RESUMEN
Tobacco stalk is a cellulose-rich material and a sustainable alternative to be applied as a plant-based nanofibrillated cellulose (NFC) source. NFC use has garnered attention in the development of oral pharmaceutical forms, despite concerns about its safety due to the adverse effects of nicotine on health. Therefore, we aimed at establishing the safety of NFC derived from tobacco stalk for its potential use as a novel pharmaceutical excipient, exploring its potential functions for tablet production. We conducted acute and subchronic oral toxicity tests in adult female Wistar rats. Initially, individual animals received sequential doses (175-5,000 mg·kg-1) for 24 hours followed by a careful observation of any toxic effects. Subsequently, 20 rats were divided into four groups for a subchronic assay, evaluating toxicity signs, body weight changes, hematological, biochemical, and histopathological parameters. No deaths or other clinical toxicity signs were observed in either the acute or the subchronic assays. We noticed a significant reduction in body weight gain (p < 0.05) after 14 days. We found statistical differences for hematological and biochemical parameters, unrelated to dosage. There were no observed toxic effects, and tobacco stalk ingestion did not adversely affect organ morphology in the histopathological evaluation. The oral administration of NFC at 5,000 mg·kg-1 per day for 28 days was well-tolerated by treated rats, with no reported deaths. In conclusion, NFC derived from tobacco stalk has shown to be a sustainable and safe alternative for use as an excipient at experimental doses, demonstrating compatibility with its proposed applications.
Asunto(s)
Celulosa , Excipientes , Nicotiana , Ratas Wistar , Animales , Femenino , Celulosa/toxicidad , Celulosa/administración & dosificación , Celulosa/química , Excipientes/toxicidad , Excipientes/química , Administración Oral , Pruebas de Toxicidad Subcrónica , Ratas , Pruebas de Toxicidad Aguda , Nanofibras/toxicidad , Tecnología Química Verde , Relación Dosis-Respuesta a DrogaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Brazilian red propolis is a natural product known due to its medicinal properties. The efficacy of this natural resin has been proved; however, few studies report the safety of its oral use. Some toxic effects of natural products may not be expressed in traditional use, and preclinical studies are necessary to guarantee their safety. Health regulatory agency currently requires these non-clinical studies to develop drugs and herbal medicines, including genotoxic and oral toxicity tests. AIM OF THE STUDY: Accomplish the preclinical toxicity studies of Brazilian red propolis extract (BRP) in rodents, including genotoxicity, acute and sub-chronic toxicities. MATERIAL AND METHODS: Genotoxicity assays followed the erythrocyte micronucleus test protocol in a range of 500-2000 mg/kg BRP oral treatment on male Swiss mice. After an up-and-down procedure, acute oral toxicity (single dose) was performed on female Wistar Hannover rats, reaching a 2000 mg/kg BRP oral gavage concentration. Animals were monitored periodically until 14 days and euthanized for a macroscopic necropsy analysis. The sub-chronic oral toxicity test (90 days) was achieved with 1000 mg/kg of BRP on Wistar Hannover rats (males/females). Animals were monitored to evaluated behavioral and biometrical changes, then were euthanized to perfomed hematological, biochemical, and histopathological analyses. RESULTS: No genotoxic effect of the BRP was detected. The acute toxicity indicated no toxicity of a single oral dose of 2000 mg/kg of BRP. The long-term oral toxicity performed with 1000 mg/kg of BRP altered water and food intake and the biometrics, hematological and biochemical parameters. Biochemical alterations in hepatic and renal parameters were detected only in the males. Despite the detection of biochemical alterations, no histopathological changes were detected in the organs of any group. CONCLUSIONS: BRP, at a higher dose, showed no signs of immediate toxicity. However, the obtained results suggest that the chemical composition and the intake of higher doses deserve special attention regarding possible toxicity.
Asunto(s)
Própolis , Ratas , Masculino , Ratones , Femenino , Animales , Própolis/toxicidad , Ratas Wistar , Roedores , Brasil , Extractos Vegetales , Ingestión de Alimentos , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad SubcrónicaRESUMEN
RESUMEN Objetivo: Evaluar la toxicidad de tres chalconas sintéticas administradas por vía intraperitoneal en ratones BALB/c. Materiales y métodos: La dosis letal media (DL50) se estimó por el método Up-and-Down de Dixon. La toxicidad subcrónica de las chalconas se evaluó a 20 y 40 mg/kg por 21 días. Se evaluó el efecto tóxico a nivel de comportamiento, fisiológico, bioquímico e histológico. Resultados: La chalcona 43 generó moco en las heces, daño visceral (hígado) y alteración en el coeficiente de órganos (riñón, p = 0,037 y cerebro, p = 0,008) en comparación con el grupo control. Además, en el análisis histológico se observó que esta chalcona produjo edema, inflamación y necrosis en los órganos evaluados, aunque no hubo diferencia significativa con el control. Todos los parámetros bioquímicos no difirieron significativamente entre los grupos de tratamiento a dosis de 40 mg/kg y el control. Conclusiones: La DL50 para las tres chalconas fue superior a 550 mg/kg de peso corporal. Las chalconas 40 y 42 son relativamente no tóxicas. Ambas pueden considerarse seguras para la aplicación vía intraperitoneal en ratones BALB/c y, en consecuencia, son posibles candidatas para ser usadas en el tratamiento contra las leishmaniosis.
