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1.
J Ethnopharmacol ; 287: 114919, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34995693

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels has been extensively used in the ancient medical system of Pakistan, India, Bangladesh, and Sri Lanka to combat diabetes, inflammation, and renal disorders. These health-promoting aspects of S. cumini are related to bioactive metabolites such as phenolic acids, anthocyanins, tannins, and flavonoids. AIM OF THE STUDY: Earlier to this study, we have reported S. cumini extracts as potential sources of bioactive compounds bearing antioxidant and anti-inflammatory properties. However, prior further suggesting S. cumini fruit extracts for consumption against inflammatory disorders, it was mandatory to validate the claim and explore toxicity of the extracts. This study aims to determine the in vivo anti-nociceptive, anti-inflammatory, acute, and subacute toxicity properties of S. cumini crude extracts, followed by identifying and quantifying bioactive metabolites. MATERIAL AND METHODS: In the present study, the anti-nociceptive and anti-inflammatory potential of S. cumini sequential crude extracts were evaluated using formalin and glutamate-induced paw licking method in mice. The acute and sub-acute toxicity assessment of active extract was performed by oral administration in rats. An acute toxicity trial was performed with two different doses, i.e., 2000 mg/kg and 3000 mg/kg for consecutive 14 days, whereas a sub-acute toxicity study was conducted at doses of 750 mg/kg and 1500 mg/kg for the next 28 days. Identification of bioactive compounds was performed using HPLC, and at the end, in silico docking calculations of identified compounds were performed. RESULTS: The 100% methanolic extract (SCME) protected the mice from painful stimulation of formalin and glutamate in a dose-dependent manner with the maximum effect of 49% and 67% at 200 mg/kg, respectively, followed by moderate and non-influential effects of 50% methanolic extract and dichloromethane (DCM) extracts when compared to control, i.e., normal saline. The results of acute toxicity recorded LD50 of SCME over 3000 mg/kg, and no antagonistic effects were recorded during the subacute study when SCME dispensed at the rate of 750 mg/kg and 1500 mg/kg. SCME was found to induce no adverse effects to kidney, heart, liver, spleen, and paired lungs examined by hematological, serum biochemical, histological analysis. HPLC analysis of S. cumini 100% methanolic extracts revealed the presence of delphinidin 3-glucoside, peonidin-3,5-diglucoside, scopoletin, and umbelliferone at the concentration of 127.4, 2104, 31.3, 10.4 µg/g whereas in 50% methanolic extract, the quinic acid, catechin, and myricetin were present at the concentration of 54.9, 63.7, 12.3 µg/g, respectively. Umbelliferone and scopoletin are newly reported compounds in the present study. In silico docking calculations of these compounds indicated the potential of anti-nociceptive and anti-inflammatory activities. CONCLUSIONS: These findings validate that S. cumini fruit extracts are a rich source of bioactive compounds that needs to be considered to enhance biological activities with lesser side effects.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Syzygium/química , Analgésicos/administração & dosagem , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Simulação de Acoplamento Molecular , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
2.
Regul Toxicol Pharmacol ; 129: 105114, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35007669

RESUMO

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.


Assuntos
Antimaláricos/toxicidade , Artemisininas/toxicidade , Hidroxicloroquina/toxicidade , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Artemisininas/administração & dosagem , Artemisininas/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/farmacologia , Dose Letal Mediana , Masculino , Nível de Efeito Adverso não Observado , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
3.
Regul Toxicol Pharmacol ; 129: 105118, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35038484

