RESUMO
Docetaxel (DTX) is a non-selective antineoplastic agent with low solubility and a series of side effects. The technology of pH-sensitive and anti-epidermal growth factor receptor (anti-EGFR) immunoliposomes aims to increase the selective delivery of the drug in the acidic tumor environment to cells with EFGR overexpression. Thus, the study aimed to develop pH-sensitive liposomes based on DOPE (dioleoylphosphatidylethanolamine) and CHEMS (cholesteryl hemisuccinate), using a Box-Behnken factorial design. Furthermore, we aimed to conjugate the monoclonal antibody cetuximab onto liposomal surface, as well as to thoroughly characterize the nanosystems and evaluate them on prostate cancer cells. The liposomes prepared by hydration of the lipid film and optimized by the Box-Behnken factorial design showed a particle size of 107.2 ± 2.9 nm, a PDI of 0.213 ± 0.005, zeta potential of -21.9 ± 1.8 mV and an encapsulation efficiency of 88.65 ± 20.3%. Together, FTIR, DSC and DRX characterization demonstrated that the drug was properly encapsulated, with reduced drug crystallinity. Drug release was higher in acidic pH. The liposome conjugation with the anti-EGFR antibody cetuximab preserved the physicochemical characteristics and was successful. The liposome containing DTX reached an IC50 at a concentration of 65.74 nM in the PC3 cell line and 28.28 nM in the DU145 cell line. Immunoliposome, in turn, for PC3 cells reached an IC50 of 152.1 nM, and for the DU145 cell line, 12.60 nM, a considerable enhancement of cytotoxicity for the EGFR-positive cell line. Finally, the immunoliposome internalization was faster and greater than that of liposome in the DU145 cell line, with a higher EGFR overexpression. Thus, based on these results, it was possible to obtain a formulation with adequate characteristics of nanometric size, a high encapsulation of DTX and liposomes and particularly immunoliposomes containing DTX, which caused, as expected, a reduction in the viability of prostate cells, with high cellular internalization in EGFR overexpressing cells.
RESUMO
Introduction: While soy is suggested as a possible risk factor, exclusive breastfeeding (EBF) has a likely protective effect in precocious puberty. Our aim was to evaluate the association between both of these variables with central precocious puberty (CPP). Methods: We performed a retrospective, case-control study. A total of 161 girls were divided into two groups: 84 patients diagnosed with CPP composed the case group and 77 patients without the diagnosis of CPP (had gone through normal onset of puberty) were the control group. Results: Our control group had a higher presence of EBF >6 months, which was an important protective factor for CPP (OR: 0.5; IC 95%: 0.3-0.9, p = 0.05) and also correlated negatively with the presence of it (r = -0.2; p < 0.05). Oppositely, the use of soy was significantly higher in the CPP group, (OR: 3.8; IC 95%: 1.5-6, p < 0.05) and positively correlating (r = 0.2; p < 0.01) with the presence of CPP. Duration of soy intake (years) correlated with bone age (r = 0.415; p < 0.05). A logistic regression was performed to evaluate the effects of EBF duration and soy on CPP. The model was significant (x² (2) = 20,715, p = <0.001) and explained 12.2% (Nagelkerke R2) of the variance, correctly classifying 62.5% of cases. EBF was associated with a reduction of likelihood of having CPP [OR = 0,187 (CI = 0.055-0,635); Wald = 7,222, p = 0.007], while soy intake increased the risk [OR = 3.505 (CI) = 1,688-7,279, Wald = 11,319, p = 0.001]. Conclusion: Our data found the use of soy was associated with CPP. Additionally, EBF was pointed as a protective factor. However, future prospective studies are needed to clarify this issue.
Assuntos
Aleitamento Materno/métodos , Glycine max/efeitos adversos , Fatores de Proteção , Puberdade Precoce/prevenção & controle , Estudos de Casos e Controles , Criança , Feminino , Seguimentos , Humanos , Prognóstico , Puberdade Precoce/induzido quimicamente , Puberdade Precoce/patologia , Estudos RetrospectivosRESUMO
Leishmaniasis is a group of infectious neglected tropical diseases caused by more than 20 pathogenic species of Leishmania sp. Due to the limitations of the current treatments available, chalcone moiety has been drawn with a lot of attention due to the simple chemistry and synthesis, being reported with antileishmanial activity in particular against amastigote form. This review aims to provide an overview towards antileishmanial activity of chalcones derivatives against amastigote form for Leishmania major, L. amazonensis, L. panamensis, L. donovani and L. infantum as well as their structure-activity relationship (SAR), molecular targets and in silico ADMET evaluation. In this way, it is expected that this review may support the research and development of new promising chalcones candidates a leishmanicidal drugs.
