RESUMEN
CONTEXT: The tuber of Amorphophallus paeoniifolius (Dennst.) Nicolson (Araceae), commonly called Suran or Jimmikand, has high medicinal value and is used ethnomedicinally for the treatment of different gastrointestinal and inflammatory disorders. OBJECTIVE: The present study evaluated the effects of extracts of Amorphophallus paeoniifolius tubers on acetic acid-induced ulcerative colitis (UC) in rats. MATERIALS AND METHODS: Wistar rats were orally administered methanol extract (APME) or aqueous extract (APAE) (250 and 500 mg/kg) or standard drug, prednisolone (PRDS) (4 mg/kg) for 7 days. On 6th day of treatment, UC was induced by transrectal instillation of 4% acetic acid (AA) and after 48 h colitis was assessed by measuring colitis parameters, biochemical estimations and histology of colon. RESULTS: APME or APAE pretreatment significantly (p < .05-.001) prevented AA-induced reduction in body weight and increase in colitis parameters viz. stool consistency, colon weight/length ratio and ulcer score, area and index. Extracts treatment attenuated (p < .001) increase in alkaline phosphatase and lactate dehydrogenase in serum and myeloperoxidase activity and cytokines in colon tissue due to AA administration. Extracts treatment prevented AA-induced elevation in lipid peroxidation and decline in activities of superoxide dismutase and catalase and reduced-glutathione content (p < .05-.001) along with histopathological alterations. PRDS also showed similar ameliorative effect on colitis. DISCUSSION AND CONCLUSION: APME and APAE showed a preventive effect on UC, and ameliorated inflammation and oxidative damage in colon. The effects may be attributed to presence of phytochemicals, betulinic acid, ß-sitosterol, and glucomannan. In conclusion, the tuber of Amorphophallus paeoniifolius exhibited an anticolitic effect through anti-inflammatory and antioxidant action.
Asunto(s)
Amorphophallus/química , Antiinflamatorios/farmacología , Colitis Ulcerosa/prevención & control , Colon/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Extractos Vegetales/farmacología , Ácido Acético , Fosfatasa Alcalina/sangre , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/toxicidad , Biomarcadores/sangre , Catalasa/metabolismo , Colitis Ulcerosa/sangre , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colon/metabolismo , Colon/patología , Citocinas/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Fármacos Gastrointestinales/aislamiento & purificación , Fármacos Gastrointestinales/toxicidad , Glutatión/metabolismo , Mediadores de Inflamación/metabolismo , L-Lactato Deshidrogenasa/sangre , Peroxidación de Lípido/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Tubérculos de la Planta , Plantas Medicinales , Prednisolona/farmacología , Ratas Wistar , Solventes/química , Superóxido Dismutasa/metabolismoRESUMEN
n-Heneicosane (C21) is one of the vital pheromone for attracting mosquitoes of Aedes spp to lay their eggs in areas of stagnant fresh water, for their subsequent destruction, thus controlling spread of dangerous disease transmission by the vectors. As part of a safety evaluation, we have investigated embryo toxic and teratogenic potential, if any, of C21 following OECD Test Guideline 414. C21 was offered at a dose of 1 g/kg body weight mixed in the standard rat pellet diet to treated rats, whereas the control group received only standard rat pellet diet. There were no mortalities and animals did not show any clinical signs of toxicity. A similar pattern of body weight gain, feed and water intake was observed in treated and control groups. Analysis of maternal toxic response, maternal end points of development of the foetus and developmental end points for litters did not show any gross structural abnormality in dams or foetus of treated group compared to that of the control group. Thus, it was concluded that C21 at a dose of 1 g/kg was neither embryo toxic nor teratogenic in Wister rats. Furthermore, the no observed adverse effect level for teratogenicity for C21 in rats may be considered as 1 g/kg body weight under the present experimental conditions.
