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15 March 2025, Volume 20 Issue 3 Previous Issue   

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Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer’s disease Yanxin Shen, Guimei Zhang, Chunxiao Wei, Panpan Zhao, Yongchun Wang, Mingxi Li, Li Sun 2025, 20 (3):  613-631.  doi: 10.4103/NRR.NRR-D-23-01343 Abstract ( 164 )   PDF (4592KB) ( 80 )   Save Alzheimer’s disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer’s disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer’s disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer’s disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer’s disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer’s disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer’s disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer’s disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer’s disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer’s disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer’s disease. Related Articles | Metrics

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Cell polarization in ischemic stroke: molecular mechanisms and advances Yuanwei Li, Xiaoxiao Xu, Xuan Wu, Jiarui Li, Shiling Chen, Danyang Chen, Gaigai Li, Zhouping Tang 2025, 20 (3):  632-645.  doi: 10.4103/NRR.NRR-D-23-01336 Abstract ( 128 )   PDF (1539KB) ( 86 )   Save Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations (microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke. Related Articles | Metrics

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Toward understanding the role of genomic repeat elements in neurodegenerative diseases Zhengyu An, Aidi Jiang, Jingqi Chen 2025, 20 (3):  646-659.  doi: 10.4103/NRR.NRR-D-23-01568 Abstract ( 83 )   PDF (8117KB) ( 24 )   Save Neurodegenerative diseases cause great medical and economic burdens for both patients and society; however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements. Related Articles | Metrics

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From single to combinatorial therapies in spinal cord injuries for structural and functional restoration Ernesto Doncel-Pérez, Gabriel Guízar-Sahagún, Israel Grijalva-Otero 2025, 20 (3):  660-670.  doi: 10.4103/NRR.NRR-D-23-01928 Abstract ( 58 )   PDF (4908KB) ( 35 )   Save Spinal cord injury results in paralysis, sensory disturbances, sphincter dysfunction, and multiple systemic secondary conditions, most arising from autonomic dysregulation. All this produces profound negative psychosocial implications for affected people, their families, and their communities; the financial costs can be challenging for their families and health institutions. Treatments aimed at restoring the spinal cord after spinal cord injury, which have been tested in animal models or clinical trials, generally seek to counteract one or more of the secondary mechanisms of injury to limit the extent of the initial damage. Most published works on structural/functional restoration in acute and chronic spinal cord injury stages use a single type of treatment: a drug or trophic factor, transplant of a cell type, and implantation of a biomaterial. Despite the significant benefits reported in animal models, when translating these successful therapeutic strategies to humans, the result in clinical trials has been considered of little relevance because the improvement, when present, is usually insufficient. Until now, most studies designed to promote neuroprotection or regeneration at different stages after spinal cord injury have used single treatments. Considering the occurrence of various secondary mechanisms of injury in the acute and sub-acute phases of spinal cord injury, it is reasonable to speculate that more than one therapeutic agent could be required to promote structural and functional restoration of the damaged spinal cord. Treatments that combine several therapeutic agents, targeting different mechanisms of injury, which, when used as a single therapy, have shown some benefits, allow us to assume that they will have synergistic beneficial effects. Thus, this narrative review article aims to summarize current trends in the use of strategies that combine therapeutic agents administered simultaneously or sequentially, seeking structural and functional restoration of the injured spinal cord. Related Articles | Metrics

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Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production Angelid Pabon, Jagannatham Naidu Bhupana, Ching-On Wong 2025, 20 (3):  671-681.  doi: 10.4103/NRR.NRR-D-23-02095 Abstract ( 96 )   PDF (5035KB) ( 21 )   Save Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation. Related Articles | Metrics

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Context-dependent role of sirtuin 2 in inflammation Noemí Sola-Sevilla, Maider Garmendia-Berges, MCarmen Mera-Delgado, Elena Puerta 2025, 20 (3):  682-694.  doi: 10.4103/NRR.NRR-D-23-02063 Abstract ( 72 )   PDF (1458KB) ( 33 )   Save Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide (NAD+ )- dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domainleucine-rich-repeat and pyrin domain-containing protein 3 (NLRP3). However, whether sirtuin 2-mediated pathways induce a pro- or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases. Related Articles | Metrics

