RESUMEN
Previous studies have shown that curcumin (Cur) induced by ultrasound has protective effects on atherosclerosis even if low bioavailability of the Cur. The enhancement of bioavailability of the Cur further improved the curative effect of sonodynamic therapy (SDT) on atherosclerosis through nanotechnology. Nanosuspensions as a good drug delivery system had obvious advantages in increasing the solubility and improving the effectiveness of insoluble drugs. The aim of this study was to develop curcumin nanosuspensions (Cur-ns) which used polyvinylpyrrolidone (PVPK30) and sodium dodecyl sulfate (SDS) as stabilizers to improve poor water solubility and bioavailability of the Cur. And then the therapeutic effects of Cur-ns-SDT on atherosclerotic plaques and its possible mechanisms would be investigated and elucidated. Cur-ns with a small particle size has been successfully prepared and the data have confirmed that Cur-ns could be more easily engulfed into RAW264.7 cells than free Cur and accumulated more under the stimulation of the ultrasound. Reactive oxygen species (ROS) inside RAW264.7 cells after SDT led to the decrease of mitochondrial membrane potential (MMP) and the higher expression of cleaved caspase-9/3. The results of in vivo experiments showed that Cur-ns-SDT reduced the level of total cholesterol (TC) and low density lipoprotein (LDL) and promoted the transformation from M1 to M2 macrophages, relieved atherosclerosis syndrome. Therefore, Cur-ns-SDT was a potential treatment of anti-atherosclerosis by enhancing macrophages apoptosis through mitochondrial pathway and inhibiting the progression of plaques by interfering with macrophages polarization.
Asunto(s)
Aterosclerosis/terapia , Curcumina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanomedicina Teranóstica/métodos , Terapia por Ultrasonido/métodos , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Aterosclerosis/sangre , Disponibilidad Biológica , Colesterol/sangre , Terapia Combinada/métodos , Curcumina/farmacocinética , Modelos Animales de Enfermedad , Humanos , Lipoproteínas LDL/sangre , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de la radiación , Ratones , Ratones Noqueados para ApoE , Nanopartículas/química , Tamaño de la Partícula , Vehículos Farmacéuticos/química , Povidona/química , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/efectos de la radiación , Dodecil Sulfato de Sodio/químicaRESUMEN
Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.