ABSTRACT Objective: To evaluate the toxicity of three synthetic chalcones administered intraperitoneally to BALB/c mice. Materials and methods: The median lethal dose (LD50) was estimated by Dixon's Up-and-Down method. Subchronic toxicity of chalcones was evaluated at 20 and 40 mg/kg for 21 days. Behavioral, physiological, biochemical, and histological toxic effects were evaluated. Results: Chalcone 43 produced mucus in feces, visceral damage (liver) and alterations in organ coefficient (kidney, p = 0.037 and brain, p = 0.008) when compared to the control group. In addition, histological analysis showed that this chalcone produced edema, inflammation and necrosis in the evaluated organs, although there was no significant difference with the control. None of the biochemical parameters differed significantly between the treatment groups at 40 mg/kg dose and the control. Conclusions: The LD50 for all three chalcones was greater than 550 mg/kg of body weight. Chalcones 40 and 42 were found to be relatively non-toxic. Both can be considered safe for intraperitoneal application in BALB/c mice and, consequently, are potential candidates for use in the treatment of leishmaniasis.
Asunto(s)
Animales , Ratones , Chalconas , Toxicidad , Ratones Endogámicos BALB C , Chalcona , Pruebas de Toxicidad Subcrónica , Desarrollo de Medicamentos , Leishmania , RatonesRESUMEN
Glyphosate is the most widely used herbicide in the world. Although some studies have shown cardiac electrophysiological changes associated to glyphosate, the histopathological changes that this herbicide may cause in the cardiovascular system are not yet established. The aim of this study was to evaluate the cardiovascular effects of subchronic oral and inhalation exposure to the glyphosate herbicide in rats. Eighty albino Wistar rats were distributed into eight groups (five males and five females/group): inhalation control: nebulization with sodium chloride solution (NaCl); oral control: nebulized feed with NaCl; low inhalation concentration: nebulization with 3.71 × 10-3 grams of active ingredient per hectare (g.a.i./ha) of glyphosate; low oral concentration: nebulized feed with 3.71 × 10-3 g.a.i./ha of glyphosate; medium inhalation concentration: nebulization with 6.19 × 10-3 g.a.i./ha of glyphosate; medium oral concentration: nebulized feed with 6.19 × 10-3 g.a.i./ha of glyphosate; high inhalation concentration: nebulization with 9.28 × 10-3 g.a.i./ha of glyphosate; and high oral concentration: nebulized feed with 9.28 × 10-3 g.a.i./ha of glyphosate. After 75 days of exposure, the animals were euthanized, and aortas and hearts were collected for histopathological analysis. Fatty streaks were observed in most animals exposed to glyphosate and were more prevalent in male rats, regardless of the route of exposure (p < 0.05). There were no differences in the measurements of the thickness of the right and left ventricle or in the collagen density of both ventricles in any of the groups evaluated (p > 0.05). Our study suggests that glyphosate has atherogenic potential, regardless of the concentration and route of exposure.
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Aorta/efectos de los fármacos , Glicina/análogos & derivados , Corazón/efectos de los fármacos , Herbicidas/toxicidad , Administración Oral , Animales , Aorta/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/patología , Femenino , Glicina/toxicidad , Corazón/fisiopatología , Exposición por Inhalación/efectos adversos , Masculino , Ratas , Ratas Wistar , Pruebas de Toxicidad Subcrónica , GlifosatoRESUMEN
Gills represent one of the major sites of gas exchange of fish, consequently they are in continuous close contact with the aquatic environment and its pollutants. In the present study the effects on gills of pejerrey fish, Odontesthes bonariensis, under glyphosate-based herbicide subchronic exposure were analyzed. Adult animals were exposed to sublethal concentrations of a glyphosate-based commercial formulation (1 and 10 PMG mg L-1, PMG: glyphosate active ingredient) for 15 days, while control group was maintained in rearing water. Ultrastructural changes in gills were observed by scanning electron microscopy (SEM). The composition of the surface epithelium and specific surface area were determined by energy dispersive spectroscopy (EDS) and N2 (g) adsorption-desorption isotherms, respectively. The herbicide exposure induced severe alterations in gill ultrastructure, as shown in the SEM micrographs. Accordingly, an increase in surface area of the gills of exposed animals was determined. These results support that gills parameters of freshwater fish are sensitive morphological biomarkers for glyphosate exposure.
