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15 September 2023, Volume 18 Issue 9 Previous Issue   

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Mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation for ferroptosis after spinal cord injury Qi-Feng Song, Qian Cui, Ya-Shi Wang, Li-Xin Zhang 2023, 18 (9):  1861-1868.  doi: 10.4103/1673-5374.367838 Abstract ( 128 )   PDF (1301KB) ( 128 )   Save Spinal cord injury is characterized by different aetiologies, complex pathogenesis, and diverse pathological changes. Current treatments are not ideal, and prognosis is generally poor. After spinal cord injury, neurons die due to various forms of cell death. Among them, ferroptosis causes dysfunction after spinal cord injury, and no existing traditional treatments have been indicated to block its occurrence. Meanwhile, emerging therapies using mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation therapy are promising for reversing spinal cord neuronal ferroptosis after spinal cord injury. However, no definitive studies have demonstrated the effectiveness of these approaches. This review summarizes the existing research on the mechanisms of ferroptosis; ferroptosis after spinal cord injury; treatment of spinal cord injury with mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation; and treatment of ferroptosis using mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation. Inhibiting ferroptosis can promote the reversal of neurological dysfunction after spinal cord injury. In addition, mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation can reverse adverse outcomes of spinal cord injury and regulate ferroptosis-related factors. Thus, it can be inferred that mesenchymal stem cells, extracellular vesicles, and transcranial magnetic stimulation have the potential to inhibit ferroptosis after spinal cord injury. This review serves as a reference for future research to confirm these conclusions. Related Articles | Metrics

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Inducing prion protein shedding as a neuroprotective and regenerative approach in pathological conditions of the brain: from theory to facts Andreu Matamoros-Angles, Behnam Mohammadi, Feizhi Song, Mohsin Shafiq, Santra Brenna, Berta Puig, Markus Glatzel, Hermann C. Altmeppen 2023, 18 (9):  1869-1875.  doi: 10.4103/1673-5374.366496 Abstract ( 184 )   PDF (1671KB) ( 64 )   Save In the last decades, the role of the prion protein (PrP) in neurodegenerative diseases has been intensively investigated, initially in prion diseases of humans (e.g., Creutzfeldt-Jakob disease) and animals (e.g., scrapie in sheep, chronic wasting disease in deer and elk, or “mad cow disease” in cattle). Templated misfolding of physiological cellular prion protein (PrPC) into an aggregation-prone isoform (termed PrP “Scrapie” (PrPSc)), self-replication and spreading of the latter inside the brain and to peripheral tissues, and the associated formation of infectious proteopathic seeds (termed “prions”) are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies. Later, key roles of the correctly folded PrPC were identified in more common human brain diseases (such as Alzheimer’s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins (such as amyloid-β, tau or α-synuclein, respectively). PrPC has also been linked with neuroprotective and regenerative functions, for instance in hypoxic/ischemic conditions such as stroke. However, despite a mixed “bouquet” of suggested functions, our understanding of pathological and, especially, physiological roles played by PrPC in the brain and beyond is certainly incomplete. Interactions with various other proteins at the cell surface or within intracellular compartments may account for the functional diversity linked with PrPC. Moreover, conserved endogenous proteolytic processing of PrPC generates several defined PrPC fragments, possibly holding intrinsic functions in physiological and pathological conditions, thus making the “true and complete biology” of this protein more complicated to be elucidated. Here, we focus on one of those released PrPC fragments, namely shed PrP (sPrP), generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surface. Similar to other soluble PrPC fragments (such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event) or experimentally employed recombinant PrP, sPrP is being suggested to act neuroprotective in Alzheimer’s disease and other protein misfolding diseases. Several lines of evidence on extracellular PrPC (fragments) suggest that induction of PrPC release could be a future therapeutic option in various brain disorders. Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM10, based on ligands binding to cell surface PrPC, may further set the stage for research into this direction.  Related Articles | Metrics

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Extracellular vesicles as a potential therapeutic for age-related macular degeneration Lorraine L. C. Chow, Ben Mead 2023, 18 (9):  1876-1880.  doi: 10.4103/1673-5374.367835 Abstract ( 109 )   PDF (447KB) ( 93 )   Save Age-related macular degeneration is a major global cause of central visual impairment and severe vision loss. With an aging population, the already immense economic burden of costly anti-vascular endothelial growth factor treatment is likely to increase. In addition, current conventional treatment is only available for the late neovascular stage of age-related macular degeneration, and injections can come with potentially devastating complications, introducing the need for more economical and risk-free treatment. In recent years, exosomes, which are nano-sized extracellular vesicles of an endocytic origin, have shown immense potential as diagnostic biomarkers and in the therapeutic application, as they are bestowed with characteristics including an expansive cargo that closely resembles their parent cell and exceptional ability of intercellular communication and targeting neighboring cells. Exosomes are currently undergoing clinical trials for various conditions such as type 1 diabetes and autoimmune diseases; however, exosomes as a potential therapy for several retinal diseases have just begun to undergo scrutinizing investigation with little literature on age-related macular degeneration specifically. This article will focus on the limited literature available on exosome transplantation treatment in age-related macular degeneration animal models and in vitro cell cultures, as well as briefly identify future research directions. Current literature on exosome therapy using age-related macular degeneration rodent models includes laser retinal injury, N-methyl-N-nitrosourea, and royal college of surgeon models, which mimic inflammatory and degenerative aspects of age-related macular degeneration. These have shown promising results in preserving retinal function and morphology, as well as protecting photoreceptors from apoptosis. Exosomes from their respective cellular origins may also act by regulating the expression of various inflammatory cytokines, mRNAs, and proteins involved in photoreceptor degeneration pathways to exert a therapeutic effect. Various findings have also opened exciting prospects for the involvement of cargo components in remedial effects on the damaged macula or retina. Related Articles | Metrics