RESUMO

Piper amalago L. (Piperaceae) is traditionally used due to its anti-inflammatory, analgesic, diuretic, and antiparasitic properties. However, few studies have focused on its adverse effects, compromising its safe use. This study evaluated the toxicological safety of ethanolic extract from Piper amalago leaves (EEPA), through subacute toxicity and genotoxicity assays in rodents. In subacute toxicity, 100, 200 or 300 mg/kg of EEPA were tested in female Wistar rats, by gavage, for 28 days. For genotoxicity test, female Swiss mice were orally treated with 17.5, 175 or 1750 mg/kg of EEPA and the comet, micronucleus, and splenic phagocytic assays were evaluated. In subacute toxicity, the extract induced an increase in the food and water intakes, as well as in the liver absolute weight, and in the heart and kidney relative weights. EEPA also provoked alterations in histopathological analysis of liver and in hemato-biochemical parameters, evidenced by a decrease in hematocrit levels and albumin levels, and an increase in the number of platelets and in alkaline phosphatase and cholesterol levels. However, EEPA did not presented genotoxic nor mutagenic properties. EEPA showed hemato-biochemical toxicity profile in rats and should be used with caution, especially when for prolonged period.


Assuntos
Piper , Extratos Vegetais/farmacologia , Animais , Sangue/efeitos dos fármacos , Análise Química do Sangue , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Fígado/efeitos dos fármacos , Camundongos , Testes de Mutagenicidade , Folhas de Planta , Distribuição Aleatória , Ratos , Ratos Wistar , Testes de Toxicidade Subaguda
4.
BMC Complement Med Ther ; 22(1): 16, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031035

RESUMO

BACKGROUND: Several local communities in Central, Western, Eastern, and Northern regions of Uganda have been using the whole leaf extracts of Aloe vera (L.) Burm. f. (Asphodelaceae) in the treatment of various ailments. Also, several commercial companies sell A. vera as soft drinks in Uganda. However, there are inadequate reports on the toxicities of such preparations. This paper reports the acute and sub-acute oral toxicity of aqueous extracts of whole leaf and green rind of A. vera in Wistar rats. METHODS: Acute oral toxicity test was carried out in female Wistar rats at doses of 175, 550, 1750, and 5000 mg/kg, p.o. The animals were observed for signs of toxicity for 14 days. Similarly, a sub-acute oral toxicity test was performed in both sexes of rats at doses of 200, 400, and 800 mg/kg, p.o. daily for 28 days. All the groups of animals were monitored for behavioral, morphological, biochemical, and physiological changes, including mortality and compared with respective controls. Body weights were measured weekly while the animals' relative organ weights, hematological, biochemical, gross, and microscopic pathology were examined on day 29. RESULTS: There was no mortality or apparent behavioral changes at the doses tested in acute and sub-acute oral toxicity tests. Thus, the Median Lethal Dose (LD50) of green rind and whole leaf aqueous extracts was above 5000 mg/kg. Gross anatomy revealed that the rats' relative spleen weight in green rind extract at 200 mg/kg significantly decreased compared to the control group. The creatinine levels in female rats that received green rind extract and the chloride ion levels in male rats administered whole leaf extract were significantly elevated. Conversely, Mean Corpuscular Hemoglobin Concentration (MCHC) levels significantly decreased at lower doses of the green rind extract compared to the control. Histopathology of the kidney revealed the renal interstitium's inflammation at doses of 200 and 800 mg/kg of the whole leaf extract. CONCLUSION: The findings demonstrated that A. vera green rind and whole leaf extracts are non-toxic at relatively high doses when used for a short duration. Prolonged use of the aqueous whole leaf extract might be associated with kidney toxicity.


Assuntos
Aloe/toxicidade , Extratos Vegetais/toxicidade , Animais , Feminino , Dose Letal Mediana , Masculino , Ratos , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Uganda
5.
J Ethnopharmacol ; 287: 114940, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34968665

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sanren decoction (SRD) is a well-known traditional Chinese medicine prescription containing eight kinds of materials. SRD has been used mainly in China for more than 200 years for the treatment of respiratory disorders that co-occur with a bad fever after midday. AIM OF THE STUDY: To evaluate the acute and 28-day subacute toxicity of an aqueous extract of SRD using in vivo methods. MATERIALS AND METHODS: To determine acute toxicity, SRD was administered by gavage at a dosage of 58.5 g/kg/day to male and female mice for 7 days. To determine subacute toxicity, SRD was administered at 3.3, 6.5, or 13 g/kg/day to male and female rats for 28 days. The general behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology of the treated animals were analyzed. RESULTS: Neither acute nor subacute concentrations of SRD caused significant changes in the body weights, general behavior, hematology and biochemical parameters, organ weights, or histopathological appearances of the liver, kidney, spleen, brain, lung or heart in mice or rats. CONCLUSIONS: The administration of SRD can be considered safe within the conditions of this study.


