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15 April 2024, Volume 19 Issue 4 Previous Issue    Next Issue

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Could mammalian inorganic polyphosphate be a crucial signaling molecule in neurological disorders? Renata Torres Da Costa, Maria E. Solesio 2024, 19 (4):  701-702.  doi: 10.4103/1673-5374.382242 Abstract ( 98 )   PDF (1488KB) ( 73 )   Save Since the early stages of life on earth, cellular metabolism has evolved to adapt to fluctuations in nutrient and oxygen availability. In this context, mammals, which are probably the organisms that show one of the highest levels of metabolic complexity, have developed an elegant system that uses constant and rechargeable energy sources of modulate their metabolism. This homeostasis is especially important in the central nervous system, as neurons and other cells in the brain are highly susceptible to fluctuations in nutrients and oxygen availability. At the molecular level, these energy sources are based on molecules that contain highly energetic bonds. The main metabolite with energy-rich bonds in mammalian cells is adenosine triphosphate. However, other molecules also present dynamic roles in cellular metabolism in these organisms. One of the lesser known of these molecules is inorganic polyphosphate (polyP). PolyP is an ancient polymer, which has been well conserved throughout evolution; it is present in every tissue of all studied organisms. PolyP bonds are isoenergetic to those found in adenosine triphosphate, and its role as a key energy metabolite has already been demonstrated by us and others in various systems, including mammalian cells (Guitart-Mampel et al., 2022). PolyP is ubiquitously distributed in the cell, although one of its preferred locations in mammals is mitochondria, where the vast majority of adenosine triphosphate is produced via oxidative phosphorylation. In fact, the levels of mitochondrial polyP seem to be intimately related to the status of the electron transfer chain. Moreover, the regulatory effects of polyP on some crucial mammalian mitochondrial processes that are closely related to the bioenergetic status of cells and usually deleteriously affected in neurological disorders; such as calcium and protein homeostasis, and the maintenance of the oxidative status; have also been described. Most likely as a consequence of its role in bioenergetics, polyP has also been reported to be involved in the cellular stress response of various organisms. For example, it has been shown that polyP can act as a primordial chaperone (Gray et al., 2014). This stress response is also often activated in neurological disorders. In fact, a recent and elegant study proposed that assessing the levels of polyP released by astrocytes could serve as a promising biomarker in amyotrophic lateral sclerosis and frontotemporal dementia (Arredondo et al., 2022). However, the molecular mechanism by which polyP exerts its effects on mitochondrial and cellular physiology, including bioenergetics, remains poorly understood, especially in mammals. One plausible explanation for these effects could be via the signaling role that polyP has shown in different organisms, including mammalian cells.  Related Articles | Metrics

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Use of an immunocapture device to detect cytokine release in discrete brain regions Matthew G. Frank, Michael V. Baratta 2024, 19 (4):  703-704.  doi: 10.4103/1673-5374.382237 Abstract ( 79 )   PDF (683KB) ( 37 )   Save Production of proinflammatory cytokines in the central nervous system is a key process in the neuroinflammatory response to trauma, infection, and neurodegenerative diseases (Kumar, 2019). These intercellular signaling molecules play multiple roles in the immune response in the central nervous system including the orchestration of the sickness response to innate immune perturbations in the brain (Dantzer et al., 2008). Brain innate immune cells such as microglia and other macrophages (perivascular, meningeal) are considered a significant source of cytokines (Ransohoff and Cardona, 2010) during neuroinflammatory conditions. Thus, quantification of cytokines in the central nervous system is essential to understanding the neuroimmune mechanisms underpinning neuroinflammatory conditions and to monitor the effects of treatment. However, quantification of brain cytokines has largely been limited to end-point measures of tissue protein levels of cytokines using techniques such as enzyme-linked immunosorbent assay (ELISA), western blot assay, or immunohistochemistry, which fail to discriminate between intracellular and extracellular levels of cytokines. In other words, an experimental change in total tissue levels of cytokines does not necessarily mean that the protein was secreted into the interstitial space within a brain region. Proinflammatory cytokine receptor antagonists as well as germ-line knockouts have been employed to block the behavioral, physiological, and neuroinflammatory response to stress (Goshen and Yirmiya, 2009) and immune challenge (McCusker and Kelley, 2013), which implicates, but does not directly demonstrate cytokine release in the brain. A further limitation of measuring cytokines in whole tissue is that measurements are restricted to a single time point post-mortem. This limitation necessitates using a between-subjects experimental design to conduct time course measurements of cytokines, which introduces error variance due to between-subject variability in biological responses. Notably, inflammatory cytokines such as interleukin (IL)-1β have very short half-lives (Liu et al., 2021). Thus, methods that are limited to measuring single time points post-immune challenge lack the temporal resolution to capture the rapid kinetic changes in inflammatory cytokines. In this Perspective piece, we explore a recent technological advance that allowed us to serially quantify cytokines within the interstitial space of discrete brain regions of freely behaving rodents. This approach not only permits quantification of cytokine release into the extracellular space, but also provides increased spatial and temporal resolution of cytokine release in the brain under neuroinflammatory conditions. Related Articles | Metrics