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Use of mesenchymal stem cell therapy in COVID-19 related strokes Mahika Rawat, Chiao Ng, Emaad Khan, Rayyan A. Shah, Suha Ashfaq, Ghaith A. Bahader, Zahoor A. Shah 2023, 18 (9):  1881-1883.  doi: 10.4103/1673-5374.367927 Abstract ( 93 )   PDF (477KB) ( 52 )   Save Coronavirus disease 2019 (COVID-19) has affected a broad demographics, eliciting a more significant effect on specific groups such as males, African Americans, and Hispanic minorities. Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies. However, immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19. Mesenchymal stem cell therapy offers regenerative, anti-inflammatory, and immunomodulatory properties that can speed up the recovery from COVID-19. Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from strokes, as COVID-19 increases the risk of strokes due to increased cytokines and clotting factors. Most stroke cases that occur in COVID-19 patients are ischemic strokes. Therefore, with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes, COVID-19-induced stroke patients might benefit from dual-ended treatment. The objective of this review was to discuss COVID-19 and stroke incidence and the available treatment options. Related Articles | Metrics

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Brain organoids are new tool for drug screening of neurological diseases Jin-Qi Zhou, Ling-Hui Zeng, Chen-Tao Li, Da-Hong He, Hao-Duo Zhao, Yan-Nan Xu, Zi-Tian Jin, Chong Gao 2023, 18 (9):  1884-1889.  doi: 10.4103/1673-5374.367983 Abstract ( 393 )   PDF (3287KB) ( 290 )   Save At the level of in vitro drug screening, the development of a phenotypic analysis system with high-content screening at the core provides a strong platform to support high-throughput drug screening. There are few systematic reports on brain organoids, as a new three-dimensional in vitro model, in terms of model stability, key phenotypic fingerprint, and drug screening schemes, and particularly regarding the development of screening strategies for massive numbers of traditional Chinese medicine monomers. This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases. The paper also highlights the prospects from model stability, induction criteria of brain organoids, and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.  Related Articles | Metrics

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Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer’s disease Qian Yue, Maggie Pui Man Hoi 2023, 18 (9):  1890-1902.  doi: 10.4103/1673-5374.367832 Abstract ( 198 )   PDF (4971KB) ( 211 )   Save Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease. Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression. Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier. For example, astrocytic coverage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions. Astrocyte activation is often observed in Alzheimer’s disease patients, with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta. Structural alterations in Alzheimer’s disease astrocytes including swollen endfeet, somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arterioles levels. In addition, Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration. In this review, we summarize the findings of existing literature on the relevance of astrocyte alteration in response to amyloid pathology in the context of blood-brain barrier dysfunction. First, we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance. Then, we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models. We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte. Finally, we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes, providing potential molecular mechanisms underlying blood-brain barrier modulation. We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease.  Related Articles | Metrics

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External anal sphincter electromyography in multiple system atrophy: implications for diagnosis, clinical correlations, and novel insights into prognosis Massimiliano Todisco, Giuseppe Cosentino, Enrico Alfonsi 2023, 18 (9):  1903-1907.  doi: 10.4103/1673-5374.367833 Abstract ( 171 )   PDF (3716KB) ( 49 )   Save Multiple system atrophy is a sporadic, progressive, adult-onset, neurodegenerative disorder characterized by autonomic dysfunction symptoms, parkinsonian features, and cerebellar signs in various combinations. An early diagnosis of multiple system atrophy is of utmost importance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients. The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging markers supporting diagnosis of multiple system atrophy. Nonetheless, especially in the early disease stage, it can be challenging to differentiate multiple system atrophy from mimic disorders, in particular Parkinson’s disease. Electromyography of the external anal sphincter represents a useful neurophysiological tool for differential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration, which is a pathological hallmark of multiple system atrophy. However, the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controversial reports in the literature. In this review, after a brief overview of the electrophysiological methodology, we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography. We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electromyography. Finally, we reported recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy. Related Articles | Metrics

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New insights into the biological roles of immune cells in neural stem cells in post-traumatic injury of the central nervous system Ning He, Xing-Jia Mao, Yue-Min Ding, Tong Zuo, Ying-Ying Chen, Lin-Lin Wang 2023, 18 (9):  1908-1916.  doi: 10.4103/1673-5374.367836 Abstract ( 253 )   PDF (2352KB) ( 110 )   Save Traumatic injuries in the central nervous system, such as traumatic brain injury and spinal cord injury, are associated with tissue inflammation and the infiltration of immune cells, which simultaneously affect the self-renewal and differentiation of neural stem cells. However, the tissue repair process instigated by endogenous neural stem cells is incapable of restoring central nervous system injuries without external intervention. Recently, resident/peripheral immune cells have been demonstrated to exert significant effects on neural stem cells. Thus, the restoration of traumatic injuries in the central nervous system by the immune intervention in neural stem cells represents a potential therapeutic method. In this review, we discuss the roles and possible mechanisms of immune cells on the self-renewal and differentiation of neural stem cells along with the prognosis of central nervous system injuries based on immune intervention. Finally, we discuss remaining research challenges that need to be considered in the future. Further elucidation of these challenges will facilitate the successful application of neural stem cells in central nervous system injuries. Related Articles | Metrics

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Gait analysis in swine, sheep, and goats after neurologic injury: a literature review Jacob W. Sveum, Raveena R. Mishra, Taylor L. Marti, Jalon M. Jones, Daniel J. Hellenbrand, Amgad S. Hanna 2023, 18 (9):  1917-1924.  doi: 10.4103/1673-5374.367839 Abstract ( 127 )   PDF (709KB) ( 162 )   Save Medical research on neurologic ailments requires representative animal models to validate treatments before they are translated to human clinical trials. Rodents are the predominant animal model used in neurological research despite limited anatomic and physiologic similarities to humans. As a result, functional testing designed to assess locomotor recovery after neurologic impairment is well established in rodent models. Comparatively, larger, more clinically relevant models have not been as well studied. To achieve similar locomotor testing standardization in larger animals, the models must be accessible to a wide array of researchers. Non-human primates are the most relevant animal model for translational research, however ethical and financial barriers limit their accessibility. This review focuses on swine, sheep, and goats as large animal alternatives for transitional studies between rodents and non-human primates. The objective of this review is to compare motor testing and data collection methods used in swine, sheep, and goats to encourage testing standardization in these larger animal models. The PubMed database was analyzed by searching combinations of swine, sheep, and goats, neurologic injuries, and functional assessments. Findings were categorized by animal model, data collection method, and assessment design. Swine and sheep were used in the majority of the studies, while only two studies were found using goats. The functional assessments included open pen analysis, treadmill walking, and guided free walking. Data collection methods included subjective behavioral rating scales and objective tools such as pressure-sensitive mats and image-based analysis software. Overall, swine and sheep were well-suited for a variety of assessment designs, with treadmill walking and guided free walking offering the most consistency across multiple trials. Data collection methods varied, but image-based gait analysis software provided the most robust analysis. Future studies should be conducted to standardize functional testing methods after neurologic impairment in large animals. Related Articles | Metrics

