RESUMEN
The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate1. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms2. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration3. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.
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Indoles , Regeneración Nerviosa , Propionatos , Cicatrización de Heridas , Animales , Ratones , Axones/efectos de los fármacos , Axones/fisiología , Quimiotaxis de Leucocito , Clostridium/metabolismo , Ayuno , Ganglios Espinales/metabolismo , Microbioma Gastrointestinal , Indoles/sangre , Indoles/metabolismo , Indoles/farmacología , Compresión Nerviosa , Factores de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa/efectos de los fármacos , Neutrófilos/citología , Neutrófilos/inmunología , Propionatos/sangre , Propionatos/metabolismo , Propionatos/farmacología , Recuperación de la Función , Nervio Ciático/lesiones , Análisis de Secuencia de ARN , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The interruption of spinal circuitry following spinal cord injury (SCI) disrupts neural activity and is followed by a failure to mount an effective regenerative response resulting in permanent neurological disability. Functional recovery requires the enhancement of axonal and synaptic plasticity of spared as well as injured fibres, which need to sprout and/or regenerate to form new connections. Here, we have investigated whether the epigenetic stimulation of the regenerative gene expression program can overcome the current inability to promote neurological recovery in chronic SCI with severe disability. We delivered the CBP/p300 activator CSP-TTK21 or vehicle CSP weekly between week 12 and 22 following a transection model of SCI in mice housed in an enriched environment. Data analysis showed that CSP-TTK21 enhanced classical regenerative signalling in dorsal root ganglia sensory but not cortical motor neurons, stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but failed to promote neurological sensorimotor recovery. This work provides direct evidence that clinically suitable pharmacological CBP/p300 activation can promote the expression of regeneration-associated genes and axonal growth in a chronic SCI with severe neurological disability.
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Regeneración Nerviosa , Traumatismos de la Médula Espinal , Animales , Axones/metabolismo , Ratones , Regeneración Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/metabolismoRESUMEN
The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
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Ganglios Espinales/fisiología , Histona Desacetilasas/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Axones , Células Cultivadas , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Femenino , Masculino , Ratones , Regeneración Nerviosa , Fosforilación/efectos de los fármacos , Transducción de SeñalRESUMEN
OBJECTIVE: To explore the clinical features and genetic basis of a patient with glycogen storage disease type VI (GSD-VI). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the proband and his parents. Genetic variants were detected by using whole exome sequencing. Candidate variants were verified by Sanger sequencing followed by bioinformatics analysis. RESULTS: The proband presented fasting hypoglycemia, hepatomegaly, growth retardation, transaminitis, metabolic acidosis and hyperlactatemia. Liver biopsy indicated GSD. Novel compound heterozygous PYGL gene variants (c.2089A>G/c.158_160delACT) were detected in the proband. Compound heterozygosity was confirmed by Sanger sequencing of the patient's genomic DNA. Provean and MutationTaster predicted the two variants as deleterious and the variant sites are highly conserved. CONCLUSION: The compound heterozygous variants (c.2089A>G/c.158_160delACT) of PYGL gene probably underlay the GSD in the patient. The two novel variants have expanded the spectrum of PYGL gene variants and provided the basis for genetic counseling of the family.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo VI , Niño , Familia , Pruebas Genéticas , Enfermedad del Almacenamiento de Glucógeno Tipo VI/genética , Humanos , Mutación , Secuenciación del ExomaRESUMEN
BACKGROUND: Gastro-intestinal (GI) tract inflammation is as a result of inflammatory hypoxia which is also induced by long-standing group of disorders like inflammatory-bowel disease (IBD). Regulation of GI immune homeostasis by macrophage involves hypoxia-inducible factor (HIF). As inhibitor of HIF prolyl hydroxylase, roxadustat (ROX) increases the levels of HIF. METHODS: We induced experimental colitis (EC) model in mice via dextran-sulfate sodium (DSS) to evaluate ROX role in above-mentioned disease. RESULTS: ROX ameliorated EC in mice by blocking colonic length shorten and loss of body weight, thereby reducing scores of disease-activity index (DAI) and histopathology. ROX significantly reduced inflammatory cytokines levels, suppressed M1 and increased M2 macrophage polarization in colonic tissues. Besides, ROX blocked declining hematocrit (HCT) level in blood and increased HIF-1-α and HIF-2-α level in colonic tissues. The inhibitor of HIF-1- α, KC7F2 decreased body weight and colonic length in ROX-treated DSS mice. Meanwhile, DAI scores and histopathology in KC7F2 treated DSS mice were markedly higher than that of treatment with ROX alone. KC7F2 treatments also significantly increased inflammatory cytokines levels, respectively promoted and reduced polarization of M1 and M2 macrophages in colonic tissue from ROX treated mice. Further, KC7F2 treatments inhibited ROX induced HCT level increasing in blood and decreased HIF-1-α and HIF-2-α level in colonic tissue. CONCLUSION: Collectively, we discovered that ROX ameliorated EC in mice by regulating macrophage polarization through promotion of HIF expression. GENERAL SIGNIFICANCE: Taken together, we developed a new application of ROX, which provides new ideas and a scientific basis for IBD treatment.
