الفهرس 
List of abbreviationsOnly 14 pages are availabe for public view
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Abstract
The main goal of the present study is to develop a new stable/safe and biocompatible nanoformulations of naturally derived compounds [Silymarin (SM) and Curcumin (CUR)] with optimum enhanced oral bioavailability and to evaluate their effect as well as their mechanism of action as superior antidiabetic agent over native candidate using streptozotocin (STZ)-induced diabetic rats. The newly developed plain, SM-loaded and CUR-loaded biodegradable pluronic nanomicelles were successfully prepared using nanoprecipitation technique through a modified procedure. The plain, SM-loaded and CUR-loaded nanomicelles were fully characterized and found to exhibit a smooth and spherical shape with a diameter of about 208 ± 7, 247 ± 11 and 333 ± 6 nm, respectively, and with high entrapment efficiency of loaded SM and CUR up to 87.3 ± 3 and 89.6 ± 1, respectively. The zeta potential of the developed plain, SM-loaded, and CUR-loaded pluronic nanomicelles were found negative with the values of -17, -14.5 and -26.1, respectively. Our approach in using oral nanoformulations of SM and CUR (SMnp and CURnp) improved significantly their antihyperglycemic, antioxidant and antihyperlipidemic properties as compared to their native candidates. Besides, SMnp and CURnp were considered more superior and efficacious agents over their native variant in management of diabetes and its possible complications due to their superior bioavailability in-vivo, and the controlled release profile of the loaded SM or CUR. This in consequence led to the achievement of optimal control of blood glucose level and normalization of Oral Glucose Tolerance Curve in STZ-diabetic rats at low dose in case of SMnp while, CURnp led to improvement in fasting blood glucose level. According to our study, modes of SMnp actions as antidiabetic agent were found to be mainly due to a significant upregulation of both Pdx-1 and NKx6.1 genes expression as well as achievement of optimum redox balance which was represented by decreased oxidative stress (pancreatic MDA) and the increased pancreatic antioxidants capacity ( pancreatic SOD and GSH). This in turn led to alleviation of STZ-induced β-cell damage through β-cell regeneration. All of these factors led to a significant upregulation in insulin gene expression proved by RTPCR studies, which was reflected in recovery of insulin secretion quantitatively (ELISA) as well as histopathologically through confocal microscope studies on pancreatic tissue for the first time. The antidiabetic action of CURnp may be mainly attributed to a significant upregulation of both Pdx-1 and NKx6.1 genes expression as important transcription factors in insulin gene expression as well as achievement of optimum redox balance which was represented by the decreased lipid peroxidation intermediate (pancreatic MDA) and increased pancreatic antioxidants capacity (pancreatic SOD). This in turn led to alleviation of STZ-induced β-cell damage through β-cell regeneration. All of these factors led to a significant upregulation in insulin gene expression proved by RTPCR studies and by the presence of 40% insulin positive cells in pancreatic sections through confocal microscope studies.