Asunto(s)
Peces/fisiología , Herbicidas/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Agua Dulce , Branquias/efectos de los fármacos , Glicina/análogos & derivados , Pruebas de Toxicidad Subcrónica , GlifosatoRESUMEN
Rhopalurus junceus is the most common scorpion in Cuba and the venom is often used as a natural product for anti-cancer therapy. Despite this, no study has been published concerning its toxicological profile. The aim of the study was characterizing the short-term, subchronic toxicity and the teratogenic potential of Rhopalurus junceus scorpion venom by oral route in mice. Short-term oral toxicity was test in both sexes NMRI mice that received 100 mg/kg/day of scorpion venom extract for 28 days. For the subchronic study, mice were administered with three doses (0.1, 10, and 100 mg/kg) by oral route for 90 days. Teratogenic potential was tested in pregnant mice administered from day 6-15 post conception. Significant differences were observed in body weight and food intake of animal treated for short-term and subchronic assays. Variations in serum urea and cholesterol were observed after 90 days oral treatment. Spontaneous findings not related to the treatment were reveal in histology evaluation. Exposure in pregnant mice did not produce maternal toxicity. Signs of embryo-fetal toxicity were not observed. The current study provides evidence that exposure to low or moderate dose of Rhopalurus junceus scorpion venom by oral route did not affect health of animals and has low impact on reproductive physiology.
Asunto(s)
Venenos de Escorpión/toxicidad , Teratógenos/toxicidad , Pruebas de Toxicidad Subcrónica , Administración Oral , Animales , Cuba , Femenino , Masculino , Ratones , Escorpiones , TeratogénesisRESUMEN
ETHNOPHARMACOLOGICAL IMPORTANCE: CORDIA MORELOSANA: Standley (Boraginaceae) is commonly used in folk medicine for the treatment of diarrhoea, kidney inflammation, diabetes, lung pain, bronchitis, asthma, hoarseness, cough and fever. AIM: Current work was conducted to develop a bio-guided isolation of antidiabetic compounds from ethanolic extract of Cordia morelosana (EECm). MATERIAL AND METHODS: The phytochemical bio-guided study was conducted by successive chromatographic techniques, and isolated compounds were characterized by 1D and 2D-NMR experiments. The in vivo antihyperglycemic and antidiabetic activities of EECm (100 mg/kg), and methyl rosmarinate (MR, 50 mg/kg) were determined on normoglycemic and diabetic murine models. Additionally, the in vitro activity was conducted to determine α-glucosidase inhibitory effect, and PPARs, GLUT4 and FATP expression on 3T3-L1 cells by RT-PCR. Acute and sub-chronic toxicological studies for EECm were conducted on rats, following the OECD guidelines (No. 420 and 407). RESULTS: EECm promotes significant α-glucosidase inhibition (55.6%) at 1 mg/kg respect to the control. Also, EECm (100 mg/kg) showed significant antihyperglycemic effect on oral glucose tolerance test (OGTT), and in non-insulin dependent type 2 diabetes (NIDD) model, had antidiabetic activity (p < 0.001) compared to controls. The bio-guided isolation allowed to obtain four known compounds described as rosmarinic acid (RA), methyl rosmarinate (MR), nicotiflorine and 1-O-methyl-scyllo-inositol. On the other hand, MR showed significant antidiabetic and anthiyperglycemic activities (p < 0.05), and overexpression of PPARγ, PPARα, GLUT-4 and FATP than control. Docking studies were conducted with PPARγ and PPARα, showing interesting binding mode profile on those targets. Finally, EECm displayed a LD50 > 2000 mg/kg and sub-chronic toxicological study reveals no toxic signs in animals tested compared to control. CONCLUSION: EECm showed significant antihyperglycemic and antidiabetic actions being RA and MR the main antidiabetic metabolites.
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Cordia , Hipoglucemiantes , Fitoquímicos , Extractos Vegetales , Células 3T3-L1 , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Proteínas de Unión a Ácidos Grasos/genética , Transportador de Glucosa de Tipo 4/genética , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Masculino , Ratones , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Fitoquímicos/análisis , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Fitoquímicos/toxicidad , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/toxicidad , Ratas Sprague-Dawley , Ratas Wistar , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subcrónica , alfa-Glucosidasas/metabolismoRESUMEN
This study aimed to compare Cd exposure by intraperitoneal (i.p.) and oral routes, evaluating the testicular subacute and subchronic effects. Adult male mice were separated into three groups subdivided according to the experimental period (7 and 42 days after Cd exposure: subacute and subchronic effects, respectively): one group received water and two groups received CdCl2 (1.2 mg/kg i.p. and 24 mg/kg oral). The testicular concentration of essential minerals and Cd, activity of antioxidant enzymes and markers of oxidative stress, histology, and testicular histomorphometry were evaluated. The subacute effect of oral Cd showed reduced Fe concentration, while Ca and Cu increased in this route. The subchronic effect promoted decreasing in Mg in i.p. and oral routes, whereas Zn decreased only in the oral, and the Fe concentration did not change. SOD activity decreased in the oral subacute evaluation and in both pathways, i.p. and oral routes, in the subchronic evaluation, while GST activity increased, and MDA concentration decreased. Labeling of apoptotic cells was increased in the subacute and subchronic evaluation. Seminiferous epithelium degeneration, death of germ cells, and Leydig cell damages occurred in i.p. and oral routes. However, these damages were more intense in the oral route, mainly evaluating the subchronic effects. The results confirm that the severity of Cd-induced testicular injury depends on the pathway, as well as the duration of exposure.
