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1.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198577

RESUMO

(1) Background: Screening of medicinal herbs is one of the most powerful approaches to identifying novel therapeutic molecules against many human diseases. To avoid potential harmful effects during medicinal use, toxicity testing is necessary in the early stages of drug discovery. The objective of this study was to identify the cytotoxic mechanisms of jegosaponin A and B from Styrax japonica Siebold et al. Zuccarini; (2) Methods: We screened Japanese medicinal herb extracts using PC-3 prostate cancer cells and found that a methanol extract isolated from the unripe fruit of Styrax japonica Siebold et al. Zuccarini (SJSZ) had an inhibitory effect on cell viability. We further performed fractionation assays with PC-3 cells and identified the bioactive compounds using LC/MS and NMR analysis. We clarified the toxic mechanisms of these compounds using PC-3 cells and zebrafish embryos; (3) Results: We identified two active molecules, jegosaponin A and jegosaponin B, in the inhibitory fractions of the methanol extract. These jegosaponins are toxic to zebrafish embryos during the early developmental stage. Jegosaponin A and B showed strong haemolytic activity in sheep defibrinated blood (EC50 = 2.1 µM, and 20.2 µM, respectively) and increased the cell membrane permeability in PC-3 cells and zebrafish embryos, which were identified using a membrane non-permeable DRAQ7, a fluorescent nucleus staining dye; (4) We identified the cytotoxic compounds jegosaponin A and B from SJSZ, which we showed to exhibit cell membrane disruptive properties using cell- and zebrafish-based testing.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Embrião não Mamífero/patologia , Neoplasias da Próstata/patologia , Saponinas/toxicidade , Styrax/química , Peixe-Zebra/embriologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Embrião não Mamífero/efeitos dos fármacos , Masculino , Saponinas/química , Ovinos , Testes de Toxicidade Aguda
2.
Toxins (Basel) ; 13(5)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063025

RESUMO

Understanding the toxicity and production rates of the various secondary metabolites produced by Gambierdiscus and cohabitating benthic dinoflagellates is essential to unravelling the complexities associated with ciguatera poisoning. In the present study, a sulphated cyclic polyether, gambierone, was purified from Gambierdiscus cheloniae CAWD232 and its acute toxicity was determined using intraperitoneal injection into mice. It was shown to be of low toxicity with an LD50 of 2.4 mg/kg, 9600 times less toxic than the commonly implicated Pacific ciguatoxin-1B, indicating it is unlikely to play a role in ciguatera poisoning. In addition, the production of gambierone and 44-methylgambierone was assessed from 20 isolates of ten Gambierdiscus, two Coolia and two Fukuyoa species using quantitative liquid chromatography-tandem mass spectrometry. Gambierone was produced by seven Gambierdiscus species, ranging from 1 to 87 pg/cell, and one species from each of the genera Coolia and Fukuyoa, ranging from 2 to 17 pg/cell. The production of 44-methylgambierone ranged from 5 to 270 pg/cell and was ubiquitous to all Gambierdiscus species tested, as well as both species of Coolia and Fukuyoa. The relative production ratio of these two secondary metabolites revealed that only two species produced more gambierone, G. carpenteri CAWD237 and G. cheloniae CAWD232. This represents the first report of gambierone acute toxicity and production by these cohabitating benthic dinoflagellate species. While these results demonstrate that gambierones are unlikely to pose a risk to human health, further research is required to understand if they bioaccumulate in the marine food web.


Assuntos
Ciguatoxinas/toxicidade , Dinoflagelados/metabolismo , Éteres/toxicidade , Animais , Cromatografia Líquida , Éteres/administração & dosagem , Éteres/isolamento & purificação , Feminino , Injeções Intraperitoneais , Dose Letal Mediana , Camundongos , Metabolismo Secundário , Espectrometria de Massas em Tandem , Testes de Toxicidade Aguda
3.
Int J Biol Macromol ; 183: 1948-1958, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34051256

