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15 October 2020, Volume 15 Issue 10 Previous Issue    Next Issue

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Transcriptional regulation of adult neural stem/ progenitor cells: tales from the subventricular zone Giancarlo Poiana, Roberta Gioia, Serena Sineri, Silvia Cardarelli, Giuseppe Lupo, Emanuele Cacci 2020, 15 (10):  1773-1783.  doi: 10.4103/1673-5374.280301 Abstract ( 95 )   PDF (826KB) ( 117 )   Save In rodents, well characterized neurogenic niches of the adult brain, such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus, support the maintenance of neural/stem progenitor cells (NSPCs) and the production of new neurons throughout the lifespan. The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation. At the same time, it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli. A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging, injury or disease. At the core of the molecular mechanisms regulating neurogenesis, several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues. Here, we focus on REST, Egr1 and Dbx2 and their roles in adult neurogenesis, especially in the subventricular zone. We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche. We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain. Finally, we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis. Related Articles | Metrics

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Targeting molecular pathways for the treatment of inherited retinal degeneration Meltem Kutluer, Li Huang, Valeria Marigo 2020, 15 (10):  1784-1791.  doi: 10.4103/1673-5374.280303 Abstract ( 82 )   PDF (519KB) ( 130 )   Save Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells. Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases. The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients. Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation. One of these targets is the increase of intracellular calcium ions, that has been detected in several murine models of inherited retinal degeneration. Recently, neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration. Here, we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches, such as the neuroprotective activity of the Pigment epithelium-derived factor. The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches. We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration. Related Articles | Metrics

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Green tea catechins inhibit microglial activation which prevents the development of neurological disorders Tahereh Farkhondeh, Ali Mohammad Pourbagher-Shahri, Milad Ashrafizadeh, Silvia Llorens Folgado, Ali Rajabpour-Sanati, Mohammad Reza Khazdair, Saeed Samarghandian 2020, 15 (10):  1792-1798.  doi: 10.4103/1673-5374.280300 Abstract ( 89 )   PDF (827KB) ( 141 )   Save The over-activated microglial cells induce neuroinflammation which has the main role in neurological disorders. The over-activated microglia can disturb neuronal function by releasing inflammatory mediators leading to neuronal dysfunctions and death. Thus, inhibition of over-activated microglia may be an effective therapeutic approach for modulating neuroinflammation. Experimental studies have indicated anti- neuroinflammatory effects of flavonoids such as green tea catechins. The current research was aimed to review the effect of green tea catechins in inhibiting microglial cells, inflammatory cascades, and subsequent neurological diseases. Related Articles | Metrics

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Reversibility of visual field defects through induction of brain plasticity: vision restoration, recovery and rehabilitation using alternating current stimulation Bernhard A. Sabel, Ying Gao, Andrea Antal 2020, 15 (10):  1799-1806.  doi: 10.4103/1673-5374.280302 Abstract ( 114 )   PDF (980KB) ( 195 )   Save For decades visual field defects were considered irreversible because it was thought that in the visual system the regeneration potential of the neuronal tissues is low. Nevertheless, there is always some potential for partial recovery of the visual field defect that can be achieved through induction of neuroplasticity. Neuroplasticity refers to the ability of the brain to change its own functional architecture by modulating synaptic efficacy. It is maintained throughout life and just as neurological rehabilitation can improve motor coordination, visual field defects in glaucoma, diabetic retinopathy or optic neuropathy can be improved by inducing neuroplasticity. In ophthalmology many new treatment paradigms have been tested that can induce neuroplastic changes, including non-invasive alternating current stimulation. Treatment with alternating current stimulation (e.g., 30 minutes, daily for 10 days using transorbital electrodes and ~10 Hz) activates the entire retina and parts of the brain. Electroencephalography and functional magnetic resonance imaging studies revealed local activation of the visual cortex, global reorganization of functional brain networks, and enhanced blood flow, which together activate neurons and their networks. The future of low vision is optimistic because vision loss is indeed, partially reversible. Related Articles | Metrics

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Role of activin receptor-like kinase 1 in vascular development and cerebrovascular diseases Jun-Mou Hong, Yi-Da Hu, Xiao-Qing Chai, Chao-Liang Tang 2020, 15 (10):  1807-1813.  doi: 10.4103/1673-5374.280305 Abstract ( 70 )   PDF (1451KB) ( 146 )   Save Activin receptor-like kinase 1 (ALK1) is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta (TGFβ) receptor superfamily. ALK1 is specifically expressed in vascular endothelial cells, and its dynamic changes are closely related to the proliferation of endothelial cells, the recruitment of pericytes to blood vessels, and functional differentiation during embryonic vascular development. The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells. Indeed, mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation. Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms, arteriovenous malformations, and cerebral atherosclerosis. In this review, we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis, and we discuss its relationship to functional dysregulation in cerebrovascular diseases. This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis, treatment, and prevention. Related Articles | Metrics