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Reviving the use of inhibitors of matrix metalloproteases in spinal cord injury: a case for specificity Zubair Ahmed 2023, 18 (9):  1925-1930.  doi: 10.4103/1673-5374.367837 Abstract ( 109 )   PDF (478KB) ( 73 )   Save At present, there are no restorative therapies in the clinic for spinal cord injury, with current treatments offering only palliative treatment options. The role of matrix metalloproteases is well established in spinal cord injury, however, translation into the clinical space was plagued by early designs of matrix metalloprotease inhibitors that lacked specificity and fears of musculoskeletal syndrome prevented their further development. Newer, much more specific matrix metalloprotease inhibitors have revived the possibility of using these inhibitors in the clinic since they are much more specific to their target matrix metalloproteases. Here, the evidence for use of matrix metalloproteases after spinal cord injury is reviewed and researchers are urged to overcome their old fears regarding matrix metalloprotease inhibition and possible side effects for the field to progress. Recently published work by us shows that inhibition of specific matrix metalloproteases after spinal cord injury holds promise since four key consequences of spinal cord injury could be alleviated by specific, next-generation matrix metalloprotease inhibitors. For example, specific inhibition of matrix metalloprotease-9 and matrix metalloprotease-12 within 24 hours after injury and for 3 days, alleviates spinal cord injury-induced edema, blood-spinal cord barrier breakdown, neuropathic pain and restores sensory and locomotor function. Attempts are now underway to translate this therapy into the clinic. Related Articles | Metrics

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Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease Nadège Hertzog, Claire Jacob 2023, 18 (9):  1931-1939.  doi: 10.4103/1673-5374.367834 Abstract ( 103 )   PDF (8979KB) ( 26 )   Save Schwann cells, the myelinating glia of the peripheral nervous system, wrap axons multiple times to build their myelin sheath. Myelin is of paramount importance for axonal integrity and fast axon potential propagation. However, myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal, demyelinating or dysmyelinating, or as intermediate. The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes: peripheral myelin protein 22, myelin protein zero and gap junction beta 1 (coding for Connexin 32) causing Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1B, and X-linked Charcot-Marie-Tooth disease type 1, respectively. The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients. No treatment to cure or slow down the disease progression is currently available on the market, however, scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies. In this review, we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease, the rodent models used in research, and the emerging therapeutic approaches to cure or counteract the progression of the disease. Related Articles | Metrics

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Tissue optical clearing for neural regeneration research Tingting Yu, Jianyi Xu, Dan Zhu 2023, 18 (9):  1940-1941.  doi: 10.4103/1673-5374.363827 Abstract ( 96 )   PDF (1524KB) ( 33 )   Save Nerve injury, whether traumatic or degenerative, disrupts the transmission of information in the nervous system, leading to dysfunction. It is widely known that neural regeneration is vital to the restoration of function after nerve injury. Still, outcomes are often limited by the misguidance of axonal regeneration and complex pathological changes in neurons and glia, as well as the long-term denervation of target organs. Morphological analyses of neural tissues and target organs are vital for outcome assessments in neural regeneration research. Related Articles | Metrics

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Effect of caffeine in the intraventricular hemorrhage of the preterm newborn Pilar Alves-Martinez, Monica Garcia-Alloza 2023, 18 (9):  1942-1943.  doi: 10.4103/1673-5374.363830 Abstract ( 104 )   PDF (662KB) ( 55 )   Save There are around 15 million preterm newborns (PT) every year (Atienza-Navarro et al., 2020). With these figures in mind, prematurity represents a major health problem worldwide and it is a leading cause of infant mortality, accounting for up to 35% of all deaths among newborns (Atienza-Navarro et al., 2020) and up to 18% of the deaths among children under 5 years of age. Although advances in neonatology have significantly reduced mortality rates associated with prematurity, related comorbidities and sequelae remain a crucial societal and economic burden (Alves-Martinez et al., 2022). PT are born at a critical time in brain development, thus they have an immature central nervous system characterized by low neuronal migration, poor myelination, impaired grey matter growth matter or a fragile vascular structure of the germinal matrix (Atienza-Navarro et al., 2020), among others. The germinal matrix is a highly vascularized subependymal region adjacent to the ventricle. This tissue is prone to bleeding, due to the high vascularisation of the region and the hemodynamic instability of the PT (Atienza-Navarro et al., 2020), causing a germinal matrix-intraventricular hemorrhage (GM-IVH). GM-IVH is the most common intracerebral hemorrhage of the PT and affects up to 20–30% of these patients (Alves-Martinez et al., 2022). When GM-IVH occurs, neuronal loss, white matter lesions and inflammation are observed. The extension of the lesions, as well as related problems and sequelae, are highly dependent on the severity of the bleeding (Atienza-Navarro et al., 2020) and may include short- and long-term, neurological, sensory, cognitive and motor disabilities or neuropsychiatric disorders (Atienza-Navarro et al., 2020). Related Articles | Metrics

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Transcranial photobiomodulation with near-infrared light: a promising therapeutic modality for Alzheimer’s disease Hanli Liu, Damir Nizamutdinov, Jason H. Huang 2023, 18 (9):  1944-1945.  doi: 10.4103/1673-5374.366499 Abstract ( 124 )   PDF (5609KB) ( 109 )   Save Transcranial photobiomodulation (tPBM) is a non-invasive neuromodulation technique that delivers near-infrared (NIR) light with low irradiance (i.e., power density in mW/cm2) in the wavelength range of 800–1070 nm. Several recently published books or collected literature (Hamblin, 2019; Gonzalez-Lima, 2021) and papers (Nizamutdinov et al., 2022) offer comprehensive reviews of the mechanism of action and potential clinical translations of tPBM for the treatment of a variety of diseases, including neurodegenerative diseases (Alzheimer’s disease (AD), and Parkinson’s disease), traumatic brain injury, stroke, and psychiatric disorders (depression and post-traumatic stress disorder). This communication focuses on the feasibility and benefits of tPBM in treating patients with AD. The socio-economic burden of AD is significant and will only increase with longer life expectancy unless effective interventions are developed. Currently, none of the therapeutic strategies have been successful in treating or alleviating the symptoms of AD. Related Articles | Metrics

