RESUMO
Considering the context of functional data analysis, we developed and applied a new Bayesian approach via the Gibbs sampler to select basis functions for a finite representation of functional data. The proposed methodology uses Bernoulli latent variables to assign zero to some of the basis function coefficients with a positive probability. This procedure allows for an adaptive basis selection since it can determine the number of bases and which ones should be selected to represent functional data. Moreover, the proposed procedure measures the uncertainty of the selection process and can be applied to multiple curves simultaneously. The methodology developed can deal with observed curves that may differ due to experimental error and random individual differences between subjects, which one can observe in a real dataset application involving daily numbers of COVID-19 cases in Brazil. Simulation studies show the main properties of the proposed method, such as its accuracy in estimating the coefficients and the strength of the procedure to find the true set of basis functions. Despite having been developed in the context of functional data analysis, we also compared the proposed model via simulation with the well-established LASSO and Bayesian LASSO, which are methods developed for non-functional data.
RESUMO
For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.
Assuntos
Lipossomos , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.
Assuntos
Ácidos Araquidônicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Diabetes Mellitus Experimental/psicologia , Endocanabinoides/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Indóis/farmacologia , Masculino , Norepinefrina/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/biossíntese , Serotonina/metabolismo , Natação/psicologiaRESUMO
Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.