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15 March 2023, Volume 18 Issue 3 Previous Issue    Next Issue

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Role of the histone methyltransferases Ezh2 and Suv4-20h1/Suv4-20h2 in neurogenesis Christopher T. Rhodes, Chin-Hsing Annie Lin 2023, 18 (3):  469-473.  doi: 10.4103/1673-5374.350188 Abstract ( 185 )   PDF (587KB) ( 88 )   Save Mechanisms regulating neurogenesis involve broad and complex processes that represent intriguing therapeutic targets in the field of regenerative medicine. One influential factor guiding neural stem cell proliferation and cellular differentiation during neurogenesis are epigenetic mechanisms. We present an overview of epigenetic mechanisms including chromatin structure and histone modifications; and discuss novel roles of two histone modifiers, Ezh2 and Suv4-20h1/Suv4-20h2 (collectively referred to as Suv4-20h), in neurodevelopment and neurogenesis. This review will focus on broadly reviewing epigenetic regulatory components, the roles of epigenetic components during neurogenesis, and potential applications in regenerative medicine. Related Articles | Metrics

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Lights at night: does photobiomodulation improve sleep? Audrey Valverde, Catherine Hamilton, Cécile Moro, Malvina Billeres, Pierre Magistretti, John Mitrofanis 2023, 18 (3):  474-477.  doi: 10.4103/1673-5374.350191 Abstract ( 159 )   PDF (4337KB) ( 113 )   Save Sleep is a critical part of our daily routine. It impacts every organ and system of our body, from the brain to the heart and from cellular metabolism to immune function. A consistent daily schedule of quality of sleep makes a world of difference to our health and well-being. Despite its importance, so many individuals have trouble sleeping well. Poor quality sleep has such a detrimental impact on many aspects of our lives; it affects our thinking, learning, memory, and movements. Further, and most poignantly, poor quality sleep over time increases the risk of developing a serious medical condition, including neurodegenerative disease. In this review, we focus on a potentially new non-pharmacological treatment that improves the quality of sleep. This treatment, called photobiomodulation, involves the application of very specific wavelengths of light to body tissues. In animal models, these wavelengths, when applied at night, have been reported to stimulate the removal of fluid and toxic waste-products from the brain; that is, they improve the brain’s inbuilt house-keeping function. We suggest that transcranial nocturnal photobiomodulation, by improving brain function at night, will help improve the health and well-being of many individuals, by enhancing the quality of their sleep. Related Articles | Metrics

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Combined cell-based therapy strategies for the treatment of Parkinson’s disease: focus on mesenchymal stromal cells Jannette Rodríguez-Pallares, María García-Garrote, Juan A. Parga, José Luis Labandeira-García 2023, 18 (3):  478-484.  doi: 10.4103/1673-5374.350193 Abstract ( 140 )   PDF (3219KB) ( 54 )   Save Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra. Levodopa is an effective and well-tolerated dopamine replacement agent. However, levodopa provides only symptomatic improvements, without affecting the underlying pathology, and is associated with side effects after long-term use. Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment. Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum, release dopamine, integrate into the host neural circuits, and improve motor functions. One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells. Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma, growth factor deprivation, hypoxia, and neuroinflammation. Neurotrophic factors play an essential role in the survival of grafted cells. However, direct, timely, and controllable delivery of neurotrophic factors into the brain faces important limitations. Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival. In this review, we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease, with a focus on neurotrophic factor-secreting cells, with a particular interest in mesenchymal stromal cells; that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.  Related Articles | Metrics

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The lymphatic drainage systems in the brain: a novel target for ischemic stroke? Ying-Jie Wang, Yan-Rong Sun, Yan-Hong Pei, Hao-Wen Ma, Ya-Kun Mu, Li-Hua Qin, Jun-Hao Yan 2023, 18 (3):  485-491.  doi: 10.4103/1673-5374.346484 Abstract ( 287 )   PDF (1267KB) ( 139 )   Save Recent studies have proposed three lymphatic drainage systems in the brain, that is, the glymphatic system, the intramural periarterial drainage pathway, and meningeal lymphatic vessels, whose roles in various neurological diseases have been widely explored. The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid. The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media. Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses. After ischemic stroke, impairment of these systems could lead to cerebral edema, accumulation of toxic factors, and activation of neuroinflammation, while restoration of their normal functions can improve neurological outcomes. In this review, we summarize the basic concepts of these drainage systems, including drainage routes, physiological functions, regulatory mechanisms, and detection technologies. We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke, as well as recent advances in therapeutic strategies targeting these drainage systems. These findings provide information for potential novel strategies for treatment of stroke. Related Articles | Metrics

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Neuroprotective role of Noggin in spinal cord injury Nadia Al-Sammarraie, Mohammed Mahmood, Swapan K. Ray 2023, 18 (3):  492-496.  doi: 10.4103/1673-5374.350190 Abstract ( 135 )   PDF (1463KB) ( 98 )   Save Spinal cord injury is one of the leading causes of morbidity and mortality among young adults in many countries including the United States. Difficulty in the regeneration of neurons is one of the main obstacles that leave spinal cord injury patients with permanent paralysis in most instances. Recent research has found that preventing acute and subacute secondary cellular damages to the neurons and supporting glial cells can help slow the progression of spinal cord injury pathogenesis, in part by reactivating endogenous regenerative proteins including Noggin that are normally present during spinal cord development. Noggin is a complex protein and natural inhibitor of the multifunctional bone morphogenetic proteins, and its expression is high during spinal cord development and after induction of spinal cord injury. In this review article, we first discuss the change in expression of Noggin during pathogenesis in spinal cord injury. Second, we discuss the current research knowledge about the neuroprotective role of Noggin in preclinical models of spinal cord injury. Lastly, we explain the gap in the knowledge for the use of Noggin in the treatment of spinal cord injury. The results from extensive in vitro and in vivo research have revealed that the therapeutic efficacy of Noggin treatment remains debatable due to its neuroprotective effects observed only in early phases of spinal cord injury but little to no effect on altering pathogenesis and functional recovery observed in the chronic phase of spinal cord injury. Furthermore, clinical information regarding the role of Noggin in the alleviation of progression of pathogenesis, its therapeutic efficacy, bioavailability, and safety in human spinal cord injury is still lacking and therefore needs further investigation. Related Articles | Metrics

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Ataxia-telangiectasia mutated plays an important role in cerebellar integrity and functionality Yulia Mitiagin, Ari Barzilai 2023, 18 (3):  497-502.  doi: 10.4103/1673-5374.350194 Abstract ( 154 )   PDF (1186KB) ( 67 )   Save Accumulating evidence indicates that ataxia-telangiectasia mutated kinase is critical for maintaining cellular homeostasis and that it has both nuclear and cytoplasmic functions. However, the functions of ataxia-telangiectasia mutated that when lost lead to cerebellar degeneration are still unknown. In this review, we first describe the role of ataxia-telangiectasia mutated in cerebellar pathology. In addition to its canonical nuclear functions in DNA damage response circuits, ataxia-telangiectasia mutated functions in various cytoplasmic and mitochondrial processes that are critically important for cellular homeostasis. We discuss these functions with a focus on the role of ataxia-telangiectasia mutated in maintaining the homeostatic redox state. Finally, we describe the unique functions of ataxia-telangiectasia mutated in various types of neuronal and glial cells including cerebellar granule neurons, astrocytes, and microglial cells.  Related Articles | Metrics

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Melatonin: a multitasking indoleamine to modulate hippocampal neurogenesis Alejandro Romero, José Ángel Morales-García, Eva Ramos 2023, 18 (3):  503-505.  doi: 10.4103/1673-5374.350189 Abstract ( 152 )   PDF (483KB) ( 74 )   Save Neurodegeneration affects a large number of cell types including neurons, astrocytes or oligodendrocytes, and neural stem cells. Neural stem cells can generate new neuronal populations through proliferation, migration, and differentiation. This neurogenic potential may be a relevant factor to fight neurodegeneration and aging. In the last years, we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis. The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules. Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis. We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration, to summarize the current knowledge and highlight the therapeutic potential of melatonin.  Related Articles | Metrics