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Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer’s disease Lige Leng, Jie Zhang 2023, 18 (9):  1946-1947.  doi: 10.4103/1673-5374.367842 Abstract ( 102 )   PDF (6702KB) ( 69 )   Save Alzheimer’s disease (AD) shares multiple characteristics of metabolic diseases: AD is an age-associated neurodegenerative disease characterized by progressive loss of memory and cognitive functions, which is classically manifested by the deposition of β-amyloid (Aβ) plaques, the neurofibrillary tangles, and neuronal loss. Mounting evidence also suggests that AD shares multiple characteristics of metabolic diseases. The impairment in cerebral glucose metabolism and insulin resistance are considered typical features of AD and its occurrence precedes cognitive dysfunction for decades in patients.   Related Articles | Metrics

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Oxidative stress: culprit or consequence in Alzheimer’s amyloidopathy Chanchal Sharma, Sang Ryong Kim 2023, 18 (9):  1948-1949.  doi: 10.4103/1673-5374.367843 Abstract ( 133 )   PDF (400KB) ( 58 )   Save Oxidative stress in Alzheimer’s disease: Oxidative stress refers to an imbalance between the pro-oxidative and anti-oxidative states that are part of normal cell metabolism that results in the elevated production of reactive oxygen species (ROS) and free radicals. These products oxidize lipids, proteins, and DNA, significantly threatening the integrity of neurons (Praticò, 2008; Padurariu et al., 2013). Specifically, free radicals such as the superoxide anion (O2•–), hydroxyl radical (OH•), and non-radical molecules including hydrogen peroxide (H2O2) and singlet oxygen (1O2), are often produced in the mitochondria during oxidative phosphorylation and can enter the cytoplasm of the cells and causes damage outside of the mitochondria (Guo et al., 2013; Padurariu et al., 2013). After this step, there is a subsequent reduction in the cell’s endogenous-antioxidant potential along with inhibition of mitochondrial respiration, reduction of  adenosine triphosphate (ATP) levels, mitochondrial bursting, Ca2+ dyshomeostasis, membrane damage, and subsequent production of insoluble aggregate which results in proteotoxicity and protein aggregation (Praticò, 2008; Guo et al., 2013; Padurariu et al., 2013). The brain is particularly vulnerable to the oxidative stress due to its high oxygen requirement and lipid-rich composition. Therefore, damage to the brain caused by oxidative stress has a high chance of impairing normal central nervous system processes and may result in progressive cell damage, neurodegeneration, and cell death (Guo et al., 2013). The term antioxidant often refers to a group of vitamins and synthetic, plant-derived, or inorganic substances that can inhibit the production of, promote the detoxification, or scavenge reactive oxidant species (Praticò, 2008). Related Articles | Metrics

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Immunological role of sulfatide in the pathogenesis of multiple sclerosis Mio Hamatani, Takayuki Kondo 2023, 18 (9):  1950-1951.  doi: 10.4103/1673-5374.366498 Abstract ( 111 )   PDF (408KB) ( 45 )   Save Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. A certain population of patients with MS present with a relapse-remitting disease course (RRMS) during the early phase and eventually advance to a progressive course (PMS). While immune modulation therapies have recently seen tremendous success in RRMS, our limited knowledge of pathogenesis hampers the development of effective treatments for PMS. Related Articles | Metrics

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Neurodevelopmental defects as a primer of neurodegeneration: lessons from spinal muscular atrophy and Huntington’s disease Stuart J. Grice, Ji-Long Liu 2023, 18 (9):  1952-1953.  doi: 10.4103/1673-5374.367844 Abstract ( 73 )   PDF (469KB) ( 34 )   Save Developmental motifs in neurodegeneration: Neurodegeneration, the prominent feature of neurodegenerative disease, is characterized by the progressive and selective loss of neuronal function. As some of the pathologies caused by neurodegeneration may be irreversible, early intervention will be required for the treatments that aim to slow or halt the manifestation of these diseases. Traditionally, neurodegeneration evokes the idea of a progressive decline of brain function, which ultimately ends with the loss of cognitive, sensory, or motor ability, and the death of specific neuronal subtypes. However, it is now starting to emerge that some neurodegenerative diseases may be caused, or at least become primed, by defects that arise during neurodevelopment.  Related Articles | Metrics

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Gene-modified neural progenitor cells for the treatment of neuropathic lysosomal storage diseases Oriana Mandolfo, Brian W. Bigger 2023, 18 (9):  1954-1955.  doi: 10.4103/1673-5374.367845 Abstract ( 92 )   PDF (601KB) ( 38 )   Save Lysosomal storage diseases: Lysosomal storage diseases (LSDs) are a family of about 70 disorders, with an overall incidence of 1:7000 live births. They are caused by dysfunctional lysosomal hydrolases, eventually leading to the accumulation of undegraded substrate into the lysosome. This results in a wide array of symptoms, which may include: the presence of dysmorphic features, cardio-respiratory disease, bone and joint disease, organomegaly, developmental delay and neurocognitive decline. The majority of these diseases have a neurological component and in the absence of treatment, death often occurs in the first decades of life, with the neurological complications drastically undermining the patient’s quality of life, as well as their families (Boustany, 2013).  Related Articles | Metrics

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Serum response factor promotes axon regeneration following spinal cord transection injury Guo-Ying Feng, Nai-Li Zhang, Xiao-Wei Liu, Ling-Xi Tong, Chun-Lei Zhang, Shuai Zhou, Lu-Ping Zhang, Fei Huang 2023, 18 (9):  1956-1960.  doi: 10.4103/1673-5374.367974 Abstract ( 150 )   PDF (6035KB) ( 96 )   Save Studies have shown that serum response factor is beneficial for axonal regeneration of peripheral nerves. However, its role after central nervous system injury remains unclear. In this study, we established a rat model of T9–T10 spinal cord transection injury. We found that the expression of serum response factor in injured spinal cord gray matter neurons gradually increased with time, reached its peak on the 7th day, and then gradually decreased. To investigate the role of serum response factor, we used lentivirus vectors to overexpress and silence serum response factor in spinal cord tissue. We found that overexpression of serum response factor promoted motor function recovery in rats with spinal cord injury. Qualitative observation of biotinylated dextran amine anterograde tracing showed that overexpression of serum response factor increased nerve fibers in the injured spinal cord. Additionally, transmission electron microscopy showed that axon and myelin sheath morphology was restored. Silencing serum response factor had the opposite effects of overexpression. These findings suggest that serum response factor plays a role in the recovery of motor function after spinal cord injury. The underlying mechanism may be related to the regulation of axonal regeneration.  Related Articles | Metrics