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New immune regulators of sciatic nerve regeneration? Lessons from the neighborhood André L. Bombeiro, Rodrigo G.Q. Fernandes, Julie C. Ribot 2024, 19 (4):  705-706.  doi: 10.4103/1673-5374.382241 Abstract ( 75 )   PDF (547KB) ( 38 )   Save For decades, the immune system has been associated with host protection against infectious pathogens or tumors, while also contributing to autoimmunity. Notwithstanding, this paradigm is now changing, with recent studies highlighting novel roles for immune mediators in the maintenance of steady-state tissue homeostasis. In this perspective, we review some of the latest findings featuring immune modulators of the nervous system pathophysiology, with a special focus on interleukin (IL)-17. Related Articles | Metrics

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Multifunctional glycolipids as multi-targeting therapeutics for neural regeneration Yutaka Itokazu 2024, 19 (4):  707-708.  doi: 10.4103/1673-5374.382244 Abstract ( 66 )   PDF (759KB) ( 24 )   Save Many patients with neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) diseases suffer from disease progression without any satisfying clinical intervention, likely due to our lack of knowledge on how normal aging impacts the pathogenic mechanisms of these debilitating diseases. A growing body of literature has emerged in recent years that clearly demonstrates the involvement of glycolipids in the protein-oligomerization of neurodegenerative disorders. We hypothesize that changes in glycolipids composition are a common mechanism underlying the shift from healthy brain aging to the neuropathological processes of neurodegenerative diseases. Related Articles | Metrics

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Astrocytes dynamically regulate the blood-brain barrier in the healthy brain Agnė Pociūtė, Augustas Pivoriūnas, Alexei Verkhratsky 2024, 19 (4):  709-710.  doi: 10.4103/1673-5374.382248 Abstract ( 109 )   PDF (2190KB) ( 81 )   Save The blood-brain barrier (BBB) (discovered and defined by Max Lewandowsky and Lina Stern, and not, as it is universally, and yet erroneously believed, by Paul Ehrlich (Verkhratsky and Pivoriunas, 2023)) that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man. The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured (in invertebrates) by septate junctions; in most vertebrates, including mammals, the barrier is associated with endothelial cells and secured with tight junctions. This, however, is a simplified view, as brain-fluid barriers in general and the BBB in particular, are complex structures, which dynamically control traffic between nervous tissue and the circulation. The vascular part of the BBB complex (Figure 1) includes hemocompatible glycocalyx, which outlines and protects the single-cell layer of brain endothelial cells (BECs) clamped together with tight and adherence junctions that restrict paracellular transport. Tight junctions form a highly efficient barrier for ion fluxes that translates into a very high (up to 5000 Ω/cm2) electrical resistance (generally referred to as transendothelial electrical resistance or TEER) of the brain endothelial barrier, which is > 100 times larger as compared to peripheral capillaries where TEER varies between 2 and 20 Ω/cm2. Brain endotheliocytes are in direct contact with pericytes, several subtypes of which are associated with capillaries and pre- and post-capillary vessels. Pericytes and endothelial cells are covered with the vascular basement membrane. In arterioles and venules, the basement membrane is surrounded by smooth muscle cells regulating vasodilatation and vasoconstriction. The parenchymal part of the BBB is made by endfeet of protoplasmic (in grey matter) or fibrous (in white matter) astrocytes; every protoplasmic astrocyte extends at least one (and usually several) perivascular processes (Hosli et al., 2022). Astrocytic endfeet rest on the parenchymal basement membrane; together they form the glia limitans perivascularis (which also includes processes of juxtavascular microglia). The composition of vascular and parenchymal basal membranes is different, reflecting distinct extracellular matrix components secreted by endotheliocytes and astrocytes. At the level of arterioles and venules, vascular and parenchymal membranes are separated by perivascular space filled with cerebrospinal fluid; this perivascular space, together with glia limitans, provides the anatomical substrate for the brain-wide glymphatic system. At the level of capillaries, both basement membranes join while perivascular space disappears.  Related Articles | Metrics

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Epigenetic memory of drug exposure history controls neural stem cell quiescence in the adult brain Masakazu Iwamoto, Taito Matsuda 2024, 19 (4):  711-712.  doi: 10.4103/1673-5374.382240 Abstract ( 57 )   PDF (6307KB) ( 29 )   Save Neural stem cells (NSCs) are the source of all neurons and glial cells (astrocytes and oligodendrocytes) in the central nervous system. The adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in the hippocampus and ventricular subventricular zone lining the lateral ventricle (Olpe and Jessberger, 2022). Adult NSCs in rodents are preserved throughout life and continuously produce new neurons that integrate into the pre-existing neuronal network. However, whether adult neurogenesis occurs in humans, especially in the hippocampus, remains yet to be proven (Olpe and Jessberger, 2022). Adult neurogenesis in the hippocampus contributes to hippocampus-dependent cognitive function (Gonçalves et al., 2016). Disruption of this neurogenesis is known to be associated with several brain disorders, such as age-dependent cognitive decline, major depressive disorders, and medial-temporal lobe epilepsy. Thus, elucidating the mechanisms underlying the regulation of NSC behavior and neurogenesis is important for developing therapeutic strategies to treat diseases related to impaired adult neurogenesis. Related Articles | Metrics