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Ferroptosis: a critical player and potential therapeutic target in traumatic brain injury and spinal cord injury Qing-Sheng Li, Yan-Jie Jia 2023, 18 (3):  506-512.  doi: 10.4103/1673-5374.350187 Abstract ( 196 )   PDF (7557KB) ( 59 )   Save Ferroptosis, a new non-necrotizing programmed cell death (PCD), is driven by iron-dependent phospholipid peroxidation. Ferroptosis plays a key role in secondary traumatic brain injury and secondary spinal cord injury and is closely related to inflammation, immunity, and chronic injuries. The inhibitors against ferroptosis effectively improve iron homeostasis, lipid metabolism, redox stabilization, neuronal remodeling, and functional recovery after trauma. In this review, we elaborate on the latest molecular mechanisms of ferroptosis, emphasize its role in secondary central nervous trauma, and update the medicines used to suppress ferroptosis following injuries.  Related Articles | Metrics

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Inflammation and retinal degenerative diseases Geetika Kaur, Nikhlesh K. Singh 2023, 18 (3):  513-518.  doi: 10.4103/1673-5374.350192 Abstract ( 293 )   PDF (7594KB) ( 90 )   Save Vision is an ability that depends on the precise structure and functioning of the retina. Any kind of stress or injury can disrupt the retinal architecture and leads to vision impairment, vision loss, and blindness. Immune system and immune response function maintain homeostasis in the microenvironment. Several genetic, metabolic, and environmental factors may alter retinal homeostasis, and these events may initiate various inflammatory cascades. The prolonged inflammatory state may contribute to the initiation and development of retinal disorders such as glaucoma, age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa, which pose a threat to vision. In the current review, we attempted to provide sufficient evidence on the role of inflammation in these retinal disorders. Moreover, this review paves the way to focus on therapeutic targets of the disease, which are found to be promising. Related Articles | Metrics

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SARS-CoV-2 getting into the brain; neurological phenotype of COVID-19, and management by nano-biotechnology Małgorzata Kujawska, Ebrahim Mostafavi, Ajeet Kaushik 2023, 18 (3):  519-520.  doi: 10.4103/1673-5374.346486 Abstract ( 129 )   PDF (783KB) ( 63 )   Save Human coronavirus infection getting into the brain: By February 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, causing the coronavirus disease 2019 (COVID-19) outbreak, has infected around 415 million people, and caused ~5.8 million deaths worldwide (WHO, https://covid19.who.int/). As SARS-CoV-2 replicates during the infection, it undergoes genetic mutation to generate variants with varying characteristics and mutation frequencies. The emerging, over time, new variants that differ with transmissibility, immunity, and infection severity pose continuous challenges to established COVID-19 management strategies and regulations. Several SARS-CoV-2 variants such as Omicron (B.1.1.529), Delta (B.1.617.2), UK (B.1.17), South Africa (B.1.351), Brazil (P.1), and New York B.1.525–B.1.526 were detected worldwide and accelerated  severity of COVID-19 pandemic (Figure 1A; McQuaid et al., 2021).  Related Articles | Metrics

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Choroid plexus imaging to track neuroinflammation – a translational model for mouse and human studies Muthuraman Muthuraman, Mohammadsaleh Oshaghi, Vinzenz Fleischer, Dumitru Ciolac, Ahmed Othman, Sven G. Meuth, Gabriel Gonzalez-Escamilla, Sergiu Groppa 2023, 18 (3):  521-522.  doi: 10.4103/1673-5374.346471 Abstract ( 139 )   PDF (1162KB) ( 64 )   Save The choroid plexus (ChP) is a highly vascularized and secretory tissue in each of the brain ventricles that represents the key structure between the blood and the cerebrospinal fluid (CSF). Besides its essential role in CSF production and brain waste clearance pathways, the ChP also contributes to the regulation of central nervous system (CNS) immunosurveillance (Ghersi-Egea et al., 2018). Indeed, the ChP forming the blood-CSF barrier (BCSFB) regulates the entry of immune cells and solute molecules into the brain and vice versa. When antigen-specific, autoreactive immune activation occurs in the periphery, inflammatory cells migrate through the brain barriers towards the CNS (Strominger et al., 2018), initiating neuroinflammatory diseases such as multiple sclerosis (MS). Related Articles | Metrics

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Striatum-specific mechanisms regulate neuronal cell cycle re-entry: the choice between life and death Paula Dietrich, Ioannis Dragatsis 2023, 18 (3):  523-524.  doi: 10.4103/1673-5374.346482 Abstract ( 136 )   PDF (732KB) ( 58 )   Save Mitochondria dysfunction occurs in the aging brain as well as in several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity to neurotoxins. In particular, defects in any of the mitochondria respiratory chain complexes lead to impaired adenosine triphosphate production resulting in diseases that often affect the central nervous system. For instance, innate deficits in succinate dehydrogenase (SDH) mitochondria respiratory chain complex II activity caused by genetic mutations in SDH subunits lead to early-onset neurodegeneration (Jain-Ghai et al., 2013), while several adult-onset genetic neurodegenerative disorders are associated with variable levels of complex II deficiency in the central nervous system (Túnez et al., 2010). Also, chemically induced complex II deficiency leads to neurodegeneration. Livestock and human poisoning by plants or fungi containing 3-nitropropionic acid (3-NP), a naturally occurring neurotoxin that irreversibly inhibits complex II SDH activity, leads to impaired mitochondrial bioenergetics, oxidative stress, and loss of adenosine triphosphate, triggering a cascade of intracellular events that ultimately result in neuronal cell death (Túnez et al., 2010). Interestingly, in all cases, whether genetic or chemically induced, despite similar reduction in SDH activity throughout the central nervous system, neuronal degeneration is restricted to the basal ganglia, with the striatum being particularly susceptible (Túnez et al., 2010; Jain-Ghai et al., 2013).  Related Articles | Metrics

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Biofabrication of nanovesicles for brain diseases Pasquale Picone, Domenico Nuzzo 2023, 18 (3):  525-526.  doi: 10.4103/1673-5374.346473 Abstract ( 127 )   PDF (2163KB) ( 43 )   Save Nanotechnologies promise to improve disease diagnosis and treatment, overcoming the limitations of conventional administrations. In particular, extracellular vesicles (EVs) and artificial vesicles (AVs) are strongly emerging tools in nanomedicine (Leggio et al., 2020). EVs are cell-derived membrane structures secreted after the fusion of endosomes with the plasma membrane (exosomes) or shed from the plasma membrane (microvesicles). EVs are released by different brain cells (neurons, oligodendrocytes, astrocytes, and microglia) and constitute a physiological intercellular communication system. Indeed, EVs can deliver different types of molecules (nucleic acids and proteins), which often influence the phenotype of the recipient cells. They play a physiological role in the central nervous system (CNS), such as development, myelination, regeneration, and synaptic activity (Lai et al., 2012). Due to their content, EVs could therefore constitute an important biomarker for neurodegenerative diseases, represent candidates for therapeutic use, enclosing regulatory molecules, or be considered as vectors for brain drug delivery (Croese et al., 2018).  Related Articles | Metrics

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Developmental exposure to thyroid disruptors: misprogramming of the brain’s stem cells in later life? Pieter Vancamp, Sylvie Remaud 2023, 18 (3):  527-528.  doi: 10.4103/1673-5374.346053 Abstract ( 127 )   PDF (1173KB) ( 43 )   Save Ever since the discovery of neural stem cells (NSCs) in the adult mammalian brain, scientists have been trying to decipher which signals govern their turnover and lineage commitment to generate neurons and glia. Understanding their role in nervous tissue homeostasis can provide new insights into the etiology of several neurological disorders, and might one day be turned to our advantage to promote endogenous brain injury repair. Others and we have identified thyroid hormone (TH) as a key factor transcriptionally regulating NSC behavior in the largest niche of the adult mammalian brain: the subventricular zone (SVZ).  Related Articles | Metrics

