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      Inhibition of mammalian target of rapamycin complex 1 signaling by n-3 polyunsaturated fatty acids promotes locomotor recovery after spinal cord injury

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          Abstract

          The present study aimed to explore the effects of n-3 polyunsaturated fatty acids (PUFAs) on autophagy and their potential for promoting locomotor recovery after spinal cord injury (SCI). Primary neurons were isolated and cultured. Sprague-Dawley rats were randomly divided into three groups and fed diets with different amounts of n-3 PUFAs. A model of spinal cord contusion was created at the T10 spinal segment and the composition of PUFAs was analyzed using gas chromatography. Spinal repair and motor function were evaluated postoperatively. Assessment of the effects of n-3 PUFAs on autophagy and mammalian target of rapamycin complex 1 (mTORC1) was performed using immunofluorescence staining and western blotting. In vitro, n-3 PUFAs inhibited mTORC1 and enhanced autophagy. The n-3 PUFA levels and the ratio of n-3 PUFA to n-6 PUFA in the spinal cord and serum of rats fed a high-n-3 PUFA diet were higher before and after operation (P<0.05). Additionally, rats in the high-n-3 PUFA group showed improved motor function recovery, spinal cord repair-related protein expression level (MBP, Galc and GFAP). Expression levels if these protiens in the high-n-3 PUFA diet group expressed the highest levels, followed by the low-n-3 PUFA diet group and finally the control group (P<0.05). high-n-3 PUFA diet promoted autophagy ability and inhibited activity of the mTORC1 signaling pathway compared with the low-n-3 PUFA diet group or the control group (P<0.05). These results suggest that exogenous dietary n-3 PUFAs can inhibit mTORC1 signaling and enhance autophagy, promoting functional recovery of rats with SCI.

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          PTEN Deletion Enhances the Regenerative Ability of Adult Corticospinal Neurons

          Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. Here we demonstrate a critical involvement of PTEN/mTOR in controlling the regenerative capacity of mouse corticospinal neurons. Upon the completion of development, the regrowth potential of CST axons lost and this is accompanied by a down-regulation of mTOR activity in corticospinal neurons. Axonal injury further diminishes neuronal mTOR activity in these neurons. Forced up-regulation of mTOR activity in corticospinal neurons by conditional deletion of PTEN, a negative regulator of mTOR, enhances compensatory sprouting of uninjured CST axons and even more strikingly, enables successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possess the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
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            The cellular inflammatory response in human spinal cords after injury.

            Spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the cord but also may contribute to its repair. Anti-inflammatory treatment of human SCI and its timing must be based on knowledge of the types of cells participating in the inflammatory response, the time after injury when they appear and then decrease in number, and the nature of their actions. Using post-mortem spinal cords, we evaluated the time course and distribution of pathological change, infiltrating neutrophils, monocytes/macrophages and lymphocytes, and microglial activation in injured spinal cords from patients who were 'dead at the scene' or who survived for intervals up to 1 year after SCI. SCI caused zones of pathological change, including areas of inflammation and necrosis in the acute cases, and cystic cavities with longer survival (Zone 1), mantles of less severe change, including axonal swellings, inflammation and Wallerian degeneration (Zone 2) and histologically intact areas (Zone 3). Zone 1 areas increased in size with time after injury whereas the overall injury (size of the Zones 1 and 2 combined) remained relatively constant from the time (1-3 days) when damage was first visible. The distribution of inflammatory cells correlated well with the location of Zone 1, and sometimes of Zone 2. Neutrophils, visualized by their expression of human neutrophil alpha-defensins (defensin), entered the spinal cord by haemorrhage or extravasation, were most numerous 1-3 days after SCI, and were detectable for up to 10 days after SCI. Significant numbers of activated CD68-immunoreactive ramified microglia and a few monocytes/macrophages were in injured tissue within 1-3 days of SCI. Activated microglia, a few monocytes/macrophages and numerous phagocytic macrophages were present for weeks to months after SCI. A few CD8(+) lymphocytes were in the injured cords throughout the sampling intervals. Expression by the inflammatory cells of the oxidative enzymes myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox)), and of the pro-inflammatory matrix metalloproteinase (MMP)-9, was analysed to determine their potential to cause oxidative and proteolytic damage. Oxidative activity, inferred from MPO and gp91(phox) immunoreactivity, was primarily associated with neutrophils and activated microglia. Phagocytic macrophages had weak or no expression of MPO or gp91(phox). Only neutrophils expressed MMP-9. These data indicate that potentially destructive neutrophils and activated microglia, replete with oxidative and proteolytic enzymes, appear within the first few days of SCI, suggesting that anti-inflammatory 'neuroprotective' strategies should be directed at preventing early neutrophil influx and modifying microglial activation.
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              The molecular machinery of autophagy: unanswered questions.

              Autophagy is a process in which cytosol and organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for degradation and recycling of the resulting macromolecules. It plays an important role in the cellular response to stress, is involved in various developmental pathways and functions in tumor suppression, resistance to pathogens and extension of lifespan. Conversely, autophagy may be associated with certain myopathies and neurodegenerative conditions. Substantial progress has been made in identifying the proteins required for autophagy and in understanding its molecular basis; however, many questions remain. For example, Tor is one of the key regulatory proteins at the induction step that controls the function of a complex including Atg1 kinase, but the target of Atg1 is not known. Although autophagy is generally considered to be nonspecific, there are specific types of autophagy that utilize receptor and adaptor proteins such as Atg11; however, the means by which Atg11 connects the cargo with the sequestering vesicle, the autophagosome, is not understood. Formation of the autophagosome is a complex process and neither the mechanism of vesicle formation nor the donor membrane origin is known. The final breakdown of the sequestered cargo relies on well-characterized lysosomal/vacuolar proteases; the roles of lipases, by contrast, have not been elucidated, and we do not know how the integrity of the lysosome/vacuole membrane is maintained during degradation.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                April 2018
                08 February 2018
                08 February 2018
                : 17
                : 4
                : 5894-5902
                Affiliations
                [1 ]Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
                [2 ]Department of Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia Autonomous Region 010050, P.R. China
                [3 ]Department of Orthopedics, Three Gorges Central Hospital of Chongqing, Chongqing 404000, P.R. China
                [4 ]Department of Orthopedics, Huhhot First Hospital, Huhhot, Inner Mongolia Autonomous Region 010020, P.R. China
                [5 ]Department of Orthopedics, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
                [6 ]Department of Orthopedics, Beijing Army General Hospital, Beijing 100700, P.R. China
                Author notes
                Correspondence to: Professor Tiansheng Sun, Department of Orthopedics, Beijing Army General Hospital, 5 Nanmengcang, Beijing 100700, P.R. China, E-mail: 2381049996@ 123456qq.com
                Professor Hao Luo, Department of Orthopedics, Three Gorges Central Hospital of Chongqing, 165 New City Road, Chongqing 404000, P.R. China, E-mail: yueer327@ 123456126.com
                [*]

                Contributed equally

                Article
                mmr-17-04-5894
                10.3892/mmr.2018.8583
                5866035
                29436695
                9cc8c126-a298-4784-a09f-2970991bc53c
                Copyright: © Nie et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 14 March 2017
                : 09 January 2018
                Categories
                Articles

                polyunsaturated fatty acids,spinal cord injury,mammalian target of rapamycin,autophagy,locomotor recovery

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