Asunto(s)
Alcanos/toxicidad , Desarrollo Fetal/efectos de los fármacos , Feto/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Teratógenos/toxicidad , Aumento de PesoRESUMEN
Sulfur mustard (SM)-induced dermatotoxicity can be prevented by an immediate use of decontamination agents. However, practically due to the time lapse between decontamination and exposure, there is always a possibility of wound formation. In view of this, a hydrophilic decontamination formulation of CC-2 (DRDE/WH-03) was fortified with Aloe vera gel and betaine (DRDE/WH-01) for improving its wound healing ability. Swiss albino mice were exposed to SM percutaneously (5 mg/kg) once, and after 24 hours, DRDE/WH-01, DRDE/WH-03, framycetin, and aloe gel were applied topically, daily for 7 days. Skin sections were subjected to histopathology, histomorphologic grading, tissue leukocytosis, and immunohistochemistry of inflammatory-reparative biomarkers on 3 and 7 days, respectively. DRDE/WH-01, framycetin, and aloe gel showed better reepithelialization, angiogenesis, and fibroplasia compared with DRDE/WH-03 and SM control. On the basis of histomorphologic scale, DRDE/WH-01, framycetin, and aloe gel were found to be equally efficacious. Up-regulation of interleukin-6 and infiltrating leukocytes, endothelial nitric oxide synthase and angiogenesis, fibroblast growth factor, and transforming growth factor-alpha with fibroplasia and reepithelialization were well correlated at various stages of the healing process. DRDE/WH-01 was equally effective as framycetin and has shown improved wound healing efficacy compared with DRDE/WH-03. Thus, DRDE/WH-01 can be recommended as a universal decontaminant and wound healant against vesicant-induced skin injury.
Asunto(s)
Aloe , Antibacterianos/farmacología , Betaína/farmacología , Quemaduras Químicas/tratamiento farmacológico , Clorobencenos/farmacología , Fármacos Dermatológicos/farmacología , Framicetina/farmacología , Compuestos de Fenilurea/farmacología , Piel/patología , Administración Cutánea , Animales , Quemaduras Químicas/patología , Sustancias para la Guerra Química/toxicidad , Descontaminación/métodos , Fármacos Dermatológicos/administración & dosificación , Quimioterapia Combinada , Femenino , Geles , Ratones , Gas Mostaza/toxicidad , Fitoterapia , Preparaciones de Plantas/farmacología , Piel/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Ammonia is a widely used industrial chemical that is recognized as a potent neurotoxin and environmental pollutant. The present study addresses the oxidative stress and tissue pathology caused by 4 weeks of exposure to ammonium acetate (AMA; 100 mg/kg daily; orally) in rats, and their response to oral treatments with alpha-ketoglutarate (A-KG; 1.0 g/kg), a potential cyanide antidote, and/or N-acetyl cysteine (NAC; 10 mg/kg), an antioxidant. The organ-body weight index of brain and liver was significantly increased by AMA but kidney was unaffected. Also, plasma ammonia levels were significantly elevated without any concomitant change in blood gas status and hematology but levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione (GSH) in the brain and liver were diminished, accompanied by elevated levels of malondialdehyde. Levels of glutathione disulfide (GSSG) were unaffected, but the ratio of GSH:GSSG was reduced. Plasma alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and total bilirubin were raised but urea, uric acid and creatinine levels were not altered. AMA also caused temporal, hepatic and renal pathology. However, the renal pathology was not supported by any biochemical alterations. A-KG or NAC alone afforded less protection against AMA as compared to both given together. The protective efficacy of A-KG can be ascribed to its ability to detoxify ammonia and additionally both A-KG and NAC have antioxidant properties as well. The study suggests a new therapeutic regimen for ammonia poisoning.