Assuntos
Peso Corporal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/toxicidade , Tamanho do Órgão/efeitos dos fármacos , Animais , Animais não Endogâmicos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
6.
Molecules ; 26(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34641627

RESUMO

Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent-solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC50 of 49 µg/mL as compared to the standard quercetin with an IC50 of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD50) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala, which justifies its use in folk medicine.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Peganum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Modelos Animais de Doenças , Edema/induzido quimicamente , Indometacina/farmacologia , Dose Letal Mediana , Camundongos , Extratos Vegetais/química , Quercetina/farmacologia , Ratos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
7.
Sci Rep ; 11(1): 19248, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34584173

RESUMO

The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.


Assuntos
Células-Tronco Mesenquimais/efeitos dos fármacos , Morfina/toxicidade , Cicatrização/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/análise , Colágeno Tipo I/metabolismo , Fibrose , Humanos , Células-Tronco Mesenquimais/fisiologia , Cultura Primária de Células , Testes de Toxicidade Subaguda
8.
Toxicology ; 462: 152934, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34509579

RESUMO

Acrylamide (ACR) is a recognized toxin that is known to induce neurotoxicity in humans and experimental animals. This study aimed to investigate the toxic effects of subacute exposure of the motor endplate (MEP) of the gastrocnemius in rats to ACR. All rats were randomly divided into control, 9, 18, and 36 mg/kg ACR groups, and ACR was administered by gastric gavage for 21 days. The behavioral tests were performed weekly. On the 22nd day, the wet weight of the gastrocnemius was measured. The changes in muscle fiber structure, nerve endings, and MEP in the gastrocnemius were examined by hematoxylin-eosin (HE) and gold chloride staining. Acetylcholinesterase (AChE) content in the gastrocnemius was detected by AChE staining. The expression of AChE and calcitonin gene-related peptide was detected by immunohistochemistry and western blot. Rats exposed to ACR showed a significant increase in gait scores and hind limb splay distance compared with the control group, and the wet weight of the gastrocnemius was reduced, HE staining showed that the muscle fiber structure of the gastrocnemius became thin and the arrangement was dense with nuclear aggregation, gold chloride staining showed that nerve branches decreased and became thin, nerve fibers became short and light, the number of MEPs was decreased, the staining became light, and the structure was not clear. AChE staining showed that the number of MEPs was significantly reduced after exposure to ACR, the shape became small, and the AChE content decreased in a dose-dependent manner. Immunohistochemistry and western blot analysis results of the expression levels of AChE and CGRP showed a decreasing trend as compared to the control group with increasing ACR exposure dose. The reduction in protein levels may be the mechanism by which ACR has a toxic effect on the MEP in the gastrocnemius of rats.


Assuntos
Acrilamida/toxicidade , Placa Motora/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Acrilamida/administração & dosagem , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Placa Motora/patologia , Músculo Esquelético/patologia , Ratos , Testes de Toxicidade Subaguda
9.
Toxins (Basel) ; 13(9)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34564631

