RESUMO
Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure-activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (-11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment.
Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase , Anti-Inflamatórios não Esteroides , Neoplasias da Mama , Desenho de Fármacos , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Células MCF-7 , Desenho Assistido por Computador , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Quantitativa Estrutura-Atividade , Simulação de Acoplamento Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Celecoxib/farmacologia , Celecoxib/química , Proliferação de Células/efeitos dos fármacosRESUMO
The modulation of TRPV1 emerges as a promising strategy for dental pain management. This study aimed to assess TRPV1 modulation in a human odontoblast-like cell model using Capsazepine (CZP) loaded in a nanogel delivery system. Gelatin nanogels, synthesized via the emulsification-gelation technique, were characterized and loaded with the TRPV1 antagonist, CZP. HPLC determined a remarkable 67.5 ± 0.04% CZP loading efficiency, with 71.7% of nanogels falling within the 300-950 nm size range, as evidenced by light microscopy. Moreover, CZP-loaded nanogels had a low cytotoxicity. An FTIR analysis showed no adverse chemical interactions, ensuring stability and active release. When examining biological responses, TRPV1 expression and channel activity were assessed in odontoblast-like cells. On the fifth day post-treatment, cells treated with CZP-loaded nanogels exhibited an increased TRPV1 expression and a reduction in calcium fluxes after agonist stimulus (F/F0 ratio 1.18 ± 0.18), resembling the response in free CZP-treated cells (1.28 ± 0.15). A two-way analysis of variance and the Tukey's test were used to determine statistical significance (p < 0.05). This delivery system, proven to be economical and straightforward, holds promise for dental pain management and potential local use. Local administration minimizes systemic adverse effects, making it a practical solution for releasing molecules in the oral cavity.
RESUMO
This study aimed to estimate the heterosis for productive traits in a two-way crossbreeding scheme. Four guinea pig lines were originally selected for the following traits: line P1 for the growth rate, P2 for the partial feed conversion rate, M1 for the growth rate of the litter at 10 days of age, and M2 for the litter size at birth. The comparison included 176 purebreds (P1: 46, P2: 43, M1: 54 and M2: 33) and 150 crosses (P1P2: 42, P2P1: 38, M1M2: 11 and M2M1: 59); body weights at birth, 10 days, weaning and 60 days of age were analyzed. A linear fixed-effect model was used, and heterosis was estimated as the difference between the average performance of the crossbred and pure-line animals. The pure line comparisons showed that P2 was lower than P1 for weight at 10 days and weaning weight, while all other comparisons between the paternal and maternal pure lines were not significant. The results indicated significant positive heterosis effects for both types of crosses, but only for birth weight: 3.7% for paternal crosses and 12.7% for maternal crosses. The heterosis estimates were mostly positive but not significant for all other traits. A reason for the low levels of heterosis could be that the lines are not very genetically differentiated. These results suggest that applying a two-way crossbreeding scheme within paternal and maternal guinea pig lines for meat production is not recommended due to the absence of heterosis for growth traits.
RESUMO
Research on collagen type I scaffolds with Aloe vera is sparse. The aim of this work was to develop collagen type I scaffolds with gelatin-collagen microparticles and loaded with a dispersion of A. vera, to assess their performance as grafting material for healing of skin wounds. Scaffolds were evaluated in a Cavia porcellus model with full-thickness skin wound and compared with wounds healed by secondary intention (controls). Animals grafted with scaffolds without A. vera and their control wounds were also included in the study. Evaluation of enzymatic degradation and percentage of the scaffolds' free amino groups-as an indirect assessment of their cross-linking-were also carried out because A. vera contains compounds which affect their stability. We found that dispersions of lyophilized A. vera extract loaded on scaffolds do not have cytotoxic potential, and they decrease collagenase degradation of scaffolds in the range of 0.1 to 0.3% w/v in a dose-dependent manner. Only the A. vera dispersion with the highest concentration (0.3% w/v) decreased the percentage of free amino groups, which are the ones involved in the cross-link of collagen fibers. This finding suggests that cross-linking is not the mechanism by which the tested dispersions stabilize the scaffolds. Preclinical, histochemical, and histomorphometric analyses of repaired wound tissue indicate that loading collagen type I scaffolds, including microparticles of gelatin-collagen, with A. vera in the concentrations tested does not improve wound healing. Low biodegradability of the tested scaffolds caused by the inhibition of collagenase activity might account for these results.