Asunto(s)
Acetatos/toxicidad , Acetilcisteína/farmacología , Ácidos Cetoglutáricos/farmacología , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Amoníaco/sangre , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Pruebas de Toxicidad SubagudaRESUMEN
Organophosphate pesticides are among the most widely used synthetic chemicals for controlling a wide variety of pests. Chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) are among the most extensively used organophosphate (OP) pesticides. The main target of action of OP compounds is the central and peripheral nervous system, although it has also been postulated that these compounds in both acute and chronic intoxication, disturb the redox processes and thus induce oxidative stress. The excessive generation of reactive oxygen species (ROS) causes damage to all vital macromolecules including lipids, proteins, and DNA. This study was aimed to investigate the genotoxicity and cytotoxicity of CPF, MPT, and MLT when given singly or in combination. The DNA damage was measured by alkaline single-cell gel electrophoresis or comet assay and expressed as DNA damage index. The results showed that both acute and chronic exposure with CPF, MPT, and MLT, caused significantly marked DNA damage in rat tissues namely, liver, brain, kidney, and spleen, when measured 24 hour posttreatment. It was also observed that MPT caused highest level of DNA damage and brain was maximally affected by these OP compounds. When these pesticides were given in mixture, the damage was not the sum of damage caused by individual pesticide, confirming that these pesticides do not potentiate the toxicity of each other. When the DNA damage was measured 48 and 72 hour posttreatment, the damage was partially repaired. Pesticide exposure also caused histopathological changes in rat tissues.
Asunto(s)
Cloropirifos/toxicidad , Daño del ADN , Insecticidas/toxicidad , Malatión/toxicidad , Metil Paratión/toxicidad , Animales , Ensayo Cometa , Interacciones Farmacológicas , Masculino , Oxidación-Reducción , Estrés Oxidativo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Sulphur mustard (SM) is a bifunctional alkylating agent that causes cutaneous blistering in humans and animals. In this study, we have presented closer views on pathogenesis of SM-induced skin injury in a mouse model. SM diluted in acetone was applied once dermally at a dose of 5 or 10 mg/kg to Swiss albino mice. Skin was dissected out at 0, 1, 3, 6, 12, 24, 48, 72 and 168 hours, post-SM exposure for studying histopathological changes and immunohistochemistry of inflammatory-reparative biomarkers, namely, transforming growth factor alpha (TGF-α), fibroblast growth factor (FGF), endothelial nitric oxide synthase (eNOS) and interlukin 6 (IL-6). Histopathological changes were similar to other mammalian species and basal cell damage resembled the histopathological signs observed with vesication in human skin. Inflammatory cell recruitment at the site of injury was supported by differential expressions of IL-6 at various stages. Time-dependent expressions of eNOS played pivotal roles in all the events of wound healing of SM-induced skin lesions. TGF-α and FGF were strongly associated with keratinocyte migration, re-epithelialisation, angiogenesis, fibroblast proliferation and cell differentiation. Furthermore, quantification of the tissue leukocytosis and DNA damage along with semiquantitative estimation of re-epithelialisation, fibroplasia and neovascularisation on histomorphologic scale could be efficiently used for screening the efficacy of orphan drugs against SM-induced skin injury.
Asunto(s)
Vesícula/inducido químicamente , Vesícula/patología , Gas Mostaza/farmacología , Gas Mostaza/toxicidad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Animales , Biopsia con Aguja , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Interleucina-6/análisis , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos , Distribución Aleatoria , Medición de Riesgo , Factores de Tiempo , Factor de Crecimiento Transformador alfa/análisis , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
This study intended to determine the effects of various concentrations of fluoride (1, 10, 50 and 100 ppm) in drinking water for a period of 12 weeks on changes in haem biosynthesis pathway, oxidative stress and neurological variables supported by histopathological observations and fluoride in rats. The data indicates significant alterations in the parameters related to haeme synthesis pathway like inhibition of blood delta-aminolevulinic acid dehydratase, delta-aminolevulinic acid synthetase, oxidative stress like depletion of glutathione (GSH) and increase in oxidized glutathione (GSSG) and thiobarbituric acid reactive substances. These changes were accompanied by depletion in GSH:GSSG ratio, whole brain biogenic amine levels and a dose-dependent increase in fluoride concentration. Interestingly and most significantly, these changes were more pronounced at lower concentrations of fluoride compared with higher fluoride dose. Biochemical changes were supported by the histological observations, which also revealed that at high concentrations of fluoride, toxic effects and damages to organs were more pronounced. These changes support our earlier findings regarding the role of decreased ionic mobility of fluoride ion at higher concentrations, leading to less pronounced toxicity.
