina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Diphenyl ditelluride (PhTe)2 is a versatile molecule used in the organic synthesis and it is a potential prototype for the development of novel biologically active molecules. The mechanism(s) involved in (PhTe)2 toxicity is(are) elusive, but thiol oxidation of critical proteins are important targets. Consequently, the possible remedy of its toxicity by thiol-containing compounds is of experimental and clinical interest. The present study aimed to investigate putative mechanisms underlying the toxicity of (PhTe)2 in vivo. We assessed behavioral and oxidative stress parameters in mice, including the modulation of antioxidant enzymatic defense systems. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered before (3 d) and simultaneously with (PhTe)2 (7 d). Mice were separated into six groups receiving daily injections of (1) TFK (2.5 ml/kg, intraperitonealy (i.p.)) plus canola oil (10 ml/kg, subcutaneously (s.c.)), (2) NAC (100 mg/kg, i.p.) plus canola oil s.c., (3) TFK i.p. plus (PhTe)2 (10 µmol/kg, s.c.), (4) TFK i.p. plus (PhTe)2 (50 µmol/kg, s.c.), (5) NAC plus (PhTe)2 (10 µmol/kg, s.c.), and (6) NAC plus (PhTe)2 (50 µmol/kg, s.c.). (PhTe)2 treatment started on the fourth day of treatment with NAC. Results demonstrated that (PhTe)2 induced behavioral alterations and inhibited important selenoenzymes (thioredoxin reductase and glutathione peroxidase). Treatments produced no or minor effects on the activities of antioxidant enzymes catalase and glutathione reductase. Contrary to expected, NAC co-administration did not protect against the deleterious effects of (PhTe)2. Other low-molecular-thiol containing molecules should be investigated to determine whether or not they can be effective against ditellurides.
Assuntos
Derivados de Benzeno/toxicidade , Poluentes Ambientais/toxicidade , Glutationa Peroxidase/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Síndromes Neurotóxicas/enzimologia , Compostos Organometálicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/antagonistas & inibidores , Glutationa Peroxidase/metabolismo , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Síndromes Neurotóxicas/prevenção & controle , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Testes de Toxicidade AgudaRESUMO
Exposure to lead induces oxidative stress and renal damage. Although most forms of oxidative stress are characterized by simultaneous elevation of nitrogen and oxidative species, lead-induced oxidative stress is unusual in that it is associated with a reduction in nitric oxide (NO) levels in the kidney. The role of NO in kidney injury is controversial; some studies suggest that it is associated with renal injury, whereas others show that it exerts protective effects. Concentration-dependent effects have also been proposed, linking low levels with vasodilatation and high levels with toxicity. The aim of this study was to evaluate the effects of melatonin co-exposure on the lead-induced reduction in renal NO levels. We found that sub-acute intraperitoneal administration of 10 mg/kg/day of lead for 15 days induced toxic levels of lead in the blood and caused renal toxicity (pathological and functional). Under our experimental conditions, lead induced an increase in lipid peroxidation and a decrease in NO. Melatonin co-treatment decreased lead-induced oxidative stress (peroxidation level) and toxic effects on kidneys without altering the lead-induced reduction in renal NO. These results suggest that, in our experimental model, the reduction in renal NO levels by lead exposure is not the only responsible factor for lead-induced kidney damage.
Assuntos
Rim/efeitos dos fármacos , Melatonina/farmacologia , Óxido Nítrico/química , Compostos Organometálicos/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Injeções Intraperitoneais , Rim/metabolismo , Rim/patologia , Masculino , Melatonina/administração & dosagem , Óxido Nítrico/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/sangue , Compostos Organometálicos/toxicidade , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The synthesis, structure and photophysical properties of a series of highly emissive europium complexes is reported. Certain complexes enter mammalian cells by macropinocytosis and stain the mitochondria selectively, allowing observation of the Eu emission in cellulo by time-gated spectral imaging.
Assuntos
Európio/análise , Európio/química , Mitocôndrias/química , Amilorida/farmacologia , Androstadienos/farmacologia , Animais , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Estrutura Molecular , Células NIH 3T3 , Compostos Organometálicos/análise , Compostos Organometálicos/antagonistas & inibidores , Compostos Organometálicos/química , Temperatura , WortmaninaRESUMO
Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.
Assuntos
Acetatos/toxicidade , Apoptose/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Acetatos/antagonistas & inibidores , Acetilcisteína/farmacologia , Apoptose/fisiologia , Caspases/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Citometria de Fluxo , Humanos , Túbulos Renais Proximais/metabolismo , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Compostos Organometálicos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Oxidative stress is thought to be involved in lead-induced toxicity. The aim of this study was to investigate the possible protective role of naringenin on lead-induced oxidative stress in the liver and kidney of rats. In the present investigation, lead acetate (500 mg Pb/L) was administered orally for 8 weeks to induce hepatotoxicity and nephrotoxicity. The levels of hepatic and renal markers such as alanine aminotransferase, aspartate aminotransferase, urea, uric acid, and creatinine were significantly (P < 0.05) increased following lead acetate administration. Lead-induced oxidative stress in liver and kidney tissue was indicated by a significant (P < 0.05) increase in the level of maleic dialdehyde and decreased levels of reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase. Naringenin markedly attenuated lead-induced biochemical alterations in serum, liver, and kidney tissues (P < 0.05). The present study suggests that naringenin shows antioxidant activity and plays a protective role against lead-induced oxidative damage in the liver and kidney of rats.
Assuntos
Antioxidantes/farmacologia , Flavanonas/farmacologia , Compostos Organometálicos/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Biomarcadores/análise , Flavanonas/administração & dosagem , Rim/química , Rim/enzimologia , Rim/metabolismo , Fígado/química , Fígado/enzimologia , Fígado/metabolismo , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
It is well known that chronic exposure to lead (Pb(+2)) alters a variety of behavioral tasks in rats and mice. Here, we investigated the effect of flaxseed oil (1,000 mg/kg) on lead acetate (20 mg/kg)-induced brain oxidative stress and neurotoxicity in rats. The levels of Pb(+2), lipid peroxidation, nitric oxide (NO), and reduced glutathione (GSH) and the activity of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) were determined in adult male albino rats. The level of Pb(+2) was markedly elevated in brain and blood of rats. This leads to enhancement of lipid peroxidation and NO production in brain with concomitant reduction in GSH, CAT, SOD, GR, GST, and GPx activities. These findings were associated with DNA fragmentation. In addition, lead acetate induced brain injury as indicated by histopathological changes of the brain. Treatment of rats with flaxseed oil resulted in marked improvement in most of the studied parameters as well as histopathological features. These findings suggest to the conclusion that flaxseed oil significantly decreased the adverse harmful effects of lead acetate exposure on the brain as well as Pb(+2)-induced oxidative stress.