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Effects of durotomy versus myelotomy in the repair of spinal cord injury Dionne Telemacque, Feng-Zhao Zhu, Zheng-Wei Ren, Kai-Fang Chen, Deepak Drepaul, Sheng Yao, Fan Yang, Yan-Zheng Qu, Ting-Fang Sun, Xiao-Dong Guo 2020, 15 (10):  1814-1820.  doi: 10.4103/1673-5374.280304 Abstract ( 153 )   PDF (694KB) ( 193 )   Save Current management for spinal cord injury aims to reduce secondary damage and recover sensation and movement. Acute spinal cord injury is often accompanied by spinal cord compartment syndrome. Decompression by durotomy and/or myelotomy attempts to relieve secondary damage by completelyrelieving the compression of the spinal cord, removing the necrotic tissue, decreasing edema, reducing hemorrhage, and improving blood circulation in the spinal cord. However, it is controversial whether durotomy and/or myelotomy after spinal cord injury are beneficial to neurological recovery. This review compares the clinical effects of durotomy with those of myelotomy in the treatment of spinal cord injury. We found that durotomy has been performed more than myelotomy in the clinic, and that durotomy may be safer and more effective than myelotomy. Durotomy performed in humans had positive effects on neurological function in 92.3% of studies in this review, while durotomy in animals had positive effects on neurological function in 83.3% of studies. Myelotomy procedures were effective in 80% of animal studies, but only one clinical study of myelotomy has reported positive results, of motor and sensory improvement, in humans. However, a number of new animal studies have reported that durotomy and myelotomy are ineffective for spinal cord injury. More clinical data, in the form of a randomized controlled study, are needed to understand the effectiveness of durotomy and myelotomy. Related Articles | Metrics

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Spinal genesis of Mayer waves George Zaki Ghali, Michael George Zaki Ghali, Emil Zaki Ghali 2020, 15 (10):  1821-1830.  doi: 10.4103/1673-5374.280306 Abstract ( 98 )   PDF (2320KB) ( 151 )   Save Variability in cardiovascular spectra was first described by Stephan Hales in 1733. Traube and Hering initially noted respirophasic variation of the arterial pressure waveform in 1865 and Sigmund Mayer noted a lower frequency oscillation of the same in anesthetized rabbits in 1876. Very low frequency oscillations were noted by Barcroft and Nisimaru in 1932, likely representing vasogenic autorhythmicity. While the origins of Traube Hering and very low frequency oscillatory variability in cardiovascular spectra are well described, genesis mechanisms and functional significance of Mayer waves remain in controversy. Various theories have posited baroreflex and central supraspinal mechanisms for genesis of Mayer waves. Several studies have demonstrated the persistence of Mayer waves following high cervical transection, indicating a spinal capacity for genesis of these oscillations. We suggest a general tendency for central sympathetic neurons to oscillate at the Mayer wave frequency, the presence of multiple Mayer wave oscillators throughout the brainstem and spinal cord, and possible contemporaneous genesis by baroreflex and vasomotor mechanisms. Related Articles | Metrics

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MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis Bridget Martinez, Philip V. Peplow 2020, 15 (10):  1831-1837.  doi: 10.4103/1673-5374.280307 Abstract ( 78 )   PDF (764KB) ( 145 )   Save Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system character- ized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while pro- gressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neu- roinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6–12 weeks of age) has confirmed miRNAs as biomarkers of experimen- tal autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis dis- ease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimen- tal autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR- 873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice. Related Articles | Metrics

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Are claudin-5 tight-junction proteins in the blood-brain barrier porous? David Fisher, Shireen Mentor 2020, 15 (10):  1838-1839.  doi: 10.4103/1673-5374.280308 Abstract ( 89 )   PDF (469KB) ( 162 )   Save The capillaries of the brain are particularly special, as they are not simply conduits for blood, but are primarily responsible to ensure that the neurons function in a strictly regulated homeostatic interstitium. Brain endothelial cells (BECs) express a plethora of ion channels on its luminal and abluminal surfaces, namely: potassium (K + ) channels (i.e., Kir2 and Kv1), chloride (Cl – )/bicarbonate (HCO3 – ) channels, as well as a number of ion-solute exchangers (Redzic et al., 2011). These channels essentially prioritize vectorial transendothelial transport, especially for the regulation of K + flux across the blood-brain barrier (BBB) (Redzic et al., 2011). The differences between the K + concentration of the brain interstitium and plasma is only 2 mM to 4 mM, but the maintenance of this ionic concentration difference provides a constancy for the neuro- nal resting membrane potential, their associated firing thresholds and the preservation of a constant level of neuronal excitability. The stability of the interstitial environment surrounding the brain’s neurons is the foundational essence of our persona, it is the basis for the continuity of our making of intellectual decisions and the stability of our psycho- logical essence. Furthermore, pathologies emanating from paracellular (PC) tight junction (TJ) permeability have been implicated in psychi- atric disorders, epilepsy, multiple sclerosis, neuroinflammation, stroke and traumatic brain injury (Greene et al., 2019). Thus, the regulation of permeability across the BBB is of interest from a physiological, psycho- logical and clinical perspective. Related Articles | Metrics

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The Janus face of N-terminal lysines in α-synuclein Ana Belén Uceda, Laura Mariño, Miquel Adrover 2020, 15 (10):  1840-1841.  doi: 10.4103/1673-5374.280309 Abstract ( 90 )   PDF (470KB) ( 128 )   Save Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative disorder after Alzheimer’s disease. PD usually starts with a tremor in the extremities (usually in the hands) and gradually evolves with other symptoms such as bradykinesia, muscle stiffness, impaired posture, loss of automatic movements or speech changes. These symptoms worsen as the condition progresses and eventually lead to death. Related Articles | Metrics