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Topical ocular administration of DPP-IV inhibitors: a new approach for treating diabetes-induced retinal neurodegeneration Rafael Simó, Cristina Hernández 2024, 19 (4):  713-714.  doi: 10.4103/1673-5374.353492 Abstract ( 73 )   PDF (397KB) ( 15 )   Save Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy (DR), the leading cause of preventable blindness. In fact, the American Diabetes Association has defined DR as a highly specific neurovascular complication (Solomon et al., 2017). Therefore, it is no longer acceptable to consider DR as merely a microvascular complication. In this regard, the term diabetic retinal disease (DRD) has been proposed as a broader term comprising microangiopathy and neurodegeneration. However, there are currently no treatments available that directly target the neurodegenerative changes of DR. This paper will give new insights into the translational research in this field with particular emphasis on glucagon-like peptide 1/dipeptidyl peptidase IV (GLP-1/DPP-IV) inhibitors. Related Articles | Metrics

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Implications of regional identity for neural stem and progenitor cell transplantation in the injured or diseased nervous system Prakruthi Amar Kumar, Jennifer N. Dulin 2024, 19 (4):  715-716.  doi: 10.4103/1673-5374.382236 Abstract ( 82 )   PDF (1457KB) ( 31 )   Save Neural stem and progenitor cell (NSPC) transplantation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease. A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models; more recently, NSPC transplantation has advanced to clinical trials. However, there are fundamental questions regarding the biology of NSPC grafting that warrant further investigation. Here, we focus on the importance of the regional identity of donor cells for determining outcomes following transplantation. We discuss key findings in models of traumatic brain injury and Parkinson’s disease, focusing on how concepts learned from this work may have potential applications for transplantation following spinal cord injury (SCI). Related Articles | Metrics

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Artificial intelligence analysis of videos to augment clinical assessment: an overview David C. Wong, Stefan Williams 2024, 19 (4):  717-718.  doi: 10.4103/1673-5374.382249 Abstract ( 84 )   PDF (3292KB) ( 79 )   Save Observation is a fundamental part of the practice of clinical medicine. Observation of movement is particularly important for the neurologist. Conditions such as Parkinson’s disease, multiple sclerosis, stroke, epilepsy, and many others affect a person’s movement in characteristic ways. In some conditions, changes in the patient’s voice can be included in this – changes in sound caused by changes in the movements of speech. The clinician’s detection of a characteristic abnormality, and their judgment of its severity, plays a central role in both diagnosis and the assessment of prognosis or response to treatment. However, that practice depends upon a limited resource of experienced experts. In addition, these experts are limited by human visual judgment, which cannot reliably or precisely detect and measure small or subtle changes in movement (Williams et al., 2023). Related Articles | Metrics

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A perspective on age-related changes in cell environment and risk of neurodegenerative diseases Alice Y. Liu 2024, 19 (4):  719-720.  doi: 10.4103/1673-5374.382234 Abstract ( 74 )   PDF (333KB) ( 17 )   Save “Age-related neurodegenerative disease” underscores human age as the primary risk factor for disease development: Alzheimer’s, Parkinson’s, and Huntington’s disease (HD) as examples. Reasons for the age-dependent delay in disease manifestation, in particular for autosomal dominant forms of the disease, and the underlying cause(s) of specific neuron dysfunction and death to manifest as memory loss, anxiety, depression, and agitation in disease subjects remain unclear. We are interested in understanding age-related changes in cell environment that can modulate the structure, function, aggregation, and pathogenicity of disease proteins implicated in neurodegenerative disease (ND), using the polyQ-expanded mutant Huntingtin protein (mHtt) that causes HD as a model for our studies. Our perspective is that age-related changes in cell milieu including a reduction in intracellular water content, increased crowding, and decreased macromolecular hydration can augment the innate propensities of disease proteins to structure, to engage in heterotypic binding to and quenching of key regulatory protein factors, to wreak havoc in cell signaling and regulation that drive disease pathogenesis, as well as to form disease protein aggregates through homotypic self-association. We are hopeful that a better understanding of age-related changes in cell milieu that are conducive to ND pathogenesis will contribute to efforts to delay or prevent neuron degeneration while supporting neuron survival and function for healthy aging. THEME: aging → decreased cell hydration and increased crowding → intrinsically disordered protein (IDP) structuring & aggregation → ND progression. Related Articles | Metrics

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ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases Hiu Chuen Lok, Glenda M. Halliday, Woojin Scott Kim 2024, 19 (4):  721-722.  doi: 10.4103/1673-5374.382239 Abstract ( 80 )   PDF (358KB) ( 28 )   Save ATP-binding cassette (ABC) transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes, including lipids, amino acids, nucleosides, sugars, and xenobiotics. Interestingly, ABC transporters are highly expressed in the brain. While their functions in the brain still need to be elucidated, several members are implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal dementia. In this perspective, we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration. Furthermore, we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases. Related Articles | Metrics

