BackgroundDiabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model.ResultsChit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 μg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague–Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats.ConclusionsChit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-017-0251-z) contains supplementary material, which is available to authorized users.
Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca 2+ properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low-and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca 2+ properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR 90 , ±dl/dt), Fura-2-fluorescence intensity change (ΔFFI), and intracellular Ca 2+ decay rate (τ). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and ±dl/dt were depressed whereas TPS and TR 90 were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, ±dl/dt, and ΔFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR 90 . The Janus kinase 2 (JAK2) inhibitor AG490, the mitogenactivated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca 2+ concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.
Contractile responses to serotonin (5-HT) of fundic smooth muscle strips isolated from both control and streptozotocin (STZ)-induced diabetic rats were investigated. Contrary to carbachol (CCh) which causes contractile hyperreactivity in DM, 5-HT response tended to decrease in DM compared to that of the control. Pindolol (10-5 M) increased the value of EC50 of the concentration-response to 5-HT about 2.5 times in both the control and DM. After treatment with pindolol, the maximal tension to 5-HT in DM significantly decreased compared to that of the control. Pindolol showed no effect on the contractile response to CCh. Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control. Mianserin (10' M) increased the EC50 of the response to 5-HT about 2-2.5 times in both groups, but did not cause a significant difference between the control and DM. The Ca2+-induced contraction caused hyperreactivity in DM in the presence of 10-6 M CCh, but that in DM was not significantly different from the control in the presence of 10-6 M 5-HT. Pretreatment of phorbol 12-myristate 13-acetate (PMA, 10-5 M) significantly attenuated the response to 5-HT in the control, but not in DM. Results suggest that the contractile response to 5-HT in DM is related to the altered Ca2+ signal transduction system via disturbed protein kinase C (PKC) activity, and that there are alterations of receptor characteristics and of the density in 5-HT receptor subtypes, especially 5-HT1A, during DM development.
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