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Neuroprotective effects of meloxicam on transient brain ischemia in rats: the two faces of anti-inflammatory treatments Irene Fernández Ugidos, Paloma González-Rodríguez, María Santos-Galdiano, Enrique Font-Belmonte, Berta Anuncibay-Soto, Diego Pérez-Rodríguez, José Manuel Gonzalo-Orden, Arsenio Fernández-López 2023, 18 (9):  1961-1967.  doi: 10.4103/1673-5374.367846 Abstract ( 112 )   PDF (27273KB) ( 29 )   Save The inflammatory response plays an important role in neuroprotection and regeneration after ischemic insult. The use of non-steroidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects. In this context, the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stroke, but its ability to inhibit both cyclooxygenase isoforms (1 and 2) could be a promising strategy to modulate post-ischemic inflammation. This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats, measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area. We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia. Moreover, meloxicam treatment modulated glial scar reactivity, which matched with an increase in axonal sprouting. However, this treatment decreased the formation of neuronal progenitor cells. This study discusses the dual role of anti-inflammatory treatments after stroke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies. Related Articles | Metrics

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Age-related hearing loss accelerates the decline in fast speech comprehension and the decompensation of cortical network connections He-Mei Huang, Gui-Sheng Chen, Zhong-Yi Liu, Qing-Lin Meng, Jia-Hong Li, Han-Wen Dong, Yu-Chen Chen, Fei Zhao, Xiao-Wu Tang, Jin-Liang Gao, Xi-Ming Chen, Yue-Xin Cai, Yi-Qing Zheng 2023, 18 (9):  1968-1975.  doi: 10.4103/1673-5374.361530 Abstract ( 111 )   PDF (6854KB) ( 189 )   Save Patients with age-related hearing loss face hearing difficulties in daily life. The causes of age-related hearing loss are complex and include changes in peripheral hearing, central processing, and cognitive-related abilities. Furthermore, the factors by which aging relates to hearing loss via changes in auditory processing ability are still unclear. In this cross-sectional study, we evaluated 27 older adults (over 60 years old) with age-related hearing loss, 21 older adults (over 60 years old) with normal hearing, and 30 younger subjects (18–30 years old) with normal hearing. We used the outcome of the upper-threshold test, including the time-compressed threshold and the speech recognition threshold in noisy conditions, as a behavioral indicator of auditory processing ability. We also used electroencephalography to identify presbycusis-related abnormalities in the brain while the participants were in a spontaneous resting state. The time-compressed threshold and speech recognition threshold data indicated significant differences among the groups. In patients with age-related hearing loss, information masking (babble noise) had a greater effect than energy masking (speech-shaped noise) on processing difficulties. In terms of resting-state electroencephalography signals, we observed enhanced frontal lobe (Brodmann’s area, BA11) activation in the older adults with normal hearing compared with the younger participants with normal hearing, and greater activation in the parietal (BA7) and occipital (BA19) lobes in the individuals with age-related hearing loss compared with the younger adults. Our functional connection analysis suggested that compared with younger people, the older adults with normal hearing exhibited enhanced connections among networks, including the default mode network, sensorimotor network, cingulo-opercular network, occipital network, and frontoparietal network. These results suggest that both normal aging and the development of age-related hearing loss have a negative effect on advanced auditory processing capabilities and that hearing loss accelerates the decline in speech comprehension, especially in speech competition situations. Older adults with normal hearing may have increased compensatory attentional resource recruitment represented by the top-down active listening mechanism, while those with age-related hearing loss exhibit decompensation of network connections involving multisensory integration. Related Articles | Metrics

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C-X-C chemokine receptor type 7 antibody enhances neural plasticity after ischemic stroke Xiao-Qian Zhang, Xiao-Yin Wang, Bing-Chao Dong, Mei-Xuan Li, Yu Wang, Ting Xiao, Shan-Shan Zhao 2023, 18 (9):  1976-1982.  doi: 10.4103/1673-5374.363835 Abstract ( 92 )   PDF (7422KB) ( 35 )   Save Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4 (CXCR4) have been shown to regulate neural regeneration after stroke. However, whether stromal cell-derived factor-1 receptor CXCR7, which is widely distributed in the developing and adult central nervous system, participates in neural regeneration remains poorly understood. In this study, we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral cortex and striatum. Starting on day 7 after injury, CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days. Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting corticospinal tract fibers in rats with cerebral ischemia, increased the expression of vesicular glutamate transporter 1 and growth-related protein 43, markers of the denervated spinal cord synapses, and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum. In addition, CXCR7 antibody increased the expression of CXCR4 in the striatum, increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway, and improved rat motor function. These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration, synaptogenesis, and myelin regeneration, which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.  Related Articles | Metrics

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miR-181b promotes angiogenesis and neurological function recovery after ischemic stroke Li-Xia Xue, Lin-Yuan Shu, Hong-Mei Wang, Kai-Li Lu, Li-Gang Huang, Jing-Yan Xiang, Zhi Geng, Yu-Wu Zhao, Hao Chen 2023, 18 (9):  1983-1989.  doi: 10.4103/1673-5374.367957 Abstract ( 247 )   PDF (14468KB) ( 127 )   Save Promotion of new blood vessel formation is a new strategy for treating ischemic stroke. Non-coding miRNAs have been recently considered potential therapeutic targets for ischemic stroke. miR-181b has been shown to promote angiogenesis in hypoxia and traumatic brain injury model, while its effect on ischemic stroke remains elusive. In this study, we found that overexpression of miR-181b in brain microvascular endothelial cells subjected to oxygen-glucose deprivation in vitro restored cell proliferation and enhanced angiogenesis. In rat models of focal cerebral ischemia, overexpression of miR-181b reduced infarction volume, promoted angiogenesis in ischemic penumbra, and improved neurological function. We further investigated the molecular mechanism by which miR-181b participates in angiogenesis after ischemic stroke and found that miR-181b directly bound to the 3′-UTR of phosphatase and tensin homolog (PTEN) mRNA to induce PTEN downregulation, leading to activation of the protein kinase B (Akt) pathway, upregulated expression of vascular endothelial growth factors, down-regulated expression of endostatin, and promoted angiogenesis. Taken together, these results indicate that exogenous miR-181b exhibits neuroprotective effects on ischemic stroke through activating the PTEN/Akt signal pathway and promoting angiogenesis.  Related Articles | Metrics