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Current controversies in glia-to-neuron conversion therapy in neurodegenerative diseases Peng Cao, Jianan Li, Zhuxi Liu, Guobiao Liang 2024, 19 (4):  723-724.  doi: 10.4103/1673-5374.382251 Abstract ( 61 )   PDF (390KB) ( 31 )   Save Loss of neurons and disruption of neural circuits are associated with many neurological diseases, including neurodegenerative diseases and mental disorders. The most prevalent pathological feature of neurodegenerative diseases is the aggregate loss of certain neuronal populations. For example, the loss of dopamine (DA) neurons in the substantia nigra pars compacta has been defined as a pathological hallmark of Parkinson’s disease (PD; Kamath et al., 2022). Therefore, methods to reverse neuronal reduction in an effort to rebuild neural circuits and improve function have become an important research focus. In the past decade, regenerative medicine has taken a momentous leap forward with a groundbreaking discovery in the field of neuroregeneration. In vivo glia-to-neuron conversion therapy has presented itself as a potential solution (Qian et al., 2020). This is a paradigm-shifting regenerative strategy to reprogram resident glial cells in situ into neurons in vivo (Figure 1). This method is obviously superior to the strategy of inducing stem cells to differentiate into neurons in vitro for in vivo transplantation, avoiding various problems, such as difficult integration, cancer degeneration, and immunogenicity. However, the evidence supporting the replacement of lost neurons with trans-differentiated cells and\ the reconstitution of neuronal circuits remains limited. Related Articles | Metrics

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Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease Jeong Hyun Yoon, Chiao-Yin Lee, Anthony HV Schapira 2024, 19 (4):  725-727.  doi: 10.4103/1673-5374.382238 Abstract ( 57 )   PDF (3554KB) ( 39 )   Save Parkinson’s disease (PD, OMIM #168600) is a common neurodegenerative disorder with a global prevalence of approximately 8.5 million. PD is characterized by four cardinal motor symptoms: bradykinesia, rigidity, resting tremor, and subsequently by postural instability. It usually involves non-motor symptoms such as rapid eye movement sleep disorder, dementia, anosmia, and autonomic dysfunction. The gene glucocerebrosidase 1 (GBA1), which encodes the lysosomal enzyme glucocerebrosidase (GCase) (IUBMB: EC 3.2.1.45), shows strong linkage with PD; variants of GBA1 are the commonest genetic association with PD (Sidransky et al., 2009). Several mechanisms may underlie the relationship between GBA1 mutations/variants and the molecular pathology of PD (Figure 1A and B). Related Articles | Metrics

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Commentary on “Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain” Lorenzo Di Cesare Mannelli, Carla Ghelardini 2024, 19 (4):  728-728.  doi: 10.4103/1673-5374.382219 Abstract ( 85 )   PDF (317KB) ( 29 )   Save In patients, as well as in animal models, hypersensitivity to external stimuli (hyperalgesia and allodynia) or spontaneous pain is often the first, and the most disabling, symptom of neuropathy (Davis et al., 2020). The increased activity of sensitive neurons drives pain development, making ion channel modulation a fundamental target for current pharmacotherapy as well as one of the most investigated by the R&D departments of pharmaceutical companies (Bennett et al., 2019). Related Articles | Metrics

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Autophagy in neural stem cells and glia for brain health and diseases Aarti Nagayach, Chenran Wang 2024, 19 (4):  729-736.  doi: 10.4103/1673-5374.382227 Abstract ( 211 )   PDF (3753KB) ( 87 )   Save Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation, maturation, and survival. Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells. Autophagy arbitrates structural and functional remodeling during the cell differentiation process. Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases. Only recently, studies have begun to shed light on autophagy regulation in glia (microglia, astrocyte, and oligodendrocyte) in the brain. Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development, synaptic function, brain metabolism, cellular debris clearing, and restoration of damaged or injured tissues. Thus, this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions, neurodevelopmental disorders, and neurodegenerative diseases. This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases. Related Articles | Metrics

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Pathophysiological changes of muscle after ischemic stroke: a secondary consequence of stroke injury Hu Qi, Dan Tian, Fei Luan, Ruocong Yang, Nan Zeng 2024, 19 (4):  737-746.  doi: 10.4103/1673-5374.382221 Abstract ( 178 )   PDF (2546KB) ( 213 )   Save Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period, and that the latter has a greater impact on the long-term prognosis of the patient. However, current stroke studies have typically focused only on lesions in the central nervous system, ignoring secondary damage caused by this disease. Such a phenomenon arises from the slow progress of pathophysiological studies examining the central nervous system. Further, the appropriate therapeutic time window and benefits of thrombolytic therapy are still controversial, leading scholars to explore more pragmatic intervention strategies. As treatment measures targeting limb symptoms can greatly improve a patient’s quality of life, they have become a critical intervention strategy. As the most vital component of the limbs, skeletal muscles have become potential points of concern. Despite this, to the best of our knowledge, there are no comprehensive reviews of pathophysiological changes and potential treatments for post-stroke skeletal muscle. The current review seeks to fill a gap in the current understanding of the pathological processes and mechanisms of muscle wasting atrophy, inflammation, neuroregeneration, mitochondrial changes, and nutritional dysregulation in stroke survivors. In addition, the challenges, as well as the optional solutions for individualized rehabilitation programs for stroke patients based on motor function are discussed. Related Articles | Metrics

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Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review Peter H. King 2024, 19 (4):  747-753.  doi: 10.4103/1673-5374.382226 Abstract ( 176 )   PDF (4465KB) ( 79 )   Save Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85–90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of “omics” technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis. Related Articles | Metrics

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Latest assessment methods for mitochondrial homeostasis in cognitive diseases Wei You, Yue Li, Kaixi Liu, Xinning Mi, Yitong Li, Xiangyang Guo, Zhengqian Li 2024, 19 (4):  754-768.  doi: 10.4103/1673-5374.382222 Abstract ( 131 )   PDF (1538KB) ( 120 )   Save Mitochondria play an essential role in neural function, such as supporting normal energy metabolism, regulating reactive oxygen species, buffering physiological calcium loads, and maintaining the balance of morphology, subcellular distribution, and overall health through mitochondrial dynamics. Given the recent technological advances in the assessment of mitochondrial structure and functions, mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, mild cognitive impairment, and postoperative cognitive dysfunction. This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences, from the perspectives of energy metabolism, oxidative stress, calcium homeostasis, and mitochondrial dynamics (including fission-fusion, transport, and mitophagy). Related Articles | Metrics