RESUMO

Regulatory limits for shellfish toxins are required to protect human health. Often these limits are set using only acute toxicity data, which is significant, as in some communities, shellfish makes up a large proportion of their daily diet and can be contaminated with paralytic shellfish toxins (PSTs) for several months. In the current study, feeding protocols were developed to mimic human feeding behaviour and diets containing three dose rates of saxitoxin dihydrochloride (STX.2HCl) were fed to mice for 21 days. This yielded STX.2HCl dose rates of up to 730 µg/kg bw/day with no effects on food consumption, growth, blood pressure, heart rate, motor coordination, grip strength, blood chemistry, haematology, organ weights or tissue histology. Using the 100-fold safety factor to extrapolate from animals to humans yields a dose rate of 7.3 µg/kg bw/day, which is well above the current acute reference dose (ARfD) of 0.5 µg STX.2HCl eq/kg bw proposed by the European Food Safety Authority. Furthermore, to reach the dose rate of 7.3 µg/kg bw, a 60 or 70 kg human would have to consume 540 or 630 g of shellfish contaminated with PSTs at the current regulatory limit (800 µg/kg shellfish flesh), respectively. The current regulatory limit for PSTs therefore seems appropriate.


Assuntos
Contaminação de Alimentos/legislação & jurisprudência , Toxinas Marinhas/toxicidade , Venenos/toxicidade , Saxitoxina/toxicidade , Animais , Feminino , Masculino , Camundongos , Intoxicação por Frutos do Mar/etiologia , Testes de Toxicidade Subaguda
10.
Biomed Res Int ; 2021: 5521516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395617

RESUMO

Dibutyl phthalate is an endocrine disruptor used in a wide range of industrial and agriculture applications. The present study focuses on elucidating the effect of subacute exposure (4-weeks) of DBP on insulin and its sensitivity indexes, oxidative status, thyroid function, energy metabolites, serum biochemistry, and anthropometry in rats. A total of 64 rats were divided into 4 treatment groups as mg DBP/Kg body weight per day: (a) 0 mg/Kg (control), (b) 10 mg/Kg (DBP-10), (c) 50 mg/Kg (DBP-50), and (d) 100 mg/Kg (DBP-100). The rats in each treatment (n = 16) were further divided into male (n = 8) and female (n = 8) rats for studying treatment and gender interactions. Intraperitoneal glucose tolerance test (IPGTT) was performed on the 21st day. Anthropometry, nutritional determinants, fasting plasma glucose, fasting plasma insulin, homeostatic model assessment (HOMA), thyroid hormones, energy metabolites, and oxidative status were studied during the experimental period. Two-way ANOVA was used to analyze the data (p < 0.05). Tukey's posthoc test was used for pair-wise comparisons. DBP increased body weight gain and feed efficiency in an inverted nonmonotonic U-shaped fashion. Hyperglycemia and increased blood glucose area under the curve were observed in DBP-100 at 120 minutes in IPGTT. The HOMA also showed a linear monotonic contrast. Thyroxin decreased significantly in the DBP-100 rats, whereas malondialdehyde, nonesterified fatty acids, and beta hydroxyl butyrate were increased with the DBP treatments. In conclusion, DBP could be attributed to the development of hyperglycemia and insulin resistance in rats. Further investigations into the lipid peroxidation pathways can improve our understanding of the mechanisms involved in metabolic disruption.


Assuntos
Dibutilftalato/toxicidade , Hiperglicemia/induzido quimicamente , Resistência à Insulina , Glândula Tireoide/fisiologia , Animais , Feminino , Teste de Tolerância a Glucose , Homeostase/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Glândula Tireoide/efeitos dos fármacos , Testes de Toxicidade Subaguda
12.
J Immunol Res ; 2021: 9957451, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337087