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Myelin positron emission tomography (PET) imaging in multiple sclerosis Daniele de Paula Faria 2020, 15 (10):  1842-1843.  doi: 10.4103/1673-5374.280311 Abstract ( 102 )   PDF (493KB) ( 119 )   Save Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and demyelination. Studies are focused on encountering remyelination therapies that can be applied to delaying, or even decreasing, the motor and cognitive disabilities caused by the disease. Related Articles | Metrics

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The mutual interaction between the host spinal cord and grafted undifferentiated stem cells fosters the production of a lesion-induced secretome Krisztián Pajer, Tamás Bellák, Antal Nógrádi 2020, 15 (10):  1844-1845.  doi: 10.4103/1673-5374.280312 Abstract ( 82 )   PDF (507KB) ( 156 )   Save Injury to the spinal cord results in loss of gray and white matter i.e., it produces a segmental spinal cord lesion and, as a consequence leads to a fatal loss of motor, sensory and autonomic functions. Spinal cord injuries in humans and other mammals are not followed by the replacement of lost neurons and oligodendrocytes and regrowth of injured axons, instead they lead to permanent, fatal and incurable functional deficits. The primary physical injury is followed by a cascade of tissue-decaying events, called secondary injury, which leads to ischemia, vascular disruption, neuroinflammation, excitotoxicity, demyelination and death of neurons and glial cells (Silva et al., 2014; Figure 1A). The direct mechanical disruption of the vasculature results in the increased permeability of the blood-spinal cord barrier. Due to the leakiness of blood-spinal cord barrier and production of cytokines by activated microglia, a number of various immune cells (T lymphocytes, neutrophils and monocytes) invade the injury site. The macrophages generate a set of inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1α, IL-1β, and IL-6, which may further augment the secondary events (Ahuja et al., 2017). In addition, a number of other disruptive processes contribute to the heterogeneous and time-sensitive pathophysiology of spinal cord injury. Related Articles | Metrics

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Progesterone for the treatment of central nervous system disorders: the many signaling roads for a single molecule Susana Laura González 2020, 15 (10):  1846-1847.  doi: 10.4103/1673-5374.280314 Abstract ( 78 )   PDF (717KB) ( 120 )   Save Central nervous system (CNS) injuries and neurodegenerative diseases show a broad spectrum of common pathophysiological processes, including oxidative stress, neuroinflammation, excitotoxicity, demyelination and neurotransmission dysfunctions. Over the past decades, valuable experimental investigations have helped to clarify the role and timing of these multiple molecular and cellular mechanisms in each of these particular disorders, which usually overlap and critically contribute to long-term disability. However, up to now, no definite cures or effective disease-modifying therapies are available for any of these conditions. This has led to an active search of novel therapeutic approaches, including the repositioning of existing drugs for new indications, as a valid approach to promptly move candidate molecules to clinical trials. Related Articles | Metrics

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The link between olfactory ensheathing cell survival and spinal cord injury repair: a commentary on common limitations of contemporary research Ronak Reshamwala, Megha Shah, James St. John, Jenny Ekberg 2020, 15 (10):  1848-1849.  doi: 10.4103/1673-5374.280310 Abstract ( 78 )   PDF (619KB) ( 98 )   Save Olfactory ensheathing cells (OECs) are crucial players in the continuous regeneration of the olfactory nervous system that occurs through out life and are thought to have unique growth-promoting properties. For this reason, OEC transplantation has been thoroughly explored for the potential to promote neural repair after both central and peripheral nervous system injuries. Numerous studies have shown that OEC transplantation is safe and can promote recovery after spinal cord injury (SCI), both in animal models and in human clinical trials. To date, a variety of injury types and time-points after injury, as well as different delivery methods, have been tested. Outcomes have been encouraging (in rodent models including, for example, restoration of locomotion, breathing and climbing ability along with induction of axonal sprouting and some axonal regeneration) but highly variable (Barnett and Riddell, 2007; Gomez et al., 2018). In their natural environment of the primary olfactory nervous system (the olfactory nerve and outer layer of the olfactory bulb), OECs provide structural support for olfactory axons and secrete a range of growth and guidance factors as well as basement membrane components. OECs also phagocytose debris arising from degenerating axons (Ekberg and St John, 2014). In the injured spinal cord, OECs (in addition to these functions) also exhibit a unique capacity for migration into scar tissue and for integration with astrocytes (Barnett and Riddell, 2007; Gomez et al., 2018). For these neural repair effects to occur, it is essential that the transplanted cells survive over time. The key factor for success is thus that the OECs must not only arrive at the right place within the injury site, but must also over time integrate and interact with the injured tissue. Related Articles | Metrics