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Nucleoredoxin-like 2 metabolic signaling impairs its potential contribution to neurodegenerative diseases Mariangela Corsi, Céline Jaillard, Thierry Léveillard 2023, 18 (3):  529-530.  doi: 10.4103/1673-5374.346476 Abstract ( 117 )   PDF (377KB) ( 30 )   Save Alzheimer’s disease (AD) threatens the foundations of humanity and our society. AD is a neurological disorder primarily affecting the elderly through memory disorders, cognitive decline, and loss of autonomy. The dramatic consequences of this late-onset disease were illustrated sensitively in Michael Haneke’s masterpiece, Amour. Researchers and governments have invested colossal efforts to develop a treatment for this terrible disease. Currently and in the past decade the amyloid cascade has dominated the therapeutic research on AD, but the absence of benefit for patients treated with drugs that reduce brain amyloid deposit questions the role of β-amyloid as a causative agent (Herrup, 2021). The recent approval of aducanumab by the United States Food and Drug Administration, a drug that targets β-amyloid, is at the center of a scandal among clinicians and researchers, as it does not provide therapeutic benefits to patients and is listed among the breakdowns of the year 2021 by Science magazine (Voosen et al., 2021). The lack of progress in curing AD and recent therapeutic failures calls for further exploratory research. Related Articles | Metrics

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Synaptic alterations as a common phase in neurological and neurodevelopmental diseases: JNK is a key mediator in synaptic changes Clara Alice Musi, Carlo Bonadonna, Tiziana Borsello 2023, 18 (3):  531-532.  doi: 10.4103/1673-5374.346488 Abstract ( 130 )   PDF (884KB) ( 79 )   Save Brain synapses play a key role in neuronal communication: this “conversation” is at the basis of all brain activities and synaptic dysfunction leads to brain disorders. We study the modulators of this crucial synaptic function and we here present the evidence supporting the c-Jun N-terminal kinase (JNK) pathway as a pivotal actor in this scenario. Related Articles | Metrics

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Axonal tuning by GABAA receptor unveils novel tricks from an old dog Veronica Bonalume, Valerio Magnaghi 2023, 18 (3):  533-534.  doi: 10.4103/1673-5374.346489 Abstract ( 113 )   PDF (2881KB) ( 47 )   Save In the last years, axonal conductance of action potential trains became a novel subject of study, changing the view of axons, from a static cable-like compartment to a more complex and dynamic system (Debanne et al., 2011). Axonal computation, indeed, is canonically constituted by the action of voltage-gated ion channels, such as the classic Na+ and K+ channels, but recent studies demonstrated that it can be modulated by the action of other ion channel pumps, and metabolic factors (Byczkowicz et al., 2019; Zang and Marder, 2021). These non-canonical mechanisms have been studied mainly in the central nervous system (Byczkowicz et al., 2019; Kamiya, 2019), and little is known about axonal conductance modulation in peripheral nerve fibers. Interestingly, the peripheral projecting neurons possess a pseudounipolar conformation and exceptionally long axons, an anatomical characteristic that make propagation and tuning of the axonal action potential more easily adjustable. Notably, unmyelinated axons (i.e. C-fiber nociceptors) prevail in all peripheral fibers as the most affected by changes in conduction velocity, since relatively small alterations cause substantial delays in action potential incoming time (Zang and Marder, 2021). Peripheral C-fiber nociceptors, indeed, are defined by specific activity-dependent slowing properties, whereby repetitive firing of nerve fibers results in the progressive slowing of their conduction velocity and concomitant increase in response latency (Gee et al., 1996). Activity-dependent slowing is so preserved to be designated as a signature mark able to discriminate among different functional C-fiber subtypes (Werland et al., 2021). Related Articles | Metrics

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CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer’s disease Daniel Romaus-Sanjurjo, Antía Custodia, Alberto Ouro, Tomás Sobrino 2023, 18 (3):  535-536.  doi: 10.4103/1673-5374.346485 Abstract ( 125 )   PDF (764KB) ( 73 )   Save Alzheimer’s disease (AD) is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly. Considering AD to be an epidemic, an increase from the current 50 million to more than 150 million patients is expected by the year 2050. AD is characterized by a slow, progressive and asymptomatic onset; making it difficult to decipher the precise etiology. It is well established that AD presents two characteristic features, extracellular β-amyloid plaques and intracellular tau tangles, that eventually lead to the impairment of cognitive functions. Unfortunately, AD symptomatology shares many similarities with other dementias once is present, which makes it difficult an accurate premortem diagnosis. Related Articles | Metrics

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Treating peripheral nerve injury-induced spinal cord degeneration and neuropathic pain with peripherally administrated stem cells Zihui Wang, Xiaofeng Jia 2023, 18 (3):  537-538.  doi: 10.4103/1673-5374.346491 Abstract ( 132 )   PDF (1822KB) ( 69 )   Save Peripheral nerve injury (PNI) causes sensory and motor deficits as well as neuropathic pain, which seriously impacts patient quality of life (Jiang et al., 2017). Morphological and molecular changes in the spinal cord and dorsal root ganglia (DRG), such as neuronal cell death, nerve fiber degeneration, and glial activation, are strongly associated with PNI-induced pathological syndromes, such as sensitization and abnormal responses to peripheral stimuli and dysregulation of spinal cord circuitry (Calvo and Bennett, 2012; Duraikannu et al., 2019; Zhang et al., 2021). To date, most therapeutic strategies for functional recovery after PNI target the peripheral nerve directly, while only a few treatments target PNI-induced pathological changes in the spinal cord, such as preventing apoptosis-induced neuronal death and inhibiting glial responses. This in part explains why despite continual improvements in therapeutic strategies of PNI over the last few decades, clinical outcomes after PNI remain unsatisfactory, such as suffering from chronic pain. Therefore, there is an urgent need for new therapeutic strategies. Considering the anatomical location of the cell bodies of the peripheral nerve in the spinal cord and DRG and the functional integration between the peripheral and central nervous system, therapeutic approaches targeting PNI-induced spinal cord lesions may benefit post-PNI outcomes. Recently, an in vivo study of the treatment of PNI-induced spinal cord pathological changes through peripheral administration of neural crest stem cells (NCSCs) (2 × 106 in a nerve conduit) achieved favorable outcomes after PNI, such as neuropathic pain relief and locomotor function improvements (Zhang et al., 2021). This preclinical study provides insight into the therapeutic potential of a new approach to PNI by targeting PNI-induced spinal cord lesions through peripheral administration of NCSCs, instead of intrathecal injection or transplantation to the injured dorsal root, which holds the potential to translate into clinical practice in the future.  Related Articles | Metrics

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Technological advances expand our knowledge of lysosomal dysfunction in neurodegeneration Chase Chen, Yu Chen, Ellen Sidransky 2023, 18 (3):  539-540.  doi: 10.4103/1673-5374.346490 Abstract ( 113 )   PDF (368KB) ( 35 )   Save In the almost seven decades since the initial discovery of the lysosome as an organelle, our understanding of the role of lysosomes has greatly evolved. We now know lysosomal function encompasses far more than its traditionally described role as the cell’s “garbage disposal”, referring to its well-established catabolic function. Lysosomes are integral to maintaining cellular health and viability, and they act as a major signaling hub within the cell (Ballabio and Bonifacino, 2020). Lysosomes regulate autophagy, a key mechanism for regulating cellular homeostasis. The aberrant regulation of different lysosomal pathways is frequently observed in neurodegenerative diseases. Studies have identified a multitude of lysosomal genes that are now implicated in disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (Udayar et al., 2022). For example, many genes associated with late-onset AD, such as APOE and PLD3, are associated with autophagy-lysosomal pathways (Van Acker et al., 2019). In addition, lysosomal dysfunction contributes to the aggregation of alpha-synuclein in PD and the build-up of beta-amyloid and tau-containing neurofibrillary tangles in AD (Mazzulli et al., 2016; Feng et al., 2020). However, the development of therapeutics targeting PD, AD, and related neurodegenerative diseases has been hindered by the fact that we still do not fully understand the cellular and molecular changes contributing to lysosomal dysfunction in neurodegeneration. Thus, an emphasis has been placed on developing new techniques that can elucidate minute alterations in cellular and molecular processes. Over the past few years, both the development of methods for the rapid isolation of intact lysosomes and new CRISPR/Cas9-based genetic screens have furthered our knowledge of many lysosomal functions. Recently, studies with isolated lysosomes have shown the dynamic nature of nutrient exchange between the lysosome and the cytosol (Abu-Remaileh et al., 2017). In parallel, the first CRISPR interference (CRISPRi)-based genetic screens in human induced pluripotent stem cell (iPSC)-derived neurons have yielded novel insights into the relationship between glycosphingolipid accumulation and elevated oxidative stress (Abu-Remaileh et al., 2017; Tian et al., 2021). These findings pave the way for expanding our knowledge on how lysosomal dysfunction relates to neurodegeneration (Figure 1). Related Articles | Metrics