RESUMO

Aflatoxin contamination is one of the most important factors jeopardizing the quality of traditional Chinese health food (TCHF) during storage. Based on our previous work, we investigated the stability of chitosan (CH) films containing turmeric essential oil (TEO) and employed CH-TEO films as inner pouches, then stored them with inoculated Coix seed, nutmeg, and Ziziphi Spinosae Semen (ZSS). We found that the stability of CH-TEO was most affected by high temperature, and these pouches dramatically decreased aflatoxin accumulation and maintained levels of marker components of each TCHF. We found that glycerol tristearat in Coix seed and jujuboside A and spinosin in ZSS were negatively correlated with aflatoxin accumulation. After three months of storage with a CH-TEO pouch, we found little change in marker components contents, but observed that Coix seed had the relative lower sensory characteristics score. In addition, acute and 90-day subchronic toxicity test in Coix seed stored with the largest amount of TEO showed no significant signs of toxicity or treatment-related changes in animals. The present study is the first report on the study of a green, efficient, and low toxicity solution for aflatoxic contamination in TCHF, and provides strong support for its future use.


Assuntos
Aflatoxinas/análise , Quitosana/química , Curcuma/química , Óleos Voláteis/química , Ziziphus/química , Animais , Coix/química , Feminino , Contaminação de Alimentos , Armazenamento de Alimentos , Temperatura Alta , Masculino , Camundongos , Myristica/química , Óleos Vegetais/química , Ratos , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica , Triglicerídeos/química
4.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946599
5.
Environ Sci Technol ; 55(10): 6907-6916, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33914518

RESUMO

The fish embryo acute toxicity (FET) test is known to be less sensitive than the fish acute test for some chemicals, including neurotoxicants. Thus, there is an interest in identifying additional endpoints that can improve FET test performance. The goal of this project was to advance alternative toxicity testing methods by determining whether select developmental abnormalities-snout-vent length, eye size, and pericardial area-are linked to adverse alterations in ecologically-relevant behaviors and delayed mortality. Fathead minnow (Pimephales promelas) FET tests were conducted with 3,4-dicholoroaniline, cadmium, and perfluorooctanesulfonic acid (PFOS) and developmental abnormalities were quantified. Surviving eleutheroembryos were reared in clean water to 14 days post fertilization (dpf), during which time behaviors and mortality were evaluated. None of the abnormalities evaluated were predictive of behavioral alterations; however, embryos with ≥14% reductions in length or ≥3.54-fold increases in pericardial area had an 80% chance of mortality by 14 dpf. When these abnormalities were used as markers of mortality, the LC50s for cadmium and PFOS were less than those calculated using only standardized FET test endpoints and similar to those obtained via larval fish tests, indicating that the snout-vent length and pericardial area warrant consideration as standard FET test endpoints.


Assuntos
Cyprinidae , Poluentes Químicos da Água , Animais , Edema , Embrião não Mamífero , Larva , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade
6.
Molecules ; 26(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918827

RESUMO

This study aims to assess the safety of the Opuntia dillenii (Ker-Gawl) haw. seed oil (ODSO) and its effect on the glucose absorption activity of the isolated rat hemidiaphragm. This oil's safety was studied by exploring its acute (doses 1, 3, 5, and 7 mL/kg) and subacute (doses 1 and 2 mL/kg) toxicities in albino mice and Wistar rats, respectively. The safety of the ODSO was also assessed by studying its effect on the HepG2 cell viability in vitro. The effect of ODSO, or combined with the insulin, on the glucose absorption activity of isolated rat hemidiaphragm was evaluated at the dose 1 g/L in vitro. The results demonstrated the safety of ODSO. Indeed, this study showed that this oil does not produce any mortality or signs of toxicity after the single-dose administration in mice. Additionally, the daily intake of the ODSO during four weeks does not induce a significant variation in the biochemical parameters and body weight of rats compared with the control group. Besides, the cell viability of HepG2 did not change in the presence of ODSO. On the other hand, the ODSO increased the glucose absorption activity of the isolated rat hemidiaphragm, and this activity was significantly enhanced when combined with insulin. This study confirms, on one side, the safety of this oil and its efficacy and, on the other side, encourages its potential use as a complement to treat diabetes.