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Limited therapeutic potential of astrocyte elevated gene-1 transduction in an animal model of Parkinson’s disease Eunju Leem, Sang Ryong Kim 2020, 15 (10):  1850-1851.  doi: 10.4103/1673-5374.280315 Abstract ( 71 )   PDF (419KB) ( 172 )   Save AEG-1, also known as metadherin, was originally identified as a human im- munodeficiency virus-1- and tumor necrosis factor-alpha-inducible gene in human fetal astrocytes. The increase in AEG-1 expression is a well-established and important oncogenic event in various types of human cancer, and its upregulation triggers evasion of cellular apoptosis, metastasis, and invasion in cancer (Emdad at al., 2016; Dhiman et al., 2019). AEG-1 can promote tumor progression via multiple phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways, contributing to an invasive phenotype and angiogenesis (Emdad at al., 2016; Dhiman et al., 2019). In addition, there is evi- dence for a functional link between AEG-1 and pro-survival mech- anisms in various cancers (Dhiman et al., 2019), suggesting that AEG-1 is a key molecule for oncogenic events in cancer. Related Articles | Metrics

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Can glucagon-like peptide-1 (GLP-1) analogues make neuroprotection a reality? Maryna V. Basalay, Sean M. Davidson, Derek M. Yellon 2020, 15 (10):  1852-1853.  doi: 10.4103/1673-5374.280313 Abstract ( 63 )   PDF (804KB) ( 109 )   Save Currently, ischemic stroke remains one of the most costly and devas- tating clinical syndromes, accounting for 9% of all deaths and being the second leading cause of death in the world (Davidson et al., 2018). Approximately 20% of strokes are caused by intracerebral hemorrhage, while the other ~80% are classified as ischemic. With the discovery of thrombolysis, reperfusion therapy became an option for the treatment of ischemic stroke. More recently, endovascular recanalization with mechanical thrombectomy has brought about a paradigm shift in the optimal management of patients with large vessel occlusion. Important- ly, early reperfusion is the only therapy that is proven to limit infarct size in patients with acute ischemic stroke. However, despite a success- ful recanalization being achieved in more than 70% of patients treated with mechanical thrombectomy +/– intravenous tissue recombinant plasminogen activator, functional independence (modified Rankin score 0–2 at 3 months after ischemic stroke) is obtained only in ~45% of cases. This reveals the further need to develop new adjunctive neuro- protective treatment strategies alongside reperfusion therapy. Related Articles | Metrics

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When the left side knows something happened to the right – sensing injury in neurons contralateral and remote to injury Valerie M.K. Verge, Jovan C.D. Hasmatali, Vikram Misra 2020, 15 (10):  1854-1855.  doi: 10.4103/1673-5374.280316 Abstract ( 78 )   PDF (302KB) ( 135 )   Save How sensory neurons encode axonal injury signals has been a longstanding area of neurological research. Insights into the cellular and transcriptional changes in the injured neurons have driven many new therapeutic strategies to improve repair. In contrast, less focus has been centered on the systemic or transneuronal changes that may arise from these injuries and how they may impact or factor into the alterations in gene expression, physiology and neuropathology, such as mirror image pain, arising in regions either directly contralateral or those remote to the injury site. Research in this area is clinically relevant. In patients with chronic unilateral pain due to multiple pathologies, many of which involve nerve trauma, there is a very high incidence of bilateral sensory abnormalities reported with 33–50% of patients with mechanical abnormalities reporting contralateral sensory abnormalities (Konopka et al., 2012). This has implications when evaluating sensory abnormalities or pain states in patients, as the contralateral side is often used as the non-affected control. Further, the bilateral nature of these sensory abnormalities, albeit usually less severe on the contralateral side, support that a systemic or central nervous system component is involved in this aspect of the pathology. It highlights the need to better understand the mechanisms underlying these bilateral responses as this will likely impact therapeutic treatments for these patients. Related Articles | Metrics

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Central nervous system and peripheral cell labeling by vascular endothelial cadherin-driven lineage tracing in adult mice Alejandro Soto-Avellaneda, Brad E. Morrison 2020, 15 (10):  1856-1866.  doi: 10.4103/1673-5374.280317 Abstract ( 55 )   PDF (6985KB) ( 12 )   Save Understanding the contribution of endothelial cells to the progenitor pools of adult tissues has the potential to inform therapies for human disease. To address whether endothelial cells transdifferentiate into non-vascular cell types, we performed cell lineage tracing analysis using transgenic mice engineered to express a fluorescent marker following activation by tamoxifen in vascular endothelial cadherin promoter-expressing cells (VEcad-CreERT2; B6 Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze). Activation of target-cell labeling following 1.5 months of ad libitum feeding with tamoxifen-laden chow in 4–5 month-old mice resulted in the tracing of central nervous system and peripheral cells that include: cerebellar granule neurons, ependymal cells, skeletal myocytes, pancreatic beta cells, pancreatic acinar cells, tubular cells in the renal cortex, duodenal crypt cells, ileal crypt cells, and hair follicle stem cells. As Nestin expression has been reported in a subset of endothelial cells, Nes-CreERT2 mice were also utilized in these conditions. The tracing of cells in adult Nes-CreERT2 mice revealed the labeling of canonical progeny cell types such as hippocampal and olfactory granule neurons as well as ependymal cells. Interestingly, Nestin tracing also labeled skeletal myocytes, ileal crypt cells, and sparsely marked cerebellar granule neurons. Our findings provide support for endothelial cells as active contributors to adult tissue progenitor pools. This information could be of particular significance for the intravenous delivery of therapeutics to downstream endothelial-derived cellular targets. The animal experiments were approved by the Boise State University Institute Animal Care and Use Committee (approval No. 006-AC15-018) on October 31, 2018. Related Articles | Metrics