Asunto(s)
Cadmio/toxicidad , Testículo/efectos de los fármacos , Pruebas de Toxicidad Subaguda/métodos , Pruebas de Toxicidad Subcrónica/métodos , Administración Oral , Animales , Cadmio/administración & dosificación , Calcio/metabolismo , Catalasa/metabolismo , Cobre/metabolismo , Inyecciones Intraperitoneales , Hierro/metabolismo , Magnesio/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Testículo/metabolismo , Testículo/patología , Zinc/metabolismoRESUMEN
The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12â¯weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive oxygen species (ROS). After 1â¯week, an early adaptive response to ROS was observed as an increase in antioxidant enzymes. After 4â¯weeks, the enzymatic antioxidants were decreased, meanwhile an increase of the glutathione was shown, as a later compensatory antioxidant response. However, redox imbalance took place, evidenced by the increased oxidized proteins, which persisted up to 12â¯weeks. At this time point, corneal epithelium hyperplasia was also observed. The inflammatory response was modulated by the increase in IL-10 levels after 1â¯week, which early regulates the release of TNF-α and IL-6. These results suggest that air pollution alters the ocular surface, supported by the observed cellular hyperplasia. The redox imbalance and the inflammatory response modulated by IL-10 play a key role in the response triggered by air pollutants on the cornea. Taking into account this time course study, the ocular surface should also be considered as a relevant target of urban air pollutants.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Epitelio Corneal/patología , Animales , Brasil , Ciudades , Epitelio Corneal/efectos de los fármacos , Hiperplasia/inducido químicamente , Hiperplasia/patología , Interleucina-10/metabolismo , Masculino , Ratones , NADPH Oxidasa 4/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Pruebas de Toxicidad Subaguda , Pruebas de Toxicidad SubcrónicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ethnopharmacological knowledge is important for the identification of active compounds from natural products. Pain may have different aetiologies with complex mechanisms. Tabernaemontana catharinensis A. DC. is well known for indole alkaloids, being used empirically in folk medicine, with antimicrobial and anti-inflammatory as well as antiofidic actions among others. AIM OF THE STUDY: This work aims to evaluate the antinociceptive and antioxidant effect in mice of the alkaloids extract from leaves of Tabernaemontana catharinensis A. DC. (AITc). MATERIALS AND METHODS: The AITc was produced by ultrasound and acid-base extraction, and the chemical composition was evaluated by high resolution mass spectrometry. Male mice (Mus musculus), Swiss, were used for in vivo tests. The AITc was administrated at doses of 1.0, 5.0, and 10.0â¯mg/kg in acetic acid model, formalin, tail-immersion, hot plate, and open field tests, and compared to saline, morphine, or diazepam controls, depending on the test. The toxicological, biochemical, haemogram and antioxidant effect were evaluated in mouse organs such as liver, brain, kidneys, spleen and stomach. RESULTS: In total, 10 compounds were identified in the AITc, being from the indole alkaloids from the ibogan and corynanthean classes. The extract in doses ranging from 5.0 to 10.0â¯mg/kg showed an antinociceptive effect for acetic acid, inhibiting by 47.7% and 61.6%. In the same line, reductions of 47.1% (first phase) and 43.6% (second phase) were observed for the 5.0â¯mg/kg dose in the formalin test. However, tail-immersion and hot plate tests did not show considerable modifications in the latency period, while in the open field test there was an inhibition of only 5.1%. It was observed no differences in NO levels and total antioxidant status of the mice in any of the studie tissues. CONCLUSIONS: The results justify the use of this plant in traditional medicine. in vivo tests indicate that these compounds possess central and peripheral mechanisms of action. This is study that reports the nociceptive action of these alkaloids, also including toxicity tests, which are intended to guarantee the safety of use of extracts of this plant.