Assuntos
Absorção Fisiológica , Diafragma/metabolismo , Glucose/metabolismo , Opuntia/química , Óleos Vegetais/farmacologia , Sementes/química , Testes de Toxicidade Aguda , Absorção Fisiológica/efeitos dos fármacos , Administração Oral , Animais , Bilirrubina/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diafragma/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Óleos Vegetais/administração & dosagem , Ratos Wistar
7.
Fish Shellfish Immunol ; 113: 154-161, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33862235

RESUMO

Abundant microplastics was found in aquatic ecosystem and aquatic organisms, which raised many concerns in public. Silver carp (Hypophthalmichthys molitrix), a species filter-feeding planktivorous fish, feed on particle between 4 and 85 µm in size, and the respiratory process works together with feeding mechanism when filtering plankton from water. The aim of this study was to assess the physiological response of silver carp exposed to 5 µm polystyrene microspheres during 48 h of exposure followed by 48 h of depuration through the gill histology, and oxidative stress biomarkers in intestine. The results revealed that microplastics can pass through the whole digestive tract of silver carp and be excreted by feces. Low microplastic concentration (80 µg/L) induced oxidative stress and up-regulation of TUB84 and HSP70 gene in intestine, and silver carp have ability to recover after the exposure to microplastic was removed. High microplastic concentration (800 µg/L) definitely cause significant damage to gills and intestines, in this situation, far beyond the possibility of fish own repair, and even when the threaten removed, silver carp can't recovery soon. Our studies assessed the dosage-effect relationship with physiological stress on silver carp when exposure to microplastics.


Assuntos
Carpas , Microplásticos/toxicidade , Estresse Oxidativo , Poliestirenos/toxicidade , Testes de Toxicidade Aguda/veterinária , Poluentes da Água/toxicidade , Animais , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Intestinos/efeitos dos fármacos , Microesferas , Material Particulado/toxicidade
8.
Arch Environ Contam Toxicol ; 81(1): 46-57, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33864096

RESUMO

The present study investigates the toxicity of the herbicide tribenuron methyl (TBM) as an anthropogenic agent and ammonia as an abiotic factor on Daphnia magna at environmentally relevant concentrations. These stressors may coexist in surface waters in agricultural regions. To achieve this objective, D. magna were exposed to TBM at a nominal concentration of 0.81 µg/L in association with a low ammonia (LA) concentration of 0.65 mg/L and a high ammonia (HA) concentration of 1.61 mg/L in acute toxicity tests of 96-h duration and chronic toxicity tests of 21-day duration. The D. magna also were exposed to TBM, HA, and LA singly. The D. magna were analysed for various biomarkers of sublethal toxicity. Glutathione peroxidase (GPx), glutathione S-transferase (GST), cholinesterase (ChE) enzyme activities, and levels of thiobarbituric acid reactive substances (TBARS) and total protein were determined spectrophotometrically. Mitochondrial membrane potential (MMP) was analysed by microscopy with fluorescence staining. Cytochrome c and 5' AMP-activated protein kinase (AMPK) were analysed by Western blotting. Morphometric properties were examined microscopically. This is the first study in which AMPK, an indicator of intracellular energy, was measured in D. magna. GST and ChE enzyme activities and TBARS and total protein levels did not change during acute exposures (i.e., 96 h) in all treatments. GPx activity increased in D. magna from the HA + TBM treatment compared with single-exposure groups. The level of cytochrome c protein was elevated in D. magna from the LA and LA + TBM treatments. AMPK protein levels increased in all treatments with daphnids, except in the LA group. MMP was depolarised in D. magna from all treatments, whereas the most notable change was observed in HA + TBM mixture group in chronic exposures. The results show that GST and ChE may not be sensitive biomarkers for evaluating the sublethal toxic effects to D. magna exposed to environmentally relevant concentrations of ammonia and TBM. Acute and chronic exposure to ammonia and TBM probably caused an energetic crisis in D. magna. Therefore, AMPK and MMP are promising biomarkers for these toxicants.


Assuntos
Daphnia , Poluentes Químicos da Água , Amônia/toxicidade , Animais , Sulfonatos de Arila , Testes de Toxicidade Aguda , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
9.
J Environ Sci Health B ; 56(5): 512-521, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33818270