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Liver as a new target organ in Alzheimer’s disease: insight from cholesterol metabolism and its role in amyloid-beta clearance Beibei Wu, Yuqing Liu, Hongli Li, Lemei Zhu, Lingfeng Zeng, Zhen Zhang, Weijun Peng 2025, 20 (3):  695-714.  doi: 10.4103/1673-5374.391305 Abstract ( 103 )   PDF (1342KB) ( 77 )   Save Alzheimer’s disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer’s disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer’s disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer’s disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer’s disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer’s disease. In this review, we explore the underlying causes of Alzheimer’s disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer’s disease. Related Articles | Metrics

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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders Xin Yang, Yu-Wen Alvin Huang, John Marshall 2025, 20 (3):  715-724.  doi: 10.4103/NRR.NRR-D-23-02000 Abstract ( 138 )   PDF (1019KB) ( 101 )   Save Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer’s disease and Huntington’s disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects. Related Articles | Metrics

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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets Benjamin R. Helmold, Angela Ahrens, Zachary Fitzgerald, P. Hande Ozdinler 2025, 20 (3):  725-739.  doi: 10.4103/NRR.NRR-D-23-02068 Abstract ( 68 )   PDF (13247KB) ( 30 )   Save Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying diseasecausing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein– protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration– approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous. Related Articles | Metrics

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Lipid droplets in the nervous system: involvement in cell metabolic homeostasis Yuchen Zhang, Yiqing Chen, Cheng Zhuang, Jingxuan Qi, Robert Chunhua Zhao, Jiao Wang 2025, 20 (3):  740-750.  doi: 10.4103/NRR.NRR-D-23-01401 Abstract ( 333 )   PDF (8205KB) ( 122 )   Save Lipid droplets serve as primary storage organelles for neutral lipids in neurons, glial cells, and other cells in the nervous system. Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum. Previously, lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis; however, recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system. In addition to their role in regulating cell metabolism, lipid droplets play a protective role in various cellular stress responses. Furthermore, lipid droplets exhibit specific functions in neurons and glial cells. Dysregulation of lipid droplet formation leads to cellular dysfunction, metabolic abnormalities, and nervous system diseases. This review aims to provide an overview of the role of lipid droplets in the nervous system, covering topics such as biogenesis, cellular specificity, and functions. Additionally, it will explore the association between lipid droplets and neurodegenerative disorders. Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases. Related Articles | Metrics

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Role of copper chelating agents: between old applications and new perspectives in neuroscience Rosalba Leuci, Leonardo Brunetti, Vincenzo Tufarelli, Marco Cerini, Marco Paparella, Nikola Puvača, Luca Piemontese 2025, 20 (3):  751-762.  doi: 10.4103/NRR.NRR-D-24-00140 Abstract ( 148 )   PDF (1070KB) ( 102 )   Save The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper (II) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer’s and other diseases (such as Parkinson’s and Wilson’s diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer’s disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions. Related Articles | Metrics

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Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases Minghuang Gao, Xinyue Wang, Shijie Su, Weicheng Feng, Yaona Lai, Kongli Huang, Dandan Cao, Qi Wang 2025, 20 (3):  763-778.  doi: 10.4103/NRR.NRR-D-23-01595 Abstract ( 137 )   PDF (4542KB) ( 51 )   Save Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity. Related Articles | Metrics

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Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies Guangyong Zhang, Qing Yao, Chubing Long, Pengcheng Yi, Jiali Song, Luojia Wu, Wei Wan, Xiuqin Rao, Yue Lin, Gen Wei, Jun Ying, Fuzhou Hua 2025, 20 (3):  779-793.  doi: 10.4103/NRR.NRR-D-23-01508 Abstract ( 166 )   PDF (8068KB) ( 38 )   Save Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases. Related Articles | Metrics