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Low-temperature 3D-printed collagen/chitosan scaffolds loaded with exosomes derived from neural stem cells pretreated with insulin growth factor-1 enhance neural regeneration after traumatic brain injury Xiao-Yin Liu, Yin-He Feng, Qing-Bo Feng, Jian-Yong Zhang, Lin Zhong, Peng Liu, Shan Wang, Yan-Ruo Huang, Xu-Yi Chen, Liang-Xue Zhou 2023, 18 (9):  1990-1998.  doi: 10.4103/1673-5374.366497 Abstract ( 155 )   PDF (12922KB) ( 64 )   Save There are various clinical treatments for traumatic brain injury, including surgery, drug therapy, and rehabilitation therapy; however, the therapeutic effects are limited. Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury. In this study, we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (3D-CC-INExos) to improve traumatic brain injury repair and functional recovery after traumatic brain injury in rats. Composite scaffolds comprising collagen, chitosan, and exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (INExos) continuously released exosomes for 2 weeks. Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model, as assessed by the Morris water maze test and modified neurological severity scores. In addition, immunofluorescence staining and transmission electron microscopy showed that 3D-CC-INExos implantation significantly improved the recovery of damaged nerve tissue in the injured area. In conclusion, this study suggests that transplanted 3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation. Related Articles | Metrics

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Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells promotes functional recovery in patients with spontaneous intracerebral hemorrhage: phase I clinical trial Xiao-Yin Li, Wu-Sheng Deng, Zi-Qi Wang, Zheng-Chao Li, Shu-Lian Chen, Zhen Song, Quan Zhang, Jin Liang, Xu-Yi Chen 2023, 18 (9):  1999-2004.  doi: 10.4103/1673-5374.366489 Abstract ( 107 )   PDF (4286KB) ( 91 )   Save Animal experiments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury. To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage, this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion criteria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People’s Armed Police Force from May 2016 to December 2020. Patients were divided into three groups according to the clinical situation and patient benefit: control (n = 18), human umbilical cord-derived mesenchymal stem cells (n = 4), and combination (n = 8). The control group did not receive any transplantation. The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation. The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells. Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intracerebral hemorrhage-related encephalomalacia. Severe adverse events associated with cell transplantation were not observed. Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.  Related Articles | Metrics

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Photobiomodulation provides neuroprotection through regulating mitochondrial fission imbalance in the subacute phase of spinal cord injury Xin Li, Xuan-Kang Wang, Zhi-Jie Zhu, Zhuo-Wen Liang, Peng-Hui Li, Yang-Guang Ma, Tan Ding, Kun Li, Xiao-Shuang Zuo, Cheng Ju, Zhi-Hao Zhang, Zhi-Wen Song, Hui-Lin Quan, Jia-Wei Zhang, Liang Luo, Zhe Wang, Xue-Yu Hu 2023, 18 (9):  2005-2010.  doi: 10.4103/1673-5374.366491 Abstract ( 141 )   PDF (18951KB) ( 60 )   Save Increasing evidence indicates that mitochondrial fission imbalance plays an important role in delayed neuronal cell death. Our previous study found that photobiomodulation improved the motor function of rats with spinal cord injury. However, the precise mechanism remains unclear. To investigate the effect of photobiomodulation on mitochondrial fission imbalance after spinal cord injury, in this study, we treated rat models of spinal cord injury with 60-minute photobiomodulation (810 nm, 150 mW) every day for 14 consecutive days. Transmission electron microscopy results confirmed the swollen and fragmented alterations of mitochondrial morphology in neurons in acute (1 day) and subacute (7 and 14 days) phases. Photobiomodulation alleviated mitochondrial fission imbalance in spinal cord tissue in the subacute phase, reduced neuronal cell death, and improved rat posterior limb motor function in a time-dependent manner. These findings suggest that photobiomodulation targets neuronal mitochondria, alleviates mitochondrial fission imbalance-induced neuronal apoptosis, and thereby promotes the motor function recovery of rats with spinal cord injury.  Related Articles | Metrics

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Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos Bing-Qiang He, Ai-Cheng Li, Yu-Xuan Hou, Hui Li, Xing-Yuan Zhang, Hui-Fei Hao, Hong-Hua Song, Ri-Xin Cai, Ying-Jie Wang, Yue Zhou, Yong-Jun Wang 2023, 18 (9):  2011-2018.  doi: 10.4103/1673-5374.366495 Abstract ( 219 )   PDF (5148KB) ( 115 )   Save The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases  and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals. Related Articles | Metrics

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Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer’s disease Li-Fen Liu, Yu-Tong Liu, Dan-Dan Wu, Jie Cheng, Na-Na Li, Ya-Ni Zheng, Liang Huang, Qiong-Lan Yuan 2023, 18 (9):  2019-2028.  doi: 10.4103/1673-5374.366492 Abstract ( 130 )   PDF (5778KB) ( 73 )   Save Extracellular amyloid beta (Aβ) plaques are main pathological feature of Alzheimer’s disease. However, the specific type of neurons that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown. In this study, we found that 5-hydroxytryptamin receptor 3A subunit (HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice (an Alzheimer’s disease model) and patients with Alzheimer’s disease. To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques, we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model. Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons. These results suggest that HTR3A -positive interneurons may partially contribute to the generation of Aβ peptides. We treated 5.0–5.5-month-old model mice with tropisetron, a HTR3 antagonist, for 8 consecutive weeks. We found that the cognitive deficit of mice was partially reversed, Aβ plaques and neuroinflammation were remarkably reduced, the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice. These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reverses the pathological changes of Alzheimer’s disease.  Related Articles | Metrics