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Colitis , Enfermedades Inflamatorias del Intestino , Ratones , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Citocinas/metabolismo , Macrófagos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Peso Corporal , HipoxiaRESUMEN
The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression programme at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C and RNA-seq. We find that cohesin is required for the full induction of the regenerative transcriptional program, by organising 3D genomic domains required for the activation of regenerative genes. Importantly, loss of cohesin results in disruption of chromatin architecture at regenerative genes and severely impaired nerve regeneration. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent chromatin interactions in neuronal regeneration.
RESUMEN
BACKGROUND: Available literature has reported the association of Helicobacter pylori (H pylori) infection with inflammatory bowel disease (IBD) in adults. However, only a few studies have addressed the disease in children. AIM: To ascertain the correlation of H pylori infection with IBD among children. METHODS: The aim of this systematic review and meta-analysis is to assess the association between H pylori infection and IBD in children. We searched databases including Cochrane, EMBASE, Google Scholar, PubMed, Medline, and Web of Science to select relevant studies. Ultimately, based on predetermined inclusion criteria, we included 6 studies that met the requirements. Review Manager and Stata software were used to extract and analyze the data from the relevant studies. In the methods, we employed both qualitative and quantitative approaches for comprehensive analysis. Qualitative analysis involved describing study designs, sample characteristics, and results, while quantitative analysis involved statistical tests such as calculating pooled risk ratios and 95% confidence intervals to evaluate the association between H pylori infection and IBD in children. Lastly, by combining the results of the individual studies, our objective is to provide a comprehensive understanding of the relationship between H pylori infection and IBD in children. RESULTS: In totality, we involved 2236 participants that were recruited in 6 studies. We detected no significant difference in H pylori prevalence (9.8% vs 12.7%, P = .12) by comparing the children IBD group to controls. Among the IBD children, we estimated odds ratio (OR) of H pylori infection to 0.62 [(95% confidence interval (CI) of 0.34-1.12)]. In children suffering from ulcerative colitis (UC) and Crohn disease (CD), the H pylori infection rates were higher than in those with IBD-unclassified (IBDU).When analyzed stratified by disease of study design, In CD group [OR = 1.42, 95% CI: 0.72-2.80)] (I2 = 0%, P = .64). but no significant difference in CD group. CONCLUSIONS: No correlation was found between H pylori infection and the occurrence of IBD in children.
Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Infecciones por Helicobacter , Helicobacter pylori , Enfermedades Inflamatorias del Intestino , Adulto , Niño , Humanos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiologíaRESUMEN
Nerve injuries cause permanent neurological disability due to limited axonal regeneration. Injury-dependent and -independent mechanisms have provided important insight into neuronal regeneration, however, common denominators underpinning regeneration remain elusive. A comparative analysis of transcriptomic datasets associated with neuronal regenerative ability revealed circadian rhythms as the most significantly enriched pathway. Subsequently, we demonstrated that sensory neurons possess an endogenous clock and that their regenerative ability displays diurnal oscillations in a murine model of sciatic nerve injury. Consistently, transcriptomic analysis showed a time-of-day-dependent enrichment for processes associated with axonal regeneration and the circadian clock. Conditional deletion experiments demonstrated that Bmal1 is required for neuronal intrinsic circadian regeneration and target re-innervation. Lastly, lithium enhanced nerve regeneration in wild-type but not in clock-deficient mice. Together, these findings demonstrate that the molecular clock fine-tunes the regenerative ability of sensory neurons and propose compounds affecting clock pathways as a novel approach to nerve repair.
Asunto(s)
Relojes Circadianos , Ratones , Animales , Relojes Circadianos/genética , Ritmo Circadiano , Regeneración Nerviosa/fisiología , Células Receptoras Sensoriales , Factores de Transcripción ARNTL/genéticaRESUMEN
The study of neuronal signaling ex vivo requires the identification of the proteins that are represented within the neuronal axoplasm. Here, we describe a detailed protocol to isolate the axoplasm of peripheral and central axonal branches of sciatic dorsal root ganglia neurons in mice. The axoplasm is separated by 2D gel and digestion followed by proteomics analysis with MS/MS-LC. This protocol can be applied to dissect the axoplasmic protein expression signatures before and after a sciatic nerve or a spinal cord injury. For complete details on the use and execution of this protocol, please refer to Kong et al. (2020).