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Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging Neville Ng, Michelle Newbery, Nicole Miles, Lezanne Ooi 2025, 20 (3):  794-796.  doi: 10.4103/NRR.NRR-D-23-02106 Abstract ( 126 )   PDF (4260KB) ( 46 )   Save Mitochondrial dysfunction and neurodegeneration: Progressive neurodegenerative diseases affect a significant proportion of the population; in a single year, there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases. Mitochondrial function, aging, and neurodegenerative processes appear to be intricately linked; central nervous system degeneration is a major feature of loss-of-function mitochondrial diseases, involving mutation of nuclear or mitochondrial DNA. Meanwhile, mitochondrial dysfunction occurs during healthy aging and is further associated with several neurological diseases, including Alzheimer’s disease (AD), Huntington’s disease, Friedreich’s ataxia, multiple sclerosis, motor neuron disease, Parkinson’s disease (PD), and vanishing white matter disease (VWMD) (Figure 1A). Aging increases neurodegenerative risk factors and processes, including progressively impaired cognitive and/or motor function due to cellular dysfunction, senescence, and/or neuronal death. Furthermore, impaired mitochondrial respiration, biogenesis, mitophagy, and axonal transport can be causative factors in dysfunctional protein synthesis, folding, aggregation, and trafficking, as well as inflammation, oxidative stress, and genomic instability. Related Articles | Metrics

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Injury/ischemia-induced stem cells: up-to-date knowledge and future perspectives for neural regeneration Takayuki Nakagomi 2025, 20 (3):  797-798.  doi: 10.4103/NRR.NRR-D-24-00180 Abstract ( 79 )   PDF (1236KB) ( 47 )   Save Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells (iSCs) are present in the post-stroke mouse (Nakagomi et al., 2009) and human brains (Beppu et al., 2019). Additionally, we demonstrated that not only mouse-derived (Nakagomi et al., 2009) but also human-derived iSCs (Beppu et al., 2019) produce electrophysiological functional neurons in vitro. Further, we recently demonstrated that transplantation of human-derived iSCs into poststroke mice improves neurological function, presumably by neural replacement and the formation of neural networks with endogenous neurons (Nakagomi et al., 2023). Thus, iSCs may play an important role in neural regeneration after brain injuries, such as ischemic stroke. Herein, we introduce the concept, origin, traits, and roles of iSCs and their future perspectives based on our recent findings. Related Articles | Metrics

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Insights from a proteomic atlas of human Alzheimer’s disease brain tissue Tomas Kavanagh, Eleanor Drummond 2025, 20 (3):  799-800.  doi: 10.4103/NRR.NRR-D-24-00215 Abstract ( 66 )   PDF (1320KB) ( 43 )   Save There is an urgent need to identify new drug targets for Alzheimer’s disease (AD). While new immunotherapies show promise, clinical benefit appears low, and side effects are high. A greater understanding of the disease mechanisms driving AD is an essential factor that will facilitate the identification of new, effective drug targets. Historically, the pathological roles of amyloid-beta and phosphorylated tau have been the primary research focus of the AD field. However, the influx of data from omics studies over the last decade has convincingly demonstrated that there are thousands of molecular changes that occur in human brain tissue throughout AD, including many that could be disease drivers, novel drug targets, and biomarkers. Excellent progress has particularly been made in the AD proteomics field (Bai et al., 2021; Rayaprolu et al., 2021). The goal of our recent study (Askenazi et al., 2023) was to amalgamate this wealth of new proteomic data into a new open-access and user-friendly resource – NeuroPro (https://neuropro.biomedical.hosting/; Askenazi et al., 2023) – which provides a comprehensive roadmap of all protein changes present in human AD brain tissue. NeuroPro currently combines data from 38 proteomic studies of human AD brain tissue that were carefully curated and harmonized. Currently, NeuroPro provides information about protein changes across thirteen brain regions, three disease stages (preclinical AD, mild cognitive impairment, and advanced AD), and three neuropathological features present in AD (amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy). Our goal is to continue to update NeuroPro as additional proteomic studies are published in the future. Related Articles | Metrics