Asunto(s)
Alcaloides , Analgésicos , Antioxidantes , Extractos Vegetales , Tabernaemontana , Ácido Acético , Alcaloides/química , Alcaloides/uso terapéutico , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Antioxidantes/química , Antioxidantes/uso terapéutico , Compuestos de Bifenilo/química , Masculino , Ratones , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Picratos/química , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad SubcrónicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei is a plant found in the Brazilian Caatinga and is popular due to its traditional uses in the treatment of inflammation. The present study was conducted to investigate the sub-acute toxicity of the saline extract from the stem of P. gounellei. AIM OF THE STUDY: To evaluate the 28-day oral toxicity (through behavioral, biochemical, hematological, and morphological analysis) and the antipyretic activity of the extract in mice. MATERIALS AND METHODS: A single oral dose (250, 500, and 1000â¯mg/kg) was administered daily over 28 consecutive days to male and female mice. Body weight, food and water intake, blood biochemical and hematological parameters, and urine composition were recorded. Histopathological examinations of the liver, kidney, spleen, lungs, and heart were performed and oxidative stress in the organs was evaluated by lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), and nitrite analysis. The antipyretic effect of the 500â¯mg/kg dose was assessed using a yeast-induced pyrexia model. RESULTS: Oral administration of the extract over 28 days did not affect body weight gain, food and water consumption, body temperature, and hematological parameters in male and female mice. Blood glucose, total cholesterol, and triglyceride levels in male and female mice were reduced. Protein in the urine and histological alterations in both the liver and lungs were detected in male and female mice treated with the highest dose of the extract. SOD levels in the liver and the spleen increased significantly in both sexes, whereas lipid peroxidation decreased in the spleen of male mice. The extract also exerted an antipyretic effect after the first 60â¯min of the evaluation until the end of the observation duration (180â¯min). CONCLUSION: The saline extract from the stem of P. gounellei did not present significant toxic effects over 28 consecutive days and demonstrated antipyretic activity when administered orally. Moreover, the results suggest that the extract has potential hypoglycemic and hypolipidemic effects. Future studies are needed to investigate its pharmacological potential.
Asunto(s)
Antipiréticos/farmacología , Cactaceae/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Administración Oral , Animales , Antipiréticos/administración & dosificación , Antipiréticos/aislamiento & purificación , Glucemia/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fiebre/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Hipolipemiantes/administración & dosificación , Hipolipemiantes/aislamiento & purificación , Hipolipemiantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Extractos Vegetales/toxicidad , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Pruebas de Toxicidad SubcrónicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Plantago australis is a perennial plant widely distributed in Latin America, and its seeds and leaves are used in folk medicine to treat many diseases and conditions. Among its various chemical compounds, verbascoside is one of the most present, and has several pharmacological activities described, but there is not much information about its toxicity. AIMS OF THE STUDY: The aims of this study were to optimize the extraction of verbascoside from P. australis leaves with ultrasound methods, to develop a validated HPLC method to quantify verbascoside, and to evaluate the toxicological safety of the extract and verbascoside using in vitro and in vivo assays. MATERIALS AND METHODS: Dried leaves of P. australis were submitted to different extraction methods (percolation and ultrasound). The optimization of the ultrasound extraction was carried out by complete factorial design (22) and response surface methodology (RSM), followed by HPLC analysis for marker compounds. HPLC analysis was performed to verify the presence of the marker compounds aucubin, baicalein, oleanolic acid, ursolic acid and verbascoside. Mutagenicity was assessed by Salmonella/microsome mutagenicity assay. Cytotoxicity and genotoxicity were evaluated in V79 cells by reduction of tetrazolium salt (MTT) and neutral red uptake (NRU) assays, and alkaline comet assay, respectively. Verbascoside phototoxicity was assessed in 3T3 cells by the NRU phototoxicity assay. Wistar rats were used to perform the acute and sub-chronic toxicity tests. RESULTS: Among the marker compounds, only verbascoside was found in the hydroethanolic extract of P. australis leaves (PAHE); its highest concentration was obtained with the ultrasound-assisted extraction (UAE) method, optimized in 40â¯min and 25⯰C, and the method validation was successfully applied. Neither PAHE nor verbascoside showed mutagenic or genotoxic activities. Cytotoxicity assays demonstrated that both PAHE and verbascoside reduced cell viability only at the highest concentrations, and verbascoside had no phototoxic properties. The in vivo toxicity evaluation of PAHE suggested that the LD50 is higher than 5000â¯mg/Kg, indicating that this extract is safe for use. In addition, no signs of toxicity were found in subchronic exposure. CONCLUSION: The HPLC method to quantify verbascoside was validated, and the extraction of verbascoside from P. australis leaves through ultrasound method was optimized, yielding an extract with 6% verbascoside. Our results suggest the toxicological safety of PAHE and verbascoside, corroborating the use of P. australis in folk medicine, and also indicate verbascoside as a potential ingredient in topical formulations.
