Результаты поиска

Identifying Potential Drug Targets in Coronary Atherosclerosis: Insights from the Druggable Genome and Mendelian Randomization.

PURPOSE: This study aims to identify therapeutic targets for coronary atherosclerosis (CA) using publicly available datasets while exploring … MR analyses revealed that GGCX was associated with increased CA risk in excitatory, inhibitory and oligodendrocyte precursor cells, whereas NPEPPS was associated with protection in oligodendrocyte lineage cells. Finally, Phe-MR analyses indicated possible indications and side effects of the targets. CONCLUSION: Our study provides genetic evidence for VAMP8, MFGE8, PDGFD, GGCX …

Outer radial glia promotes white matter regeneration after neonatal brain injury.

The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets a

N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) promote growth and inhibit differentiation of glioma stem-like cells.

Metabolic reprogramming is a pathological feature of cancer and a driver of tumor cell transformation. N-Acetylaspartate (NAA) is one of the most abundant amino acid derivatives in the brain and serves as a source of metabolic acetate for oligodendrocyte myelination and protein/histone acetylation or a precursor for the synthesis of the neurotransmitter N-acetylaspartylglutamate (NAAG). NAA and NAAG as well as aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors, suggesting a possible role for decreased acetate metabolism in tumorigenesi

Quantitative MRI maps of human neocortex explored using cell type-specific gene expression analysis.

Quantitative magnetic resonance imaging (qMRI) allows extraction of reproducible and robust parameter maps. However, the connection to under … and MTsat at 3T), microglia (${R_{1}}$ and MTsat at 3T, ${R_{1}}$ at 7T), and oligodendrocytes and oligodendrocyte precursor cells (${R_{1}}$ at 7T). These results advance the potential use of qMRI parameters as biomarkers for specific cell types.

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury.

Recent studies have indicated oligodendroglial-vascular crosstalk during brain development, but the underlying mechanisms are incompletely understood. We report that oligodendrocyte precursor cells (OPCs) contact sprouting endothelial tip cells in mouse, ferret, and human neonatal white matter. Using transgenic mice, we show that increased or decreased OPC density results in cognate changes in white matter vascular investment. Hypoxia induced increases in OPC numbers, vessel density and endothelial cell expression of the Wnt pathway targets Apcdd1 and Axin2 in white matter, suggesting paracrin…

JC virus infection in cells from lymphoid tissue.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease characterized by infection of oligodendrocytes by JC virus. The exact nature of the pathogenesis of PML is not known. The nature of the primary infection, the site of viral latency, and the route by which JCV enters the brain remain to be elucidated. Different laboratories have shown the presence of JCV in peripheral lymphocytes from immunosuppressed individuals, suggesting these cells as possible carriers of JCV to the brain. To examine this observation, we tested the susceptibility to JCV infection of cells from lymp

Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings.

Axons wrapped around the myelin sheath enable fast transmission of neuronal signals in the Central Nervous System (CNS). Unfortunately, myelin can be damaged by injury, viral infection, and inflammatory and neurodegenerative diseases. Remyelination is a spontaneous process that can restore nerve conductivity and thus movement and cognition after a demyelination event. Cumulative evidence indicates that remyelination can be pharmacologically stimulated, either by targeting natural inhibitors of Oligodendrocyte Precursor Cells (OPCs) differentiation or by reactivating quiescent Neural Stem Cells…

Metabolic reallocation in spinal cord oligodendrocytes drives chronic pain in mice through neuronal Aβ42 production.

Recent evidence implicates a metabolic switch in afferent spinal circuits as a key driver of the transition from acute pain- to chronic pain-related behaviors in mice after tissue injury, yet the cellular substrates and functional consequences remain incompletely defined. Using a combination of pharmacological and genetic approaches, we investigated whether metabolic reprogramming in spinal cord cell populations constitutes a causal mechanism linking peripheral injury to the progression to pain chronicity. After peripheral injury induced by a hindpaw formalin injection in mice, single-nucleus

Subcutaneous Transplantation of Neural Precursor Cells in Experimental Autoimmune Encephalomyelitis Reduces Chemotactic Signals in the Central Nervous System.

UNLABELLED: Neural precursor cell (NPC) transplantation has been proposed as a therapy for multiple sclerosis (MS) and other degenerative disorders of the central nervous system (CNS). NPCs are suggested to exert immune modulation when they are transplanted in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Herein, we explore whether the effect of NPC transplantation on the clinical course and the pathological features of EAE is combined with the modulation of chemokines levels expressed in the inflamed CNS. NPCs were isolated from brains of neonatal C57/Bl6 mice and w

A single nucleotide polymorphism that affects oligodendroglial lineage cells may augment the consequences of neurotoxicants.

An increasing number of toxicants are found to target oligodendroglia lineage cells. Among them, environmental lead and oral alcohol reduce oligodendrogenesis and affect oligodendrocyte precursor cells (OPCs). OPCs perform a multitude of functions within the neuronal synaptic space and serve as progenitors to myelin capable oligodendrocytes. Aberrant OPCs result in neurobehavioral deficits in humans. A single nucleotide polymorphism (SNP) for the gene encoding the lysosomal enzyme arylsulfatase A (ASA) causes reduced cellular levels of the enzyme and potentially affects OPC homeostasis. A cont…

Clobetasol promotes remyelination in a mouse model of neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can produce marked neurological deficit. Current NMO therapies include immunosuppressants, plasma exchange and B-cell depletion. Here, we evaluated 14 potential remyelinating drugs emerging from prior small molecule screens done to identify drugs for repurposing in multiple sclerosis and other demyelinating neurological diseases. Compounds were initially evaluated in oligodendrocyte precursor cell (OPC) and cerebellar slice cultures, and then in a mouse model of NMO produced by intracerebral

Could the inhibitor of DNA binding 2 and 4 play a role in white matter injury?