RESUMO

BACKGROUND: Solanum diploconos (Mart.) Bohs is a native Brazilian plant belonging to the Solanaceae family, popularly known as "tomatinho do mato" and poorly investigated. Herein, we presented for the first time evidence for the anti-inflammatory and wound healing activities of S. diploconos fruit hydroalcoholic extract. Material and Methods. In vitro fMLP-induced chemotaxis, LPS-induced inflammatory mediator levels (cytokines by ELISA and NO release by Griess reaction), and adhesion molecule expression (CD62L, CD49d, and CD18, by flow-cytometry) were assessed in neutrophils treated with different concentrations of the extract. Inflammation resolution was measured by the efferocytosis assay and the healing activity by in vivo and in vitro assays. The air pouch model of carrageenan-induced inflammation in Swiss mice was used to investigate the in vivo anti-inflammatory effects of the extract. Leukocyte influx (by optical microscopy) and cytokine release were quantified in the pouch exudates. Additionally, the acute and subacute toxic and genotoxic effects of the extract were evaluated. RESULTS: In vitro, the extract impaired neutrophil chemotaxis and its ability to produce and/or release cytokines (TNFα, IL-1ß, and IL-6) and NO upon LPS stimuli (p < 0.01). LPS-treated neutrophils incubated with the extract presented increased CD62L expression (p < 0.01), indicating a reduced activation. An enhanced efferocytosis of apoptotic neutrophils by macrophages was observed and accompanied by higher IL-10 and decreased TNFα secretion (p < 0.01). In vivo, similar results were noted, including reduction of neutrophil migration, protein exudation, and cytokine release (p < 0.01). Also, the extract increased fibroblast proliferation and promoted skin wound healing (p < 0.01). No signs of toxicity or genotoxicity were observed for the extract. CONCLUSION: S. diploconos fruit extract is anti-inflammatory by modulating neutrophil migration/activation as well macrophage-dependent efferocytosis and inflammatory mediator release. It also indicates its potential use as a healing agent. Finally, the absence of acute toxic and genotoxic effects reinforces its possible use as medicinal product.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Solanum/química , Cicatrização/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Carragenina/administração & dosagem , Carragenina/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Frutas/química , Humanos , Inflamação/imunologia , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Ratos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Cicatrização/imunologia
13.
Regul Toxicol Pharmacol ; 124: 104999, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34242706

RESUMO

Tea tree oil (TTO) is a popular topical use to treat skin infections. However, its poor aqueous solubility and stability have substantially limited its widespread application, including oral administration that might be therapeutic for enteric infections. In this study, mechanical ultrasonic methods were used to prepare TTO nanoemulsion (nanoTTO) with a mean droplet diameter of 161.80 nm ± 3.97, polydispersity index of 0.21 ± 0.01, and zeta potential of -12.33 ± 0.72 mV. The potential toxicity of nanoTTO was assessed by studying the oral median lethal dose (LD50) and repeated 28-day oral toxicity to provide a reference for in vivo application. Results showed that nanoTTO had no phase separation under a centrifugation test and displayed good stability during storage at -20, 4 and 25 °C over 60 days. Repeated-dose 28-day oral toxicity evaluation revealed no significant effects on growth and behavior. Assessments of hematology, clinical biochemistry, and histopathology indicated no obvious adverse effects in mice at 50, 100 and 200 mg/mL. These data suggest that nanoTTO can be considered a potential antimicrobial agent by oral administration due to its inhibitory effect on bacteria and relatively lower toxicity.


Assuntos
Nanopartículas/toxicidade , Óleo de Melaleuca/toxicidade , Administração Oral , Administração Tópica , Animais , Estabilidade de Medicamentos , Emulsões , Dose Letal Mediana , Masculino , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Óleo de Melaleuca/administração & dosagem , Óleo de Melaleuca/química , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
14.
Regul Toxicol Pharmacol ; 124: 104988, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34224799

RESUMO

Here, we present a non-animal testing battery to identify PSLT (poorly soluble, low toxicity) substances based on their solubility in phagolysosomal lung fluid simulant, surface reactivity and effects on alveolar macrophages in vitro. This is exemplified by eleven organic pigments belonging to five chemical classes that cover a significant share of the European market. Three of the pigments were tested as both, nanoform and non-nanoform. The results obtained in this integrated non-animal testing battery qualified two pigments as non PSLT, one pigment as poorly soluble and eight pigments as poorly soluble and low toxicity in vitro. The low toxic potency of the eight PSLT and the one poorly soluble pigment was corroborated by short-term inhalation studies with rats. These pigments did not elicit apparent toxic effects at 10 mg/m3 (systemic and in the respiratory tract). One of the pigments, Diarylide Pigment Yellow 83 transparent, however, caused minimal infiltration of neutrophils; hence its low toxicity is ambiguous and needs further verification or falsification. The present test battery provides an opportunity to identify PSLT-properties of test substances to prioritise particles for further development. Thus, it can help to reduce animal testing and steer product development towards safe applications.


