RESUMO
A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/farmacologia , Glioblastoma/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Astrócitos , Neoplasias Encefálicas/patologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/patologia , Humanos , Masculino , Cultura Primária de Células , Pró-Fármacos/uso terapêutico , Ratos , Solubilidade , Técnicas EstereotáxicasRESUMO
The effect of an individualized exercise programme on a non-alcoholic steatohepatitis case is presented. Before entering the programme the patient was treated with conventional recommendations on diet plus aerobic exercise during fourteen years, without major improvements of his analytical parameters.Two years after including him in a tailored exercise programme, aimed to fulfil the recommendations of the American College of Sports Medicine, his blood markers of liver dysfunction and cardiometabolic risk tended to improve. Consequently, our data support the idea that in non-alcoholic steatohepatitis the exercise-based therapeutic interventions should be individualized taking into account the cardio-respiratory and muscular fitness of the patient, rather than using generic behavioural recommendations.
Assuntos
Terapia por Exercício/métodos , Hepatopatia Gordurosa não Alcoólica/terapia , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Medicina de Precisão , Resultado do TratamentoRESUMO
The synthesis and characterization of two new water soluble 2,6-bis(imidazolylmethyl)-4-methylphenoxy-containing perylenediimides, PDI-1 and PDI-2, are described. These compounds demonstrate a high fluorescence quantum yield in water and were investigated as potential photosensitizers for generating reactive oxygen species with applications in anticancer activities. The HeLa cell line (VPH18) was used to evaluate their efficacy. Fluorescence microscopy was employed to confirm the successful internalization of PDI-1 and PDI-2, while confocal microscopy revealed the specific locations of both PDIs within the lysosomes and mitochondria. In vitro studies were conducted to evaluate the anticancer activity of PDI-1 and PDI-2. Remarkably, these photosensitizers demonstrated a significant ability to selectively eliminate cancer cells when exposed to a specific light wavelength. The water solubility, high fluorescence quantum yield, and selective cytotoxicity of these PDIs toward cancer cells highlight their potential as effective agents for targeted photodynamic therapy. In conclusion, the findings presented here provide a strong foundation for the future exploration and optimization of PDI-1 and PDI-2 as effective photosensitizers in photodynamic therapy, potentially leading to improved treatment strategies for cancer patients.
RESUMO
Cationic polypeptides and cationic polymers have cell-penetrating capacities and have been used in gene transfer studies. In this study, we investigate the capability of a polymer of d-lysine (PDL), a chiral form of α-Poly-lysine, as a possible nonviral vector for releasing genetic materials to neuroblastoma cells and evaluate its stability against proteases. We tested and compared its transfection effectiveness in vitro as a vehicle for the EGFP plasmid DNA (pDNA) reporter in the SH-SY5Y human neuroblastoma, HeLa, and 3T3 cell lines. Using fluorescent microscopy and flow cytometry, we demonstrated high transfection efficiencies based on EGFP fluorescence in SH-SY5Y cells, compared with HeLa and 3T3. Our results reveal PDL as an efficient vector for gene delivery specifically in the SH-SY5Y cell line and suggest that PDL can be used as a synthetic cell-penetrating polypeptide for gene therapy in neuroblastoma cells.
RESUMO
Exercise intensity usually correlates with increased oxidative stress and enhanced cytokine production. However, it is unknown if all types of exercise that induce muscle damage can cause a parallel response in the oxidation balance and cytokine production. To this end, the effect of a 2000-m running test in a group of volunteers that regularly train in aerobic routines was studied. Different circulating parameters were measured, oxidative stress markers (protein carbonyls and malondialdehyde), antioxidant enzyme activity, and cytokine levels in plasma as well as in the main circulating cells of blood samples obtained in basal conditions and after test execution. As a result, the test caused muscle damage evidenced by an increase in circulating creatine kinase and myoglobin. This was accompanied by an increase in protein carbonyls in plasma and peripheral blood mononuclear cells. Activities of antioxidant enzymes (catalase, glutathione peroxidase and reductase, superoxide dismutase) were elevated in peripheral blood mononuclear cells, neutrophils, and erythrocytes after the test. Regarding cytokine production, interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α exhibited no significant changes after the test. Results suggest that this short but intense running exercise (2000 m) can induce muscle damage and elicit a good balance between oxidant/antioxidant responses with no changes in the circulating concentration of pro-inflammatory cytokines.