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      Ulinastatin Promotes Regeneration of Peripheral Nerves After Sciatic Nerve Injury by Targeting let-7 microRNAs and Enhancing NGF Expression


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          Peripheral nerve injury is characterized as a common clinical problem. Ulinastatin (UTI) is a serine protease inhibitor with many biological activities including anti-inflammatory and antioxidant effects. Nonetheless, it is unknown whether UTI has a protective effect on peripheral nerve injury.


          Thirty rats were divided into the sham operation group, the sciatic nerve injury group (injected with normal saline), and the UTI treatment group (80mg/kg/day for two consecutive weeks). Sciatic nerve function index (SFI) was used to assess the biological functions of the sciatic nerve, and compound muscle action potential (CMAP) was measured by electrophysiology. The expressions of let-7 miRNA members were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Nerve growth factor (NGF), nerve regeneration-related proteins GAP43 and NF200, and myelin formation-related proteins MAG and PMP22 expressions were explored by Western blot. After Schwann cells were transfected with let-7 mimics, pcDNA3.1-NGF, let-7 inhibitors, NGF siRNA and their corresponding controls, 5-ethynyl-2ʹ-deoxyuridine (EdU) assay, and Transwell assays were employed to investigate the proliferation and migration of Schwann cells. H 2O 2 was utilized to construct oxidative injury to cells, and the contents of MDA, SOD, GSH, and CAT were determined.


          UTI treatment remarkably increased SFI of the rats and CMAP of sciatic nerve, enhanced nerve regeneration, and myelin regeneration, and raised the production of GAP43, NF200, MAG, and PMP22. Furthermore, it was found that UTI markedly reduced let-7 miRNAs’ expressions and increased NGF expression after sciatic nerve injury. The dual-luciferase reporter assay validated that let-7 miRNAs targeted NGF, and functional experiments demonstrated that low expression of let-7 miRNAs and NGF overexpression contributed to Schwann cells’ proliferation and migration. Additionally, UTI treatment repressed the oxidative stress regulated by let-7/NGF axis.


          UTI modulates the let-7/NGF axis to inhibit oxidative stress, promote nerve regeneration, and facilitate function recovery after peripheral nerve injury.

          Most cited references43

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          The Success and Failure of the Schwann Cell Response to Nerve Injury

          The remarkable plasticity of Schwann cells allows them to adopt the Remak (non-myelin) and myelin phenotypes, which are specialized to meet the needs of small and large diameter axons, and differ markedly from each other. It also enables Schwann cells initially to mount a strikingly adaptive response to nerve injury and to promote regeneration by converting to a repair-promoting phenotype. These repair cells activate a sequence of supportive functions that engineer myelin clearance, prevent neuronal death, and help axon growth and guidance. Eventually, this response runs out of steam, however, because in the long run the phenotype of repair cells is unstable and their survival is compromised. The re-programming of Remak and myelin cells to repair cells, together with the injury-induced switch of peripheral neurons to a growth mode, gives peripheral nerves their strong regenerative potential. But it remains a challenge to harness this potential and devise effective treatments that maintain the initial repair capacity of peripheral nerves for the extended periods typically required for nerve repair in humans.
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            How does Lin28 let-7 control development and disease?

            One of the most ancient and highly conserved microRNAs (miRNAs), the let-7 family, has gained notoriety owing to its regulation of stem cell differentiation and essential role in normal development, as well as its tumor suppressor function. Mechanisms controlling let-7 expression have recently been uncovered, specifically the role of the RNA-binding protein Lin28 - a key developmental regulator - in blocking let-7 biogenesis. This review focuses on our current understanding of the Lin28-mediated control of let-7 maturation and highlights the central role of Lin28 in stem cell biology, development, control of glucose metabolism, and dysregulation in human disease. Manipulating the Lin28 pathway for the precise control of let-7 expression may provide novel therapeutic opportunities for cancer and other diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Nerve growth factor: from the early discoveries to the potential clinical use

              The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher’s attention, in view of possible clinical use in Alzheimer’s disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                09 July 2020
                : 14
                : 2695-2705
                [1 ]Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine , Shanghai, 200065, People’s Republic of China
                Author notes
                Correspondence: Yeqing Sun Department of OrthopedicsTongji Hospital,Tongji University School of Medicine , 389 Xincun Road, Putuo, Shanghai, 200065People's Republic of China Email leafsun306@163.com
                Author information
                © 2020 Zhang 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).

                : 23 March 2020
                : 16 May 2020
                Page count
                Figures: 6, References: 51, Pages: 11
                Funded by: the Youth Research Programme of Tongji Hospital Affiliated to Tongji University
                This study is supported by Shanghai Shenkang Hospital Development Center Clinical Research cultivation project (NO. SHDC12017X15.
                Original Research

                Pharmacology & Pharmaceutical medicine
                ulinastatin,let-7 micrornas,ngf,peripheral nerve injury
                Pharmacology & Pharmaceutical medicine
                ulinastatin, let-7 micrornas, ngf, peripheral nerve injury


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