RESUMO

Controlled-release formulations (CRFs) have potential applications in modern agriculture, for it can not only prolong the duration of agrochemicals but also alleviate the adverse effect on non-target organism. In this study, we constructed pyraclostrobin@SiO2@polydopamine microcapsule (Pyr@SiO2@PDA MC). The resulting microcapsule is a near-rod shape (about 1.15 µm), which has a drug-loading efficiency of 55%. Fourier transform infrared (FTIR) and thermogravimetric analysis (TG) revealed the successful entrapment of the pesticide. The coating of polydopamine (PDA) endowing the microcapsule with superior UV-shielding properties than pyraclostrobin@SiO2 microcapsule (Pyr@SiO2 MC). Compared with pyraclostrobin emulsifiable concentrate (EC), the Pyr@SiO2@PDA MC exhibited 9.07-, 5.50-, 4.93- and 4.16-fold higher fungicidal activity against Rice blast fungus (Pyricularia oryzae) at concentrations of 0.5, 1, 2 and 4 mg/L. Moreover, acute toxicity tests demonstrated that the sample on zebrafish with lower toxicity on the first day. These results showed that the obtained microcapsule may process broader application potential in agriculture.


Assuntos
Indóis/química , Praguicidas/química , Polímeros/química , Poluentes Químicos da Água/química , Animais , Ascomicetos/efeitos dos fármacos , Cápsulas/química , Cápsulas/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Indóis/farmacologia , Praguicidas/farmacologia , Polímeros/farmacologia , Dióxido de Silício/química , Estrobilurinas/química , Estrobilurinas/farmacologia , Testes de Toxicidade Aguda , Poluentes Químicos da Água/farmacologia , Peixe-Zebra
10.
Oxid Med Cell Longev ; 2021: 6683836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688393

RESUMO

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.


Assuntos
Protetores contra Radiação/efeitos adversos , Protetores contra Radiação/farmacocinética , Administração Oral , Amifostina/efeitos adversos , Amifostina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/efeitos da radiação , Dano ao DNA , Relação Dose-Resposta à Radiação , Sequestradores de Radicais Livres/farmacologia , Histonas/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Protetores contra Radiação/administração & dosagem , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Fatores de Tempo , Testes de Toxicidade Aguda , Resultado do Tratamento , Irradiação Corporal Total
11.
BMC Cancer ; 21(1): 270, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711962

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.


Assuntos
Drogas em Investigação/administração & dosagem , Imunoconjugados/administração & dosagem , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/toxicidade , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/toxicidade , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Estabilidade de Medicamentos , Drogas em Investigação/farmacologia , Drogas em Investigação/toxicidade , Receptores ErbB/antagonistas & inibidores , Feminino , Meia-Vida , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/toxicidade , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/toxicidade , Aplicação de Novas Drogas em Teste , Masculino , Camundongos , Neoplasias/patologia , Neoplasias/cirurgia , Cirurgia Assistida por Computador/métodos , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Environ Sci Technol ; 55(6): 3505-3513, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33656853

RESUMO

Addressing the shift from classical animal testing to high-throughput in vitro and/or simplified in vivo proxy models has been defined as one of the upcoming challenges in aquatic toxicology. In this regard, the fish embryo toxicity test (FET) has gained significant popularity and wide standardization as one of the sensitive alternative approaches to acute fish toxicity tests in chemical risk assessment and water quality evaluation. Nevertheless, despite the growing regulatory acceptance, the actual manipulation, dispensing, and analysis of living fish embryos remains very labor intensive. Moreover, the FET is commonly performed in plastic multiwell plates under static or semistatic conditions, potentially inadequate for toxicity assessment of some organic, easily degradable or highly adsorptive toxicants. Recent technological advances in the field of mechatronics, fluidics and digital vision systems demonstrate promising future opportunities for automation of many analytical stages in embryo toxicity testing. In this review, we highlight emerging advances in fluidic and laboratory automation systems that can prospectively enable high-throughput FET testing (HT-FET) akin to pipelines commonly found in in vitro drug discovery pipelines. We also outline the existing challenges, barriers to future development and provide an outlook of ground-breaking fluidic technologies in embryo toxicity testing.