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Glucósidos/toxicidad , Fenoles/toxicidad , Extractos Vegetales/toxicidad , Plantago , Células 3T3 , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cricetulus , Ratones , Hojas de la Planta , Ratas Wistar , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad SubcrónicaRESUMEN
This study evaluated the acute and sub-chronic toxicities of ethanol leaf extract of Dryopteris filix-mas. Acute toxicity and phytochemical tests on ethanol leaf extract were determined. In sub-chronic toxicity test, animals were treated with 62.5, 125, 250 and 500 mg/kg of extract every day for 90 days. Blood samples were collected via retro-orbital puncture for baseline studies and at 31, 61 and 91st days for determination of hematological, kidney and liver function parameters. Liver and kidneys were harvested for histopathology analyses on 91st day. Also, a 28 day recovery study was carried out to determine reversibility in toxicological effects. Phytochemical screening revealed the presence of tannins, phenols, flavonoids, saponins, steroids, alkaloids, terpenoids, reducing sugar and cardiac glycosides. Acute toxicity test did not show toxicity or death at 5000 mg/kg. There was significant (p<0.005) reduction in white blood cell and lymphocyte counts, significant (p<0.05) increase in some liver and kidney biomarkers as well as alterations in liver and kidney histo-architecture on 91st days in animals that were treated with 250 and 500 mg/kg extract. However, toxicities observed on 91st day were reversible in recovery studies. The leaf extract of Dryopteris filix-mas may be hepatotoxic and nephrotoxic when used for long periods
Asunto(s)
Animales , Masculino , Femenino , Ratas , Extractos Vegetales/análisis , /efectos adversos , Dryopteris/toxicidad , Pruebas de Toxicidad Subcrónica/instrumentación , Etanol/toxicidadRESUMEN
Depression is one of the most frequent neuropsychiatric diseases in the western world and its physiological causes are not yet fully understood. Since the available antidepressants failed to provide a complete illness remission, the diversification of the therapy in the management of depression could be a useful contribution. The present study aimed to investigate the cholecalciferol capability to revert depressive-like behavior induced by chronic corticosterone (CORT) treatment in mice and its implication on the oxidative stress modulation. Sixty minutes after having orally received different doses of cholecalciferol, adult male mice were evaluated in the forced swimming and tail suspension tests, whereas in the seven-day treatment they were only tested in tail suspension. Additionally, for 21 days, the animals received CORT (20â¯mg/kg, p.o.) and cholecalciferol or fluoxetine, once a day for the last 7-days of the CORT treatment. Moreover, the markers of oxidative stress, lipid peroxidation, protein carbonyl and nitrite levels were assessed in the plasma and brain's mice after the splash and tail suspension tests. It was observed that corticosterone treatment resulted in depressive-like behavior with established oxidative stress in mice, while cholecalciferol ameliorated both, behavioral (immobility time and grooming latency) and biochemical (protein carbonyl and nitrite levels) changes induced by CORT model, suggesting that cholecalciferol has antidepressant-like effect with the involvement of the oxidative stress modulation.
Asunto(s)
Colecalciferol/farmacología , Depresión/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Vitaminas/farmacología , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Colecalciferol/uso terapéutico , Corticosterona/toxicidad , Depresión/inducido químicamente , Modelos Animales de Enfermedad , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subcrónica , Resultado del Tratamiento , Vitaminas/uso terapéuticoRESUMEN
The objective of this study was to analyze the toxicological responses of the estuarine polychaete Laeonereis acuta after acute (96h), subchronic (7 days) and chronic (14 days) exposure to cadmium (Cd). Concentrations of metallothioneins (MT), lipid peroxidation (LPO), total Cd and metal-rich granules (MRG) were evaluated. Seasonal variations of MT and LPO levels in the wild were also measured. Polychaetes were obtained in the Quequén estuary located southeast of Buenos Aires Province, Argentina. For the acute toxicity assay, individuals were exposed to 10; 30, 65; 310; 600; 1300; 2000; 4300; 8100; 16300µgCdL-1, which included levels of environmental relevance and median lethal concentrations (LC50) for related species of polychaete. Based on 96h LC50 values, polychaetes were exposed to sublethal doses of Cd. The concentrations for both subchronic and chronic assays were: 10; 30; 65; 310; 600; 1300; 2000; 4300µgCdL-1. The 96h LC50 value was 8234.9µgL-1, which was within the values reported for other species of polychaete, indicating a high tolerance to Cd. MT induction was not observed for any time exposure. In additoin, LPO levels showed no differences with respect to control levels, which indicated an absence of oxidative damage caused by Cd. However, the total Cd and MRG-Cd concentrations in L. acuta in all tested treatments showed significant differences with respect to control levels. L. acuta were able to accumulate Cd in their tissues in the form of granules which are the main mechanism of Cd detoxification.