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Ganglios Espinales , Proteómica , Animales , Axones , Ganglios Espinales/metabolismo , Ratones , Proteínas/metabolismo , Proteómica/métodos , Nervio Ciático , Espectrometría de Masas en TándemRESUMEN
Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice. Lymphotoxin activated the transcription factor NF-κB, which induced expression of the chemokine CXCL13 by neurons. This in turn recruited CXCR5+CD8+ T cells to injured DRG neurons overexpressing major histocompatibility complex class I. CD8+ T cells repressed the axonal regeneration of DRG neurons via caspase 3 activation. CXCL13 neutralization prevented CXCR5+CD8+ T cell recruitment to the DRG and reversed aging-dependent regenerative decline, thereby promoting neurological recovery after SNI. Thus, axonal regeneration can be facilitated by antagonizing cross-talk between immune cells and neurons.
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Envejecimiento , Axones , Linfocitos T CD8-positivos , Ganglios Espinales , Regeneración Nerviosa , Neuronas , Nervio Ciático , Envejecimiento/metabolismo , Animales , Axones/fisiología , Linfocitos T CD8-positivos/metabolismo , Ganglios Espinales/metabolismo , Ratones , Neuronas/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/fisiologíaRESUMEN
Shp2 is a member of the protein tyrosine phosphatase (PTP) family, which regulates a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Using a recombinant Shp2-GST protein as the target and GST as a counter target, we have identified two classes of single-stranded DNA aptamers that selectively bind to Shp2 with a K(d) in the nanomolar range. Structural studies of the most abundant sequence in the enriched library, HJ24, revealed a parallel G-quadruplex as the core binding domain. Furthermore, this aptamer was found to be an effective inhibitor of Shp2 phosphatase, an effect which was readily reversed by using the cDNA of HJ24. In view of these characteristics, this aptamer has the potential to be used for further development of Shp2 assays and therapeutics for the treatment of Shp2-dependent cancers and other diseases.
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Aptámeros de Nucleótidos/química , G-Cuádruplex , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Aptámeros de Nucleótidos/farmacología , Secuencia de Bases , Datos de Secuencia Molecular , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Técnica SELEX de Producción de AptámerosRESUMEN
Tyrosine phosphatase Src-homology phosphotyrosyl phosphatase 2 (Shp2) was identified as a potential molecular target for therapeutic treatment of diabetes and obesity. However, there is still no systematic research on the enhancers for the Shp2 enzyme. The present study established a novel powerful model for the high-throughput screening of Shp2 enhancers and successfully identified a new specific Shp2 enhancer, oleanolic acid, from Chinese herbs.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Medicamentos Herbarios Chinos/química , Forsythia/química , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Ácido Oleanólico/uso terapéutico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus/enzimología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Humanos , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Ratones , Obesidad/enzimología , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacologíaRESUMEN
Src homology-2 domain-containing protein tyrosine phosphatase (Shp2), a novel proto-oncogenic protein, is an important target in cancer therapy research. Approximately 2000 plant extracts were screened to find its natural specific inhibitors, with the ethyl acetate (EtOAc) active extract of the root of Angelica dahurica showing considerable inhibitory effects (IC(50)=21.6 mg/L). Bioguided isolation of EtOAc extract led to 13 compounds, including 10 fatty acids and derivatives. All these compounds were isolated from the plant for the first time. The inhibitory effects of these compounds on the enzyme activities of Shp2, VH1-related human protein (VHR), and hematopoietic protein tyrosine phosphatase (HePTP) were investigated. 8Z,11Z-Feptadecadienoic acid (4), 14Z,17Z-tricosadienoic acid (5), caffeic acid (9), and 2-hydroxy-3-[(1-oxododecyl) oxy]propyl-ß-d-glucopyranoside (11) showed considerable selective inhibition of Shp2 activity. After treatment of HepG2 cells with the compounds, only compound 5, a polyunsaturated fatty acid, strongly induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose- and time-dependent manner and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 µM. Compound 5 also inhibited colony formation of HepG2 cells in a dose-dependent manner. Thus, this study reported fatty acids as specific Shp2 inhibitors and provided the molecular basis of one active compound as novel potential anticancer drug.