Assuntos
Embrião não Mamífero , Peixes , Animais , Substâncias Perigosas , Testes de Toxicidade Aguda , Peixe-Zebra
13.
Int J Nanomedicine ; 16: 2203-2217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33762821

RESUMO

Background: It is well known that smoking is harmful to health; however, it can also ameliorate anxiety. To date, it is unclear whether any nanoparticles found in cigarette mainstream smoke (CS) contribute to this effect. Aim: The aim of this study was to assess the particle composition of CS to identify novel anti-anxiety components. Methods: Carbon dots (CDs) from CS (CS-CDs) were characterised using high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-anxiety effects of CS-CDs in mouse models were evaluated and confirmed with the elevated plus maze and open-field tests. Results: The quantum yield of CS-CDs was 13.74%, with a composition of C, O, and N. In addition, the surface groups contained O-H, C-H, C=O, C-N, N-H, C-O-C, and COO- bonds. Acute toxicity testing revealed that CS-CDs had low in vitro and in vivo toxicity within a certain concentration range. The results of the elevated plus maze and open-field tests showed that CS-CDs had a significant anti-anxiety effect and a certain sedative effect in mice. The mechanism of these effects may be related to the decrease in glutamate levels and promotion of norepinephrine production in the mouse brain, and the decrease in dopamine in mouse serum due to CS-CDs. Conclusion: CS-CDs may have anti-anxiety and certain sedative effects. This study provides a new perspective for a more comprehensive understanding of the components, properties, and functions of CS. Furthermore, it offers a novel target for the development of smoking cessation treatments, such as nicotine replacement therapy.


Assuntos
Comportamento Animal , Carbono/química , Fumar Cigarros/efeitos adversos , Sistema Endócrino/metabolismo , Neurotransmissores/metabolismo , Pontos Quânticos/química , Água/química , Hormônio Adrenocorticotrópico/sangue , Animais , Ansiedade/sangue , Ansiedade/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão , Corticosterona/sangue , Hormônio Liberador da Corticotropina/sangue , Dopamina/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Espectroscopia Fotoeletrônica , Pontos Quânticos/ultraestrutura , Células RAW 264.7 , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Testes de Toxicidade Aguda , Difração de Raios X
14.
Sci Total Environ ; 764: 142902, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33757253

RESUMO

To avoid potential risks of biofuels on the environment and human, ecotoxicity investigation should be integrated into the early design stage for promising biofuel candidates. In the present study, a green toxicology testing strategy combining experimental bioassays with in silico tools was established to investigate the potential ecotoxicity of biofuel candidates. Experimental results obtained from the acute immobilisation test, the fish embryo acute toxicity test and the in vitro micronucleus assay (Chinese hamster lung fibroblast cell line V79) were compared with model prediction results by ECOSAR and OECD QSAR Toolbox. Both our experimental and model prediction results showed that 1-Octanol (1-Oct) and Di-n-butyl ether (DNBE) were the most toxic to Daphnia magna and zebrafish among all the biofuel candidates we investigated, while Methyl ethyl ketone (MEK), Dimethoxymethane (DMM) and Diethoxymethane (DEM) were the least toxic. Moreover, both in vitro micronucleus assay and OECD QSAR Toolbox evaluation suggested that the metabolites present higher genotoxicity than biofuel candidates themselves. Overall, our results proved that this green toxicology testing strategy is a useful tool for assessing ecotoxicity of biofuel candidates.


Assuntos
Biocombustíveis , Poluentes Químicos da Água , Animais , Biocombustíveis/toxicidade , Linhagem Celular , Cricetinae , Daphnia , Humanos , Testes de Toxicidade Aguda , Peixe-Zebra
15.
Molecules ; 26(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668635

RESUMO

Launaea nudicaulis is used in folk medicine worldwide to treat several diseases. The present study aimed to assess the antidiabetic activity of L. nudicaulis ethanolic extract and its effect on diabetic complications in streptozotocin-induced hyperglycemic rats. The extract was orally administrated at 250 and 500 mg/kg/day for 5-weeks and compared to glibenclamide as a reference drug at a dose of 5 mg/kg/day. Administration of the extract exhibited a potential hypoglycemic effect manifested by a significant depletion of serum blood glucose concurrent with a significant elevation in serum insulin secretion. After 5-weeks, extract at 250 and 500 mg/kg/day decreased blood glucose levels by about 53.8 and 68.1%, respectively, compared to the initial values (p ≤ 0.05). The extract at the two dosages prevented weight loss of rats from the 2nd week till the end of the experiment, compared to diabetic control rats. The extract further exhibited marked improvement in diabetic complications including liver, kidney and testis performance, oxidative stress, and relative weight of vital organs, with respect to diabetic control. Histopathological examinations confirmed the previous biochemical analysis, where the extract showed a protective effect on the pancreas, liver, kidney, and testis that degenerated in diabetic control rats. To characterize extract composition, UPLC-ESI-qTOF-MS identified 85 chromatographic peaks belonging to flavonoids, phenolics, acyl glycerols, nitrogenous compounds, and fatty acids, with four novel phenolics reported. The potential anti-diabetic effect warrants its inclusion in further studies and or isolation of the main bioactive agent(s).