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GFAP expression in the optic nerve and increased Н2S generation in the integration centers of the rainbow trout (Oncorhynchus mykiss) brain after unilateral eye injury Evgeniya V. Pushchina, Anatoly A. Varaksin, Dmitry K. Obukhov, Igor M. Prudnikov 2020, 15 (10):  1867-1886.  doi: 10.4103/1673-5374.280320 Abstract ( 68 )   PDF (13519KB) ( 14 )   Save Hydrogen sulfide (H2S) is considered as a protective factor against cardiovascular disorders. However, there are few reports on the effects of H2S in the central nervous system during stress or injury. Previous studies on goldfish have shown that astrocytic response occurs in the damaged and contralateral optic nerves. Glial fibrillary acidic protein (GFAP) concentration in the optic nerves of rainbow trout has not been measured previously. This study further characterized the astrocytic response in the optic nerve and the brain of a rainbow trout (Oncorhynchus mykiss) after unilateral eye injury and estimated the amount of H2S-producing enzyme cystathionine β-synthase (CBS) in the brain of the rainbow trout. Within 1 week after unilateral eye injury, a protein band corresponding to a molecular weight of 50 kDa was identified in the ipsi- and contralateral optic nerves of the rainbow trout. The concentration of GFAP in the injured optic nerve increased compared to the protein concentration on the contralateral side. The results of a quantitative analysis of GFAP+ cell distribution in the contralateral optic nerve showed the largest number of GFAP+ cells and fibers in the optic nerve head. In the damaged optic nerve, patterns of GFAP+ cell migration and large GFAP+ bipolar activated astrocytes were detected at 1 week after unilateral eye injury. The study of H2S-producing system after unilateral eye injury in the rainbow trout was conducted using enzyme-linked immunosorbent assay, western blot analysis, and immunohistochemistry of polyclonal antibodies again st CBS in the integrative centers of the brain: telencephalon, optic tectum, and cerebellum. Enzyme-linked immunosorbent assay results showed a 1.7-fold increase in CBS expression in the rainbow trout brain at 1 week after unilateral eye injury compared with that in intact animals. In the ventricular and subventricular regions of the rainbow trout telencephalon, CBS+ radial glia and neuroepithelial cells were identified. After unilateral eye injury, the number of CBS+ neuroepithelial cells in the pallial and subpallial periventricular regions of the telencephalon increased. In the optic tectum, unilateral eye injury led to an increase in CBS expression in radial glial cells; simultaneously, the number of CBS+ neuroepithelial cells decreased in intact animals. In the cerebellum of the rainbow trout, neuroglial interrelationships were revealed, where H2S was released, apparently, from astrocyte-like cells. The organization of H2S-producing cell complexes suggests that, the amount of glutamate produced in the rainbow trout cerebellum and its reuptake was controlled by astrocyte-like cells, reducing its excitotoxicity. In the dorsal matrix zone and granular eminences of the rainbow trout cerebellum, CBS was expressed in neuroepithelial cells. After unilateral eye injury, the level of CBS activity increased in all parts of the cerebellum. An increase in the number of H2S-producing cells was a response to oxidative stress after unilateral eye injury, and the overproduction of H2S in the cerebellum occurred to neutralize reactive oxygen species, providing the cells of the rainbow trout cerebellum with a protective effect. A structural reorganization in the dorsal matrix zone, associated with the appearance of an additional CBS+ apical zone, and a decrease in the enzyme activity in the dorsal matrix zone, was revealed in the zones of constitutive neurogenesis. All experiments were approved by the Commission on Biomedical Ethics, A.V. Zhirmunsky National Scientific Center of Marine Biology (NSCMB), Far Eastern Branch, Russian Academy of Science (FEB RAS) (approval No. 1) on July 31, 2019. Related Articles | Metrics

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Differences in clinical and genetic characteristics between early- and late-onset narcolepsy in a Han Chinese cohort Hui Ouyang, Fang Han, Ze-Chen Zhou, Jun Zhang 2020, 15 (10):  1887-1893.  doi: 10.4103/1673-5374.280322 Abstract ( 92 )   PDF (733KB) ( 718 )   Save Early- and late-onset narcolepsy constitutes two distinct diagnostic subgroups. However, it is not clear whether symptomology and genetic risk factors differ between early- and late-onset narcoleptics. This study compared clinical data and single-nucleotide polymorphisms (SNPs) between early- and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients. Blood, cerebrospinal fluid, and clinical data were prospectively collected from patients, and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs. Genetic risk scores (GRSs), associations of five different sets of SNPs (GRS1–GRS5) with early- and late-onset narcolepsy, were evaluated using logistic regression and receiver operating characteristic curves. Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases. Symptom severity was greater among late-onset patients, with higher rates of sleep paralysis, hypnagogic hallucinations, health-related quality of life impairment, and concurrent presentation with four or more symptoms. Hypocretin levels did not differ significantly between early- and late-onset cases. Only rs3181077 (CCR1/CCR3) and rs9274477 (HLA-DQB1) were more prevalent among early-onset cases. Only GRS1 (26 SNPs; OR = 1.513, 95% CI: 0.893–2.585; P < 0.05) and GRS5 (6 SNPs; OR = 1.893, 95% CI: 1.204–2.993; P < 0.05) were associated with early-onset narcolepsy, with areas under the receiver operating characteristic curves of 0.731 and 0.732, respectively. Neither GRS1 nor GRS5 included SNPs in HLA regions. Our results indicate that symptomology and genetic risk factors differ between early- and late-onset narcolepsy. This protocol was approved by the Institutional Review Board (IRB) Panels on Medical Human Subjects at Peking University People’s Hospital, China (approval No. Yuanlunshenlinyi 86) in October 2011. Related Articles | Metrics