Asunto(s)
Cadmio/toxicidad , Poliquetos/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Argentina , Relación Dosis-Respuesta a Droga , Estuarios , Dosificación Letal Mediana , Peroxidación de Lípido/efectos de los fármacos , Metalotioneína/metabolismo , Poliquetos/metabolismo , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Crónica , Pruebas de Toxicidad SubcrónicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Copaifera malmei Harms (Fabaceae), known mainly as óleo-mirim, is a native and endemic plant found in the states of Mato Grosso and Goiás of Brazil. The plant's leaves infusion is popularly used by riverine communities of the northern Araguaia microregion, Mato Grosso, Brazil, for the treatment of gastric ulcers and inflammatory diseases of the respiratory tract. The gastric antiulcer activity of the standardized leaves infusion extract of Copaifera malmei (SIECm) in rodents has been reported. The objective of this study was to advance the investigation of the safety profile of SIECm by evaluating the genotoxicity and subchronic toxicity using in vitro and in vivo experimental models. MATERIALS AND METHODS: SIECm was prepared by infusion, by incubating the powdered dried leaves material in boiled water for 15min. In vitro genotoxicity of SIECm (10, 30 or 100µg/mL) was assessed by micronucleus and comet tests using Chinese hamster ovary (CHO-k1) epithelial cells. The evaluation of subchronic toxicity profile was performed by daily oral administration of SIECm (100, 400 or 1000mg/kg) to Wistar rats for 30 days. Clinical observations of toxicological related parameters were done every 6 days. After the treatment period, blood was collected for hematological and biochemical analysis, and some organs were removed for macroscopic and histopathological analysis. RESULTS: In the micronucleus assay, SIECm demonstrated anti-mutagenic activity. In the comet assay, SIECm presented anti-genotoxic effect preventing DNA damage at all the three concentrations tested with pre-treatment, while the same effect was only observed in the co-treatment at the lowest concentration. Post-treatment with SIECm increased the genetic damage induced by hydrogen peroxide (H2O2) at the highest concentration. In the subchronic toxicity test, few changes were observed, such as increase in feed consumption in the group of animals treated with 100mg/kg of the SIECm, which reversed after 6 days. There were no macroscopic, histological and relative weights changes in the organs of animals treated with SIECm. No toxicologically relevant changes were observed in the hematological analysis. Subchronic administration of SIECm reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in animals treated with 100mg/kg and serum triglyceride levels at 400 and 1000mg/kg. However, the hematological and biochemical changes observed are within the physiological ranges for this animal species. CONCLUSION: The results demonstrate that SIECm is not genotoxic, and does not present toxicity when used orally for up to 30 days. In addition, it showed protection to the genetic damage induced by H2O2. The SIECm therefore has a high safety margin for therapeutic use.
Asunto(s)
Antimutagênicos/toxicidad , Fabaceae , Extractos Vegetales/toxicidad , Animales , Células CHO , Ensayo Cometa , Cricetulus , Daño del ADN/efectos de los fármacos , Femenino , Peróxido de Hidrógeno/toxicidad , Pruebas de Micronúcleos , Hojas de la Planta , Ratas Wistar , Pruebas de Toxicidad SubcrónicaRESUMEN
BACKGROUND: The constant pursuit of improved athletic performance characterizes high-performance sport and the use of medicinal plants as dietary supplements is becoming widespread among athletes to enhance long-term endurance performance. AIM: The present study evaluated the toxicity of Heteropterys tomentosa (HEHt) and its acute adaptogenic effects. METHODS: The in vitro safety profile was evaluated on CHO-k1 cells using the alamar Blue assay, at concentrations ranging from 3.125 to 200 µg/mL. In vivo acute oral toxicity was conducted in male and female mice with oral administration of graded doses of HEHt from 400 to 2000 mg/kg. A subchronic oral toxicity study was completed by oral administration of HEHt (50, 200 or 1000 mg/kg) and vehicle for 30 days in male Wistar rats. Clinical observations and toxicological related parameters were determined. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Thereafter, an adaptogenic test consisting of progressive loads until exhaustion was conducted in rats ( n = 5/group) orally pre-treated with the vehicle and HEHt (25, 100 or 400 mg/kg). RESULTS: HEHt exhibited no cytotoxic effects on the CHO-k1 cells and, apparently, no acute toxicity in mice and no subchronic toxicity in rats. An ergogenic effect was observed only at the dose of 25 mg/kg compared with the vehicle in relation to time to exhaustion and exercise load ( p = .011 and .019, respectively). HEHt is safe at up to 400 mg/kg, contains astilbin and taxifolin as the major phytochemical compounds, and exhibited a potential adaptogenic effect. CONCLUSIONS: These results justify its anecdotal usage as a tonic, show that the hydroethanolic maceration of the root does not cause toxicity, and provide scientific evidence of its potential as a source of new adaptogenic substance(s).
