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      Thymol polymeric nanoparticle synthesis and its effects on the toxicity of high glucose on OEC cells: involvement of growth factors and integrin‐linked kinase

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          Abstract

          Background

          Nowadays, the drug delivery system is important in the treatment of diseases.

          Purpose

          A polymeric nanoparticle modified by oleic acid (NPMO) as a Thymol (Thy) drug release system was synthesized from Thymbra spicata and its neurotrophic and angiogenic effects on rat’s olfactory ensheathing cells (OECs) in normal (NG) and high glucose (HG) conditions were studied.

          Methods

          The NPMO was characterized by using different spectroscopy methods, such as infrared, HNMR, CNMR, gel permeation chromatography, dynamic light scattering, and atomic force microscopy. Load and releasing were investigated by HPLC. The toxicity against OECs diet-induced by MTT assay. ROS and generation of nitric oxide (NO) were evaluated using dichloro-dihydro-fluorescein and Griess method, respectively. The expression of protein integrin-linked kinase (ILK), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were evaluated by Western blotting.

          Results

          ThyNPMO is desirable for transferring drug as a carrier. The amount of Thy and extract (E) loaded on NPMO estimated at 43±2.5% and 41±1.8%, respectively. Then, 65% and 63% of the drug load were released, respectively. Thy, ThyNPMO, E, and ENPMO prevented HG-induced OECs cell death (EC50 33±1.5, 22±0.9, 35±1.8, and 25±1.1 μM, respectively). Incubation with Thy, ThyNPMO, E ,and ENPMO at high concentrations increased cell death with LC50 105±3.5, 82±2.8, 109±4.3, and 86±3.4 μM, respectively in HG states.

          Conclusion

          OECs were protected by ThyNPMO and ENPMO in protective concentrations by reducing the amount of ROS and NO, maintaining ILK, reducing VEGF, and increasing BDNF and NGF. The mentioned mechanisms were totally reversed at high concentrations.

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          Most cited references 79

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          Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles.

          Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio- and macro-molecules.
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            Amphiphilic block copolymers for drug delivery.

            Amphiphilic block copolymers (ABCs) have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery. The utility of ABCs for delivery of therapeutic agents results from their unique chemical composition, which is characterized by a hydrophilic block that is chemically tethered to a hydrophobic block. In aqueous solution, polymeric micelles are formed via the association of ABCs into nanoscopic core/shell structures at or above the critical micelle concentration. Upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate. Although the Pluronics, composed of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), are the most widely studied ABC system, copolymers containing poly(L-amino acid) and poly(ester) hydrophobic blocks have also shown great promise in delivery applications. Because each ABC has unique advantages with respect to drug delivery, it may be possible to choose appropriate block copolymers for specific purposes, such as prolonging circulation time, introduction of targeting moieties, and modification of the drug-release profile. ABCs have been used for numerous pharmaceutical applications including drug solubilization/stabilization, alteration of the pharmacokinetic profile of encapsulated substances, and suppression of multidrug resistance. The purpose of this minireview is to provide a concise, yet detailed, introduction to the use of ABCs and polymeric micelles as delivery agents as well as to highlight current and past work in this area. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association
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              High glucose-induced oxidative stress and mitochondrial dysfunction in neurons.

              The current study examines the association between glucose induction of reactive oxygen species (ROS), mitochondrial (Mt) depolarization, and programmed cell death in primary neurons. In primary dorsal root ganglion (DRG) neurons, 45 mM glucose rapidly induces a peak rise in ROS corresponding to a 50% increase in mean Mt size at 6 h (P<0.001). This is coupled with loss of regulation of the Mt membrane potential (Mt membrane hyperpolarization, followed by depolarization, MMD), partial depletion of ATP, and activation of caspase-3 and -9. Glucose-induced activation of ROS, MMD, and caspase-3 and -9 activation is inhibited by myxothiazole and thenoyltrifluoroacetone (P<0.001), which inhibit specific components of the Mt electron transfer chain. Similarly, MMD and caspase-3 activation are inhibited by 100 microM bongkrekic acid (an inhibitor of the adenosine nucleotide translocase ANT). These results indicate that mild increases in glucose induce ROS and Mt swelling that precedes neuronal apoptosis. Glucotoxicity is blocked by inhibiting ROS induction, MMD, or caspase cleavage by specific inhibitors of electron transfer, or by stabilizing the ANT.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                25 July 2019
                2019
                : 13
                : 2513-2532
                Affiliations
                [1 ] Department of Chemistry, Ilam Branch, Islamic Azad University , Ilam, Iran
                [2 ] Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences , Ilam, Iran
                [3 ] Department of Chemistry, Faculty of Science, Ilam University , Ilam, Iran
                [4 ] Department of Pharmacology, Medical School, Ilam University of Medical Sciences , Ilam, Iran
                Author notes
                Correspondence: Shahryar AbbasiDepartment of Chemistry, Faculty of Science, Ilam University , new campus of Ilam University, building 3, appt.304., Ilam, IranTel/Fax +98 841 222 7022 Email abosina2000@ 123456yahoo.com
                Article
                214454
                10.2147/DDDT.S214454
                6664260
                © 2019 Karimi et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 15, References: 94, Pages: 20
                Categories
                Original Research

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