White matter injury (WMI) prevents the normal development of myelination, leading to central nervous system myelination disorders and the production of chronic sequelae associated with WMI, such as chronic dyskinesia, cognitive impairment and cerebral palsy. This results in a large emotional and socioeconomic burden. Decreased myelination in preterm infant WMI is associated with the delayed development or destruction of oligodendrocyte (OL) lineage cells, particularly oligodendrocyte precursor cells (OPCs). The development of cells from the OL lineage involves the migration, proliferation and …

Transmission Electron Microscopy and Morphometry of the CNS White Matter.

Transmission electron microscopy of central nervous system white matter has provided unparalleled access to the ultrastructural features of axons, their myelin sheaths, and the major cells of white matter; namely, oligodendrocytes, oligodendrocyte precursors, astrocytes, and microglia. In particular, it has been invaluable in elucidating pathological changes in axons and myelin following experimentally induced injury or genetic alteration, in animal models. While also of value in the examination of human white matter, the tissue is rarely fixed adequately for the types of detailed analyses tha

Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington's disease mouse model.

OBJECTIVES: To investigate whether human HLA-homozygous induced pluripotent stem cell (iPSC)-derived neural precursor cells (iPSC-NPCs) can provide functional benefits in Huntington's disease (HD), we transplanted them into the YAC128 transgenic HD mouse model. MATERIALS AND METHODS: CHAi001-A, an HLA-homozygous iPSC line (A*33:03-B*44:03-DRB1*13:02), was differentiated into neural precursor cells, and then, they were transplanted into 6 months-old YAC128 mice. Various behavioural and histological analyses were performed for five months after transplantation. RESULTS: Motor and cognitive fun

Разработка минимально инвазивной генной терапии для множественных склерозов.

Множественный склероз (MS) — неврологическое заболевание, характеризующееся демилиническими повреждениями в CNS. В этом исследовании рассматривался вопрос о том, может ли вектор адено-инвазивного вируса (ААВ) (AAV.PHP.eB) направлять трансгенное выражение в типах клеток CNS, имеющих отношение к MS, включая астроциты, олигодендроциты, клетки-прекурсоры олигодендроцитов (OPC), микроглию и нейроны в экспериментальном аутоиммунном энцефалите, широко используемой модели MS. В Vivo биолюминесценция и гистологический анализ после передачи генов через AAV.PHP.eB в здоровых мышах с использованием повсем

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a neurological disease characterized by demyelinating lesions in the CNS. This study investigated whether a minimally invasive adeno-associated virus (AAV) vector (AAV.PHP.eB) can direct transgene expression in CNS cell types relevant to MS, including astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPCs), microglia, …

Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice.

Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelinating lesions, astrocytes downregulate cholesterol synthesis, and the cholesterol that is essential for remyelination has to originate from other cellular sources. Here, we show that repair following acute versus chronic demyelination involves distinct processes. In particular, in chronic myelin disease, when recycling of lipids is often defective, de novo neuronal cholesterol synthesis is critical for regeneration. By gene expression profiling, genetic loss-of-function experiments, and compr

ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases.

Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT-1004-1239 is a potent, selective, insurmountable, and orally avai

Deletion of the chd7 Hinders Oligodendrocyte Progenitor Cell Development and Myelination in Zebrafish.

CHD7, an encoding ATP-dependent chromodomain helicase DNA-binding protein 7, has been identified as the causative gene involved in CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia choanae, Retardation of growth and/or development, Genital abnormalities and Ear abnormalities). Although studies in rodent models have expanded our understanding of CHD7, its role in oligodendrocyte (OL) differentiation and myelination in zebrafish is still unclear. In this study, we generated a chd7-knockout strain with CRISPR/Cas9 in zebrafish. We observed that knockout (KO) of chd7 intensely impeded t

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination.

Regeneration of myelin, following injury, can occur within the central nervous system to reinstate proper axonal conductance and provide trophic support. Failure to do so renders the axons vulnerable, leading to eventual degeneration, and neuronal loss. Thus, it is essential to understand the mechanisms by which remyelination or failure to remyelinate occur, particularly in the context of demyelinating and neurodegenerative disorders. In multiple sclerosis, oligodendrocyte progenitor cells (OPCs) migrate to lesion sites to repair myelin. However, during disease progression, the ability of OPCs

Identifying Lanthionine Ketimine Derivatives for Maturation and Proliferative Effects in Oligodendrocyte Progenitor Cells.

Previous studies have shown that lanthionine ketimine ethyl ester (LKE) reduces clinical scores in the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis, induces differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, and accelerates remyelination following cuprizone induced demyelination. In a search for derivatives with greater efficacy to induce OPC maturation or proliferation, we screened a panel of 2-alkyl and 3-phosphonate substituted LK derivatives. Incubation of Oli-neu oligodendrocyte cells with 2-n-butyl- or 2-n-hexyl-LKE-phosphonate reduc