Asunto(s)
Suplementos Dietéticos/efectos adversos , Malpighiaceae/química , Sustancias para Mejorar el Rendimiento/efectos adversos , Extractos Vegetales/efectos adversos , Raíces de Plantas/química , Animales , Conducta Animal , Células CHO , Cricetulus , Etnofarmacología , Fatiga/etiología , Fatiga/prevención & control , Femenino , Flavonoles/administración & dosificación , Flavonoles/efectos adversos , Flavonoles/metabolismo , Flavonoles/uso terapéutico , Masculino , Malpighiaceae/crecimiento & desarrollo , Medicina Tradicional , Ratones , Sustancias para Mejorar el Rendimiento/administración & dosificación , Sustancias para Mejorar el Rendimiento/metabolismo , Sustancias para Mejorar el Rendimiento/uso terapéutico , Esfuerzo Físico , Extractos Vegetales/administración & dosificación , Extractos Vegetales/metabolismo , Extractos Vegetales/uso terapéutico , Raíces de Plantas/crecimiento & desarrollo , Quercetina/administración & dosificación , Quercetina/efectos adversos , Quercetina/análogos & derivados , Quercetina/metabolismo , Quercetina/uso terapéutico , Distribución Aleatoria , Ratas Wistar , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad SubcrónicaRESUMEN
Smallanthus sonchifolius (Yacón) es una planta usada comúnmente por largos periodos de tiempo con el fin de ayudar en el control de la diabetes y otros desordenes metabólicos, por lo que con el propósito de evaluar la toxicidad subcrónica de la variedad colombiana de esta planta, fueron tratadas 30 ratas hembra de 8 semanas de edad dividas en 6 grupos. A cada uno de ellos se administró durante 28 días una de las siguientes dosis de infusión acuosa liofilizada (500, 250 y 125 mg/kg de peso), evaluando paralelamente grupos control (positivo y negativo) e incluyendo entre ellos grupos con y sin dieta hipercalórica. Para el seguimiento del perfil metabólico de los animales, se tomaron muestras de sangre periódicamente durante el ensayo y se evaluaron los niveles séricos de: glucemia, triglicéridos, colesterol total y HDL. Además, también se realizó el control del peso, así como estudios comportamentales que incluyeron el Test de Irwin y el Test Hipocrático. Al final de estudio (28 días), se realizó el análisis anatomopatológico e histológico comparativo con el fin de detectar posibles daños tisulares. Como resultado pudo observase que el liofilizado, si bien puede tener un efecto antihiperglucemiante, no modificó significativamente el perfil lipídico. Además, a pesar de que la administración se hizo durante 28 días, no se observaron cambios comportamentales que evidencien toxicidad, pero sí pudieron observarse cambios histológicos en el tejido cardiaco como hialinización, separación y redondeo de fibras.
Abstract. Smallanthus sonchifolius (Yacón) is a plant commonly used over long periods of time to help control diabetes and other metabolic disorders. To assess the sub-chronic toxicity of the Colombia variety of this plant, it was tested on 30 eight-week-old female rats, divided into six groups. For 28 days each group was administered with the following doses: three groups with lyophilized aqueous infusion (500 mg, 250 mg and 125 mg per kg of weight), two control groups (positive and negative) being assessed in parallel; this groups receiving hyper-caloric diet, and the last group was the general control or normal control. To monitor the animals' metabolic profile, blood samples were taken from time to time during the test period, and the serum levels of glycemia, triglycerides, total cholesterol and HDL were measured. Weight tracking was also carried out, as well as behavioral studies, including the Irwin Test and the Hippocratic Test. At the end of the study (28 days), comparative anatomo-pathological and histological analyses were performed to detect possible tissue damage. The results showed that, although the lyophilized infusion could have an antihyperglycemic effect, it did not significantly change the lipid profile. Moreover, though the infusion was administered during 28 days, it was found that it did not lead to any behavioral changes indicating toxicity, but did produce in heart tissue histological changes such as hyalinization, separation and rounding of fibers.
Asunto(s)
Ratas , Extractos Vegetales/toxicidad , Medicamento Fitoterápico , Pruebas de Toxicidad Subcrónica/métodos , Extractos Vegetales/uso terapéutico , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3-treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability.
Asunto(s)
Viabilidad Fetal/efectos de los fármacos , Óxidos/toxicidad , Testículo/efectos de los fármacos , Animales , Trióxido de Arsénico , Arsenicales/administración & dosificación , Modelos Animales de Enfermedad , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Fertilidad/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Óxidos/administración & dosificación , Receptores Androgénicos/metabolismo , Reproducción/efectos de los fármacos , Epitelio Seminífero/efectos de los fármacos , Epitelio Seminífero/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Testículo/metabolismo , Pruebas de Toxicidad Subcrónica , Aumento de Peso/efectos de los fármacosRESUMEN
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.