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1.
Pharmaceutics ; 15(8)2023 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-37631386

RESUMO

Due to cartilage's limited capacity for regeneration, numerous studies have been conducted to find new drugs that modify osteoarthrosis's progression. Some evidence showed the capability of chitosan nanoparticles with glutathione (Np-GSH) to regulate the oxide-redox status in vitro in human chondrocytes. This work aimed to evaluate the capacity of Np-GSH in vivo, using Wistar rats with induced surgical osteoarthritis. Radiographic, biochemical (GSH and TBARS quantification), histopathological, and immunohistochemical (Col-2 and MMP-13) analyses were performed to evaluate the progress of the osteoarthritic lesions after the administration of a single dose of Np-GSH. According to the results obtained, the GSH contained in the NPs could be vectored to chondrocytes and used by the cell to modulate the oxidative state reduction, decreasing the production of ROS and free radicals induced by agents oxidizing xenobiotics, increasing GSH levels, as well as the activity of GPx, and decreasing lipid peroxidation. These results are significant since the synthesis of GSH develops exclusively in the cell cytoplasm, and its quantity under an oxidation-reduction imbalance may be defective. Therefore, the results allow us to consider these nanostructures as a helpful study tool to reduce the damage associated with oxidative stress in various diseases such as osteoarthritis.

2.
Pharmaceutics ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34452212

RESUMO

In this report, we investigated whether the use of chitosan-carrying-glutathione nanoparticles (CH-GSH NPs) can modify proliferation and apoptosis, and reduce cell damage induced by doxorubicin on breast cancer cells. Doxorubicin is a widely used antineoplasic agent for the treatment of various types of cancer. However, it is also a highly toxic drug because it induces oxidative stress. Thus, the use of antioxidant molecules has been considered to reduce the toxicity of doxorubicin. CH-GSH NPs were characterized in size, zeta potential, concentration, and shape. When breast cancer cells were treated with CH-GSH nanoparticles, they were localized in the cellular cytoplasm. Combined doxorubicin exposure with nanoparticles increased intracellular GSH levels. At the same time, decreasing levels of reactive oxygen species and malondialdehyde were observed and modified antioxidant enzyme activity. Levels of the Ki67 protein were evaluated as a marker of cell proliferation and the activity of the Casp-3 protein related to cell apoptosis was measured. Our data suggests that CH-GSH NPs can modify cell proliferation by decreasing Ki67 levels, induce apoptosis by increasing caspase-3 activity, and reduce the oxidative stress induced by doxorubicin in breast cancer cells by modulating molecules associated with the cellular redox state. CH-GSH NPs could be used to reduce the toxic effects of this antineoplastic. Considering these results, CH-GSH NPs represent a novel delivery system offering new opportunities in pharmacy, material science, and biomedicine.

3.
J Pharm Biomed Anal ; 195: 113817, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33303268

RESUMO

Zilpaterol and Clenbuterol are ß-adrenergic agonists that have been widely used to feed cattle. Although the use of Zilpaterol has been approved, Clenbuterol is still used illegally at unknown doses. However, the research of both substances has been based mainly on the evaluation of residues. To our knowledge, this is the first time that a cellular model using Hep G2 cells treated with Zilpaterol and Clenbuterol is presented as an alternative approach to quantify both drugs at the cellular level. Thus, a complete analytical methodology has been developed for the accurate quantitation of these ß-adrenergic agonists in both cellular compartments. We propose the use of ultra-performance liquid chromatography with photodiode array detector (UPLC-PDA) for extracellular determinations while UPLC coupled to a tandem mass spectrometer (UPLC-MS/MS) for intracellular analysis. The methods were fully validated in terms of selectivity, linearity, accuracy, and precision, limits of detection and quantitation (LOD and LOQ, respectively), stability, carryover, and matrix effect. The method for intracellular content was linear ranging from 0.25 to 8 ng/mL while for extracellular content, the concentration of Zilpaterol and Clenbuterol ranged from 0.125 to 4 µg/mL, with correlation coefficients of R > 0.98 and >0.99, respectively. The combination of the two methodologies in the cellular model showed intracellular concentrations of 0.344 ± 0.06 µg/mL and 2.483 ± 0.36 µg/mL for Zilpaterol and Clenbuterol, respectively. Extracellular concentration was 0.728 ± 0.14 µg/mL and 0.822 ± 0.11 µg/mL for Zilpaterol and Clenbuterol, respectively. This work shows the potential applications of cellular modelling in the study of toxicity for the mentioned drugs.