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Machine learning applications in stroke medicine: advancements, challenges, and future prospectives Mario Daidone, Sergio Ferrantelli, Antonino Tuttolomondo 2024, 19 (4):  769-773.  doi: 10.4103/1673-5374.382228 Abstract ( 176 )   PDF (815KB) ( 138 )   Save Stroke is a leading cause of disability and mortality worldwide, necessitating the development of advanced technologies to improve its diagnosis, treatment, and patient outcomes. In recent years, machine learning techniques have emerged as promising tools in stroke medicine, enabling efficient analysis of large-scale datasets and facilitating personalized and precision medicine approaches. This abstract provides a comprehensive overview of machine learning’s applications, challenges, and future directions in stroke medicine. Recently introduced machine learning algorithms have been extensively employed in all the fields of stroke medicine. Machine learning models have demonstrated remarkable accuracy in imaging analysis, diagnosing stroke subtypes, risk stratifications, guiding medical treatment, and predicting patient prognosis. Despite the tremendous potential of machine learning in stroke medicine, several challenges must be addressed. These include the need for standardized and interoperable data collection, robust model validation and generalization, and the ethical considerations surrounding privacy and bias. In addition, integrating machine learning models into clinical workflows and establishing regulatory frameworks are critical for ensuring their widespread adoption and impact in routine stroke care. Machine learning promises to revolutionize stroke medicine by enabling precise diagnosis, tailored treatment selection, and improved prognostication. Continued research and collaboration among clinicians, researchers, and technologists are essential for overcoming challenges and realizing the full potential of machine learning in stroke care, ultimately leading to enhanced patient outcomes and quality of life. This review aims to summarize all the current implications of machine learning in stroke diagnosis, treatment, and prognostic evaluation. At the same time, another purpose of this paper is to explore all the future perspectives these techniques can provide in combating this disabling disease. Related Articles | Metrics

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Versatile strategies for adult neurogenesis: avenues to repair the injured brain Junyi Zhao, Siyu Liu, Xianyuan Xiang, Xinzhou Zhu 2024, 19 (4):  774-780.  doi: 10.4103/1673-5374.382224 Abstract ( 158 )   PDF (697KB) ( 106 )   Save Brain injuries due to trauma or stroke are major causes of adult death and disability. Unfortunately, few interventions are effective for post-injury repair of brain tissue. After a long debate on whether endogenous neurogenesis actually happens in the adult human brain, there is now substantial evidence to support its occurrence. Although neurogenesis is usually significantly stimulated by injury, the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient. Alternatively, exogenous stem cell transplantation has shown promising results in animal models, but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use. Recently, a high focus was placed on glia-to-neuron conversion under single-factor regulation. Despite some inspiring results, the validity of this strategy is still controversial. In this review, we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury. We also discuss their advantages and drawbacks, as to provide a comprehensive account of their potentials for further studies. Related Articles | Metrics

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Succinylation modification: a potential therapeutic target in stroke Jie Lian, Wenwu Liu, Qin Hu , Xiaohua Zhang 2024, 19 (4):  781-787.  doi: 10.4103/1673-5374.382229 Abstract ( 241 )   PDF (3979KB) ( 125 )   Save Stroke is a leading cause of mortality and disability worldwide. Ischemic cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of stroke-induced brain injury. Impaired mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of neuropathology. Recently, a new type of post-translational modification, known as lysine succinylation, has been recognized to play a significant role in mitochondrial energy metabolism after ischemia. However, the role of succinylation modification in cell metabolism after stroke and its regulation are not well understood. We aimed to review the effects of succinylation on energy metabolism, reactive oxygen species generation, and neuroinflammation, as well as Sirtuin 5 mediated desuccinylation after stroke. We also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of stroke. The succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by desuccinylases. Mounting evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic enzymes. Sirtuins, especially Sirtuin 5, are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic enzymes. Imbalance between succinylation and desuccinylation has been implicated in the pathophysiology of stroke. Pharmacological agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism, and neuroprotective effects of these agents have been observed in experimental stroke studies. However, their therapeutic efficacy in stroke patients should be validated. Related Articles | Metrics

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Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies R. Scott Duncan, Sean M. Riordan, Matthew C. Gernon, Peter Koulen 2024, 19 (4):  788-799.  doi: 10.4103/1673-5374.382220 Abstract ( 98 )   PDF (703KB) ( 140 )   Save Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders. Related Articles | Metrics

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The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis Xinxin Wang, Yushu Hu, Renshi Xu 2024, 19 (4):  800-806.  doi: 10.4103/1673-5374.382233 Abstract ( 199 )   PDF (1284KB) ( 94 )   Save The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation). Related Articles | Metrics