Assuntos
Asteraceae/química , Diabetes Mellitus Experimental/tratamento farmacológico , Etanol/química , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/farmacologia , Insulina/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Malondialdeído/sangue , Metabolômica , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos Wistar , Estreptozocina , Testes de Toxicidade Aguda
16.
Oxid Med Cell Longev ; 2021: 9703682, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613827

RESUMO

Background: The liver is one of the most commonly affected organs in multiple organ dysfunction syndrome (MODS). In recent years, there have been many studies on Ganoderma lucidum polysaccharides (GLP), but the role of GLP in MODS is still unclear. The purpose of this work was to explore the antioxidant, anti-inflammatory, and protective effects of GLP on the liver in MODS model mice. Methods: The characteristic properties of GLP were processed by physicochemical analysis. The MODS models were successfully established with intraperitoneal injection of zymosan in Kunming strain mice. The antioxidant, anti-inflammatory, and hepatoprotective effects of GLP were processed both in vitro and in vivo by evaluating the oxidative parameters, inflammatory factors, and liver pathological observations. Results: The characterization analysis revealed that GLP was a pyranose mainly composed of glucose with the molecular weights (Mw) of 8309 Da. The experimental results proved that GLP had potential hepatoprotection possibly by improving the antioxidant status (scavenging excessive oxygen radicals, increasing the antioxidant enzyme activities, and reducing the lipid peroxide), alleviating the inflammatory response (reducing the inflammatory factor levels), and guaranteeing the liver functions. Conclusions: This research suggested that GLP had the potential to be developed as a natural medicine for the treatment of multiple organ failure.


Assuntos
Fígado/patologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/fisiopatologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Reishi/química , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Catalase/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/toxicidade , Substâncias Protetoras/farmacologia , Superóxido Dismutase/metabolismo , Síndrome , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica
17.
Oxid Med Cell Longev ; 2021: 8845064, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574982

RESUMO

Alzheimer's disease (AD) is a debilitating and irreversible brain disease that affects an increasing number of aged individuals, mandating the development of protective nutraceuticals. Biobran/MGN-3, an arabinoxylan from rice bran, has potent antioxidant, antiaging, and immunomodulatory effects. The aim of the present study was to investigate the protective effect of Biobran against sporadic Alzheimer's disease (SAD). SAD was induced in mice via intracerebroventricular injection of streptozotocin (STZ) (3 mg/kg). STZ-treated mice were administered with Biobran for 21 days. The effects of Biobran on memory and learning were measured via the Morris water maze, novel object recognition, and Y-maze tests. Biomarkers for apoptosis, oxidative stress, and amyloidogenesis were measured using ELISA and western blot analysis. Histopathological examination was performed to confirm neuronal damage and amyloid-beta deposition. Biobran reversed the spatial memory deficit in SAD-induced mice, and it increased the expression of glutathione, reduced malondialdehyde, decreased IL-6, decreased intercellular adhesion molecule-1 (ICAM-1), and significantly increased nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). Moreover, Biobran exerted a protective effect against amyloid-beta-induced apoptosis via the suppression of both cleaved caspase-3 and the proapoptotic protein Bax and via the upregulation of the antiapoptotic protein Bcl-2. Furthermore, it reduced the expression of forkhead box class O proteins. It could be concluded from this study that Biobran may be a useful nutritional antioxidant agent for protection against SAD through its activation of the gene expression of Nrf2/ARE, which in turn modulates the apoptotic and amyloidogenic pathways.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Apoptose , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Xilanos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Elementos de Resposta Antioxidante/genética , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Caspase 3/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Proteína Forkhead Box O3/metabolismo , Glutationa/metabolismo , Inflamação/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Teste do Labirinto Aquático de Morris , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Teste de Campo Aberto , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide/patologia , Estreptozocina , Testes de Toxicidade Aguda , Xilanos/química , Xilanos/farmacologia , Proteína X Associada a bcl-2/metabolismo
18.
Oxid Med Cell Longev ; 2021: 8891445, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574987