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Chimera RNA interference knockdown of γ-synuclein in human cortical astrocytes results in mitotic catastrophe Timmy Le, Cynthia . Winham, Fotis Andromidas, Adam C. Silver, Evan R. Jellison, Aime A. Levesque, Andrew O. Koob 2020, 15 (10):  1894-1902.  doi: 10.4103/1673-5374.280329 Abstract ( 74 )   PDF (2288KB) ( 132 )   Save Elevated levels of γ-synuclein (γ-syn) expression have been noted in the progression of glioblastomas, and also in the cerebrospinal fluid of patients diagnosed with neurodegenerative diseases. γ-Syn can be either internalized from the extracellular milieu or expressed endogenously by human cortical astrocytes. Internalized γ-syn results in increased cellular proliferation, brain derived neurotrophic factor release and astroprotection. However, the function of endogenous γ-syn in primary astrocytes, and the relationship to these two opposing disease states are unknown. γ-Syn is expressed by astrocytes in the human cortex, and to gain a better understanding of the role of endogenous γ-syn, primary human cortical astrocytes were treated with chimera RNA interference (RNAi) targeting γ-syn after release from cell synchronization. Quantitative polymerase chain reaction analysis demonstrated an increase in endogenous γ-syn expression 48 hours after release from cell synchronization, while RNAi reduced γ-syn expression to control levels. Immunocytochemistry of Ki67 and 5-bromodeoxyuridine showed chimera RNAi γ-syn knockdown reduced cellular proliferation at 24 and 48 hours after release from cell synchronization. To further investigate the consequence of γ-syn knockdown on the astrocytic cell cycle, phosphorylated histone H3 pSer10 (pHH3) and phosphorylated cyclin dependent kinase-2 pTyr15 (pCDK2) levels were observed via western blot analysis. The results revealed an elevated expression of pHH3, but not pCDK2, indicating γ-syn knockdown leads to disruption of the cell cycle and chromosomal compaction after 48 hours. Subsequently, flow cytometry with propidium iodide determined that increases in apoptosis coincided with γ-syn knockdown. Therefore, γ-syn exerts its effect to allow normal astrocytic progression through the cell cycle, as evidenced by decreased proliferation marker expression, increased pHH3, and mitotic catastrophe after knockdown. In this study, we demonstrated that the knockdown of γ-syn within primary human cortical astrocytes using chimera RNAi leads to cell cycle disruption and apoptosis, indicating an essential role for γ-syn in regulating normal cell division in astrocytes. Therefore, disruption to γ-syn function would influence astrocytic proliferation, and could be an important contributor to neurological diseases. Related Articles | Metrics

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Combination of olfactory ensheathing cells and human umbilical cord mesenchymal stem cell-derived exosomes promotes sciatic nerve regeneration Yang Zhang, Wen-Tao Wang, Chun-Rong Gong, Chao Li, Mei Shi 2020, 15 (10):  1903-1911.  doi: 10.4103/1673-5374.280330 Abstract ( 159 )   PDF (6414KB) ( 373 )   Save Olfactory ensheathing cells (OECs) are promising seed cells for nerve regeneration. However, their application is limited by the hypoxic environment usually present at the site of injury. Exosomes derived from human umbilical cord mesenchymal stem cells have the potential to regulate the pathological processes that occur in response to hypoxia. The ability of OECs to migrate is unknown, especially in hypoxic conditions, and the effect of OECs combined with exosomes on peripheral nerve repair is not clear. Better understanding of these issues will enable the potential of OECs for the treatment of nerve injury to be addressed. In this study, OECs were acquired from the olfactory bulb of Sprague Dawley rats. Human umbilical cord mesenchymal stem cell-derived exosomes (0–400 μg/mL) were cultured with OECs for 12–48 hours. After culture with 400 μg/mL exosomes for 24 hours, the viability and proliferation of OECs were significantly increased. We observed changes to OECs subjected to hypoxia for 24 hours and treatment with exosomes. Exosomes significantly promoted the survival and migration of OECs in hypoxic conditions, and effectively increased brain-derived neurotrophic factor gene expression, protein levels and secretion. Finally, using a 12 mm left sciatic nerve defect rat model, we confirmed that OECs and exosomes can synergistically promote motor and sensory function of the injured sciatic nerve. These findings show that application of OECs and exosomes can promote nerve regeneration and functional recovery. This study was approved by the Institutional Ethical Committee of the Air Force Medical University, China (approval No. IACUC-20181004) on October 7, 2018; and collection and use of human umbilical cord specimens was approved by the Ethics Committee of the Linyi People’s Hospital, China (approval No. 30054) on May 20, 2019. Related Articles | Metrics