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Decoding complexity: the need to enhance precision and streamline spatial understanding in neuroscience Sameehan Mahajani, Armita Salahi, Brenda Gonzalez, Charlotte Nelson, Frank Hsiung 2025, 20 (3):  801-802.  doi: 10.4103/NRR.NRR-D-23-02067 Abstract ( 71 )   PDF (4735KB) ( 19 )   Save Neuroscience is the ultimate frontier in our quest for a comprehensive understanding of human behavior. Since its launch in 2009, the Human Connectome Project has emerged as a pioneering force, making heroic strides in elucidating the intricate correlation between structural information and the functioning of the human brain. However, this ambitious endeavor is just one facet of a broader and ongoing active exploration that seeks to provide insight into the underlying cellular mechanisms that govern the functional dynamics of neural circuits where cellular morphology, function, and gene expression profiles reflect the heterogeneity and diversity of cell types in the central nervous system. Related Articles | Metrics

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Antisense oligonucleotides provide optimism to the therapeutic landscape for tauopathies Glenn A. Harris, Lauren R. Hirschfeld 2025, 20 (3):  803-804.  doi: 10.4103/NRR.NRR-D-23-02057 Abstract ( 84 )   PDF (407KB) ( 20 )   Save Tauopathies are a group of neurodegenerative diseases characterized by abnormal metabolism of the misfolded tau protein. Tau is encoded by the microtubule-associated protein tau gene (MAPT) and can be classified as either 3-repeat (3R) or 4-repeat (4R) based on the number of repeat domains from alternative splicing of exon 10 of the MAPT gene. Tauopathies are subdivided into primary tauopathies and secondary tauopathies (Chung et al., 2021). Primary tauopathies involve tau protein aggregation and tangling as a predominant feature. Primary tauopathies exhibit clinical heterogeneity, and their neuropathological features guide definitive diagnosis. Examples of primary tauopathies include progressive supranuclear palsy, frontotemporal dementia, Pick’s disease, chronic traumatic encephalopathy, corticobasal degeneration, primary age-related tauopathy, aging-related tau astrogliopathy, globular glia tauopathy, tangle-only dementia, and argyrophilic grain disease. Secondary tauopathies, such as Alzheimer’s disease (AD) and Down’s syndrome, feature tau protein aggregates coexisting with other protein abnormalities. Related Articles | Metrics

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Mitochondria–cGAS–STING axis is a potential therapeutic target for senescence-dependent inflammaging-associated neurodegeneration José M. Izquierdo 2025, 20 (3):  805-807.  doi: 10.4103/NRR.NRR-D-24-00245 Abstract ( 87 )   PDF (571KB) ( 49 )   Save The word “senescence” comes from the Latin senescens, meaning “to begin to age”, and is characterized by a long-lasting but reversible block in proliferation, resulting from stress-induced cell cycle arrest of previously replication-competent cells. Many stress situations lead to senescence, including telomere shortening, genotoxic stress, oncogene- and oxidative-induced stress, and mitochondrial dysfunction (Mico et al., 2021). It is also characterized by a proinflammatory senescence-associated secretory phenotype (SASP) that potentiates chronic low-grade inflammation and inflammaging-associated dysfunction, resulting in loss of tissue function and health (Figure 1; Mico et al., 2021). Related Articles | Metrics

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Transient receptor potential channels and calcium dysregulation: a pathogenic duo in Parkinson’s disease Iqira Saeed, Linlin Ma 2025, 20 (3):  808-810.  doi: 10.4103/NRR.NRR-D-24-00172 Abstract ( 61 )   PDF (1340KB) ( 14 )   Save Parkinson’s disease (PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium (Ca2+) homeostasis and the subsequent development of PD. Ca2+ regulation is crucial for neuronal survival, differentiation, exocytosis at synapses, gene transcription, and proliferation. In PD, disturbances in calcium homeostasis have been correlated with the selective degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), compared to neurons within other regions of the brain. More recently, there has been growing evidence to support the contribution of transient receptor potential (TRP) channels in calcium-mediated excitotoxicity and oxidative stress-induced death of dopaminergic neurons in PD. Related Articles | Metrics

