RESUMO
AIMS/HYPOTHESIS: TNF-related apoptosis-inducing ligand (TRAIL) is implicated in the regulation of diabetes and is reduced in patients with cardiovascular disease. Although TRAIL receptors are widespread, and TRAIL can promote cell proliferation and apoptosis, it is not known how TRAIL might protect against diabetes and atherosclerosis. METHODS: We examined the development of atherosclerosis and diabetes in Apoe (-/-), Trail (also known as Tnfsf10)( -/- ) Apoe ( -/- ) and Trail ( -/- ) mice that were fed a high-fat diet. Plasma cholesterol, triacylglycerol, glucose and insulin, as well as changes in various metabolic enzymes and regulators were assessed. Glucose and insulin tolerance tests were performed. Pancreatic islets were examined for insulin and beta cell dysfunction (apoptosis and macrophage infiltration). RESULTS: Compared with Apoe ( -/- ) mice, Trail ( -/- ) Apoe ( -/- ) and Trail ( -/- ) mice exhibited several features of diabetes, including increased weight, hyperglycaemia, reduced plasma insulin, impaired glucose tolerance, beta cell dysfunction, reduced islet insulin, macrophage infiltration and increased apoptosis. Trail ( -/- ) Apoe ( -/- ) mice had increased plasma cholesterol, triacylglycerol, and VLDL- and LDL-cholesterol, and increased expression of genes involved in cholesterol synthesis and lipogenesis. Trail ( -/- ) Apoe ( -/- ) mice also had increased atherosclerosis, with several features of plaque instability. CONCLUSIONS/INTERPRETATION: We show for the first time that TRAIL deficiency promotes numerous features of diabetes that are typical of human disease, and are associated with reduced insulin and pancreatic inflammation/apoptosis. TRAIL also regulates cholesterol and triacylglycerol homeostasis in Apoe ( -/- ) mice by increasing the expression of genes involved in (1) cholesterol synthesis and absorption, and (2) triacylglycerol production.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Diabetes Mellitus/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Apoptose , Aterosclerose/metabolismo , Aterosclerose/patologia , Glicemia/análise , Colesterol/biossíntese , Colesterol/sangue , Colesterol/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/metabolismo , Insulina/administração & dosagem , Insulina/sangue , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Lipogênese/genética , Macrófagos/metabolismo , Masculino , Camundongos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Triglicerídeos/biossíntese , Triglicerídeos/sangue , Triglicerídeos/genéticaRESUMO
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.