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Genetic modification of miR-34a enhances efficacy of transplanted human dental pulp stem cells after ischemic stroke Jianfeng Wang, Peibang He, Qi Tian, Yu Luo, Yan He, Chengli Liu, Pian Gong, Yujia Guo, Qingsong Ye, Mingchang Li 2023, 18 (9):  2029-2036.  doi: 10.4103/1673-5374.367831 Abstract ( 185 )   PDF (26396KB) ( 45 )   Save Human dental pulp stem cells (hDPSCs) promote recovery after ischemic stroke; however, the therapeutic efficacy is limited by the poor survival of transplanted cells. For in vitro experiments in the present study, we used oxygen-glucose deprivation/reoxygenation in hDPSCs to mimic cell damage induced by ischemia/reperfusion. We found that miRNA-34a-5p (miR-34a) was elevated under oxygen-glucose deprivation/reoxygenation conditions in hDPSCs. Inhibition of miR-34a facilitated the proliferation and antioxidant capacity and reduced the apoptosis of hDPSCs. Moreover, dual-luciferase reporter gene assay showed WNT1 and SIRT1 as the targets of miR-34a. In miR-34a knockdown cell lines, WNT1 suppression reduced cell proliferation, and SIRT1 suppression decreased the antioxidant capacity. Together, these results indicated that miR-34a regulates cell proliferation and antioxidant stress via targeting WNT1 and SIRT1, respectively. For in vivo experiments, we injected genetically modified hDPSCs (anti34a-hDPSCs) into the brains of mice. We found that anti34a-hDPSCs significantly inhibited apoptosis, reduced cerebral edema and cerebral infarct volume, and improved motor function in mice. This study provides new insights into the molecular mechanism of the cell proliferation and antioxidant capacity of hDPSCs, and suggests a potential gene that can be targeted to improve the survival rate and efficacy of transplanted hDPSCs in brain after ischemic stroke. Related Articles | Metrics

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Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson’s disease associated with nuclear receptor-related factor 1 defect Piniel Alphayo Kambey, Wen-Ya Liu, Jiao Wu, Bakwatanisa Bosco, Iqra Nadeem, Kouminin Kanwore, Dian-Shuai Gao 2023, 18 (9):  2037-2046.  doi: 10.4103/1673-5374.366493 Abstract ( 128 )   PDF (37219KB) ( 23 )   Save Previous studies have found that deficiency in nuclear receptor-related factor 1 (Nurr1), which participates in the development, differentiation, survival, and degeneration of dopaminergic neurons, is associated with Parkinson’s disease, but the mechanism of action is perplexing. Here, we first ascertained the repercussion of knocking down Nurr1 by performing liquid chromatography coupled with tandem mass spectrometry. We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency, 14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis. To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms, we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model. The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes, the preponderance of which encode components of the major histocompatibility II complex. Cd74, H2-Ab1, H2-Aa, H2-Eb1, Lyz2, Mrc1, Slc6a3, Slc47a1, Ms4a4b, and Ptprc2 were the top 10 differentially expressed genes. Immunofluorescence staining showed that, after Nurr1 knockdown, the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased. In addition, Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine. Taken together, our results suggest that Nurr1 deficiency results in an increase in Cd74 expression, thereby leading to the destruction of dopaminergic neurons. These findings provide a potential therapeutic target for the treatment of Parkinson’s disease. Related Articles | Metrics

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5-Hydroxytryptamine: a potential therapeutic target in amyotrophic lateral sclerosis Shi-Shi Jiang, Meng-Ni Gong, Wei Rao, Wen Chai, Wen-Zhi Chen, Xiong Zhang, Hong-Bing Nie, Ren-Shi Xu 2023, 18 (9):  2047-2055.  doi: 10.4103/1673-5374.367929 Abstract ( 110 )   PDF (21222KB) ( 47 )   Save Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis (ALS) is closely linked to 5-hydroxytryptamine (5-HT). To investigate this further, we administered 5-HT receptor antagonists to SOD1*G93A transgenic (ALS mouse model) and wide-type mice. This involved intraperitoneal injections of either granisetron, piboserod, or ritanserin, which inhibit the 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. The transgenic mice were found to have fewer 5-HT-positive cells in the spinal cord compared with wide-type mice. We found that the administration of granisetron reduced the body weight of the transgenic mice, while piboserod and ritanserin worsened the motor functioning, as assessed using a hanging wire test. However, none of the 5-HT receptor antagonists affected the disease progression. We analyzed the distribution and/or expression of TAR DNA binding protein 43 (TDP-43) and superoxide dismutase 1 G93A (SOD1-G93A), which form abnormal aggregates in ALS. We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists. In addition, the disease-related mislocalization of TDP-43 to the cytoplasm increased markedly for all three drugs. In certain anatomical regions, the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons. These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells. 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis. Related Articles | Metrics

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Transcriptional regulatory network during axonal regeneration of dorsal root ganglion neurons: laser-capture microdissection and deep sequencing Li-Li Zhao, Tao Zhang, Wei-Xiao Huang, Ting-Ting Guo, Xiao-Song Gu 2023, 18 (9):  2056-2066.  doi: 10.4103/1673-5374.366494 Abstract ( 104 )   PDF (5005KB) ( 109 )   Save The key regulators and regeneration-associated genes involved in axonal regeneration of neurons after injury have not been clarified. In high-throughput sequencing, various factors influence the final sequencing results, including the number and size of cells, the depth of sequencing, and the method of cell separation. There is still a lack of research on the detailed molecular expression profile during the regeneration of dorsal root ganglion neuron axon. In this study, we performed laser-capture microdissection coupled with RNA sequencing on dorsal root ganglion neurons at 0, 3, 6, and 12 hours and 1, 3, and 7 days after sciatic nerve crush in rats. We identified three stages after dorsal root ganglion injury: early (3–12 hours), pre-regeneration (1 day), and regeneration (3–7 days). Gene expression patterns and related function enrichment results showed that one module of genes was highly related to axonal regeneration. We verified the up-regulation of activating transcription factor 3 (Atf3), Kruppel like factor 6 (Klf6), AT-rich interaction domain 5A (Arid5a), CAMP responsive element modulator (Crem), and FOS like 1, AP-1 transcription factor Subunit (Fosl1) in dorsal root ganglion neurons after injury. Suppressing these transcription factors (Crem, Arid5a, Fosl1 and Klf6) reduced axonal regrowth in vitro. As the hub transcription factor, Atf3 showed higher expression and activity at the pre-regeneration and regeneration stages. G protein-coupled estrogen receptor 1 (Gper1), interleukin 12a (Il12a), estrogen receptor 1 (ESR1), and interleukin 6 (IL6) may be upstream factors that trigger the activation of Atf3 during the repair of axon injury in the early stage. Our study presents the detailed molecular expression profile during axonal regeneration of dorsal root ganglion neurons after peripheral nerve injury. These findings may provide reference for the clinical screening of molecular targets for the treatment of peripheral nerve injury. Related Articles | Metrics

