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Ferroptosis, a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation, is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury. Thus, in this study, bulk RNA sequencing data (GSE47681 and GSE5296) and single-cell RNA sequencing data (GSE162610) were acquired from gene expression databases. We then conducted differential analysis and immune infiltration analysis. Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms. Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes. Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells, confirming the high expression of Atf3 and Piezo1 in these cells. Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide. In a mouse model of T8 spinal cord injury, low-dose cycloheximide treatment was found to improve neurological function, decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase, and increase levels of the anti-inflammatory cytokine arginase 1. Correspondingly, the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia, while the expression of Acsl4 decreased. Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury, identify the key cell types and genes involved in ferroptosis after spinal cord injury, and validate the efficacy of potential drug therapies, pointing to new directions in the treatment of spinal cord injury.
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BACKGROUND: Follow-up of cochlear implant effectiveness is mainly focused on 3 years postoperatively, and studies with more than 5 years of observation are rare, especially for local Chinese brands. OBJECTIVES: Nurotron (Chinese domestic cochlear implant brand) CI recipients who participated in the clinical trial in 2009 were followed-up for 10 years prospectively, providing data to guide doctors and patients. MATERIAL AND METHODS: From December 2009 to April 2010, 57 subjects underwent Nurotron Venus CI surgery at multiple-centers, and were continued to be followed up and assessed at 1, 2, 3, 4, 5, and 10 years after switch on. RESULTS: All recipients were successfully implanted with CIs with no difficulty in subsequent use with one reported case of re-implantation at 9 years after implantation. The aided hearing thresholds were significantly improved at one month after switch on (p < 0.0001) and remained stable afterwards for 10 years. Speech recognition scores were significantly higher than pre-operative results (p < 0.05) and continued to improve till 3 years after switch on. At 10 years post-operation, most subjects had improved QOL scores in most sub-items. CONCLUSIONS AND SIGNIFICANCE: Nurotron Venus CI System provides long-term, stable results in hearing speech assistance capabilities and can improve the quality of life of CI recipients.
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Implantes Cocleares , Humanos , Estudios de Seguimiento , Masculino , Femenino , Adulto , Persona de Mediana Edad , China , Calidad de Vida , Adulto Joven , Implantación Coclear , Pérdida Auditiva/cirugía , Estudios Prospectivos , Adolescente , Anciano , Niño , Percepción del Habla , Pueblos del Este de AsiaRESUMEN
Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair.
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Spinal cord injury (SCI) has no effective treatment modalities. It faces a significant global therapeutical challenge, given its features of poor axon regeneration, progressive local inflammation, and inefficient systemic drug delivery due to the blood-spinal cord barrier (BSCB). To address these challenges, a new nano complex that achieves targeted drug delivery to the damaged spinal cord is proposed, which contains a mesoporous silica nanoparticle core loaded with microRNA and a cloaking layer of human umbilical cord mesenchymal stem cell membrane modified with rabies virus glycoprotein (RVG). The nano complex more readily crosses the damaged BSCB with its exosome-resembling properties, including appropriate size and a low-immunogenic cell membrane disguise and accumulates in the injury center because of RVG, where it releases abundant microRNAs to elicit axon sprouting and rehabilitate the inflammatory microenvironment. Culturing with nano complexes promotes axonal growth in neurons and M2 polarization in microglia. Furthermore, it showed that SCI mice treated with this nano complex by tail vein injection display significant improvement in axon regrowth, microenvironment regulation, and functional restoration. The efficacy and biocompatibility of the targeted delivery of microRNA by nano complexes demonstrate their immense potential as a noninvasive treatment for SCI.
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Modelos Animales de Enfermedad , MicroARNs , Virus de la Rabia , Dióxido de Silicio , Traumatismos de la Médula Espinal , Animales , MicroARNs/genética , MicroARNs/administración & dosificación , Traumatismos de la Médula Espinal/terapia , Ratones , Dióxido de Silicio/química , Virus de la Rabia/genética , Glicoproteínas/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Membrana Celular/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/químicaRESUMEN
Background: Sensorineural hearing loss can be cured by cochlear implantation (CI), but complications can occur. Based on when the complications develop, they are categorized as intraoperative complications, early postoperative complications, or delayed postoperative complications (>3 months after the surgery).Aims/objectives: We aimed to investigate the occurrence of delayed complications after CI surgery, and identify appropriate management methods.Material and methods: We analyzed 624 sensorineural hearing loss patients who had been consecutively treated with CI using the conventional surgical technique in our institution and had been followed-up until September 2017.Results: A total of 43 (6.86%) patients out of the 624 CIs (627 ears) reported complications, and 9 (1.44%) were major complications and 34 (5.42%) were minor complications. Wound infection and device failure were the most common major complications, and hematoma was the most common minor complication.Conclusions and significance: CI surgery is a relatively mature technology; the incidence of complications is low, and with early diagnosis and treatment most complications have a good prognosis. Head trauma was the main reason for children's complications, and patients and guardians should be given good education preoperatively about how to manage the CI postoperatively.
