RESUMO
The Spike glycoprotein of SARS-CoV-2, the virus responsible for coronavirus disease 2019, binds to its ACE2 receptor for internalization in the host cells. Elderly individuals or those with subjacent disorders, such as obesity and diabetes, are more susceptible to COVID-19 severity. Additionally, several SARS-CoV-2 variants appear to enhance the Spike-ACE2 interaction, which increases transmissibility and death. Considering that the fruit fly is a robust animal model in metabolic research and has two ACE2 orthologs, Ance and Acer, in this work, we studied the effects of two hypercaloric diets (HFD and HSD) and aging on ACE2 orthologs mRNA expression levels in Drosophila melanogaster. To complement our work, we analyzed the predicted binding affinity between the Spike protein with Ance and Acer. We show for the first time that Ance and Acer genes are differentially regulated and dependent on diet and age in adult flies. At the molecular level, Ance and Acer proteins exhibit the potential to bind to the Spike protein in different regions, as shown by a molecular docking approach. Acer, in particular, interacts with the Spike protein in the same region as in humans. Overall, we suggest that the D. melanogaster is a promising animal model for translational studies on COVID-19 associated risk factors and ACE2.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Diabetes Mellitus , Drosophila melanogaster , Obesidade , Envelhecimento/genética , Enzima de Conversão de Angiotensina 2/genética , Animais , COVID-19/genética , Diabetes Mellitus/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Metaloendopeptidases/metabolismo , Simulação de Acoplamento Molecular , Obesidade/genética , RNA Mensageiro , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
This study was designed to develop a rodent model of hydrochlorothiazide (HCTZ) toxicity by associating its intake with a high-fat (HF) diet. Rats were fed for 16 weeks with a control diet or with an HF diet supplemented or not with different doses of HCTZ. HCTZ, in a similar way to the HF diet, caused a significant increase in fructosamine levels. HCTZ and HF diet intake caused a significant reduction in magnesium and potassium levels, as well as an increase in lipid peroxidation and vitamin C in liver. Importantly, negative correlations were found between magnesium and glucose levels as well as between magnesium and fructosamine levels. The association between HCTZ and the HF diet caused additional worsening of biochemical parameters related to glucose homeostasis, and further increased hepatic oxidative stress. Our results suggest that chronic intake of HCTZ or an HF diet causes metabolic changes that are consistent with the development of insulin resistance. In addition, the association of an HF diet and HCTZ treatment can exacerbate some of these biochemical alterations, suggesting that this model might be useful for studying HCTZ metabolic toxicity.
Assuntos
Dieta Hiperlipídica , Hidroclorotiazida/farmacologia , Fígado/patologia , Magnésio/sangue , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/metabolismo , Peso Corporal/efeitos dos fármacos , Frutosamina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Potássio/sangue , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Cognitive deficits have been observed in different animal models of adult-onset hypothyroidism. Thus, this study was delineated to evaluate whether diphenyl diselenide, an organoselenium compound with neuroprotective and antioxidant properties, could afford protection against the detrimental effects of hypothyroidism on behavioral parameters. Hypothyroidism condition was induced in female rats by continuous exposure to methimazole (MTZ) at 20 mg/100 ml in the drinking water, during 3 months. MTZ-induced hypothyroid rats were fed with either standard or a diet containing 5 ppm of diphenyl diselenide for 3 months. Behavioral assessments were performed monthly, in the following order: elevated plus maze, open field and Morris water maze. The levels of thyroid hormones in the animals exposed to MTZ were lower than control until the end of experimental period. The rats exposed to MTZ had a significant weight loss from the first month, which was not modified by diphenyl diselenide supplementation. In elevated plus maze test, MTZ exposure caused a reduction on the number of entries of animals in closed arms, which was avoided by diphenyl diselenide supplementation. In Morris water maze, the parameters latency to reach the platform and distance performed to find the escape platform in the test session were significantly greater in MTZ group when compared to control. These cognitive deficits observed in MTZ-induced hypothyroid rats were restored by dietary diphenyl diselenide. The group fed with diphenyl diselenide alone exhibited a better spatial learning and memory capability in some parameters of Morris water maze when compared to the control group. In summary, our data provide evidence of the effectiveness of dietary diphenyl diselenide in improving the performance of control and hypothyroid rats in the water maze test.
Assuntos
Derivados de Benzeno/administração & dosagem , Hipotireoidismo/fisiopatologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Compostos Organosselênicos/administração & dosagem , Hormônios Tireóideos/deficiência , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Alimentos Formulados , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/complicações , Transtornos da Memória/etiologia , Ratos , Ratos WistarRESUMO
This study evaluated the effect of possible synergic interaction between high fat diet (HF) and hydrochlorothiazide (HCTZ) on biochemical parameters of oxidative stress in brain. Rats were fed for 16 weeks with a control diet or with an HF, both supplemented with different doses of HCTZ (0.4, 1.0, and 4.0 g kg(-1) of diet). HF associated with HCTZ caused a significant increase in lipid peroxidation and blood glucose levels. In addition, HF ingestion was associated with an increase in cerebral lipid peroxidation, vitamin C and non-protein thiol groups (NPSH) levels. There was an increase in vitamin C as well as NPSH levels in HCTZ (1.0 and 4.0 g kg(-1) of diet) and HF plus HCTZ groups. Na(+)-K(+)-ATPase activity of HCTZ (4.0 g kg(-1) of diet) and HCTZ plus HF-fed animals was significantly inhibited. Our data indicate that chronic intake of a high dose of HCTZ (4 g kg(-1) of diet) or HF change biochemical indexes of oxidative stress in rat brain. Furthermore, high-fat diets consumption and HCTZ treatment have interactive effects on brain, showing that a long-term intake of high-fat diets can aggravate the toxicity of HCTZ.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Hidroclorotiazida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/metabolismo , Glicemia/metabolismo , Encéfalo/enzimologia , Encéfalo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
This study was designed to evaluate the effect of diphenyl diselenide in a classical model of alloxan-induced diabetes in rats. Oxidative stress is involved in alloxan toxic effects and we have hypothesized that diphenyl diselenide via its antioxidant properties could confer protection against alloxan pancreatic toxicity. Diabetes was induced by administration of alloxan (150 mg/kg, intravenously). Diphenyl diselenide (10 mg/kg, subcutaneously) was administered for 6 d before (prevention group) or for 6 d after (remediation group) diabetes induction. Diphenyl diselenide treatment reduced the blood glucose and fructosamine levels, which were increased in alloxan-treated rats. However, the delta-aminolevulinate dehydratase (delta-ALA-D) activity inhibited by alloxan was not restored by diphenyl diselenide. Moreover, diphenyl diselenide caused by itself an inhibition in hepatic and renal delta-ALA-D activity. Our findings suggest that the acute treatment with diphenyl diselenide reduces the hyperglycemia but does not improve delta-ALA-D activity decreased by alloxan. Although the dose of diphenyl diselenide used here for treating diabetic animals has been relatively high and produced toxic effects, the compound or analogous molecules might not be rejected as a promising anti-hyperglycemic agent.