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Cell replacement with stem cell-derived retinal ganglion cells from different protocols Ziming Luo, Kun-Che Chang 2024, 19 (4):  807-810.  doi: 10.4103/1673-5374.381494 Abstract ( 110 )   PDF (771KB) ( 60 )   Save Glaucoma, characterized by a degenerative loss of retinal ganglion cells, is the second leading cause of blindness worldwide. There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury. Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases. In this review, we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture, including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes. Next, we discuss using 3D retinal organoids for retinal ganglion cell transplantation, comparing cell suspensions and clusters. This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation, with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies. Related Articles | Metrics

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In vivo imaging of the neuronal response to spinal cord injury: a narrative review Junhao Deng, Chang Sun, Ying Zheng, Jianpeng Gao, Xiang Cui, Yu Wang, Licheng Zhang, Peifu Tang 2024, 19 (4):  811-817.  doi: 10.4103/1673-5374.382225 Abstract ( 221 )   PDF (664KB) ( 80 )   Save Deciphering the neuronal response to injury in the spinal cord is essential for exploring treatment strategies for spinal cord injury (SCI). However, this subject has been neglected in part because appropriate tools are lacking. Emerging in vivo imaging and labeling methods offer great potential for observing dynamic neural processes in the central nervous system in conditions of health and disease. This review first discusses in vivo imaging of the mouse spinal cord with a focus on the latest imaging techniques, and then analyzes the dynamic biological response of spinal cord sensory and motor neurons to SCI. We then summarize and compare the techniques behind these studies and clarify the advantages of in vivo imaging compared with traditional neuroscience examinations. Finally, we identify the challenges and possible solutions for spinal cord neuron imaging. Related Articles | Metrics

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Regenerative medicine strategies for chronic complete spinal cord injury Shogo Hashimoto, Narihito Nagoshi, Masaya Nakamura, Hideyuki Okano 2024, 19 (4):  818-824.  doi: 10.4103/1673-5374.382230 Abstract ( 100 )   PDF (740KB) ( 49 )   Save Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases. While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable, most research in this field has focused on the early phase of incomplete injury. However, the majority of patients have chronic severe injuries; therefore, treatments for these situations are of fundamental importance. The reason why the treatment of complete spinal cord injury has not been studied is that, unlike in the early stage of incomplete spinal cord injury, there are various inhibitors of neural regeneration. Thus, we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies. First, we established a combination therapy of cell transplantation and drug-releasing scaffolds, which contributes to functional recovery after chronic complete transection spinal cord injury, but we found that functional recovery was limited and still needs further investigation. Here, for the further development of the treatment of chronic complete spinal cord injury, we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss, with reference to the literature, which combination of treatments is most effective in achieving functional recovery. Related Articles | Metrics

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Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage Jiatong Zhang, Qi Zhu, Jie Wang, Zheng Peng, Zong Zhuang, Chunhua Hang, Wei Li 2024, 19 (4):  825-832.  doi: 10.4103/1673-5374.381493 Abstract ( 179 )   PDF (3785KB) ( 121 )   Save The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage. Related Articles | Metrics

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Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence Xiaoyan Liu, Yi Liu, Junlin Liu, Hantao Zhang, Chaofan Shan, Yinglu Guo, Xun Gong, Mengmeng Cui, Xiubin Li, Min Tang 2024, 19 (4):  833-845.  doi: 10.4103/1673-5374.382223 Abstract ( 172 )   PDF (1487KB) ( 512 )   Save A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis. As a contributing factor, microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota’s diverse microorganisms, and for both neuroimmune and neuroendocrine systems. Here, we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases, with an emphasis on multi-omics studies and the gut virome. The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated. Finally, we discuss the role of diet, prebiotics, probiotics, postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases. Related Articles | Metrics

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Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer’s agents Willian Orlando Castillo-Ordoñez, Nohelia Cajas-Salazar, Mayra Alejandra Velasco-Reyes 2024, 19 (4):  846-854.  doi: 10.4103/1673-5374.382232 Abstract ( 223 )   PDF (1062KB) ( 102 )   Save Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer’s disease, known as familial Alzheimer’s disease (onset < 65 years) and late-onset or sporadic Alzheimer’s disease (onset ≥ 65 years). Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and  PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer’s disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes. Related Articles | Metrics

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Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system Mingyue Jin, Shengming Wang, Xiaodie Gao, Zhenyou Zou, Shinji Hirotsune, Liyuan Sun 2024, 19 (4):  855-862.  doi: 10.4103/1673-5374.382231 Abstract ( 168 )   PDF (2351KB) ( 114 )   Save α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons, respectively. Previous works have revealed that intracellular deposition of α-synuclein and/or tau causes many neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Despite intense investigation, the normal physiological functions and roles of α-synuclein and tau are still unclear, owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes. Interestingly, the co-occurrence of α-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies, some of which share similarities in clinical manifestations. Furthermore, the direct interaction of α-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo. On the other hand, our recent findings have revealed that α-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner. These findings indicate strong cross-talk between the two proteins in physiology and pathology. In this review, we provide a summary of the recent findings on the functional roles of α-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases. A deep understanding of the interplay between α-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases. Related Articles | Metrics