Asunto(s)
Encéfalo , Fluoruros , Hemo/biosíntesis , Animales , Aminas Biogénicas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Fluoruros/administración & dosificación , Fluoruros/metabolismo , Fluoruros/farmacología , Fluoruros/toxicidad , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Agua/químicaRESUMEN
Sulphur mustard, [bis (2-chloroethyl)] sulphide (SM), is a bifunctional alkylating agent. SM forms sulphonium ion in the body which alkylates DNA and several other macromolecules, and induces oxidative stress. Although several antidotes have been screened for the treatment of systemic toxicity of SM in experimental animals none of them are recommended so far. In the search for more effective and less toxic antidotes, various combinations were tried against SM induced toxicity and skin lesions. SM exposed through percutaneous route was used to evaluate the prophylactic efficacy of various combinations. Low dose of DRDE-07 (S-2(2-aminoethylamino) ethyl phenyl sulphide), DRDE-30 [S-2(2-aminoethyl amino) ethyl propyl sulphide], DRDE-35 [S-2(2-aminoethyl amino) ethyl butyl sulphide] with amifostine combinations, were given orally 30 min prior to SM exposure. Significant depletion was observed in body weight, organ body weight index and hepatic GSH and GSSG content in mice after SM exposure. Pretreatment with low dose of different combinations of DRDE-07, DRDE-30 and DRDE-35 with amifostine could recover biochemical alterations and histopathological changes caused by SM exposures.
Asunto(s)
Amifostina/análogos & derivados , Amifostina/uso terapéutico , Sustancias para la Guerra Química/toxicidad , Gas Mostaza/toxicidad , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Administración Cutánea , Administración Oral , Amifostina/química , Animales , Peso Corporal/efectos de los fármacos , Quimioterapia Combinada , Femenino , Glutatión/metabolismo , Ratones , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Protectores contra Radiación/uso terapéutico , Enfermedades de la Piel/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Amorphophallus paeoniifolius (Dennst.) Nicolson (Family- Araceae) is a crop of south East Asian origin. In India, its tuber is widely used in ethnomedicinal practices by different tribes for the treatment of piles (hemorrhoids). AIM: The present study evaluated the effect of methanolic and aqueous extract of Amorphophallus paeoniifolius tuber on croton oil induced hemorrhoids in rats. MATERIALS AND METHODS: The methanolic extract was standardized with the major phenolic compound, betulinic acid, by HPLC. The hemorrhoids were induced by applying 6% croton oil preparation in the ano-rectal region. Rats were orally administered methanolic and aqueous extract at doses of 250 and 500mg/kg, each for 7 days. Pilex (200mg/kg) was used as reference anti-hemorrhoidal drug. Hemorrhoids were assessed on eighth day by measuring hemorrhoidal and biochemical parameters along with histology of ano-rectal tissue. RESULTS: Croton oil application caused induction of hemorrhoids as indicated by significant (p<0.001) increase in plasma exudation of Evans blue in ano-rectal tissue, macroscopic severity score and ano-rectal coefficient as compared to normal rats. It significantly (p<0.001) elevated lactate dehydrogenase and cytokines (TNF-α and IL-6) levels in serum and increased myeloperoxidase activity and lipid peroxidation in ano-rectal tissue along with marked histological damage as compared to normal rats. Treatment with tuber extracts and pilex significantly (p<0.05-p<0.001) ameliorated Evans blue exudation, hemorrhoidal parameters and other biochemical parameters with attenuation of tissue damage compared to hemorrhoid control rats. The results indicate that tuber extracts exhibited curative action on hemorrhoids. The aqueous extract showed more pronounced effect than methanolic extract. The effects may be attributed to anti-inflammatory and antioxidant properties. CONCLUSION: Results indicate that tuber of Amorphophallus paeoniifolius exhibited curative action on hemorrhoids through anti-inflammatory and antioxidant properties. The study validates the ethnomedicinal use of tuber in hemorrhoids and implicates its therapeutic potential as an anti-hemorrhoidal agent.
