Transferrin Modified GSH Sensitive Hyaluronic Acid Derivative Micelle to Deliver HSP90 Inhibitors to Enhance the Therapeutic Efficacy of Brain Cancers
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Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence microscopy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cytotoxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was simultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accumulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.Keywords:
PLGA
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The low molecular weight hyaluronic acid(LMWHA) and hyaluronic acid oligosaccharides(o-HA) have the activities of antioxidation,immunomodulation,wound healing,angiogenesis and antitumor.Hyaluronic acid(HA) can be degraded by oxidants to LMWHA and o-HA.This paper introduces the oxidation degradation of HA.
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Hyaluronic acid, is extract by different procedures from various sources like pig, rabbit, oxes and human are available, but these processes have certain imitations like low yield, and also it requires the killing of these animals which is against the experimental ethics. In the present study, we have carried out the extraction of hyaluronic acid from cock’s comb which was further analyzed with qualitative test, viscosity, UV absorption, endotoxin detection assay. Also, the protein contamination of extracted hyaluronic acid was determined by using SDS-PAGE of hyaluronic acid was studied for checking the protein contaminants and it was noted that there were no bands observed in the well loaded with extracted hyaluronic acid sample indicating that the final extract of hyaluronic acid is not contaminated with the protein. The extraction and purification of hyaluronic acid by using the method reported here give pure hyaluronic acid. The viscosity of extracted hyaluronic acid was found to be 2.55 poise which is economical and can be used for industrial production of hyaluronic acid having clinical applications
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Reverse Micelles Formation of Reverse Micelles Micelle Size and Structure Reverse Micelles Dynamics pH and Effect of the Ionic Strength in the Reverse Micelles Enzymes, in Reverse Micelles Enzymes Inside Reverse Micelles Biocatalysis in Reverse Micelles Lipases in Reverse Micelles Lipase Applications in Reverse Micelles Liquid–Liquid Extraction of Enzymes Using Reverse Micelles Concluding Remarks Bibliography
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Sir: We would like to thank Dr. Andrea Sisti and colleagues for their interest and thoughtful comments regarding our article. As they highlighted, hyaluronic acid fillers have multiple effects. Hyaluronic acid acts not only as a tissue augmenter but also as a biostimulatory inducer (i.e., it enhances the formation of extracellular matrix and the production of new tissue). Physicians dealing with hyaluronic acid fillers should sufficiently understand these pleiotropic properties. We performed this study because we occasionally observed a sustained tissue-volumizing effect in the clinical setting more than 1 year after hyaluronic acid filler treatment when hyaluronic acid was subcutaneously injected using the bolus injection technique. We examined the histologic changes inside and outside the injected hyaluronic acid filler using an in vivo rodent model. This experiment revealed that hyaluronic acid stimulated the surrounding tissues and acted as a scaffold for autologous tissue proliferation, thereby resulting in the development of lattice structures by fibroblasts and induction of collagen fibers. The hyaluronic acid filler–injected space was gradually replaced by autologous tissues composed of fibroblasts, connective tissue, blood vessels, and adipocytes. Therefore, the partial replacement by autologous tissues caused a long-lasting effect despite the hyaluronic acid filler being gradually metabolized and absorbed. In several clinical cases of treatment with hyaluronic acid filler, hyaluronic acid–injected sites could not be recovered to their original condition even when hyaluronidase was injected into the treatment site. Thus, newly generated autologous tissues within the hyaluronic acid filler–injected space may be associated with these irreversible mechanisms. Although there are some differences between an animal model and a human, the results of our experiment can be applied to clinical hyaluronic acid treatments. It may be beneficial to not only inject the hyaluronic acid filler into the intradermal layer but also add a bolus injection into the subcutaneous layer to obtain a long-lasting effect. Furthermore, physicians should consider hydrophilicity (the volume of the hyaluronic acid filler increases by approximately 1.8-fold 4 weeks after injection), shape deformation (the height of the hyaluronic acid filler reduces by two-thirds 4 weeks after injection), and autologous tissue production characteristics over time for controlling the amount of hyaluronic acid filler during the initial treatment. Two concerns are considered as future perspectives. Currently, there are various types of commercially available hyaluronic acid fillers that differ in viscosity, elasticity, and concentration. However, in the present experiment, we elucidated the in vivo kinetics of only one hyaluronic acid filler (Juvéderm Vista ULTRA PLUS; Allergan plc, Dublin, Ireland). Therefore, it is necessary to examine which hyaluronic acid fillers act as a scaffold and which cause calcification or granulation, resulting in a risk of developing a lump in the future. Second, hyaluronic acid fillers may be developed into regenerative medicine in the near future if specific cells (adipocytes or chondrocytes) can be grown in hyaluronic acid–injected spaces by incorporating them into the filler before injection. DISCLOSURE None of the authors has a financial interest in any of the products, devices, or companies mentioned in this communication. No funding was obtained. Noriyuki Aoi, M.D.Masato Mochizuki, M.D.Department of Plastic, Oral, and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan Koichi Gonda, M.D.Department of Plastic SurgeryTohoku Medical and Pharmaceutical University HospitalSendai, Japan Shinichi Hirabayashi, M.D.Yuzo Komuro, M.D.Department of Plastic, Oral and Maxillofacial SurgeryTeikyo University School of MedicineTokyo, Japan
Hyaluronidase
Hyaluronan synthase
Filler (materials)
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Hyaluronic acid is an acidic polysaccharide that is widely distributed in various parts of the body. Hyaluronic acid has anti-inflammation,anti-infection,anti-edema effect and accelerates the tissue remodeling and healing in the wound. The article mainly reviewed the physiological function of hyaluronic acid and its application in the field of oral medicine.
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The most important studies on hyaluronic acid carried out within the recent 5-7 years are reviewed. Chemical structure, physical parameters and properties of hyaluronic acid are considered. Various functions of hyaluronic acid are discussed on the basis of current information.
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Electron micrographs
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Hyaluronic acid is a naturally derived, non - immunogenic, non - adhesive glycosaminoglycan that plays a prominent role in various wound - healing processes, as it as it is naturally angiogenic when degraded to small fragments. Hyaluronic acid promotes early inflammation which is critical for initiating wound healing, but then moderates later stages of the process, allowing matrix stabilization and reduction of long term inflammation. Hyaluronic acid is widely distributed in mammalian cells and tissue but is primarily found in synovial fluid, vitreous humor of the eye and loose connective tissue such as rooster comb, umbilical cord, dermis and arterial wall. It is also found in the capsular component of certain bacterial such as Streptococcus sp. and Staphylococcus sp. These have been biotechnologically developed and are now a main source of commercial Hyaluronic acid for pharmaceutical, medical and cosmetic application. The present review was based on Hyaluronic acid production and application. This review assesses the following topics: Structural features and properties of Hyaluronic acid, Rheological properties of Hyaluronic acid, Lubricity of Hyaluronic acid, Hydrophilicity of Hyaluronic acid, Hyaluronic acid production by bacterial fermentation, Biosynthesis of Hyaluronic acid in Streptococcus, Enzymes involved in Hyaluronic acid biosynthesis, Optimization and extraction of Hyaluronic acid, Analysis of Hyaluronic acid and Applications of Hyaluronic acid.
Hyaluronan synthase
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