Assuntos
Clembuterol , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Células Hep G2 , Fígado , Espectrometria de Massas em Tandem , Compostos de Trimetilsilil
4.
Biomolecules ; 9(5)2019 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083605

RESUMO

Breast cancer is the most commonly occurring cancer in women worldwide and the second most common cancer overall. The development of new therapies to treat this devastating malignancy is needed urgently. Nanoparticles are one class of nanomaterial with multiple applications in medicine, ranging from their use as drug delivery systems and the promotion of changes in cell morphology to the control of gene transcription. Nanoparticles made of the natural polymer chitosan are easy to produce, have a very low immunogenic profile, and diffuse easily into cells. One hallmark feature of cancer, including breast tumours, is the genome instability caused by defects in the spindle-assembly checkpoint (SAC), the molecular signalling mechanism that ensures the timely and high-fidelity transmission of the genetic material to an offspring. In recent years, the use of nanoparticles to treat cancer cells has gained momentum. This is in part because nanoparticles made of different materials can sensitise cancer cells to chemotherapy and radiotherapy. These advances prompted us to study the potential sensitising effect of chitosan-based nanoparticles on breast cancer cells treated with reversine, which is a small molecule inhibitor of Mps1 and Aurora B that induces premature exit from mitosis, aneuploidy, and cell death, before and after exposure of the cancer cells to X-ray irradiation. Our measurements of metabolic activity as an indicator of cell viability, DNA damage by alkaline comet assay, and immunofluorescence using anti-P-H3 as a mitotic biomarker indicate that chitosan nanoparticles elicit cellular responses that affect mitosis and cell viability and can sensitise breast cancer cells to X-ray radiation (2Gy). We also show that such a sensitisation effect is not caused by direct damage to the DNA by the nanoparticles. Taken together, our data indicates that chitosan nanoparticles have potential application for the treatment of breast cancer as adjunct to radiotherapy.


Assuntos
Antineoplásicos/farmacologia , Quitosana/análogos & derivados , Mitose/efeitos dos fármacos , Morfolinas/farmacologia , Nanopartículas/química , Purinas/farmacologia , Antineoplásicos/administração & dosagem , Aurora Quinase B/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Humanos , Células MCF-7 , Mitose/efeitos da radiação , Morfolinas/administração & dosagem , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Purinas/administração & dosagem , Raios X
5.
Biomed Res Int ; 2014: 956456, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24883331

RESUMO

The acute oral and dermal toxicity of two new ethyl-carbamates (ethyl-4-bromophenyl-carbamate and ethyl-4-chlorophenyl-carbamate) with ixodicide activity was determined in rats. The oral LD50 of each carbamate was 300 to 2000 mg/kg, and the dermal LD50 of each carbamate was >5000 mg/kg. Clinically, the surviving rats that had received oral doses of each carbamate showed decreased weight gain (P < 0.05) and had slight nervous system manifestations. These clinical signs were evident from the 300 mg/kg dose and were reversible, whereas the 2000 mg/kg dose caused severe damage and either caused their death or was motive for euthanasia. At necropsy, these rats had dilated stomachs and cecums with diffuse congestion, as well as moderate congestion of the liver. Histologically, the liver showed slight degenerative lesions, binucleated hepatocytes, focal coagulative necrosis, and congestion areas; the severity of the lesions increased with dosage. Furthermore, an slight increase in gamma-glutamyltransferase, lactate dehydrogenase, and creatinine was observed in the plasma. The dermal application of the maximum dose (5000 mg/kg) of each carbamate did not cause clinical manifestations or liver and skin alterations. This finding demonstrates that the carbamates under study have a low oral hazard and low acute dermal toxicity.