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Convergence of human and veterinary medicine: leveraging canine naturally occurring neurological disorders to develop regenerative treatments Kaitlin C. Clark, Ashley Amador, Aijun Wang 2023, 18 (3):  541-542.  doi: 10.4103/1673-5374.350195 Abstract ( 144 )   PDF (471KB) ( 37 )   Save In recent years, large animal models of naturally occurring diseases have become increasingly studied, with the rationale that their disease attributes may better recapitulate the pathological features of corresponding human diseases as compared to induced disease models (Hoffman and Dow, 2016). Of the available naturally occurring disease models, the canine is increasingly recognized as a valuable pre-clinical animal model in translational medicine for numerous human diseases, including cancer, respiratory disease, and inflammatory disease (Kol et al., 2015; Hoffman and Dow, 2016). The canine also frequently suffers from central nervous system (CNS) disorders, such as brain and spinal cord injuries, neurodevelopmental diseases (e.g., spina bifida (SB)), and neurodegenerative diseases (e.g., inflammatory brain disease (IBD)) that have comparable pathological features to human CNS disorders (Hoffman and Dow, 2016; Song et al., 2016). Additionally, canines live in similar environmental conditions as humans and can receive long-term monitored medical care. While research-induced animal disease modeling systems are the standard in vivo approach to evaluate therapeutics, there are notable limitations, including inconsistency from natural disease in phenotypic heterogenicity, clinical and pathological features, and responsiveness to treatments. Furthermore, effective treatments are extremely underdeveloped for dogs with these conditions, and therefore many animals are left untreated or euthanized. The comparable features of canine CNS to human CNS disorders could allow the advancement of new standard care practices for companion animals, as well as provide critical insights for the development of regenerative medicine therapies for human clinical use. Related Articles | Metrics

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Could serotonin play a role in abnormal brain outcomes in fetal growth restriction? Kate Beecher, Julie A. Wixey 2023, 18 (3):  543-544.  doi: 10.4103/1673-5374.346481 Abstract ( 113 )   PDF (813KB) ( 49 )   Save Fetal growth restriction (FGR) describes a fetus that has not grown to its expected biological potential in utero. FGR can result from maternal, fetal, or placental complications, though it is commonly caused by placental insufficiency. The prolonged hypoxic environment the FGR fetus is exposed to has detrimental effects on the newborn, which extends to adverse long-term neurological outcomes in a significant proportion of FGR infants (Malhotra et al., 2019). Unfortunately, there are currently no therapies to reduce the adverse neurological outcomes in FGR. Neuronal injury is evident in the FGR brain, and therefore understanding which neurons are lost and how they are lost will aid in the selection of treatment options for FGR. Related Articles | Metrics

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Ferroptosis and glaucoma: implications in retinal ganglion cell damage and optic nerve survival Ming Yang, Kwok-Fai So, Wai-Ching Lam, Amy Cheuk Yin Lo 2023, 18 (3):  545-546.  doi: 10.4103/1673-5374.350196 Abstract ( 217 )   PDF (951KB) ( 127 )   Save Glaucoma is the leading cause of irreversible blindness worldwide, which leads to a progressive loss of vision. Glaucoma can be classified into two types: primary open-angle glaucoma and primary closed-angle glaucoma. Primary open-angle glaucoma can be caused by the blockage of the trabecular meshwork, and this results in elevation of the intraocular pressure (IOP), leading to retinal ganglion cell (RGC) death. However, many glaucoma patients have normal IOP; this is known as normal-tension glaucoma. Nevertheless, excitotoxic damage and oxidative stress can also lead to RGC damage in normal-tension glaucoma (Almasieh et al., 2012). Glaucomatous genes such as TIGR, OPTN, and CYP1B1 have been suggested to contribute to the pathogenesis of glaucoma. However, some glaucomatous patients may remain asymptomatic in the early, moderate, and late stages. Another type of glaucoma is primary closed-angle glaucoma. In this clinical condition, a relative pupillary block is contributed by the iris obstructing aqueous outflow. The patients may suffer from corneal swelling, headache, nausea, and blurred vision during the acute phase.  Related Articles | Metrics

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Axon degeneration: new actor in an old play Marina Herwerth, Matthias T. Wyss 2023, 18 (3):  547-548.  doi: 10.4103/1673-5374.350200 Abstract ( 125 )   PDF (904KB) ( 66 )   Save After an insult of white matter tracts, e.g. in the spinal cord or optic nerve, axons react in general by the activation of a tightly regulated self-destruction program. This so-called axon degeneration cascade can be triggered by various causes, including injury, toxins, and genetic defects, and is a shared pathway in many different neurological diseases (Coleman and Hoke, 2020). Axonal degeneration is thought to be responsible for disease progression and accumulation of disability across many neurological conditions. The hallmark of early axonal injury is the appearance of local spheroid formations along the axon, often referred to as a “pearl-on-string” pattern or axonal beading or swelling. Although this striking shape change has been observed after various types of injury, such as mechanical, chemical, or inflammatory stimuli, we know little about its exact mechanism and its immediate impact on axonal functionality. In this perspective, we would like to contrast the classical calcium-dependent form of axonal degeneration with a recently described form of a calcium-independent mechanism underlying axonal beading. Related Articles | Metrics

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Sortilins in the blood-brain barrier: impact on barrier integrity Andrea E. Toth, Morten S. Nielsen 2023, 18 (3):  549-550.  doi: 10.4103/1673-5374.350197 Abstract ( 148 )   PDF (492KB) ( 38 )   Save Sortilin was discovered in 1997 by Petersen and his colleagues. The single transmembrane receptor was isolated as a 95 kDa membrane glycoprotein by receptor-associated protein affinity chromatography and therefore initially named gp95. The cDNA library screening revealed sequence homology between the luminal segment of gp95/sortilin and the yeast vacuolar sorting protein 10 protein (Vps10p) domain  (Petersen et al., 1997). The Vps10p domain was first identified in the Saccharomyces cerevisiae protein Vps10p that directs lysosomal enzymes from the Golgi to the vacuole (Marcusson et al., 1994). The trafficking path is even more complex for the mammalian Vps10p domain receptors that can shuttle between vesicles in the endo-lysosomal system and the cell (Nielsen et al., 2001). The Vps10p domain is evolutionary conserved and has a unique 10-bladed β-propeller structure (Quistgaard and Thirup, 2009). In mammalians, five receptors with Vps10p domains have been reported: sortilin (also known as neurotensin receptor 3), sortilin-related receptor central nervous system expressed 1, 2, and 3 (SORCS1, SORCS2, SORCS3), and sorting protein-related receptor with A-type repeats (SORLA; also known as LR11 and SORL1). The members of this gene family are collectively known as Vps10p-domain receptors or simply sortilins. They are all type-1 transmembrane receptors with a short cytoplasmatic tail and a large extracellular domain. The cytoplasmatic domain contains sorting motifs for specific adaptor proteins that direct intracellular trafficking. The Vps10p domain is located on the extracellular part that is the place for protein binding. Sortilin has this basic structure, while the other receptors have additional motifs (Figure 1A), indicating a more comprehensive target-recognition profile (Willnow et al., 2008). The sortilins are involved in several physiological functions of the cells and are therefore characterized as multifunctional receptors. Sortilin acts as a receptor or co-receptor in endocytosis, cell survival, signal transduction and directs proteins such as neurotrophins. Similarly, SORLA sorts different kinases, phosphatases, and signaling receptors to their correct intracellular location. SORLA is also a receptor for apolipoprotein E in the brain and is involved in processing amyloid precursor protein. SORCS1 and SORCS3 regulate energy homeostasis as intracellular trafficking receptors for tropomyosin-related kinase B. Furthermore, SORCS1 participate also in amyloid precursor protein processing and insulin secretion in the pancreas. SORCS2 is a co-receptor for proneurothrophins and contributes to producing the oxygen species scavenger glutathione under oxidative stress in neurons. A complete list of sortilins’ binding partners can be found in a more recent review (Malik and Willnow, 2020). Sortilins are expressed throughout the central and the peripheral nervous system in defined cell populations (Willnow et al., 2008). Accordingly, they have mainly been investigated in neurons and glial cells, but their role in the cells of the blood-brain barrier (BBB) has been completely neglected until now.  Related Articles | Metrics