Asunto(s)
Amorphophallus/química , Canal Anal/efectos de los fármacos , Antiinflamatorios/farmacología , Hemorroides/tratamiento farmacológico , Extractos Vegetales/farmacología , Tubérculos de la Planta/química , Recto/efectos de los fármacos , Canal Anal/metabolismo , Canal Anal/patología , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Aceite de Crotón , Modelos Animales de Enfermedad , Hemorroides/sangre , Hemorroides/inducido químicamente , Hemorroides/patología , Mediadores de Inflamación/sangre , Interleucina-6/sangre , L-Lactato Deshidrogenasa/sangre , Peroxidación de Lípido/efectos de los fármacos , Masculino , Metanol/química , Triterpenos Pentacíclicos , Peroxidasa/metabolismo , Extractos Vegetales/aislamiento & purificación , Ratas Wistar , Recto/metabolismo , Recto/patología , Inducción de Remisión , Índice de Severidad de la Enfermedad , Solventes/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/sangre , Agua/química , Ácido BetulínicoRESUMEN
While a number of studies have documented the persistent presence of chikungunya virus (CHIKV) in muscle tissue with primary fibroblast as the preferable cell target, little is known regarding the alterations that take place in muscle tissue in response to CHIKV infection. Hence, in the present study a permissive mouse model of CHIKV infection was established and characterized in order to understand the pathophysiology of the disease. The two dimensional electrophoresis of muscle proteome performed for differential analysis indicated a drastic reprogramming of the proteins from various classes like stress, inflammation, cytoskeletal, energy and lipid metabolism. The roles of the affected proteins were explained in relation to virus induced myopathy which was further supported by the histopathological and behavioural experiments proving the lack of hind limb coordination and other loco-motor abnormalities in the infected mice. Also, the level of various pro-inflammatory mediators like IL-6, MCP-1, Rantes and TNF-α was significantly elevated in muscles of infected mice. Altogether this comprehensive study of characterizing CHIKV induced mouse myopathy provides many potential targets for further evaluation and biomarker study.
Asunto(s)
Fiebre Chikungunya/inmunología , Virus Chikungunya/inmunología , Citocinas/inmunología , Músculo Esquelético/inmunología , Miositis/inmunología , Animales , Conducta Animal , Línea Celular , Fiebre Chikungunya/patología , Fiebre Chikungunya/fisiopatología , Cricetinae , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , Actividad Motora/inmunología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Músculo Esquelético/virología , Miositis/patología , Miositis/fisiopatología , Miositis/virologíaRESUMEN
AIMS: Exposure to toxic metals remains a widespread occupational and environmental problem in world. Chelation therapy is a mainstream treatment used to treat heavy metal poisoning. This paper describes the synthesis, characterization and therapeutic evaluation of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)-encapsulated polymeric nanoparticles as a detoxifying agent for arsenic poisoning. MATERIALS & METHODS: Polymeric nanoparticles entrapping the DMSA monoester, which can evade the reticulo-endothelial system and have a long circulation time in the blood, were prepared. Particle characterization was carried out by transmission electron microscopy and dynamic light scattering. An in vivo study was conducted to investigate the therapeutic efficacy of MiADMSA-encapsulated polymeric nanoparticles (nano- MiADMSA; 50 mg/kg orally for 5 days) and comparison drawn with bulk MiADMSA. Swiss albino mice exposed to sodium arsenite for 4 weeks were treated for 5 days to evaluate alterations in blood, brain, kidney and liver oxidative stress variables. The study also evaluated the histopathological changes in tissues and the chelating potential of the nanoformulation. RESULTS: Our results show that nano-MiADMSA have a narrow size distribution in the 50-nm range. We observed an enhanced chelating potential of nano-MiADMSA compared with bulk MiADMSA as evident in the reversal of biochemical changes indicative of oxidative stress and efficient removal of arsenic from the blood and tissues. Histopathological changes and urinary 8-OHdG levels also prove better therapeutic efficacy of the novel formulation for arsenic toxicity. CONCLUSION: The results from our study show better therapeutic efficacy of nano-MiADMSA in removing arsenic burden from the brain and liver.