Assuntos
Alternativas aos Testes com Animais/métodos , Corantes/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Administração por Inalação , Animais , Linhagem Celular , Corantes/química , Masculino , Tamanho da Partícula , Ratos , Solubilidade , Testes de Toxicidade Subaguda/métodos
15.
PLoS One ; 16(7): e0253802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228739

RESUMO

Microplastic continues to be an environmental concern, especially for filter feeding bivalves known to ingest these particles. It is important to understand the effects of microplastic particles on the physiological performance of these bivalves and many studies have investigated their impact on various physiological processes. This study investigated the effects of microplastic (10 µm) on digestive enzyme (amylase) activity of Mytilus galloprovincialis at 55,000 and 110,000 microplastic particles/L under laboratory conditions. Additionally, our study measured the expression of an isoform of Hsp70 in the gills to assess whether or not these particles may cause protein denaturation. Results revealed that this regime negatively affect the ability of M. galloprovincialis to digest starch under high food conditions but not low food conditions. Exposure to extreme levels of microplastic raised amylase activity. Furthermore, Hsp70 transcript abundance was not elevated in treatment mussels. These results show that mussels may be resilient to current microplastic pollution levels in nature.


Assuntos
Amilases/metabolismo , Microplásticos/toxicidade , Mytilus edulis/enzimologia , Poluentes Químicos da Água/toxicidade , Animais , Ensaios Enzimáticos , Desnaturação Proteica , Amido/metabolismo , Testes de Toxicidade Subaguda
16.
Int J Toxicol ; 40(5): 453-465, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34286615

RESUMO

The present study investigated the potential subchronic toxicity of self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG) in mice. The test reagent was administered once-daily by intravenous injection for 4 weeks at 0, 100, 200, or 300 mg/kg/day doses. Additional recovery groups (vehicle control and high dose groups) were observed for a 2-week recovery period. During the test period, mortality, clinical signs, body weight, food consumption, ophthalmology, urinalysis, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. An increase in the percentages of basophil and large unstained cells was observed in the 200 and 300 mg/kg/day groups of both sexes. In addition, the absolute and relative weights of the spleen were higher in males given 300 mg/kg/day relative to the concurrent controls. However, these findings were considered of no toxicological significance because the changes were minimal, were not accompanied by other relevant results (eg, correlating microscopic changes), and were not observed at the end of the 2-week recovery period indicating recovery of the findings. Based on the results, SAMiRNA-AREG did not cause treatment-related adverse effects at dose levels of up to 300 mg/kg/day in mice after 4-week repeated intravenous doses. Under these conditions, the no-observed-adverse-effect level of the SAMiRNA-AREG was ≥300 mg/kg/day in both sexes and no target organs were identified.


Assuntos
Anfirregulina/administração & dosagem , Nanopartículas/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Anfirregulina/toxicidade , Animais , Feminino , Injeções Intravenosas , Masculino , Camundongos Endogâmicos ICR , Micelas , Nanopartículas/toxicidade , Nível de Efeito Adverso não Observado , RNA Interferente Pequeno/toxicidade , Testes de Toxicidade Subaguda
17.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065933

RESUMO

Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3ß4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3ß4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 µM, but it was stronger at 500 µM. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3ß4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms.