RESUMO

Euryops arabicus Steud (E. arabicus) belongs to the family Asteraceae. It has several uses in folk medicine in the Arabian Peninsula. The current study aimed at evaluating the wound healing properties of the E. arabicus extract in rats. Primarily, E. arabicus successfully accelerated cell migration in vitro and it also showed no signs of dermal toxicity. Topical application of E. arabicus extract (5% or 20%) expedited healing of excised skin in rats. Histological examinations indicated that E. arabicus shortened epithelization period, stimulated fibroblast activity, and increased collagen deposition in wound tissues. The plant extract exerted antioxidant activity as evidenced by inhibition of GSH depletion and MDA accumulation and enhanced mRNA expression of Sod1 in wound tissues collected at the end of the experiment. Further, E. arabicus inhibited the rise of TNF-α and IL-1ß in the skin wound region. The anti-inflammatory was confirmed by the observed down regulation of Ptgs2, Nos2, IL-6, and NF-κB mRNA expression. In addition, the extract enhanced the expression of TGF-ß1 and HIF-1α in wounded skin tissues as indicated immunohistochemically. Conclusively, E. arabicus expedites excision wound healing in rats. Collagen-enhancing, anti-inflammatory, and antioxidant properties mediate the observed wound healing activity. These findings might contribute to our understanding of the ethnobotanical use of E. arabicus in wounds.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Asteraceae/química , Colágeno/metabolismo , Pele/patologia , Cicatrização , Animais , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Recém-Nascido , Concentração Inibidora 50 , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Masculino , Malondialdeído/metabolismo , Oxirredução/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade Aguda , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização/efeitos dos fármacos
19.
Int J Nanomedicine ; 16: 951-976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603362

RESUMO

Purpose: Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers. Methods: For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice. Results and Conclusion: The mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from -12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.


Assuntos
Lipídeos/química , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Fotoquimioterapia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração Inibidora 50 , Cinética , Lipossomos , Testes de Função Hepática , Mesoporfirinas/farmacologia , Mesoporfirinas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Neoplasias Ovarianas/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade Aguda
20.
Toxicol Appl Pharmacol ; 414: 115424, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524444

RESUMO

For the determination of acute toxicity of chemicals in zebrafish (Danio rerio) embryos, the OECD test guideline 236, relative to the Fish Embryo Toxicity Test (FET), stipulates a dose-response analysis of four lethal core endpoints and a quantitative characterization of abnormalities including their time-dependency. Routinely, the data are analyzed at the different observation times separately. However, observations at a given time strongly depend on the previous effects and should be analyzed jointly with them. To solve this problem, we developed multistate models for occurrence of developmental malformations and live events in zebrafish embryos exposed to eight concentrations of valproic acid (VPA) the first five days of life. Observations were recorded daily per embryo. We statistically infer on model structure and parameters using a numerical Bayesian framework. Hatching probability rate changed with time and we compared five forms of its time-dependence; a constant rate, a piecewise constant rate with a fixed hatching time at 48 h post fertilization, a piecewise constant rate with a variable hatching time, as well as a Hill and Gaussian form. A piecewise constant function of time adequately described the hatching data. The other transition rates were conditioned on the embryo body concentration of VPA, obtained using a physiologically-based pharmacokinetic model. VPA impacted mostly the malformation probability rate in hatched and non-hatched embryos. Malformation reversion probability rates were lowered by VPA. Direct mortality was low at the concentrations tested, but increased linearly with internal concentration. The model makes full use of data and gives a finer grain analysis of the teratogenic effects of VPA in zebrafish than the OECD-prescribed approach. We discuss the use of the model for obtaining toxicological reference values suitable for inter-species extrapolation. A general result is that complex multistate models can be efficiently evaluated numerically.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Modelos Biológicos , Teratógenos/toxicidade , Testes de Toxicidade Aguda , Ácido Valproico/toxicidade , Anormalidades Induzidas por Medicamentos/embriologia , Animais , Teorema de Bayes , Simulação por Computador , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Análise Numérica Assistida por Computador , Teratógenos/farmacocinética , Toxicocinética , Ácido Valproico/farmacocinética , Peixe-Zebra/embriologia
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