Asunto(s)
Intoxicación por Arsénico/tratamiento farmacológico , Quelantes/administración & dosificación , Portadores de Fármacos/química , Nanopartículas/química , Succímero/análogos & derivados , Animales , Arsénico/sangre , Arsénico/metabolismo , Intoxicación por Arsénico/sangre , Intoxicación por Arsénico/metabolismo , Intoxicación por Arsénico/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Quelantes/uso terapéutico , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Nanopartículas/ultraestructura , Conejos , Ratas , Ratas Wistar , Succímero/administración & dosificación , Succímero/uso terapéuticoRESUMEN
Time-dependent cyanide generation and acute toxicity of six different cyanogens were reported earlier, out of which malononitrile (MCN), propionitrile (PCN), and sodium nitroprusside (SNP) were found to be very toxic. We report here 14 d sub-acute toxicity of MCN, PCN, and SNP (oral; 1/10 LD50 daily) in female rats, and its amelioration by α-ketoglutarate (α-KG; oral; 5.26 mmol/kg; +5 min), a potential cyanide antidote. Significant decrease in white blood cells (PCN, SNP), platelets count (PCN), and blood glucose levels (MCN, PCN, SNP) was accompanied by elevated levels of alanine aminotransferase, lactate dehydrogenase (MCN, PCN, SNP), and aspartate aminotransferase (PCN, SNP). Oxidative damage was evidenced by diminished total antioxidant status in plasma and enhanced malondialdehyde levels in liver and kidney. This was accompanied by diminished levels of reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the brain, liver and kidney. We also observed increased levels of blood cyanide and thiocyanate, together with inhibition of cytochrome c oxidase and thiosulfate-sulfur transferase activities in total brain and liver homogenate, respectively. Cyanogens also produced several histological changes in all the organs studied. Post-treatment with α-KG significantly abrogated the toxicity of cyanogens, indicating its utility as an antidote for long-term cyanogen exposure.
Asunto(s)
Ácidos Cetoglutáricos/farmacología , Nitrilos/toxicidad , Administración Oral , Animales , Femenino , Ratas , Ratas WistarRESUMEN
Water-soluble nanoparticles of curcumin were synthesized, characterized and applied as a stable detoxifying agent for arsenic poisoning. Chitosan nanoparticles of less than 50 nm in diameter containing curcumin were prepared. The particles were characterized by TEM, DLS and FT-IR. The therapeutic efficacy of the encapsulated curcumin nanoparticles (ECNPs) against arsenic-induced toxicity in rats was investigated. Sodium arsenite (2mg/kg) and ECNPs (1.5 or 15 mg/kg) were orally administered to male Wistar rats for 4 weeks to evaluate the therapeutic potential of ECNPs in blood and soft tissues. Arsenic significantly decreased blood δ-aminolevulinic acid dehydratase (δ-ALAD) activity, reduced glutathione (GSH) and increased blood reactive oxygen species (ROS). These changes were accompanied by increases in hepatic total ROS, oxidized glutathione, and thiobarbituric acid-reactive substance levels. By contrast, hepatic GSH, superoxide dismutase and catalase activities significantly decreased on arsenic exposure, indicative of oxidative stress. Brain biogenic amines (dopamine, norepinephrine and 5-hydroxytryptamine) levels also showed significant changes on arsenic exposure. Co-administration of ECNPs provided pronounced beneficial effects on the adverse changes in oxidative stress parameters induced by arsenic. The results indicate that ECNPs have better antioxidant and chelating potential (even at the lower dose of 1.5 mg/kg) compared to free curcumin at 15 mg/kg. The significant neurochemical and immunohistochemical protection afforded by ECNPs indicates their neuroprotective efficacy. The formulation provides a novel therapeutic regime for preventing arsenic toxicity.