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Multiple sclerosis is at a checkpoint: advancing the program Brandon C. Smith, Jessica L. Williams 2025, 20 (3):  811-812.  doi: 10.4103/NRR.NRR-D-23-02094 Abstract ( 59 )   PDF (1089KB) ( 36 )   Save Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). Patients with MS experience sensory and motor function loss due to myelin and/or axon damage perpetuated by infiltrating immune cells (Hauser and Cree, 2020). Before modern therapies, most patients experienced heightened symptoms followed by partial recovery. A significant proportion of these patients would then advance to a progressive disease state which features continual neuroaxonal loss and less frequent recovery (Degenhardt et al., 2009). However, with the advancement of several treatment strategies, the view of MS within the field has also begun to evolve. Current therapies reduce or eliminate the occurrence of relapse, yet there is still progression independent of relapse activity (Tur et al., 2023). These treatments prevent relapses primarily by limiting new lesions formed by the infiltration of T cells, B cells, and macrophages from the periphery, inciting inflammation and myelin damage. Newly formed lesions are often called active lesions due to their inflammatory nature. Ocrelizumab, which depletes CD20+ B cells, and Natalizumab, which targets the α4-integrin subunit of α4β1 to hinder lymphocytes from entering the CNS, are examples of commonly used treatments to prevent active lesion formation (Hauser and Cree, 2020). Related Articles | Metrics

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Human endogenous retrovirus type-W and multiple sclerosis–related smoldering neuroinflammation Joel Gruchot, Laura Reiche, Andrew Chan, Robert Hoepner, Patrick Küry 2025, 20 (3):  813-814.  doi: 10.4103/NRR.NRR-D-24-00121 Abstract ( 65 )   PDF (684KB) ( 13 )   Save Introduction to human endogenous retrovirus type-W (HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA. Such so-called human endogenous retroviruses (HERVs) come in different classes and families and have attained physiological functions, hence have been domesticated, or appear to be silenced and non-functional (Jakobsson and Vincendeau, 2022). It is believed, that multiple integration events have taken place, leading to the generation of a unique interindividual genomic HERV content. Additional genetic recombination events resulted in more than 100,000 identified HERV loci within the human genome (see for more details Gruchot et al., 2023a). Related Articles | Metrics

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Monogenic gene therapy for glaucoma and optic nerve injury Chikako Harada, Xiaoli Guo, Takayuki Harada 2025, 20 (3):  815-816.  doi: 10.4103/NRR.NRR-D-24-00133 Abstract ( 76 )   PDF (1288KB) ( 12 )   Save The prevalence of glaucoma, the second leading cause of global blindness, is increasing due to aging populations. In glaucoma, degeneration of the optic nerve and retinal ganglion cells (RGCs) causes visual field defects and eventual blindness. Elevated intraocular pressure (IOP) stands out as the best-known factor affecting glaucoma. However, there exists a subtype of glaucoma, known as normal tension glaucoma, that is not associated with high IOP. A recent study has identified various factors involved in glaucoma pathogenesis, including altered retinal blood flow, glutamate neurotoxicity, oxidative stress, and others (Shinozaki et al., 2024). Furthermore, glaucoma patients may exhibit reduced amounts of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor compared with age-matched controls. Studies indicate that intraocular injections of BDNF can rescue RGCs in a mouse model of optic nerve crush (ONC) through activation of its high-affinity receptor Tropomyosin receptor kinase B (TrkB). However, the transient nature of ligand-dependent activation poses limitations on the efficacy of this treatment. We have developed several systems, described in the following sections, to address and overcome these limitations. Related Articles | Metrics