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Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway Tong-Tong Lin, Chun-Yi Jiang, Lei Sheng, Li Wan, Wen Fan, Jin-Can Li, Xiao-Di Sun, Chen-Jie Xu, Liang Hu, Xue-Feng Wu, Yuan Han, Wen-Tao Liu, Yin-Bing Pan 2023, 18 (9):  2067-2074.  doi: 10.4103/1673-5374.366490 Abstract ( 116 )   PDF (5240KB) ( 43 )   Save Opioids, such as morphine, are the most potent drugs used to treat pain. Long-term use results in high tolerance to morphine. High mobility group box-1 (HMGB1) has been shown to participate in neuropathic or inflammatory pain, but its role in morphine tolerance is unclear. In this study, we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days. We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1. HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4 receptor expression in microglia, thereby inducing morphine tolerance. Glycyrrhizin, an HMGB1 inhibitor, markedly attenuated chronic morphine tolerance in the mouse model. Finally, compound C (adenosine 5′-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin (heme oxygenase-1 inhibitor) alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tolerance, and alleviated morphine tolerance in the mouse model. These findings suggest that morphine induces HMGB1 release via the adenosine 5′-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway, and that inhibiting this signaling pathway can effectively reduce morphine tolerance.  Related Articles | Metrics

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Fasting produces antidepressant-like effects via activating mammalian target of rapamycin complex 1 signaling pathway in ovariectomized mice Zi-Qian Cheng, Jie Fan, Fang-Yi Zhao, Jing-Yun Su, Qi-Han Sun, Ran-Ji Cui, Bing-Jin Li 2023, 18 (9):  2075-2081.  doi: 10.4103/1673-5374.367928 Abstract ( 95 )   PDF (6018KB) ( 53 )   Save Recent studies have shown that a 9-hour fast in mice reduces the amount of time spent immobile in the forced swimming test. However, whether 9-hour fasting has therapeutic effects in female mice with depressive symptoms has not been established. Therefore, in this study, we simulated perimenopausal depression via an ovariectomy in mice, and subjected them to a single 9-hour fasting 7 days later. We found that the ovariectomy increased the time spent immobile in the forced swimming test, inhibited expression of the mammalian target of rapamycin complex 1 signaling pathway in the hippocampus and prefrontal cortex, and decreased the density of dendritic spines in the hippocampus. The 9-hour acute fasting alleviated the above-mentioned phenomena. Furthermore, all of the antidepressant-like effects of 9-hour fasting were reversed by an inhibitor of the mammalian target of rapamycin complex 1. Electrophysiology data showed a remarkable increase in long-term potentiation in the hippocampal CA1 of the ovariectomized mice subjected to fasting compared with the findings in the ovariectomized mice not subjected to fasting. These findings show that the antidepressant-like effects of 9-hour fasting may be related to the activation of the mammalian target of the rapamycin complex 1 signaling pathway and synaptic plasticity in the mammalian hippocampus. Thus, fasting may be a potential treatment for depression. Related Articles | Metrics

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Survival of rat sciatic nerve segments preserved in storage solutions ex vivo assessed by novel electrophysiological and morphological criteria Liwen Zhou, Monzer Alatrach, Ted Zhao, Paul Oliphint, George D. Bittner 2023, 18 (9):  2082-2088.  doi: 10.4103/1673-5374.367848 Abstract ( 83 )   PDF (2780KB) ( 50 )   Save Most organ or tissue allografts with viable cells are stored in solutions ex vivo for hours to several days. Most allografts then require rapid host revascularization upon transplantation to maintain donor-cell functions (e.g., cardiac muscle contractions, hepatic secretions). In contrast, peripheral nerve allografts stored ex vivo do not require revascularization to act as scaffolds to guide outgrowth by host axons at 1–2 mm/d, likely aided by viable donor Schwann cells. Using current storage solutions and protocols, axons in all these donor organ/tissue/nerve transplants are expected to rapidly become non-viable due to Wallerian degeneration within days. Therefore, ex vivo storage solutions have not been assessed for preserving normal axonal functions, i.e., conducting action potentials or maintaining myelin sheaths. We hypothesized that most or all organ storage solutions would maintain axonal viability. We examined several common organ/tissue storage solutions (University of Wisconsin Cold Storage Solution, Normosol-R, Normal Saline, and Lactated Ringers) for axonal viability in rat sciatic nerves ex vivo as assessed by maintaining: (1) conduction of artificially-induced compound action potentials; and (2) axonal and myelin morphology in a novel assay method. The ten different storage solution conditions for peripheral nerves with viable axons (PNVAs) differed in their solution composition, osmolarity (250–318 mOsm), temperature (4°C vs. 25°C), and presence of calcium. Compound action potentials and axonal morphology in PNVAs were best maintained for up to 9 days ex vivo in calcium-free hypotonic diluted (250 mOsm) Normosol-R (dNR) at 4°C. Surprisingly, compound action potentials were maintained for only 1–2 days in UW and NS at 4°C, a much shorter duration than PNVAs maintained in 4°C dNR (9 days) or even in 25°C dNR (5 days). Viable axons in peripheral nerve allografts are critical for successful polyethylene glycol (PEG)-fusion of viable proximal and distal ends of host axons with viable donor axons to repair segmental-loss peripheral nerve injuries. PEG-fusion repair using PNVAs prevents Wallerian degeneration of many axons within and distal to the graft and results in excellent recovery of sensory/motor functions and voluntary behaviors within weeks. Such PEG-fused PNVAs, unlike all other types of conventional donor transplants, are immune-tolerated without tissue matching or immune suppression. Preserving axonal viability in stored PNVAs would enable the establishment of PNVA tissue banks to address the current shortage of transplantable nerve grafts and the use of stored PEG-fused PNVAs to repair segmental-loss peripheral nerve injuries. Furthermore, PNVA storage solutions may enable the optimization of ex vivo storage solutions to maintain axons in other types of organ/tissue transplants. Related Articles | Metrics