Assuntos
Epinefrina/metabolismo , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Nicotina/toxicidade , Receptores Nicotínicos/metabolismo , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Agonismo Parcial de Drogas , Gânglios/efeitos dos fármacos , Gânglios/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanidinas/toxicidade , Masculino , Ratos , Tiazóis/toxicidade , Testes de Toxicidade Subaguda
18.
Regul Toxicol Pharmacol ; 124: 104974, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34139276

RESUMO

Sida rhombifolia (Malvaceae) is popularly used as a treatment for several pathological conditions; however, there is a lack of studies that identify its compounds and that evaluate comprehensively the safety of its consumption. Therefore, the aim of this study was to determinate the phytochemical constitution of the crude extract of Sida rhombifolia (CESR), and its safety in models of acute and repeated doses (28 days) toxicity. The tested dose for the model of acute toxicity was 2000 mg/kg doses for the repeated dose model were 150, 300 e 600 mg/kg. Hematological, biochemical, histopathological and oxidative markers were investigated. HPLC-DAD-MS analysis evidenced the presence of caffeic acid, coumarin, and rutin. In the acute toxicity model the only altered parameters were tissue ROS, and AST and BUN in serum. As for the repeated dose experiment both hematological and biochemical markers remained within the values of reference for the species. Obtained results demonstrate that the CESR did not present significant toxic effects when administrated orally to male and female rats in acute and repeated doses.


Assuntos
Malvaceae/química , Extratos Vegetais/toxicidade , Administração Oral , Animais , Ácidos Cafeicos/análise , Ácidos Cafeicos/toxicidade , Cumarínicos/análise , Cumarínicos/toxicidade , Feminino , Masculino , Componentes Aéreos da Planta/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Rutina/análise , Rutina/toxicidade , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
19.
Regul Toxicol Pharmacol ; 124: 104973, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34146638

RESUMO

Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless, there have been some concerns in the scientific literature regarding orotic acid, and pharmaceutical lithium salts are known to have a narrow therapeutic window, albeit, at lithium equivalent therapeutic doses 5.5-67 times greater than typically recommended for supplemental lithium orotate. To our knowledge, the potential toxicity of lithium orotate has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test in order to further explore its safety. Lithium orotate was not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 28-day, repeated-dose oral toxicity study, rats were administered 0, 100, 200, or 400 mg/kg body weight/day of lithium orotate by gavage. No toxicity or target organs were identified; therefore, a no observed adverse effect level was determined as 400 mg/kg body weight/day. These results are supportive of the lack of a postmarket safety signal from several decades of human consumption.


Assuntos
Suplementos Nutricionais/toxicidade , Compostos Organometálicos/toxicidade , Administração Oral , Animais , Linhagem Celular , Aberrações Cromossômicas/induzido quimicamente , Cricetulus , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Testes para Micronúcleos , Nível de Efeito Adverso não Observado , Compostos Organometálicos/administração & dosagem , Ratos , Testes de Toxicidade Subaguda
20.
Regul Toxicol Pharmacol ; 124: 104962, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34019964

RESUMO

Afidopyropen is an insecticide that acts as a transient receptor potential vanilloid subtype (TRPV) channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including chronic toxicity and carcinogenicity in rats and mice. The current study evaluates the toxicokinetic properties of afidopyropen and its plasma metabolites in rats at dose levels where the pharmacokinetics (PK) are linear and nonlinear in an attempt to identify a point of inflection. Based on the results of this study and depending on the analysis method used, the kinetically derived maximum dose (KMD) is estimated to be between 2.5 and 12.5 mg/kg bw/d with linearity observed at doses below 2.5 mg/kg bw/d. A defined point of inflection could not be determined. These data demonstrate that consideration of PK is critical for improving the dose-selection in toxicity studies as well as to enhance human relevance of the interpretation of animal toxicity studies. The study also demonstrates the technical difficulty in obtaining a defined point of inflection from in vivo PK data.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Inseticidas/toxicidade , Lactonas/toxicidade , Testes de Toxicidade Subaguda/métodos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Lactonas/administração & dosagem , Lactonas/farmacocinética , Masculino , Modelos Animais , Ratos , Organismos Livres de Patógenos Específicos , Testes de Toxicidade , Toxicocinética
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