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Motor rehabilitation of aphasic stroke patient: the possibility of Rood’s approach Poonam Chaturvedi, Anuradha Kalani 2023, 18 (3):  551-551.  doi: 10.4103/1673-5374.346467 Abstract ( 166 )   PDF (267KB) ( 73 )   Save Aphasia is an acquired neurogenic language disorder that makes patients unable to comprehend or formulate language. Along with language impairment, patients suffering from aphasia face difficulties in reading, writing, and expressing themselves. The causes of aphasia are stroke, trauma, brain tumors, infections, and injury, particularly to the left hemisphere. About 20% of acute stroke cases in the world account for aphasia. Aphasia is categorized into: non-fluent and fluent forms. Non-fluent is further classified based on language and comprehension into: 1) Broca’s aphasia, 2) transcortical motor aphasia, 3) global aphasia, and 4) transcortical mixed aphasia. In transcortical motor aphasia, the language and comprehension are intact, whereas, in global aphasia, they are distorted. Transcortical mixed aphasia is also called isolation aphasia and it is equivalent to global aphasia. Comprehension of spoken language is severely disturbed in patients having this syndrome. It is common in occlusion of the internal carotid artery. Like non-fluent aphasia, fluent aphasia is also classified according to language and comprehension into conduction aphasia, anomic aphasia, Wernicke’s aphasia, and transcortical sensory aphasia. The language and comprehension in anomic aphasia are intact, while they are impaired in Wernicke’s aphasia and transcortical sensory aphasia. Aphasias such as crossed aphasia and subcortical aphasia are considered “exceptional aphasias,” since they do not fit neatly into this or similar classification systems. A person with conduction aphasia demonstrates language impairment after a brain injury to the dominant hemisphere of the body instead of the alternate side. Therefore, an individual with right-handedness who has suffered a stroke in the right hemisphere would exhibit crossed aphasia. Likewise, damage to subcortical brain regions (e.g., the thalamus or basal ganglia) can lead to subcortical aphasia, and the symptoms can mimic those seen in cortical lesions (Goodglass and Kaplan, 1972; Rogers, 2004; Davis, 2007; Code, 2021) . Related Articles | Metrics

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Eradication of human immunodeficiency virus-1 reservoir in the brain microglia Yuyang Tang, Guochun Jiang 2023, 18 (3):  552-553.  doi: 10.4103/1673-5374.350198 Abstract ( 121 )   PDF (600KB) ( 49 )   Save Antiretroviral therapy (ART) effectively decreases active HIV replication to undetectable levels. Therefore, it greatly improves the quality of life for people living with HIV (PLWH). However, except for a few exceptional cases after stem-cell transplantation from CCR5Δ32 mutation donors, such as in Berlin and London patients, there is no cure for HIV, due to the latent HIV reservoirs harbored in the long-lived HIV permissive cells. HIV quickly rebounds upon the disruption of ART, causing the life-long burden of ART for PLWH in order to control viral replication. Similar to peripheral blood, HIV establishes reservoirs in the brain very early in infection (Putatunda et al., 2019), which is associated with HIV-associated neurocognitive disorders despite ART in PLWH, potentially caused directly by residual HIV replication or indirectly by neuroinflammation. Animal model studies suggest that brain myeloid cells (BMCs) are latently infected and contribute to viral reservoirs in the central nervous system (CNS) (Honeycutt et al., 2016; Avalos et al., 2017). To achieve a cure for HIV, latently infected replication-competent HIV hosted in both periphery and CNS must be targeted by viral eradication strategies.  Related Articles | Metrics

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Brain-derived neurotrophic factor in main neurodegenerative diseases Serena Camuso, Sonia Canterini 2023, 18 (3):  554-555.  doi: 10.4103/1673-5374.350199 Abstract ( 131 )   PDF (624KB) ( 41 )   Save Discovered in pig brains in 1982, the brain-derived neurotrophic factor (BDNF) is one of the most studied and characterized neurotrophins in the central nervous system. In recent years, BDNF has received considerable attention for its importance in the development and maintenance of normal brain function. This is because BDNF plays an important role in crucial functions of the nervous system, such as the survival, differentiation, and maturation of neurons and glial cells as well as the actions of neuroprotection in adverse conditions, such as glutamatergic overstimulation, cerebral ischemia, hypoglycemia, and neurotoxicity (Kowiański et al., 2018). Related Articles | Metrics

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The best of both worlds: mastering nerve regeneration combining biological and nanotechnological tools Paula A. Soto, Marcela B. Fernández van Raap, C. Patricia Setton-Avruj 2023, 18 (3):  556-557.  doi: 10.4103/1673-5374.350201 Abstract ( 116 )   PDF (1755KB) ( 37 )   Save Over the last decade, remarkable developments in nanotechnology have powered medical research, unveiling new approaches for the solution of public health issues such as the treatment of traumatic peripheral neuropathies. Related Articles | Metrics

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Strategies to treat neurodegeneration in neuronal ceroid lipofuscinosis: a view onto the retina Udo Bartsch 2023, 18 (3):  558-559.  doi: 10.4103/1673-5374.350202 Abstract ( 129 )   PDF (876KB) ( 31 )   Save Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is the umbrella term for a group of neurodegenerative lysosomal storage disorders with onset mainly in childhood. The total 13 genetically distinct NCLs are caused by mutations in genes encoding soluble or transmembrane proteins, and have been classified according to the affected gene into CLN1 to CLN8 and CLN10 to CLN14. Intracellular accumulation of autofluorescent storage material due to lysosomal dysfunction is a hallmark of all NCLs. Patients affected by this fatal life-limiting disorder typically present with mental retardation, motor impairment, epileptic seizures, and brain atrophy. Progressive retinal degeneration and vision loss are other hallmarks of the majority of NCLs (for details, see Kohlschutter et al., 2019). Rare cases of patients presenting with non-syndromic retinal dystrophies indicate that the retina is particularly sensitive to lysosomal dysfunctions in some NCLs. With the only exception of a brain-directed enzyme replacement therapy (ERT) for CLN2 disease, a condition caused by dysfunctions of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1), there are currently no approved treatment options for these fatal disorders. Studies on animal models of different NCLs have demonstrated the efficacy of various treatment strategies to attenuate neurodegeneration in the brain, and some of them are currently being evaluated in clinical trials (Kohlschutter et al., 2019). The preclinical data and first results from an ERT and a gene therapy trial on CLN2 patients suggest, however, that brain-directed treatments have no or only a minor therapeutic impact on retinal degeneration and vision loss (discussed in Liu et al., 2022). Thus, there is a need to combine retina- and brain-directed therapies to combat both vision loss and neurological symptoms. In fact, preservation of vision not only requires preservation of retina function but additionally functional preservation of the visual centers in the brain. Related Articles | Metrics

