Abstract
Nanotized phytochemicals are being explored by researchers for promoting their uptake and effectiveness at lower concentrations. In this study, O-hexadecyl-dextran entrapped berberine chloride nanoparticles (BC-HDD NPs) were prepared, and evaluated for their cytoprotective efficacy in high glucose stressed primary hepatocytes and the results obtained compared with bulk berberine chloride (BBR) treatment. The nanotized formulation treated primary hepatocytes that were exposed to high glucose (40 mM), showed increased viability compared to the bulk BBR treated cells. BC-HDD NPs reduced the ROS generation by ∼3.5 fold during co-treatment, prevented GSH depletion by ∼1.6 fold, reduced NO formation by ∼5 fold and significantly prevented decline in SOD activity in stressed cells. Lipid peroxidation was also prevented by ∼1.9 fold in the presence of these NPs confirming the antioxidant capacity of the formulation. High glucose stress increased Bax/Bcl2 ratio followed by mitochondrial depolarization and activation of caspase-9/−3 confirming involvement of mitochondrial pathway of apoptosis in the exposed cells. Co- and post-treatment of BC-HDD NPs prevented depolarization of mitochondrial membrane, reduced Bax/Bcl2 ratio and prevented externalization of phosphatidyl-serine confirming their anti-apoptotic capacity in those cells. Sub-G1 phase apparent in high glucose stressed cells was not seen in BC-HDD NPs treated cells. The present study reveals that BC-HDD NPs at ∼20 fold lower concentration are as effective as BBR in preventing high glucose induced oxidative stress, mitochondrial depolarization and downstream events of apoptotic cell death.
Highlights
Diabetes mellitus is a chronic metabolic disorder caused by relative deficiency of insulin secretion and is characterized by high circulating glucose [1]
Various pathways involved in glucose metabolism such as polyol pathway, sorbitol pathway, Advance Glycation End product (AGE) pathway and hexosamine pathway are considered to be responsible for the generation of reactive oxygen species (ROS) during high glucose stress
We showed that O-hexadecyl-dextran entrapped berberine chloride nanoparticles (BC-HDD NPs) have improved cytoprotective effect on high glucose stressed primary hepatocytes by altering many critical control points of mitochondria-mediated apoptosis
Summary
Diabetes mellitus is a chronic metabolic disorder caused by relative deficiency of insulin secretion and is characterized by high circulating glucose [1]. Various pathways involved in glucose metabolism such as polyol pathway, sorbitol pathway, Advance Glycation End product (AGE) pathway and hexosamine pathway are considered to be responsible for the generation of reactive oxygen species (ROS) during high glucose stress. Due to continuous high circulating glucose during diabetes, natural antioxidant defence system is compromised leading to generation of oxidative stress. Excessive generation of ROS has been shown to be responsible for metabolic abnormalities and chronic complications [3]. An effective and beneficial strategy for management of diabetes can be through the use of antioxidants, which can effectively ameliorate the ROS or stress generated due to hyperglycemia. There is a need to find a pharmacologically efficacious molecule which is cost-effective and can prevent oxidative stress mediated damage to cells during hyperglycemia
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