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Neuroinflammation as a therapeutic target in Huntington’s disease Andrea Kwakowsky, Thulani H. Palpagama 2025, 20 (3):  817-818.  doi: 10.4103/NRR.NRR-D-24-00195 Abstract ( 80 )   PDF (451KB) ( 12 )   Save In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington’s disease (HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control, cognitive impairment, and mood and psychiatric changes in patients. These symptoms lead to the progressive loss of independence of patients, with severe symptoms ultimately resulting in death. The critical need for continued research into the pathology of HD is emphasized by the lack of a cure for HD thus far. The genetic origin of HD is a mutation in the interesting transcript 15 (IT15) gene encoding the huntingtin protein. A CAG (cytosine, adenine, guanine) expansion in the gene leads to the formation of a mutant huntingtin protein (mHTT) with an expanded polyglutamine sequence at the N-terminus. mHTT is cleaved into toxic fragments that can aggregate, form intracellular inclusions, and disrupt cellular processes which are hypothesized to lead to neurodegeneration. This contribution of mHTT to neurotoxicity is further postulated to result in the pathological atrophic changes that are hallmarks of the disease. One major pathological anatomical hallmark of HD is the atrophy of the striatum. Medium spiny neurons, which make up 90%–95% of neurons in the striatum, show particular vulnerability to degeneration in HD. The loss of these neurons is hypothesized to underlie motor impairment in HD. The atrophy of the cortex and basal ganglia is also well documented alongside striatal degeneration. Much like with the striatum, cortical atrophy is observed to underlie symptoms of HD, with atrophy of certain regions of the brain contributing to specific symptom profiles that patients present with. A better understanding of the contribution of regional degeneration of the brain to specific symptom profiles can possibly lead to targeted, symptom-specific therapies in the future (Palpagama et al., 2019; Testa and Jankovic, 2019). Related Articles | Metrics

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Neuroprotection by resveratrol-glucuronide and quercetin-glucuronide via binding to polyphenol- and glycosaminoglycan-binding sites in the laminin receptor Rayudu Gopalakrishna, Jennifer Aguilar, Emily Lee, William J. Mack 2025, 20 (3):  819-820.  doi: 10.4103/NRR.NRR-D-24-00160 Abstract ( 80 )   PDF (2547KB) ( 21 )   Save The dietary polyphenolic compounds resveratrol and quercetin prevent neurodegenerative diseases in experimental models; however, they reach the brain only in nanomolar concentrations in the glucuronidated and sulfated forms, and not as the aglycone parent form (Pasinetti et al., 2015). Recently, we found that these polyphenol aglycones and glucuronide metabolites bind with high affinity to two sites present within the peptide G region of 67-kDa laminin receptor (67LR): the “A” site, which is supported by the more hydrophobic palindromic sequence in peptide G and the “B” site, which is supported by the less hydrophobic N-terminal half of peptide G (Gopalakrishna et al., 2023, 2024). The glycosaminoglycan (GAG)-binding motif present in peptide G recognizes both the glucuronic acid moiety of glucuronide metabolites of polyphenols and the gallic acid moiety of (–)-epigallocatechin-3-gallate (EGCG) in A and B sites (Figure 1). These glucuronidated metabolites protect neuronal cells from cell death more effectively than the aglycone parent polyphenols (Gopalakrishna et al., 2023). Some dietary polyphenols may have common targets and mechanisms of neuroprotective action and may produce additive/synergistic interactions. This information may help optimize the prevention of neurodegenerative diseases with a rational combination of low doses of polyphenols for safer dietary supplementation in humans. Related Articles | Metrics

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Repetitive traumatic brain injury–induced complement C1–related inflammation impairs long-term hippocampal neurogenesis Jing Wang, Bing Zhang, Lanfang Li, Xiaomei Tang, Jinyu Zeng, Yige Song, Chao Xu, Kai Zhao, Guoqiang Liu, Youming Lu, Xinyan Li, Kai Shu 2025, 20 (3):  821-835.  doi: 10.4103/NRR.NRR-D-23-01446 Abstract ( 100 )   PDF (5927KB) ( 25 )   Save Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/β-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction. Related Articles | Metrics

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Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise Do-Hun Lee, Dan Cao, Younghye Moon, Chen Chen, Nai-Kui Liu, Xiao-Ming Xu, Wei Wu 2025, 20 (3):  836-844.  doi: 10.4103/NRR.NRR-D-23-01585 Abstract ( 107 )   PDF (3018KB) ( 35 )   Save Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group (10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury. Related Articles | Metrics

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Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke Lin-Yan Huang, Yi-De Zhang, Jie Chen, Hai-Di Fan, Wan Wang, Bin Wang, Ju-Yun Ma, Peng-Peng Li, Hai-Wei Pu, Xin-Yian Guo, Jian-Gang Shen, Su-Hua Qi 2025, 20 (3):  845-857.  doi: 10.4103/1673-5374.392889 Abstract ( 133 )   PDF (5119KB) ( 40 )   Save It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 μM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 μM) promoted nuclear translocation of β-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the β-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function. Related Articles | Metrics