Assuntos
Aloe/química , Colágeno Tipo I/química , Gelatina/administração & dosagem , Extratos Vegetais/administração & dosagem , Pele/lesões , Cicatrização/efeitos dos fármacos , Animais , Bovinos , Colagenases/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Liofilização , Gelatina/química , Cobaias , Masculino , Extratos Vegetais/química , Proteólise , Pele/efeitos dos fármacos , Resultado do TratamentoRESUMO
Aiming to develop biological skin dresses with improved performance in the treatment of skin wounds, acellular collagen I scaffolds were modified with polymeric microparticles and the subsequent loading of a hydroglycolic extract of Calendula officinalis flowers. Microparticles made of gelatin-collagen were produced by a water-in-oil emulsion/cross-linking method. Thereafter, these microparticles were mixed with collagen suspensions at three increasing concentrations and the resulting mixtures lyophilized to make microparticle-loaded porous collagen scaffolds. Resistance to enzymatic degradation, ability to associate with the C. officinalis extract, and the extract release profile of the three gelatin-collagen microparticle-scaffold prototypes were assessed in vitro and compared to collagen scaffolds without microparticles used as control. Data indicated that the incorporation of gelatin-collagen microparticles increased the resistance of the scaffolds to in vitro enzymatic degradation, as well as their association with the C. officinalis flower extract. In addition, a sharp decrease in cytotoxicity, as well as more prolonged release of the extract, was attained. Overall results support the potential of these systems to develop innovative dermal substitutes with improved features. Furthermore, the gelatin-collagen mixture represents a low-cost and scalable alternative with high clinical transferability, especially appealing in developing countries.
Assuntos
Anti-Inflamatórios não Esteroides/química , Antioxidantes/química , Calendula/química , Fármacos Dermatológicos/química , Portadores de Fármacos/química , Flores/química , Extratos Vegetais/química , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Composição de Medicamentos , Estabilidade de Medicamentos , Liofilização , Gelatina/química , Camundongos , Microesferas , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Pele/efeitos dos fármacos , Pele/lesões , Solubilidade , Cicatrização/efeitos dos fármacosRESUMO
The identification and characterization of hypothetical membrane proteins from Mycobacterium tuberculosis have led to a better understanding of the mechanisms used by this pathogen to invade and survive inside host cells. This study assessed the presence, transcription, localization and possible biological activity of the conserved hypothetical protein Rv0180c from M. tuberculosis. Bioinformatics analyses indicated that Rv0180c contains a signal peptide, six possible transmembrane helices and a Plasmodium Export Element (PEXEL)-like motif. PCR analyses showed the presence of the Rv0180c gene in strains from the M. tuberculosis complex; but transcription was not detected in Mycobacterium microti. Sera against synthetic peptides of Rv0180c recognized two protein bands in M. tuberculosis H37Rv sonicate: a â¼48-kDa band close to the predicted molecular mass of Rv0180c (47.6 kDa), and a 63-kDa band probably caused by protein modifications. Moreover, the same sera located the protein on the surface of M. tuberculosis H37Rv bacilli by immunoelectron microscopy. Twenty-three synthetic peptides spanning the entire length of Rv0180c were tested for their ability to bind to U937 and A549 cells, finding nine high-activity binding peptides (HABPs) specific for both cell types, two HABPs specific for A549 cells (namely 31032 and 31044) and two HABPs specific for U937 cells (namely 31025 and 31041). HABPs inhibited invasion of M. tuberculosis H37Rv into A549 or U937 cells by significant percentages and facilitated internalization of latex beads in A549 cells. The Rv0180c HABPs herein reported could be preliminary candidates to be assessed as components of a multiepitope, chemically synthesized, subunit-based vaccine against tuberculosis.