Asunto(s)
Intoxicación por Arsénico/tratamiento farmacológico , Arsénico/toxicidad , Curcumina/administración & dosificación , Nanopartículas/administración & dosificación , Nanopartículas/química , Animales , Arsénico/farmacocinética , Intoxicación por Arsénico/sangre , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Curcumina/farmacología , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Distribución TisularRESUMEN
T-2 toxin is one of the most toxic among several trichothecenes involved in both human and animal poisoning cases. We investigated the biochemical and histological alterations behind inflammation and cutaneous injury caused by T-2 toxin. Swiss albino mice were exposed to T-2 toxin topically at doses of 0.5, 1 and 2 LD50 (2.97, 5.94 and 11.88 mg/kg respectively) and observed till 3, 24 and 72 h. Topical application of T-2 toxin resulted in skin oxidative stress in terms of increased reactive oxygen species generation, lipid peroxidation and neutrophil mediated myeloperoxidase activity. The histological alterations include degenerative changes like vacuolation, ballooning of basal keratinocytes and infiltration of inflammatory cells in dermis. The mRNA levels of skin pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß showed significant up regulation. Anti-inflammatory cytokines IL-10 showed significant up regulation at 24h whereas IL-4 showed down regulation for all the doses and time points. Gelatin zymography and immunoblot analysis of matrix metalloproteinases (MMP)-9 and 2 indicated MMP activation and their role in degenerative skin histological changes. Time dependent increase in inducible nitric oxide synthase levels was seen. Immunoblot analysis revealed significant increase in the levels of phosphorylated p38 mitogen activated protein kinase (MAPK). Flow cytometry analysis of propidium iodide stained epidermal cells showed increase in sub-G1 population at all the doses and time points indicating apoptosis. In summary, T-2 toxin induced skin inflammation and cutaneous injury is mediated through oxidative stress, activation of myeloperoxidase, MMP activity, increase in inflammatory cytokines, activation of p38 MAPK and apoptosis of epidermal cells leading to degenerative skin histological changes.
Asunto(s)
Dermatitis/patología , Estrés Oxidativo/efectos de los fármacos , Toxina T-2/toxicidad , Animales , Apoptosis/efectos de los fármacos , Dermatitis/etiología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Fusarium/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Dosificación Letal Mediana , Peroxidación de Lípido/efectos de los fármacos , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/metabolismo , Fosforilación , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno , Piel/efectos de los fármacos , Piel/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Inhalation toxicity of silicon dioxide aerosol (150, 300 mg/m(3)) daily over a period of 28 days was carried out in rats. The changes in respiratory variables during the period of exposure were monitored using a computer programme that recognizes the modifications of the breathing pattern. Exposure to the aerosol caused a time dependent decrease in tidal volume, with an increase in respiratory frequency compared to the control. Biochemical variables and histopathological observation were noted at 28th day following the start of exposure. Biochemical markers of silica induced lung injury like plasma alkaline phosphatase, lactate dehydrogenase and angiotensine converting enzyme activities increased in a concentration dependent manner compared to control. Increase in the plasma enzymatic activities indicates endothelial lung damage, increased lung membrane permeability. Histopathological observation of the lungs confirmed concentration dependent granulomatous inflammation, fibrosis and proteinacious degeneration. Aggregates of mononuclear cells with entrapped silica particles circumscribed by fibroblast were observed in 300 mg/m(3) silica aerosol exposed group at higher magnification. Decrease in tidal volume and increase in respiratory frequency might be due to the thickening of the alveolar wall leading to a decreased alveolar volume and lowered elasticity of the lung tissue. The trends in histological and biochemical data are in conformity with the respiratory data in the present study. This study reports for the first time, the changes in respiratory variables during silica aerosol exposure over a period of 28 days.
Asunto(s)
Aerosoles/toxicidad , Pulmón/efectos de los fármacos , Dióxido de Silicio/toxicidad , Acetilcolinesterasa/metabolismo , Animales , Biomarcadores/metabolismo , Exposición por Inhalación/efectos adversos , L-Lactato Deshidrogenasa/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Alveolos Pulmonares , Ratas , Ratas Wistar , Volumen de Ventilación PulmonarRESUMEN
This study was planned to design a mouse model for studying sulphur mustard (SM)-induced skin injury. SM was applied dermally at dose of 5 or 10 mg kg(-1) in polyethyleneglycol-300 (PEG-300) or dimethylsulphoxide (DMSO) or acetone once. The changes in body weight, organ body weight indices (OBWI) and haematological and oxidative stress parameters were investigated over a period of 3-7 days and supported by histopathological observations. Exposure to SM in PEG-300 or DMSO resulted in a significant depletion in body weight, OBWI, hepatic glutathione (GSH) and elevation in hepatic lipid peroxidation, without affecting the blood GSH and hepatic oxidised glutathione (GSSG) levels. Interestingly, no aforesaid change was observed after dermal application of SM diluted in acetone. These biochemical changes were supported by the histological observations, which revealed pronounced toxic effect and damage to liver, kidney and spleen after dermal application of SM diluted in PEG-300 or DMSO. The skin showed similar microscopic changes after dermal application of SM in all the three diluents, however; the severity of lesions was found to be time and dose dependent. It can be concluded that dermal exposure of SM diluted in acetone can be used to mimic SM-induced skin toxicity without systemic toxicity in a mouse model.