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Implantación Coclear/efectos adversos , Implantes Cocleares , Complicaciones Posoperatorias/epidemiología , Falla de Prótesis , Adolescente , Adulto , Anciano , Niño , Preescolar , Implantes Cocleares/efectos adversos , Femenino , Estudios de Seguimiento , Pérdida Auditiva Sensorineural/cirugía , Humanos , Lactante , Masculino , Persona de Mediana Edad , Seroma/etiología , Infección de la Herida Quirúrgica/epidemiología , Factores de Tiempo , Adulto JovenRESUMEN
The development of therapeutic interventions for hearing loss requires a detailed understanding of the genes and proteins involved in hearing. The FOXG1 protein plays an important role in early neural development and in a variety of neurodevelopmental disorders. Previous studies have shown that there are severe deformities in the inner ear in Foxg1 knockout mice, but due to the postnatal lethality of Foxg1 knockout mice, the role of FOXG1 in hair cell (HC) development and survival during the postnatal period has not been investigated. In this study, we took advantage of transgenic mice that have a specific knockout of Foxg1 in HCs, thus allowing us to explore the role of FOXG1 in postnatal HC development and survival. In the Foxg1 conditional knockout (CKO) HCs, an extra row of HCs appeared in the apical turn of the cochlea and some parts of the middle turn at postnatal day (P)1 and P7; however, these HCs gradually underwent apoptosis, and the HC number was significantly decreased by P21. Auditory brainstem response tests showed that the Foxg1 CKO mice had lost their hearing by P30. The RNA-Seq results and the qPCR verification both showed that the Wnt, Notch, IGF, EGF, and Hippo signaling pathways were down-regulated in the HCs of Foxg1 CKO mice. The significant down-regulation of the Notch signaling pathway might be the reason for the increased numbers of HCs in the cochleae of Foxg1 CKO mice at P1 and P7, while the down-regulation of the Wnt, IGF, and EGF signaling pathways might lead to subsequent HC apoptosis. Together, these results indicate that knockout of Foxg1 induces an extra row of HCs via Notch signaling inhibition and induces subsequent apoptosis of these HCs by inhibiting the Wnt, IGF, and EGF signaling pathways. This study thus provides new evidence for the function and mechanism of FOXG1 in HC development and survival in mice.
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Supervivencia Celular/fisiología , Cóclea/crecimiento & desarrollo , Cóclea/metabolismo , Factores de Transcripción Forkhead/metabolismo , Células Ciliadas Auditivas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/fisiología , Cóclea/patología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Factores de Transcripción Forkhead/genética , Células Ciliadas Auditivas/patología , Pérdida Auditiva/metabolismo , Pérdida Auditiva/patología , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Receptores Notch/metabolismo , Transducción de SeñalRESUMEN
Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses.
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Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva/metabolismo , Pérdida Auditiva/patología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/patología , Animales , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Gentamicinas/administración & dosificación , Pérdida Auditiva/inducido químicamente , Ratones Endogámicos C57BL , Receptores AMPA/metabolismoRESUMEN
Enlarged vestibular aqueduct (EVA)associated hearing loss is frequently detected in individuals carrying the SLC26A4 mutation in the Chinese population. The present study aimed to identify the causative SLC26A4 coding mutations in a patient group with nonsyndromic hearing loss (NSHL) and EVA. Genomic DNA was extracted from blood samples obtained from 52 NSHL patients with EVA and from 60 normal controls. The mutation analysis for 20 coding exons of SLC26A4 was performed by direct sequencing. The results of the mutational analysis showed that there were two probands from two separate families suffering from bilateral sensorineural hearing loss with EVA, carrying the same novel compound heterozygous mutation of SLC26A4 (c.1644_1645insA and c.2168A>G). Other members of the two families had heterozygous monoallelic mutations with normal hearing. However, neither of these mutations were detected in the 60 normal controls. These results are the first, to the best of our knowledge, to link the compound heterozygote mutation, c.1644_1645insA and c.2168A>G, in the SLC26A4 gene to NSHL patients with EVA. The two mutations identified in the present study were located in the antisigma factor antagonist domain, the core region for plasma membrane targeting of anion transporters, which suggested that the reduced or complete loss of SLC26A4 function was the direct cause of hearing loss in the two patients. These results provide a foundation for further elucidating the genetic factors responsible for EVAassociated NSHL.