RESUMO
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.
Assuntos
Aterosclerose , Pró-Proteína Convertase 9 , Camundongos , Animais , Pró-Proteína Convertase 9/metabolismo , LDL-Colesterol/metabolismo , LDL-Colesterol/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Receptores de LDL/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , AutofagiaRESUMO
Nitric oxide (NO) is an essential cellular messenger molecule involved in various physiological and pathological processes. Thus, monitoring the dynamic presence of endogenous NO in living cells is of great significance. In this paper, we developed an activatable fluorescent nanoprobe BOD-NH-NP for endogenous NO detection. In the probe BOD-NH-NP, the fast responding reaction site towards NO, incorporating a BODIPY fluorescent dye with good optical features, enables the probe to be applied for the detection of endogenous NO via the eNOS enzymatic pathway in living cells and screening nitric oxide synthases (NOSs) inhibitors and agonists.
Assuntos
Corantes Fluorescentes/química , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/análise , Animais , Linhagem Celular , Estrutura Molecular , Óxido Nítrico/metabolismo , Imagem Óptica , RatosRESUMO
Hydrogen Sulfide (H2S) mediates biological effects in a variety of ways. Due to its strong reducing potential, H2S has been recognized to have an important role in oxidative stress induced hypoxia. It has been reported that H2S production and miRNA can mutually regulate each other. H2S is produced by the catalytic activity of cystathionine-ß-synthase (CBS), which is under the regulation of miRNAs. In this study, we used target gene prediction software, and identified miR-203 as a potential regulator of CBS. We verified this finding using an oxygen and glucose deprivation (OGD) hypoxia cell model in SH-SY5Y cells and pMIR-REPORT™ luciferase miRNA expression reporter vector. Furthermore, transfecting SH-SY5Y cells with miRNA agomir (agonist) and antagomir (antagonist) by lipofectamin RNAiMAX, we further validated miR-203 as a direct regulator of CBS. We also found that miR-203 protects from cell injury by regulating lipid peroxidation, cell apoptosis, and mitochondrial membrane potential. These findings suggest that while over-expression of miR-203 can aggravate OGD induced cell injury, inhibition of miR-203 can protect against OGD induced cell injury. Based on our data and that of others, we propose that miR-203 may regulate oxidative stress induced cell injury by regulating CBS expression and adjusting the levels of H2S production.