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Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage Liu-Ting Hu, Bing-Yang Wang, Yu-Hua Fan, Zhi-Yi He, Wen-Xu Zheng 2023, 18 (3):  560-567.  doi: 10.4103/1673-5374.346551 Abstract ( 192 )   PDF (7185KB) ( 46 )   Save Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.  Related Articles | Metrics

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Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice Lu-Yao Li, Qi Wang, Lu Deng, Zhen Lin, Jing-Jing Lin, Xin-Ye Wang, Tian-Yang Shen, Yi-Hui Zheng, Wei Lin, Pei-Jun Li, Xiao-Qin Fu, Zhen-Lang Lin 2023, 18 (3):  568-576.  doi: 10.4103/1673-5374.350203 Abstract ( 146 )   PDF (11899KB) ( 24 )   Save Recent studies have shown that chlorogenic acid (CGA), which is present in coffee, has protective effects on the nervous system. However, its role in neonatal hypoxic-ischemic brain injury remains unclear. In this study, we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA. We found that CGA intervention effectively reduced the volume of cerebral infarct, alleviated cerebral edema, restored brain tissue structure after injury, and promoted axon growth in injured brain tissue. Moreover, CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival. In addition, changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA. Furthermore, CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2. In summary, our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis, providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury. Related Articles | Metrics

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DUSP2 deletion with CRISPR/Cas9 promotes Mauthner cell axonal regeneration at the early stage of zebrafish Guo-Jian Shao, Xin-Liang Wang, Mei-Li Wei, Da-Long Ren, Bing Hu 2023, 18 (3):  577-581.  doi: 10.4103/1673-5374.350208 Abstract ( 136 )   PDF (5605KB) ( 75 )   Save Axon regeneration of central neurons is a complex process that is tightly regulated by multiple extrinsic and intrinsic factors. The expression levels of distinct genes are changed after central neural system (CNS) injury and affect axon regeneration. A previous study identified dusp2 as an upregulated gene in zebrafish with spinal cord injury. Here, we found that dual specificity phosphatase 2 (DUSP2) is a negative regulator of axon regeneration of the Mauthner cell (M-cell). DUSP2 is a phosphatase that mediates the dephosphorylation of JNK. In this study, we knocked out dusp2 by CRISPR/Cas9 and found that M-cell axons of dusp2–/– zebrafish had a better regeneration at the early stage after birth (within 8 days after birth), while those of dusp2+/– zebrafish did not. Overexpression of DUSP2 in Tg (Tol 056)  zebrafish by single-cell electroporation retarded the regeneration of M-cell axons. Western blotting results showed that DUSP2 knockout slightly increased the levels of phosphorylated JNK. These findings suggest that knocking out DUSP2 promoted the regeneration of zebrafish M-cell axons, possibly through enhancing JNK phosphorylation.  Related Articles | Metrics

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Association between brain N-acetylaspartate levels and sensory and motor dysfunction in patients who have spinal cord injury with spasticity: an observational case-control study Jia-Yi Liu, Ya-Jing Li, Xin-Ying Cong, Zuliyaer Talifu, Xin Zhang, Feng Gao, Jian-Jun Li 2023, 18 (3):  582-586.  doi: 10.4103/1673-5374.350216 Abstract ( 169 )   PDF (3097KB) ( 47 )   Save Spinal cord injury is a severe and devastating disease, and spasticity is a common and severe complication that is notoriously refractory to treatment. However, the pathophysiological mechanisms underlying spasticity and its development remain largely unknown. The goal of the present study was to find differences, if any, in metabolites of the left precentral gyrus and basal ganglia of patients who have spinal cord injury with or without spasticity, and to explore the relationship between the brain metabolite concentrations and clinical status. Thirty-six participants were recruited for magnetic resonance spectroscopic examination: 23 with spinal cord injury (12 with spasticity and 11 without spasticity) and 13 healthy controls. We acquired localized proton spectra from the precentral gyrus and basal ganglia via 10 mm3 voxels. Notably, univariate linear regression analysis demonstrated that the lower that the N-acetylaspartate concentration (a marker for neuronal loss) was in the precentral gyrus of the patients, the lower their ASIA (American Spinal Injury Association) light-touch scores, pinprick scores, and motor scores. Additionally, longer durations of injury were associated with higher N-acetylaspartate levels in the precentral gyrus. Compared with the healthy participants and patients without spasticity, N-acetylaspartate levels in the patients with spasticity were significantly lower in both the precentral gyrus and basal ganglia. Lower N-acetylaspartate levels also correlated with greater sensory and motor dysfunction in the patients who had spinal cord injury with spasticity. Related Articles | Metrics

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Proteomics of serum exosomes identified fibulin-1 as a novel biomarker for mild cognitive impairment Bo Chen, Li Song, Juan Yang, Wei-Ying Zhou, Yuan-Yuan Cheng, Yu-Jie Lai 2023, 18 (3):  587-593.  doi: 10.4103/1673-5374.347740 Abstract ( 358 )   PDF (9660KB) ( 86 )   Save Mild cognitive impairment (MCI) is a prodrome of Alzheimer’s disease pathology. Cognitive impairment patients often have a delayed diagnosis because there are no early symptoms or conventional diagnostic methods. Exosomes play a vital role in cell-to-cell communications and can act as promising biomarkers in diagnosing diseases. This study was designed to identify serum exosomal candidate proteins that may play roles in diagnosing MCI. Mass spectrometry coupled with tandem mass tag approach-based non-targeted proteomics was used to show the differentially expressed proteins in exosomes between MCI patients and healthy controls, and these differential proteins were validated using immunoblot and enzyme-linked immunosorbent assays. Correlation of cognitive performance with the serum exosomal protein level was determined. Nanoparticle tracking analysis suggested that there was a higher serum exosome concentration and smaller exosome diameter in individuals with MCI compared with healthy controls. We identified 69 exosomal proteins that were differentially expressed between MCI patients and healthy controls using mass spectrometry analysis. Thirty-nine exosomal proteins were upregulated in MCI patients compared with those in control patients. Exosomal fibulin-1, with an area under the curve value of 0.81, may be a biomarker for an MCI diagnosis. The exosomal protein signature from MCI patients reflected the cell adhesion molecule category. In particular, higher exosomal fibulin-1 levels correlated with lower cognitive performance. Thus, this study revealed that exosomal fibulin-1 is a promising biomarker for diagnosing MCI. Related Articles | Metrics

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Activation of metabotropic glutamate receptor 1 regulates hippocampal CA1 region excitability in rats with status epilepticus by suppressing the HCN1 channel Xiao-Dan Luo, Tao Xiang, Si-Jun Li, Mei-Gang Ma, Mei-Ling Chen, Yuan Wu 2023, 18 (3):  594-602.  doi: 10.4103/1673-5374.350206 Abstract ( 149 )   PDF (6655KB) ( 128 )   Save Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels alters neuronal excitability. However, the role of HCN channels in status epilepticus is not fully understood. In this study, we established rat models of pentylenetetrazole-induced status epilepticus. We performed western blot assays and immunofluorescence staining. Our results showed that HCN1 channel protein expression, particularly HCN1 surface protein, was significantly decreased in the hippocampal CA1 region, whereas the expression of HCN2 channel protein was unchanged. Moreover, metabolic glutamate receptor 1 (mGluR1) protein expression was increased after status epilepticus. The mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of pentylenetetrazole-induced status epilepticus, whereas application of the mGluR1 antagonist (+)-2-methyl-4-carboxyphenylglycine (LY367385) alleviated the severity of pentylenetetrazole-induced status epilepticus. The results from double immunofluorescence labeling revealed that mGluR1 and HCN1 were co-localized in the CA1 region. Subsequently, a protein kinase A inhibitor (H89) administered intraperitoneally successfully reversed HCN1 channel inhibition, thereby suppressing the severity and prolonging the latency of pentylenetetrazole-induced status epilepticus. Furthermore, H89 reduced the level of mGluR1, downregulated cyclic adenosine monophosphate (cAMP)/protein kinase A expression, significantly increased tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) (1a-4) expression, and restored TRIP8b (1b-2) levels. TRIP8b (1a-4) and TRIP8b (1b-2) are subunits of Rab8b interacting protein that regulate HCN1 surface protein.  Related Articles | Metrics