Assuntos
Antiprotozoários/farmacologia , Chalcona/farmacologia , Leishmania/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
FES-assisted cycling has been recommended to people struggling to emerge from a disability to more functioning life after spinal cord injury. Recommendations issued by a gowing number of scientific papershas promised toimprove body composition and physical activity levels, as well as to controlinvoluntary muscle response; favoring activity and participation which break new grounds in expanding locomotion, leisure and occupational options for people with paraplegia and tetraplegia. In this report we described our experience to select and prepare a pilot to compete in the FES Bike Race modality at Cybathlon 2016 in Kloten (Zurick). He was a man, 38 years old, with a complete spinal cord injury, level T9, three years of injury. He took part in a two preparation phases lasting respectively 18 and 12 weeks each: (1st) pre-FES-cycling and a (2nd) FES-cycling. The 1st phase aimed to explore electrical stimulation response in the quadricps, hamstrings and gluteus muscles; searching for a standard muscular recruitment enable to propel the pedals of a trike. Following, in the 2nd phase, stationary to mobile FES-cycling was performed at the same time the development of the automation and control systems were being incorporated in the trike. We adapted a commercial tadpole trycicle anda pilot controlled system. Although we had planned a three session by week protocol, for reasons of term and time to finish the trike development and be prepared to compete, in the last two weeks before the Cybatlhon an intense level of exercise was maintained. After the race, we noticedinflammatory signs on the left knee which later revealed a patella fracture. The video footage analysis confirmed ithappened during the race's first lap.
RESUMO
Metabolomics is one of the most recent trends in the "omics" era that investigates the end products of an organism activity, that is, all metabolites in a biological system, which are small molecules (less than 1000 Da) from different chemical classes. Metabolomics represents a tool to assess the biochemical activity of a living system through the analysis of substrates and products processed during the metabolism. The analysis of the metabolic profile (nontargeted analysis, i.e. a comparison between samples profiles of individuals) and of specific metabolites (targeted analysis, which quantifies a selected group of metabolites) in biological samples provides an insight into the metabolic state and the biochemical processes of the organism and, therefore, may indicate the onset and the stage of different diseases. An early and accurate diagnosis is essential for successful treatment and probable cure of most illnesses; hence, the investigation of metabolites as disease biomarkers has increased considerably in recent years. This review aims to present the most relevant works that address the nontargeted and targeted analysis of metabolites in different diseases for the past 10 years, including kidney and neurological disorders, cardiovascular diseases, diabetes, and cancer, using CE and LC coupled with the accurate detection of mass spectroscopy.
Assuntos
Biomarcadores/análise , Cromatografia Líquida/métodos , Eletroforese Capilar/métodos , Espectrometria de Massas/métodos , Metabolômica , Diabetes Mellitus/metabolismo , Humanos , Neoplasias/metabolismo , Doenças do Sistema Nervoso/metabolismoRESUMO
Renal failure is common in patients with glomerular disease. Although renal failure may result from the glomerular lesion itself, it is also observed in patients with minimal glomerular alterations. Degenerative changes and necrosis of the tubular epithelium are common findings in kidney biopsies from these patients. The aim of this work is to examine the association between acute tubular necrosis (ATN) and renal failure in patients with glomerulopathy and to estimate the relationship between the degree of ATN and renal failure in these patients. Data on age, sex, presence of nephrotic syndrome, and renal failure were recorded for 149 patients, who underwent a renal biopsy for the diagnosis of glomerulopathy. The biopsies were reviewed, and ATN, when present, was classified as one of four grades depending on its intensity. The mean age of the patients was 21 ± 16 years. Eighty patients (54%) were male, 43 (42%) had renal failure, 104 (72%) had nephrotic syndrome, and 66 (45%) had minimal change disease or focal segmental glomerulosclerosis. ATN was present in 115 (77%) patients. The frequency of renal failure was directly correlated with the intensity of ATN [odds ratio (OR) of 26.0 for patients with grade 2 lesions and OR of 45.5 for patients with grade 3 lesions]. ATN is a common finding in the biopsies of patients with glomerulopathy. The severity of ATN is directly associated with the frequency of renal failure in these patients.
Assuntos
Glomerulonefrite/complicações , Glomerulosclerose Segmentar e Focal/complicações , Necrose Tubular Aguda/complicações , Insuficiência Renal/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Necrose Tubular Aguda/epidemiologia , Necrose Tubular Aguda/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/epidemiologia , Adulto JovemRESUMO
Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer's disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2= 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.
Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase/química , Holografia , Fenol/química , Relação Quantitativa Estrutura-Atividade , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Humanos , Modelos Moleculares , Fenol/farmacologiaRESUMO
In this study, the cytotoxicity of pouterin in tumorigenic and non-tumorigenic mammalian cell lines was investigated. We found that HeLa, Hep-2 and HT-29 tumor cells were highly sensitive to pouterin cytotoxicity in a dose-dependent manner, whereas non-tumorigenic Vero cells and human lymphocytes were relatively resistant to the protein. Among the tumor cell lines, HeLa cells showed the highest susceptibility to pouterin cytotoxicity, exhibiting a time-dependent increase in LDH leakage and an IC(50) value of 5mug/mL. Morphological alterations such as rounding, cell shrinkage and chromatin condensation, consistent with apoptotic cell death were observed. Apoptosis induction was demonstrated by DNA fragmentation as detected by terminal dUTP nick-end labeling (TUNEL). Furthermore, HeLa cells incubated with pouterin showed disruption of the actin cytoskeleton. Western blot analysis revealed that pouterin caused increased expression of p21, thus indicating cell cycle arrest. Subsequent studies provided evidence that apoptosis may be partially explained in the activation of the tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, a time-dependent decrease of the expression of p65 nuclear factor kappa B (NFkappaB) subunit, concomitant with a downregulation of the inhibitor of apoptosis protein 1 (IAP1) was observed, suggesting that TNFR-mediated apoptosis is the predominant pathway induced by pouterin in HeLa cells.