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Rbm8a regulates neurogenesis and reduces Alzheimer’s disease-associated pathology in the dentate gyrus of 5×FAD mice Chenlu Zhu, Xiao Ren, Chen Liu, Yawei Liu, Yonggang Wang 2024, 19 (4):  863-871.  doi: 10.4103/1673-5374.382254 Abstract ( 199 )   PDF (8939KB) ( 48 )   Save Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline, which can be partly attributed to impaired hippocampal neurogenesis. Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging, especially in Alzheimer’s disease. Recent evidence indicated that RNA-binding protein 8A (Rbm8a) promotes the proliferation of neural progenitor cells, with lower expression levels observed in Alzheimer’s disease patients compared with healthy people. This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease. Therefore, Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis. Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes (such as plaque formation, gliosis reaction, and dystrophic neurites), leading to ameliorated memory performance in 5×FAD mice. RNA sequencing data further substantiated these findings, showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis, cell proliferation, and amyloid protein formation. In conclusion, overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis. Related Articles | Metrics

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Long non-coding RNA H19 regulates neurogenesis of induced neural stem cells in a mouse model of closed head injury Mou Gao, Qin Dong, Zhijun Yang, Dan Zou, Yajuan Han, Zhanfeng Chen, Ruxiang Xu 2024, 19 (4):  872-880.  doi: 10.4103/1673-5374.382255 Abstract ( 134 )   PDF (7747KB) ( 113 )   Save Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury. We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement. However, the neural regeneration efficiency of induced neural stem cells remains limited. In this study, we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells. We found that H19 was the most downregulated neurogenesis-associated lncRNA in induced neural stem cells compared with induced pluripotent stem cells. Additionally, we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons. We predicted the target genes of H19 and discovered that H19 directly interacts with miR-325-3p, which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells. Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation, and miR-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition. Furthermore, H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells. Notably, silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice. Our results reveal that H19 regulates the neurogenesis of induced neural stem cells. H19 inhibition may promote the neural differentiation of induced neural stem cells, which is closely associated with neurological recovery following closed head injury. Related Articles | Metrics

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Activation of cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 promotes post-ischemic stroke functional recovery in aged mice Fan Bu, Jia-Wei Min, Md Abdur Razzaque, Ahmad El Hamamy, Anthony Patrizz, Li Qi, Akihiko Urayama, Jun Li 2024, 19 (4):  881-886.  doi: 10.4103/1673-5374.382256 Abstract ( 154 )   PDF (34215KB) ( 25 )   Save Brain functional impairment after stroke is common; however, the molecular mechanisms of post-stroke recovery remain unclear. It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke. Mounting evidence suggests that axonal regeneration and angiogenesis, the major forms of brain plasticity responsible for post-stroke recovery, diminished with advanced age. Previous studies suggest that Ras-related C3 botulinum toxin substrate (Rac) 1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model. Here, we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged (male, 18 to 22 months old C57BL/6J) brain after ischemic stroke. We found that as mice aged, Rac1 expression declined in the brain. Delayed overexpression of Rac1, using lentivirus encoding Rac1 injected day 1 after ischemic stroke, promoted cognitive (assessed using novel object recognition test) and sensorimotor (assessed using adhesive removal tests) recovery on days 14–28. This was accompanied by the increase of neurite and proliferative endothelial cells in the peri-infarct zone assessed by immunostaining. In a reverse approach, pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells. Furthermore, Rac1 inhibition reduced the activation of p21-activated kinase 1, the protein level of brain-derived neurotrophic factor, and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke. Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke. Related Articles | Metrics

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Sustained release of vascular endothelial growth factor A and basic fibroblast growth factor from nanofiber membranes reduces oxygen/glucose deprivation-induced injury to neurovascular units#br# Yifang Wu, Jun Sun, Qi Lin, Dapeng Wang, Jian Hai 2024, 19 (4):  887-894.  doi: 10.4103/1673-5374.382252 Abstract ( 144 )   PDF (66481KB) ( 30 )   Save Upregulation of vascular endothelial growth factor A/basic fibroblast growth factor (VEGFA/bFGF) expression in the penumbra of cerebral ischemia can increase vascular volume, reduce lesion volume, and enhance neural cell proliferation and differentiation, thereby exerting neuroprotective effects. However, the beneficial effects of endogenous VEGFA/bFGF are limited as their expression is only transiently increased. In this study, we generated multilayered nanofiber membranes loaded with VEGFA/bFGF using layer-by-layer self-assembly and electrospinning techniques. We found that a membrane containing 10 layers had an ideal ultrastructure and could efficiently and stably release growth factors for more than 1 month. This 10-layered nanofiber membrane promoted brain microvascular endothelial cell tube formation and proliferation, inhibited neuronal apoptosis, upregulated the expression of tight junction proteins, and improved the viability of various cellular components of neurovascular units under conditions of oxygen/glucose deprivation. Furthermore, this nanofiber membrane decreased the expression of Janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3), Bax/Bcl-2, and cleaved caspase-3. Therefore, this nanofiber membrane exhibits a neuroprotective effect on oxygen/glucose-deprived neurovascular units by inhibiting the JAK2/STAT3 pathway. Related Articles | Metrics

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Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies Andrés Berardo, Cristian R. Bacaglio, Bárbara B. Báez, Rubén Sambuelli, Kazim A. Sheikh, Pablo H. H. Lopez 2024, 19 (4):  895-899.  doi: 10.4103/1673-5374.382258 Abstract ( 105 )   PDF (5350KB) ( 71 )   Save Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrè syndrome, mostly related to halted axon regeneration. Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration. These effects involve the activation of the small GTPase RhoA/ROCK signaling pathways, which negatively modulate growth cone cytoskeleton, similarly to well stablished inhibitors of axon regeneration described so far. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in a mouse model of axon regeneration of peripheral nerves, where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the in vivo participation of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system. Related Articles | Metrics