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β2-Microglobulin exacerbates neuroinflammation, brain damage, and cognitive impairment after stroke in rats Feng Chen, Jing Liu, Fa-Qiang Li, Shuai-Shuai Wang, Yan-Yan Zhang, Yun-Yun Lu, Fang-Fang Hu, Rui-Qin Yao 2023, 18 (3):  603-608.  doi: 10.4103/1673-5374.350204 Abstract ( 140 )   PDF (6376KB) ( 56 )   Save β2-Microglobulin (β2M), a component of the major histocompatibility complex class I molecule, is associated with aging-related cognitive impairment and Alzheimer’s disease. Although upregulation of β2M is considered to be highly related to ischemic stroke, the specific role and underlying mechanistic action of β2M are poorly understood. In this study, we established a rat model of focal cerebral ischemia by occlusion of the middle cerebral artery. We found that β2M levels in the cerebral spinal fluid, serum, and brain tissue were significantly increased in the acute period but gradually decreased during the recovery period. RNA interference was used to inhibit β2M expression in the acute period of cerebral stroke. Tissue staining with 2,3,5-triphenyltetrazolium chloride and evaluation of cognitive function using the Morris water maze test demonstrated that decreased β2M expression in the ischemic penumbra reduced infarct volume and alleviated cognitive deficits, respectively. Notably, glial cell, caspase-1 (p20), and Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation as well as production of the inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α were also effectively inhibited by β2M silencing. These findings suggest that β2M participates in brain injury and cognitive impairment in a rat model of ischemic stroke through activation of neuroinflammation associated with the NLRP3 inflammasome. Related Articles | Metrics

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Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes Hai-Li Lang, Yan-Zhi Zhao, Ren-Jie Xiao, Jing Sun, Yong Chen, Guo-Wen Hu, Guo-Hai Xu 2023, 18 (3):  609-617.  doi: 10.4103/1673-5374.350205 Abstract ( 150 )   PDF (6766KB) ( 47 )   Save Postoperative cognitive dysfunction (POCD) is a common surgical complication. Diabetes mellitus (DM) increases risk of developing POCD after surgery. DM patients with POCD seriously threaten the quality of patients’ life, however, the intrinsic mechanism is unclear, and the effective treatment is deficiency. Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD. In this study, we constructed a mouse model of DM by intraperitoneal injection of streptozotocin, and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion. We found that mouse models of DM-POCD exhibited the most serious cognitive impairment, as well as the most hippocampal neural stem cells (H-NSCs) loss and neurogenesis decline. Subsequently, we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) might promote neurogenesis and restore cognitive function in patients with DM-POCD. iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery, and then once every 3 days for 1 month thereafter. Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs, and reversed cognitive impairment in mouse models of DM-POCD. Furthermore, miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs. We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis. As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C, while miR-486-5p can inhibit FoxO1 in NSCs. We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4, CDKN2C, and FoxO1 expression in H-NSCs. Collectively, these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD, the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction. Related Articles | Metrics

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Neuroprotective effects of neural stem cells pretreated with neuregulin1β on PC12 cells exposed to oxygen-glucose deprivation/reoxygenation Qiu-Yue Zhai, Yuan-Hua Ye, Yu-Qian Ren, Zhen-Hua Song, Ke-Li Ge, Bao-He Cheng, Yun-Liang Guo 2023, 18 (3):  618-625.  doi: 10.4103/1673-5374.350207 Abstract ( 163 )   PDF (6339KB) ( 54 )   Save Studies on ischemia/reperfusion (I/R) injury suggest that exogenous neural stem cells (NSCs) are ideal candidates for stem cell therapy reperfusion injury. However, NSCs are difficult to obtain owing to ethical limitations. In addition, the survival, differentiation, and proliferation rates of transplanted exogenous NSCs are low, which limit their clinical application. Our previous study showed that neuregulin1β (NRG1β) alleviated cerebral I/R injury in rats. In this study, we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1β on PC12 cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R). Our results found that 5 and 10 nM NRG1β promoted the generation and proliferation of NSCs. Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1β improved the level of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, nicotinamide adenine dinucleotide phosphate, and nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial damage in injured PC12 cells; these indexes are related to ferroptosis. Research has reported that p53 and solute carrier family 7 member 11 (SLC7A11) play vital roles in ferroptosis caused by cerebral I/R injury. Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4 (GPX4) was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells, but this change was alleviated after co-culturing NSCs with damaged PC12 cells. These findings suggest that NSCs pretreated with NRG1β exhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway. Related Articles | Metrics

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Bioinformatics analysis of ferroptosis in spinal cord injury Jin-Ze Li, Bao-You Fan, Tao Sun, Xiao-Xiong Wang, Jun-Jin Li, Jian-Ping Zhang, Guang-Jin Gu, Wen-Yuan Shen, De-Rong Liu, Zhi-Jian Wei, Shi-Qing Feng 2023, 18 (3):  626-633.  doi: 10.4103/1673-5374.350209 Abstract ( 221 )   PDF (7155KB) ( 73 )   Save Ferroptosis plays a key role in aggravating the progression of spinal cord injury (SCI), but the specific mechanism remains unknown. In this study, we constructed a rat model of T10 SCI using a modified Allen method. We identified 48, 44, and 27 ferroptosis genes that were differentially expressed at 1, 3, and 7 days after SCI induction. Compared with the sham group and other SCI subgroups, the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower. These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression. Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI: STAT3, JUN, TLR4, ATF3, HMOX1, MAPK1, MAPK9, PTGS2, VEGFA, and RELA. Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3, JUN, TLR4, ATF3, HMOX1, PTGS2, and RELA mRNA levels were up-regulated and VEGFA, MAPK1 and MAPK9 mRNA levels were down-regulated. Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI. We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs, 10 miRNAs, and 12 genes. Our results help further the understanding of the mechanism underlying ferroptosis in SCI. Related Articles | Metrics

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Chronic spinal cord compression associated with intervertebral disc degeneration in SPARC-null mice Zhuo-Yao Li, Ai-Fang Zhou, Gan Li, Long-Yun Zhou, Pei-Min Pu, Ke Zhu, Zhong Zheng, Yong-Jun Wang, Qian-Qian Liang, Min Yao, Xue-Jun Cui 2023, 18 (3):  634-642.  doi: 10.4103/1673-5374.350210 Abstract ( 121 )   PDF (8915KB) ( 41 )   Save Chronic spinal cord compression (CSCC) is induced by disc herniation and other reasons, leading to movement and sensation dysfunction, with a serious impact on quality of life. Spontaneous disc herniation rarely occurs in rodents, and therefore establishing a chronic spinal cord compression (CSCC) animal model is of crucial importance to explore the pathogenesis and treatment of CSCC. The absence of secreted protein, acidic, and rich in cysteine (SPARC) leads to spontaneous intervertebral disc degeneration in mice, which resembles human disc degeneration. In this study, we evaluated whether SPARC-null mice may serve as an animal model for CSCC. We performed rod rotation test, pain threshold test, gait analysis, and Basso Mouse Scale score. Our results showed that the motor function of SPARC-null mice was weakened, and magnetic resonance images revealed compression at different spinal cord levels, particularly in the lumbar segments. Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes, activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype; it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway. Notably, these findings are characteristics of CSCC. Therefore, we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation. Related Articles | Metrics

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TMEM16F may be a new therapeutic target for Alzheimer’s disease Zhi-Qiang Cui, Xiao-Ying Hu, Tuo Yang, Jing-Wei Guan, Ying Gu, Hui-Yuan Li, Hui-Yu Zhang, Qing-Huan Xiao, Xiao-Hong Sun 2023, 18 (3):  643-651.  doi: 10.4103/1673-5374.350211 Abstract ( 189 )   PDF (33747KB) ( 42 )   Save TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ25–35) to stimulate human microglia to construct microglia models of Alzheimer’s disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ25–35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer’s disease treatment. Related Articles | Metrics