Asunto(s)
Quemaduras Químicas/etiología , Sustancias para la Guerra Química/toxicidad , Gas Mostaza/toxicidad , Piel/lesiones , Acetona/farmacología , Animales , Recuento de Células Sanguíneas , Peso Corporal/efectos de los fármacos , Quemaduras Químicas/sangre , Quemaduras Químicas/patología , Modelos Animales de Enfermedad , Glutatión/análisis , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , Bazo/patologíaRESUMEN
BACKGROUND: Host immune response particularly through the induction of proinflammatory cytokines and chemokines in Japanese encephalitis virus infection has not been clearly understood in relation with pathogenicity and disease severity. The newly identified host mediators of pathogenesis could be the future target for diagnostic and therapeutics purpose. OBJECTIVES: We investigated the mechanism of JE virus induced pathogenesis in terms of proinflammatory cytokine and chemokine secretion at molecular level in young one-week-old BALB/c mouse after subcutaneous administration of JEV. STUDY DESIGN: Histopathology of brain was done to observe the morphological changes after JEV infection and genes relevant to macrophage activation, chemokine secretion, inflammatory cell infiltration, and blood-brain barrier permeability were examined at their gene and protein expression level for various time points after infection. RESULTS: At 6-day post-infection 100% mortality was observed. At 5-day post-infection, there was a robust expression of proinflammatory cytokines and chemokines with increased number of infiltrating inflammatory cells into the brain. Histopathology data confirms the infiltration of leucocytes and there was a marked upregulation in expression of genes relevant to infiltration. The expression pattern of macrophage receptor CLEC5A/DAP-12 signaling has shown the involvement in this robust neuroinflammation. CONCLUSIONS: This is the first report that shows the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in JEV infection of brain. This study at gene expression level provides a hypothesis of neuroinflammation, a new lead in development of appropriate therapeutic, and prophylactics against Japanese encephalitis.
Asunto(s)
Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Animales , Barrera Hematoencefálica , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/mortalidad , Encefalitis Japonesa/patología , Encefalitis Japonesa/virología , Perfilación de la Expresión Génica , Inflamación/inmunología , Inflamación/virología , Lectinas Tipo C , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa , Receptores de Superficie Celular , Índice de Severidad de la Enfermedad , Regulación hacia ArribaRESUMEN
OBJECTIVES: Persistent hyperglycaemia results in oxidative stress along with the generation of oxygen free radicals and appears to be an important factor in the production of secondary complications in diabetes. The aim of this work was to evaluate markers of oxidative stress in heart tissue along with the protective, antioxidant and antidiabetic activity of 30%Aloe vera gel in diabetic rats. METHODS: Streptozocin was given as a single intravenous injection and 30%Aloe vera gel was given in two doses for 20 days, orally. Blood glucose, glycosylated haemoglobin, blood reduced glutathione, serum lactate dehydrogenase and serum creatine kinase levels were measured on day 21 after drug treatment. Heart rate and mean blood pressure were recorded at the end of the study. Different biochemical variables were evaluated in the heart tissue, including thiobarbituric acid reactive substance (TBARS), reduced glutathione, superoxide dismutase and catalase in diabetic and in Aloe vera-treated diabetic rats. KEY FINDINGS: In streptozocin diabetic rats, the TBARS level was increased significantly, superoxide dismutase and reduced glutathione significantly decreased, and the catalase level was significantly increased. Aloe vera 30% gel (200 mg/kg) treatment in diabetic rats reduced the increased TBARS and maintained the superoxide dismutase and catalase activity up to the normal level. Aloe vera gel increased reduced glutathione by four times in diabetic rats. CONCLUSIONS: Aloe vera gel at 200 mg/kg had significant antidiabetic and cardioprotective activity.