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Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats Haoshuai Tang, Junjin Li, Hongda Wang, Jie Ren, Han Ding, Jun Shang, Min Wang, Zhijian Wei, Shiqing Feng 2024, 19 (4):  900-907.  doi: 10.4103/1673-5374.380911 Abstract ( 201 )   PDF (18115KB) ( 121 )   Save Complete transverse injury of peripheral nerves is challenging to treat. Exosomes secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue regeneration. In previous studies, a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal regeneration. This three-dimensional (3D) composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly (lactic-co-glycolic acid) tube. However, whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains unknown. In this study, we tested a comprehensive strategy for repairing long-gap (10 mm) peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived exosomes. Repair effectiveness was evaluated by sciatic functional index, sciatic nerve compound muscle action potential recording, recovery of muscle mass, measuring the cross-sectional area of the muscle fiber, Masson trichrome staining, and transmission electron microscopy of the regenerated nerve in rats. The results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function, similar to autograft transplantation. More CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes, which may have contributed to the observed increase in axon regeneration and distal nerve reconnection. Therefore, the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury. Related Articles | Metrics

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Multiple factors to assist human-derived induced pluripotent stem cells to efficiently differentiate into midbrain dopaminergic neurons Yalan Chen, Junxin Kuang, Yimei Niu, Hongyao Zhu, Xiaoxia Chen, Kwok-Fai So, Anding Xu, Lingling Shi 2024, 19 (4):  908-914.  doi: 10.4103/1673-5374.378203 Abstract ( 154 )   PDF (7362KB) ( 74 )   Save Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases. They also represent a potential source of transplanted cells for therapeutic applications. In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development. Emerging evidence and impressive advances in human induced pluripotent stem cells, with tuned neural induction and differentiation protocols, makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible. Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol, we obtained multiple subtypes of neurons, including 20% tyrosine hydroxylase-positive dopaminergic neurons. To obtain more dopaminergic neurons, we next added sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8) on day 8 of induction. This increased the proportion of dopaminergic neurons, up to 75% tyrosine hydroxylase-positive neurons, with 15% tyrosine hydroxylase and forkhead box protein A2 (FOXA2) co-expressing neurons. We further optimized the induction protocol by applying the small molecule inhibitor, CHIR99021 (CHIR).This helped facilitate the generation of midbrain dopaminergic neurons, and we obtained 31–74% midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining. Thus, we have established three induction protocols for dopaminergic neurons. Based on tyrosine hydroxylase and FOXA2 immunostaining analysis, the CHIR, SHH, and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons, which could be an ideal resource for tackling midbrain-related diseases. Related Articles | Metrics

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STAT3 ameliorates truncated tau-induced cognitive deficits Bingge Zhang, Huali Wan, Maimaitijiang Maierwufu, Qian Liu, Ting Li, Ye He, Xin Wang, Gongping Liu, Xiaoyue Hong, Qiong Feng 2024, 19 (4):  915-922.  doi: 10.4103/1673-5374.382253 Abstract ( 128 )   PDF (4068KB) ( 79 )   Save Proteolytic cleavage of tau by asparagine endopeptidase (AEP) creates tau-N368 fragments, which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s disease patients. Nonetheless, the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear. Evidence suggests that signal transduction and activator of transcription-3 (STAT3) is associated with modulating synaptic plasticity, cell apoptosis, and cognitive function. Using luciferase reporter assays, electrophoretic mobility shift assays, western blotting, and immunofluorescence, we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus. Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss, thereby improving the cognitive deficits in tau-N368 mice. Moreover, in tau-N368 mice, activation of STAT3 increased N-methyl-D-aspartic acid receptor levels, decreased Bcl-2 levels, reversed synaptic damage and neuronal loss, and thereby alleviated cognitive deficits caused by tau-N368. Taken together, STAT3 plays a critical role in truncated tau-related neuropathological changes. This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits. STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology. Related Articles | Metrics

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Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial Xiangjun Li, Chunyan Li, Hai Huang, Dan Bai, Jingyi Wang, Anqi Chen, Yu Gong, Ying Leng 2024, 19 (4):  923-928.  doi: 10.4103/1673-5374.382104 Abstract ( 137 )   PDF (553KB) ( 87 )   Save The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells, affecting vision. The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation. However, although the macular thickness can be normalized with each of these two therapies used alone, the vision does not improve in many patients. This might result from the incomplete recovery of retinal ganglion cell injury. Therefore, a prospective, non-randomized, controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery. In this trial, 150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods, followed by treatment with anti-vascular endothelial growth factor drugs, laser photocoagulation therapy, and their combination. All patients will be followed up for 12 months. The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment. The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1, 3, 6, and 9 months after treatment, retinal nerve fiber layer thickness, best-corrected visual acuity, macular area thickness, and choroidal thickness before and 1, 3, 6, 9, and 12 months after treatment. Safety measure is the incidence of adverse events at 1, 3, 6, 9, and 12 months after treatment. The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period. The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity. The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No. (2023)(26) on April 25, 2023, and was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2300072478, June 14, 2023, protocol version: 2.0). Related Articles | Metrics