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Hypoxic pre-conditioned adipose-derived stem/progenitor cells embedded in fibrin conduits promote peripheral nerve regeneration in a sciatic nerve graft model Julius M. Mayer, Christian Krug, Maximilian M. Saller, Annette Feuchtinger, Riccardo E. Giunta, Elias Volkmer, Thomas Holzbach 2023, 18 (3):  652-656.  doi: 10.4103/1673-5374.346464 Abstract ( 146 )   PDF (6827KB) ( 164 )   Save Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells (ADSPCs) in peripheral nerve recovery. Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs. This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned (2% oxygen for 72 hours) autologous ADSPCs (n = 9). This treatment mode was compared with three others: fibrin conduit seeded with ADSPCs cultivated under normoxic conditions (n = 9); non-cell-carrying conduit (n = 9); and nerve autograft only (n = 9). A 16-week follow-up included functional testing (sciatic functional index and static sciatic index) as well as postmortem muscle mass analyses and morphometric nerve evaluations (histology, g-ratio, axon density, and diameter). At 8 weeks, the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups, indicating faster functional regeneration. Furthermore, histologic evaluation showed significantly increased axon outgrowth/branching, axon density, remyelination, and a reduced relative connective tissue area. Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts. Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice. Related Articles | Metrics

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A hyaluronic acid granular hydrogel nerve guidance conduit promotes regeneration and functional recovery of injured sciatic nerves in rats Jie Yang, Chia-Chen Hsu, Ting-Ting Cao, Hua Ye, Jing Chen, Yun-Qing Li 2023, 18 (3):  657-663.  doi: 10.4103/1673-5374.350212 Abstract ( 185 )   PDF (4582KB) ( 98 )   Save A hyaluronic acid granular hydrogel can promote neuronal and astrocyte colony formation and axonal extension in vitro, suggesting that the hydrogel can simulate an extracellular matrix structure to promote neural regeneration. However, in vivo experiments have not been conducted. In this study, we transplanted a hyaluronic acid granular hydrogel nerve guidance conduit to repair a 10-mm long sciatic nerve gap. The Basso, Beattie, and Bresnahan locomotor rating scale, sciatic nerve compound muscle action potential recording, Fluoro-Gold retrograde tracing, growth related protein 43/S100 immunofluorescence staining, transmission electron microscopy, gastrocnemius muscle dry/wet weight ratio, and Masson’s trichrome staining results showed that the nerve guidance conduit exhibited similar regeneration of sciatic nerve axons and myelin sheath, and recovery of the electrophysiological function and motor function as autologous nerve transplantation. The conduit results were superior to those of a bulk hydrogel or silicone tube transplant. These findings suggest that tissue-engineered nerve conduits containing hyaluronic acid granular hydrogels effectively promote the morphological and functional recovery of the injured sciatic nerve. The nerve conduits have the potential as a material for repairing peripheral nerve defects.  Related Articles | Metrics

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A decellularized nerve matrix scaffold inhibits neuroma formation in the stumps of transected peripheral nerve after peripheral nerve injury Shuai Qiu, Pei-Jun Deng, Fu-Lin He, Li-Wei Yan, Zhe-Hui Tu, Xiao-Lin Liu, Da-Ping Quan, Ying Bai, Can-Bin Zheng, Qing-Tang Zhu 2023, 18 (3):  664-670.  doi: 10.4103/1673-5374.350213 Abstract ( 132 )   PDF (44106KB) ( 37 )   Save Traumatic painful neuroma is an intractable clinical disease characterized by improper extracellular matrix (ECM) deposition around the injury site. Studies have shown that the microstructure of natural nerves provides a suitable microenvironment for the nerve end to avoid abnormal hyperplasia and neuroma formation. In this study, we used a decellularized nerve matrix scaffold (DNM-S) to prevent against the formation of painful neuroma after sciatic nerve transection in rats. Our results showed that the DNM-S effectively reduced abnormal deposition of ECM, guided the regeneration and orderly arrangement of axon, and decreased the density of regenerated axons. The epineurium-perilemma barrier prevented the invasion of vascular muscular scar tissue, greatly reduced the invasion of α-smooth muscle actin-positive myofibroblasts into nerve stumps, effectively inhibited scar formation, which guided nerve stumps to gradually transform into a benign tissue and reduced pain and autotomy behaviors in animals. These findings suggest that DNM-S-optimized neuroma microenvironment by ECM remodeling may be a promising strategy to prevent painful traumatic neuromas.  Related Articles | Metrics

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Sequential expression of miR-221-3p and miR-338-3p in Schwann cells as a therapeutic strategy to promote nerve regeneration and functional recovery Li-Li Wen, Tian-Hao Yu, Yi-Zhan Ma, Xiao-Yan Mao, Tian-Rang Ao, Rabia Javed, Hirotomo Ten, Akira Matsuno, Qiang Ao 2023, 18 (3):  671-682.  doi: 10.4103/1673-5374.350214 Abstract ( 119 )   PDF (37434KB) ( 43 )   Save The functional properties of endogenous Schwann cells (SCs) during nerve repair are dynamic. Optimizing the functional properties of SCs at different stages of nerve repair may have therapeutic benefit in improving the repair of damaged nerves. Previous studies showed that miR-221-3p promotes the proliferation and migration of SCs, and miR-338-3p promotes the myelination of SCs. In this study, we established rat models of sciatic nerve injury by bridging the transected sciatic nerve with a silicone tube. We injected a miR-221 lentiviral vector system together with a doxycycline-inducible Tet-On miR-338 lentiviral vector system into the cavity of nerve conduits of nerve stumps to sequentially regulate the biological function of endogenous SCs at different stages of nerve regeneration. We found that the biological function of SCs was sequentially regulated, the diameter and density of myelinated axons were increased, the expression levels of NF200 and myelin basic protein were increased, and the function of injured peripheral nerve was improved using this system. miRNA Target Prediction Database prediction, Nanopore whole transcriptome sequencing, quantitative PCR, and dual luciferase reporter gene assay results predicted and verified Cdkn1b and Nrp1 as target genes of miR-221-3p and miR-338-3p, respectively, and their regulatory effects on SCs were confirmed in vitro. In conclusion, here we established a new method to enhance nerve regeneration through sequential regulation of biological functions of endogenous SCs, which establishes a new concept and model for the treatment of peripheral nerve injury. The findings from this study will provide direct guiding significance for clinical treatment of sciatic nerve injury. Related Articles | Metrics

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An ultrasound-guided percutaneous electrical nerve stimulation regimen devised using finite element modeling promotes functional recovery after median nerve transection Xiao-Lei Chu, Xi-Zi Song, Yu-Ru Li, Zi-Ren Wu, Qi Li, Qing-Wen Li, Xiao-Song Gu, Dong Ming 2023, 18 (3):  683-688.  doi: 10.4103/1673-5374.350215 Abstract ( 179 )   PDF (4821KB) ( 45 )   Save Percutaneous electrical nerve stimulation of an injured nerve can promote and accelerate peripheral nerve regeneration and improve function. When performing acupuncture and moxibustion, locating the injured nerve using ultrasound before percutaneous nerve stimulation can help prevent further injury to an already injured nerve. However, stimulation parameters have not been standardized. In this study, we constructed a multi-layer human forearm model using finite element modeling. Taking current density and activated function as optimization indicators, the optimal percutaneous nerve stimulation parameters were established. The optimal parameters were parallel placement located 3 cm apart with the injury site at the midpoint between the needles. To validate the efficacy of this regimen, we performed a randomized controlled trial in 23 patients with median nerve transection who underwent neurorrhaphy. Patients who received conventional rehabilitation combined with percutaneous electrical nerve stimulation experienced greater improvement in sensory function, motor function, and grip strength than those who received conventional rehabilitation combined with transcutaneous electrical nerve stimulation. These findings suggest that the percutaneous electrical nerve stimulation regimen established in this study can improve global median nerve function in patients with median nerve transection. Related Articles | Metrics