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Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury Bo-Tao Tan, Hui Jiang, Aaron J. Moulson, Xiao-Liang Wu, Wen-Chun Wang, Jie Liu, Ward T. Plunet, Wolfram Tetzlaff 2020, 15 (10):  1912-1919.  doi: 10.4103/1673-5374.280327 Abstract ( 132 )   PDF (2333KB) ( 205 )   Save We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015. Related Articles | Metrics

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Neuroprotective mechanism of L-cysteine after subarachnoid hemorrhage Ye Xiong, Dan-Qing Xin, Quan Hu, Ling-Xiao Wang, Jie Qiu, Hong-Tao Yuan, Xi-Li Chu, De-Xiang Liu, Gang Li, Zhen Wang 2020, 15 (10):  1920-1930.  doi: 10.4103/1673-5374.280321 Abstract ( 111 )   PDF (9808KB) ( 54 )   Save Hydrogen sulfide, which can be generated in the central nervous system from the sulfhydryl-containing amino acid, L-cysteine, by cystathionine- β-synthase, may exert protective effects in experimental subarachnoid hemorrhage; however, the mechanism underlying this effect is unknown. This study explored the mechanism using a subarachnoid hemorrhage rat model induced by an endovascular perforation technique. Rats were treated with an intraperitoneal injection of 100 mM L-cysteine (30 μL) 30 minutes after subarachnoid hemorrhage. At 48 hours after subarachnoid hemorrhage, hematoxylin-eosin staining was used to detect changes in prefrontal cortex cells. L-cysteine significantly reduced cell edema. Neurological function was assessed using a modified Garcia score. Brain water content was measured by the wet-dry method. L-cysteine significantly reduced neurological deficits and cerebral edema after subarachnoid hemorrhage. Immunofluorescence was used to detect the number of activated microglia. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the levels of interleukin 1β and CD86 mRNA in the prefrontal cortex. L-cysteine inhibited microglial activation in the prefrontal cortex and reduced the mRNA levels of interleukin 1β and CD86. RT-PCR and western blot analysis of the complement system showed that L-cysteine reduced expression of the complement factors, C1q, C3α and its receptor C3aR1, and the deposition of C1q in the prefrontal cortex. Dihydroethidium staining was applied to detect changes in reactive oxygen species, and immunohistochemistry was used to detect the number of NRF2- and HO-1-positive cells. L-cysteine reduced the level of reactive oxygen species in the prefrontal cortex and the number of NRF2- and HO-1-positive cells. Western blot assays and immunohistochemistry were used to detect the protein levels of CHOP and GRP78 in the prefrontal cortex and the number of CHOP- and GRP78-positive cells. L-cysteine reduced CHOP and GRP78 levels and the number of CHOP- and GRP78-positive cells. The cystathionine-β-synthase inhibitor, aminooxyacetic acid, significantly reversed the above neuroprotective effects of L-cysteine. Taken together, L-cysteine can play a neuroprotective role by regulating neuroinflammation, complement deposition, oxidative stress and endoplasmic reticulum stress. The study was approved by the Animals Ethics Committee of Shandong University, China on February 22, 2016 (approval No. LL-201602022). Related Articles | Metrics

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A rapid absorbance-based growth assay to screen the toxicity of oligomer Aβ42 and protect against cell death in yeast Prashant Bharadwaj, Ralph Martins 2020, 15 (10):  1931-1936.  doi: 10.4103/1673-5374.280318 Abstract ( 35 )   PDF (880KB) ( 145 )   Save Multiple lines of evidence show that soluble oligomer forms of amyloid β protein (Aβ42) are the most neurotoxic species in the brain and correlates with the degree of neuronal loss and cognitive deficit in Alzheimer’s disease. Although many studies have used mammalian cells to investigate oligomer Aβ42 toxicity, the use of more simple eukaryotic cellular systems offers advantages for large-scale screening studies. We have previously established and validated budding yeast, Saccharomyces cerevisiae to be a simple and a robust model to study the toxicity of Aβ. Using colony counting based methods, oligomeric Aβ42 was shown to induce dose-dependent cell death in yeast. We have adapted this method for high throughput screening by developing an absorbance-based growth assay. We further validated the assay with treatments previously shown to protect oligomer Aβ42 induced cell death in mammalian and yeast cells. This assay offers a platform for studying underlying mechanisms of oligomer Aβ42 induced cell death using gene deletion/overexpression libraries and developing novel agents that alleviate Aβ42 induced cell death. Related Articles | Metrics