Assuntos
Rhipicephalus/efeitos dos fármacos , Pele/efeitos dos fármacos , Uretana/farmacologia , Administração Oral , Animais , Creatinina/sangue , Fígado/efeitos dos fármacos , Masculino , Ratos , Uretana/análogos & derivados , Uretana/toxicidade
6.
Biomed Res Int ; 2014: 467105, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24818142

RESUMO

Female and male Wistar rats were used to determine the subchronic oral toxicities of two new ethyl-carbamates with ixodicidal activities (ethyl-4-bromphenyl-carbamate and ethyl-4-chlorphenyl-carbamate). The evaluated carbamates were administered in the drinking water (12.5, 25 and 50 mg/kg/day) for 90 days. Exposure to the evaluated carbamates did not cause mortality or clinical signs and did not affect food consumption or weight gain. However, exposure to these carbamates produced alterations in water consumption, hematocrit, percentages of reticulocytes, plasma proteins, some biochemical parameters (aspartate aminotransferase, gamma-glutamyl transpeptidase, cholinesterase, and creatinine activities), thiobarbituric acid reactive substances, and the relative weight of the spleen. Histologically, slight pathological alterations were found in the liver that were consistent with the observed biochemical alterations. The nonobserved adverse effect levels (NOAELs) of the evaluated carbamates were 12.5 mg/kg/day for both the female and male rats. The low severity and reversibility of the majority of the observed alterations suggest that the evaluated carbamates have low subchronic toxicity.


Assuntos
Acaricidas/toxicidade , Testes de Toxicidade Crônica , Uretana/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Peso Molecular , Tamanho do Órgão/efeitos dos fármacos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Uretana/química
7.
J Food Sci ; 79(5): T1024-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24689855

RESUMO

UNLABELLED: In vitro cytotoxicity and genotoxicity induction by aflatoxin B1 (AFB1) from maize (ME) and tortillas (TE) produced by microwave nixtamalization were investigated in monkey kidney (Vero cells) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the induction of lipid peroxidation, the oxidative damage by means of glutathione (GSH) depletion, and the Salmonella-microsomal screening system (Ames test). Our results showed that, at higher concentrations, both ME and TE extracts that contained varying amounts of aflatoxin caused a considerable decrease in Vero cell viability (up to 37%) after 4 h of exposure. Aflatoxins from ME induced greater oxidative damage by enhancing lipid peroxidation (up to 6.05 ± 0.14 µmol/mg protein) as compared to TE; however, TE also induced significant malondialdehyde formation in particular at the higher aflatoxin concentration tested (up to 2.7 ± 0.19 µmol/mg protein). The decrease in GSH level was also more pronounced in ME as compared to TE. Moreover, the Ames test results indicated that the mutagenic activity of TE was greatly reduced compared with that of ME based on his(-) → his(+) reversions in the Salmonella TA100 strain. According to these results, it is concluded that the microwave nixtamalization procedure reduced aflatoxins and their in vitro toxicity and mutagenic activity. PRACTICAL APPLICATION: In Mexico, aflatoxins are often found in maize destined for the tortilla industry; consequently, tortilla consumption invariably leads to an important intake of intact and/or modified aflatoxin molecules caused by the thermal-alkaline treatment used during production. Therefore, it is of the highest importance to check whether such intake has the potential to lead to higher risk for adverse human health effects. In view of these considerations, in vitro tests may thus be useful for predicting the potential cytotoxicity and genotoxicity of tortillas produced for human consumption using aflatoxin-contaminated maize.


Assuntos
Aflatoxina B1/efeitos adversos , Pão , Dano ao DNA , Manipulação de Alimentos/métodos , Micro-Ondas , Estresse Oxidativo , Zea mays , Aflatoxina B1/análise , Animais , Sobrevivência Celular , Chlorocebus aethiops , Culinária , Contaminação de Alimentos , Glutationa/metabolismo , Calefação , Temperatura Alta , Humanos , Peroxidação de Lipídeos , Malondialdeído/metabolismo , México , Mutagênicos/análise , Salmonella/efeitos dos fármacos , Salmonella/genética , Células Vero
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