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Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model Xintian Ding, Chun Chen, Heng Zhao, Bin Dai, Lei Ye, Tao Song, Shuai Huang, Jia Wang, Tao You 2025, 20 (3):  858-872.  doi: 10.4103/NRR.NRR-D-23-01925 Abstract ( 162 )   PDF (15724KB) ( 87 )   Save Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury. Related Articles | Metrics

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Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia Ying Wang, Xiang Zhang, Henrik Biverstål, Nicolas G. Bazan, Shuai Tan, Nailin Li, Makiko Ohshima, Marianne Schultzberg, Xiaofei Li 2025, 20 (3):  873-886.  doi: 10.4103/NRR.NRR-D-23-01688 Abstract ( 81 )   PDF (8837KB) ( 21 )   Save Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer’s disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer’s disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer’s disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer’s disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer’s disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer’s disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer’s disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer’s disease, highlighting its potential as a therapeutic target for Alzheimer’s disease. Related Articles | Metrics

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Salsolinol as an RNA m6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy Jianan Wang, Yuanyuan Ran, Zihan Li, Tianyuan Zhao, Fangfang Zhang, Juan Wang, Zongjian Liu, Xuechai Chen 2025, 20 (3):  887-899.  doi: 10.4103/NRR.NRR-D-23-01592 Abstract ( 155 )   PDF (5501KB) ( 32 )   Save Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an environmental toxin that causes Parkinson’s disease. However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal significantly enhanced the global level of N6-methyladenosine (m6A) RNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5). RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway. The m6A reader YTH domain-containing family protein 2 (YTHDF2) promoted the degradation of m6A-containing Yes-associated protein 1 (YAP1) mRNA, which is a downstream key effector in the Hippo signaling pathway. Additionally, downregulation of YAP1 promoted autophagy, indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity. These findings reveal the role of Sal on m6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson’s disease. Related Articles | Metrics

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Postnatal development of rat retina: a continuous observation and comparison between the organotypic retinal explant model and in vivo development Baoqi Hu, Rui Wang, Hanyue Zhang, Xiou Wang, Sijia Zhou, Bo Ma, Yan Luan, Xin Wang, Xinlin Chen, Zhichao Zhang, Qianyan Kang 2025, 20 (3):  900-912.  doi: 10.4103/NRR.NRR-D-23-01557 Abstract ( 79 )   PDF (7477KB) ( 25 )   Save The organotypic retinal explant culture has been established for more than a decade and offers a range of unique advantages compared with in vivo experiments and cell cultures. However, the lack of systematic and continuous comparison between in vivo retinal development and the organotypic retinal explant culture makes this model controversial in postnatal retinal development studies. Thus, we aimed to verify the feasibility of using this model for postnatal retinal development studies by comparing it with the in vivo retina. In this study, we showed that postnatal retinal explants undergo normal development, and exhibit a consistent structure and timeline with retinas in vivo. Initially, we used SOX2 and PAX6 immunostaining to identify retinal progenitor cells. We then examined cell proliferation and migration by immunostaining with Ki-67 and doublecortin, respectively. Ki-67- and doublecortin-positive cells decreased in both in vivo and explants during postnatal retinogenesis, and exhibited a high degree of similarity in abundance and distribution between groups. Additionally, we used Ceh-10 homeodomain-containing homolog, glutamate-ammonia ligase (glutamine synthetase), neuronal nuclei, and ionized calcium-binding adapter molecule 1 immunostaining to examine the emergence of bipolar cells, Müller glia, mature neurons, and microglia, respectively. The timing and spatial patterns of the emergence of these cell types were remarkably consistent between in vivo and explant retinas. Our study showed that the organotypic retinal explant culture model had a high degree of consistency with the progression of in vivo early postnatal retina development. The findings confirm the accuracy and credibility of this model and support its use for long-term, systematic, and continuous observation. Related Articles | Metrics