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Rac1 relieves neuronal injury induced by oxygenglucose deprivation and re-oxygenation via regulation of mitochondrial biogenesis and function Ping-Ping Xia, Fan Zhang, Cheng Chen, Zhi-Hua Wang, Na Wang, Long-Yan Li, Qu-Lian Guo, Zhi Ye 2020, 15 (10):  1937-1946.  doi: 10.4103/1673-5374.280325 Abstract ( 150 )   PDF (2637KB) ( 141 )   Save Certain microRNAs (miRNAs) can function as neuroprotective factors after reperfusion/ischemia brain injury. miRNA-142-3p can participate in the occurrence and development of tumors and myocardial ischemic injury by negatively regulating the activity of Rac1, but it remains unclear whether miRNA-142-3p also participates in cerebral ischemia/reperfusion injury. In this study, a model of oxygen-glucose deprivation/re-oxygenation in primary cortical neurons was established and the neurons were transfected with miR-142-3p agomirs or miR-142-3p antagomirs. miR-142-3p expression was down-regulated in neurons when exposed to oxygen-glucose deprivation/re-oxygenation. Over-expression of miR-142-3p using its agomir remarkably promoted cell death and apoptosis induced by oxygen-glucose deprivation/re-oxygenation and improved mitochondrial biogenesis and function, including the expression of peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, and nuclear respiratory factor 1. However, the opposite effects were produced if miR-142-3p was inhibited. Luciferase reporter assays verified that Rac Family Small GTPase 1 (Rac1) was a target gene of miR- 142-3p. Over-expressed miR-142-3p inhibited NOX2 activity and expression of Rac1 and Rac1-GTPase (its activated form). miR-142-3p antagomirs had opposite effects after oxygen-glucose deprivation/re-oxygenation. Our results indicate that miR-142-3p down-regulates the expression and activation of Rac1, regulates mitochondrial biogenesis and function, and inhibits oxygen-glucose deprivation damage, thus exerting a neuroprotective effect. The experiments were approved by the Committee of Experimental Animal Use and Care of Central South University, China (approval No. 201703346) on March 7, 2017. Related Articles | Metrics

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An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage Jun-Hui Chen, Ting Wu, Wen-Yuan Xia, Zhong-Hua Shi, Chun-Lei Zhang, Lei Chen, Qian-Xue Chen, Yu-Hai Wang 2020, 15 (10):  1947-1954.  doi: 10.4103/1673-5374.280326 Abstract ( 155 )   PDF (2999KB) ( 129 )   Save Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage, but its mechanism is not clear. In this study, rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna. Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage, 12 and 36 hours after subarachnoid hemorrhage. Compared with the controls, atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage, neurological function had clearly improved; brain edema was remarkably relieved; cell apoptosis was markedly reduced in the cerebral cortex of rats; the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only. The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated. The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage. However, these were contrary to the results of 3-methyladenine injection, which inhibits the signaling pathway of autophagy. These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy. The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University, China (904 Hospital of Joint Logistic Support Force of PLA; approval No. YXLL-2017-09) on February 22, 2017. Related Articles | Metrics

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Lithium promotes proliferation and suppresses migration of Schwann cells Xiao-Kun Gu, Xin-Rui Li, Mei-Ling Lu, Hui Xu 2020, 15 (10):  1955-1961.  doi: 10.4103/1673-5374.280324 Abstract ( 101 )   PDF (3106KB) ( 160 )   Save Schwann cell proliferation, migration and remyelination of regenerating axons contribute to regeneration after peripheral nervous system injury. Lithium promotes remyelination by Schwann cells and improves peripheral nerve regeneration. However, whether lithium modulates other phenotypes of Schwann cells, especially their proliferation and migration remains elusive. In the current study, primary Schwann cells from rat sciatic nerve stumps were cultured and exposed to 0, 5, 10, 15, or 30 mM lithium chloride (LiCl) for 24 hours. The effects of LiCl on Schwann cell proliferation and migration were examined using the Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, Transwell and wound healing assays. Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assays showed that 5, 10, 15, and 30 mM LiCl significantly increased the viability and proliferation rate of Schwann cells. Transwell-based migration assays and wound healing assays showed that 10, 15, and 30 mM LiCl suppressed the migratory ability of Schwann cells. Furthermore, the effects of LiCl on the proliferation and migration phenotypes of Schwann cells were mostly dose-dependent. These data indicate that lithium treatment significantly promotes the proliferation and inhibits the migratory ability of Schwann cells. This conclusion will inform strategies to promote the repair and regeneration of peripheral nerves. All of the animal experiments in this study were ethically approved by the Administration Committee of Experimental Animal Center of Nantong University, China (approval No. 20170320-017) on March 2, 2017. Related Articles | Metrics

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Expression profiles of long noncoding RNAs in retinopathy of prematurity Yue Wang, Xue Wang, Yuan Ma, Yue-Xia Wang, Yu Di 2020, 15 (10):  1962-1968.  doi: 10.4103/1673-5374.280328 Abstract ( 78 )   PDF (2792KB) ( 151 )   Save Long noncoding RNA (lncRNA) regulates the proliferation and migration of human retinal endothelial cells, as well as retinal neovascularization in diabetic retinopathy. Based on similarities between the pathogenesis of retinopathy of prematurity (ROP) and diabetic retinopathy, lncRNA may also play a role in ROP. Seven-day-old mice were administered 75 ± 2% oxygen for 5 days and normoxic air for another 5 days to establish a ROP model. Expression of lncRNA and mRNA in the retinal tissue of mice was detected by high-throughput sequencing technology, and biological functions of the resulted differentially expressed RNAs were evaluated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results showed that compared with the control group, 57 lncRNAs were differentially expressed, including 43 upregulated and 14 downregulated, in the retinal tissue of ROP mice. Compared with control mice, 42 mRNAs were differentially expressed in the retinal tissue of ROP mice, including 24 upregulated and 18 downregulated mRNAs. Differentially expressed genes were involved in ocular development and related metabolic pathways. The differentially expressed lncRNAs may regulate ROP in mice via microRNAs and multiple signaling pathways. Our results revealed that these differentially expressed lncRNAs may be therapeutic targets for ROP treatment. This study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University on February 25, 2016 (approval No. 2016PS074K). Related Articles | Metrics