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      Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms

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          Abstract

          Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.

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          Most cited references158

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          Astrocytes: biology and pathology

          Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.
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            Molecular mechanisms of T cell co-stimulation and co-inhibition.

            Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.
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              Genomic analysis of reactive astrogliosis.

              Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                13 October 2020
                October 2020
                : 21
                : 20
                : 7533
                Affiliations
                [1 ]Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaccob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; anamanjum40@ 123456gmail.com (A.A.); dain@ 123456ukm.edu.my (M.D.Y.); angela@ 123456ppukm.ukm.edu.my (A.M.H.N.)
                [2 ]Institute of Medical Science Technology, Universiti Kuala Lumpur Malaysia, Kajang 43000, Malaysia; mfauzid@ 123456unikl.edu.my (M.F.D.); jalilahidris@ 123456unikl.edu.my (J.I.)
                [3 ]Department of Orthopaedics & Traumatology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; amara@ 123456ppukm.ukm.edu.my (A.S.N.); ohnmar@ 123456ppukm.ukm.edu.my (O.H.R.I.)
                [4 ]Department of Surgery, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; rameshkumar@ 123456ppukm.ukm.edu.my
                Author notes
                [* ]Correspondence: lyoges@ 123456ppukm.ukm.edu.my ; Tel.: +60-3-9145-7704
                Author information
                https://orcid.org/0000-0003-4675-9728
                https://orcid.org/0000-0001-6162-4405
                https://orcid.org/0000-0002-9680-6599
                https://orcid.org/0000-0002-9548-6490
                Article
                ijms-21-07533
                10.3390/ijms21207533
                7589539
                33066029
                17964c20-2d8a-4de6-9d30-a01930a2c012
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 August 2020
                : 24 September 2020
                Categories
                Review

                Molecular biology
                spinal cord injury,primary injury,secondary injury,neurodegeneration,neuroprotection,neuro-regeneration

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