Asunto(s)
Angelica/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ácidos Grasos/química , Ácidos Grasos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Ácidos Grasos/aislamiento & purificación , Células Hep G2 , Humanos , Neoplasias/tratamiento farmacológico , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Raíces de Plantas/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
Regeneration after injury occurs in axons that lie in the peripheral nervous system but fails in the central nervous system, thereby limiting functional recovery. Differences in axonal signalling in response to injury that might underpin this differential regenerative ability are poorly characterized. Combining axoplasmic proteomics from peripheral sciatic or central projecting dorsal root ganglion (DRG) axons with cell body RNA-seq, we uncover injury-dependent signalling pathways that are uniquely represented in peripheral versus central projecting sciatic DRG axons. We identify AMPK as a crucial regulator of axonal regenerative signalling that is specifically downregulated in injured peripheral, but not central, axons. We find that AMPK in DRG interacts with the 26S proteasome and its CaMKIIα-dependent regulatory subunit PSMC5 to promote AMPKα proteasomal degradation following sciatic axotomy. Conditional deletion of AMPKα1 promotes multiple regenerative signalling pathways after central axonal injury and stimulates robust axonal growth across the spinal cord injury site, suggesting inhibition of AMPK as a therapeutic strategy to enhance regeneration following spinal cord injury.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Axones , Ganglios Espinales/metabolismo , Regeneración Nerviosa , Células Receptoras Sensoriales/metabolismo , Traumatismos de la Médula Espinal/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Animales , Transporte Axonal , Axotomía , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Femenino , Ganglios Espinales/patología , Ratones , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteómica , Nervio Ciático/metabolismo , Nervio Ciático/patología , Células Receptoras Sensoriales/patología , Traumatismos de la Médula Espinal/patologíaRESUMEN
Cyclin-dependent-like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)-derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.
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Células Receptoras Sensoriales , Transducción de Señal , Animales , Ciclinas , Modelos Animales de Enfermedad , Humanos , Ratones , Dolor , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)-mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.
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Axones/fisiología , Proteína de Unión a CREB/metabolismo , Ambiente , Histonas/metabolismo , Regeneración Nerviosa , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Acetilación , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Proteína p300 Asociada a E1A/metabolismo , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Ratones , Neuronas Motoras/patología , Propiocepción , Recuperación de la Función , Células Receptoras Sensoriales/patología , Transducción de Señal , Traumatismos de la Médula Espinal/patologíaRESUMEN
Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-ß1-dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K-phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2-PI3K-p-Akt signalling pathway.
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Axones/enzimología , Exosomas/enzimología , Ganglios Espinales/enzimología , NADPH Oxidasa 2/metabolismo , Degeneración Nerviosa , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/enzimología , Especies Reactivas de Oxígeno/metabolismo , Nervio Ciático/enzimología , Traumatismos de la Médula Espinal/enzimología , Animales , Axones/patología , Receptor 1 de Quimiocinas CX3C/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Dineínas/metabolismo , Endocitosis , Endosomas/enzimología , Endosomas/patología , Exosomas/patología , Ganglios Espinales/lesiones , Ganglios Espinales/patología , Macrófagos/enzimología , Macrófagos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 2/deficiencia , NADPH Oxidasa 2/genética , Proteínas Nucleares/metabolismo , Fosfohidrolasa PTEN/metabolismo , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/fisiopatología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/patología , Nervio Ciático/fisiopatología , Transducción de Señal , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , beta CarioferinasRESUMEN
In the version of this Article originally published, the affiliations for Roland A. Fleck and José Antonio Del Río were incorrect due to a technical error that resulted in affiliations 8 and 9 being switched. The correct affiliations are: Roland A. Fleck: 8Centre for Ultrastructural Imaging, Kings College London, London, UK. José Antonio Del Río: 2Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain; 9Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 10Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. This has now been amended in all online versions of the Article.
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OBJECTIVE: To study the infected information, clinical symptom and molecular epidemiological characteristics of HuCV infection among children under 5 years old in Nanjing. METHODS: In Nanjing Children's Hospital of Nanjing Medical University from July 2010 to June 2011, we collected 428 stool specimens from children with diarrhea and 428 asymptomatic controls. Human Calicivirus were tested by using RT-PCR. Then we sequenced the nucleic acid of PCR amplifications and identified the genotype and gene group of prevalent strains. RESULTS: 63 (14.72%) out of 428 stool samples were detected as HuCV. 58 were norovirus and 5 were sapovirus, while GII-4 2006b was the predominant strain of NoV. In the 428 control samples, 19 samples were positive for calicivirus, there were 8 NoV and 13 SaV (Including 3 co-infection cases). CONCLUSION: Human caliciviruses with different genotypes circulated among children in Nanjing,and GII. 2006b is the dominant genotype.