New strategy to treat spinal cord injury: Nafamostat mesilate suppressed NLRP3-mediated pyroptosis during acute phase.

Spinal cord injury (SCI) is a devastating condition for which effective clinical treatment is currently lacking. During the acute phase of SCI, myriad pathological changes give rise to subsequent secondary injury. The results of our previous studies indicated that treating rats post-SCI with nafamostat mesilate (NM) protected the blood-spinal cord barrier (BSCB) and exerted an antiapoptotic effect. However, the optimal dosage for mice with SCI and the underlying mechanisms potentially contributing to recovery, especially during the acute phase of SCI, have not been determined. In this study, we first determined the optimal dosage of NM for mice post-SCI (5 mg/kg/day). Subsequently, our RNA-seq findings revealed that NM has the potential to inhibit pyroptosis after SCI. These findings were further substantiated by subsequent Western blot (WB) and Immunofluorescence (IF) analyses in vivo. These results indicate that NM can alleviate NLRP3 (NOD-like receptor thermal protein domain associated protein 3)-mediated pyroptosis by modulating the NF-κB signaling pathway and reducing the protein expression levels of NIMA-related kinase 7 (NEK7) and cathepsin B (CTSB). In vitro experimental results supported our in vivo findings, revealing the effectiveness of NM in suppressing pyroptosis induced by adenosine triphosphate (ATP) and lipopolysaccharide (LPS) in BV2 cells. These results underscore the potential of NM to regulate NLRP3-mediated pyroptosis following SCI. Notably, compared with other synthetic compounds, NM exhibits greater versatility, suggesting that it is a promising clinical treatment option for SCI.

Epidemiological age-based differences in traumatic spinal cord injury patients: A multicenter study based on 13,334 inpatients.

CONTEXT: Compared with younger traumatic spinal cord injury (TSCI) patients, the elderly had longer delays in admission to surgery, higher proportion of incomplete injury, and longer hospital stays. However, in China, the country with the largest number of TSCI patients, there have been no large-scale reports on their age differences. OBJECTIVES: To explore the age-based differences among TSCI inpatients, focusing on the demographic and clinical characteristics, treatment status, and economic burden. METHODS: We collected the medical records of 13,334 inpatients with TSCI in the 30 hospitals of China, from January 1, 2013 to December 31, 2018. Trends are expressed as annual percentage changes (APCs) and 95% confidence intervals (CIs). RESULTS: A total of 13,334 inpatients were included. Both the number and proportion of the elderly showed an increasing trend. The APC of the number and proportion in patients ≥85 years were 39.5% (95% CI, 14.3 to 70.3; P < 0.01) and 30.5% (95% CI, 8.6 to 56.9; P < 0.01), respectively. Younger patients were more likely to undergo decompression surgery, and older patients were more likely to receive high-dose methylprednisolone sodium succinate/methylprednisolone (MPSS/MP). Of the patients ≥85 years, none underwent decompression surgery within 8 h, and only 1.4% received a high dose of MPSS/MP within 8 h after injury. Elderly patients had lower hospitalization costs than younger. The total and daily medical costs during hospitalization of patients ≥85 years were 8.06 ± 18.80 (IQR: 5.79) and 0.61 ± 0.73 (IQR: 0.55) thousands dollars, respectively. CONCLUSIONS: As the first study to focus on age differences of TSCI patients in China, this study found many differences, in demographic and clinical characteristics, treatment status, and economic costs, between older and younger TSCI patients. The number and proportion of elderly patients increased, and the rate of early surgery for elderly patients is low.

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

N1-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction.

N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5' and 3' untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson's disease (PD) and Alzheimer's disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.

Sex-related Differences in Epidemiology, Treatment, and Economic Burden of Traumatic Spinal Cord Injury in China (2013-2018).

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVE: To describe differences based on biological sex in the epidemiology and treatment of the economic burden of traumatic spinal cord injury (TSCI) in China (2013-2018). SUMMARY OF BACKGROUND DATA: Although there have been many regional single-center studies on TSCI in China, there are few reports involving multicenter data, especially those that report on discrepancies related to biological sex. MATERIALS AND METHODS: This study is a nationally representative hospital-based retrospective study. The treatment data of TSCI patients in 30 hospitals in 11 provinces/cities from January 2013 to December 2018 were analyzed. Sociodemographic characteristics, accident and related injury characteristics, treatment methods, and hospital costs were obtained. Regression models were used to evaluate differences in the outcomes of interest based on biological sex and other factors. RESULTS: There were 13,465 individuals with TSCI, with a mean age of 50.0 years, and females (52.2) older than males (49.3). Overall, the average ratio of males to females was 3.1:1, ranging from 3.0:1 in 2013 to 2.8:1 in 2018. The overall proportion of patients with TSCI increased from 2013 to 2018 [annual percentage change (APC)=6.8%, 95% CI, 3.3-10.4] ( P < 0.05). The percent increase in females (APC=8.2%, 95% CI, 5.6-10.8) was greater than that of males (APC=6.3%, 95% CI, 2.1-10.6). Overall, high-level falls mainly affected males (30.8%), and low-level falls mainly occurred in females (36.6%). Females demonstrated a higher frequency of thoracolumbar trauma and less severe neurological impairment. CONCLUSIONS: This study suggests that although the main population of TSCI is male, the average ratio of males to females is decreasing. The frequency of TSCI may be increasing faster in females than in males. Therefore, it is necessary to develop sex-specific public prevention measures. In addition, more medical resources should be devoted to improving the ability of hospitals to perform early surgery.

Crosstalk between m6A mRNAs and m6A circRNAs and the time-specific biogenesis of m6A circRNAs after OGD/R in primary neurons.

Cerebral ischaemiareperfusion injury is an important pathological process in nervous system diseases during which neurons undergo oxygenglucose deprivation and reoxygenation (OGD/R) injury. No study has used epitranscriptomics to explore the characteristics and mechanism of injury. N6methyladenosine (m6A) is the most abundant epitranscriptomic RNA modification. However, little is known about m6A modifications in neurons, especially during OGD/R. m6A RNA immunoprecipitation sequencing (MeRIPseq) and RNA-sequencing data for normal and OGD/R-treated neurons were analysed by bioinformatics. MeRIP quantitative real-time polymerase chain reaction was used to determine the m6A modification levels on specific RNAs. We report the m6A modification profiles of the mRNA and circRNA transcriptomes of normal and OGD/R-treated neurons. Expression analysis revealed that the m6A levels did not affect m6A mRNA or m6A circRNA expression. We found crosstalk between m6A mRNAs and m6A circRNAs and identified three patterns of m6A circRNA production in neurons; thus, distinct OGD/R treatments induced the same genes to generate different m6A circRNAs. Additionally, m6A circRNA biogenesis during distinct OGD/R processes was found to be time specific. These results expand our understanding of m6A modifications in normal and OGD/R-treated neurons, providing a reference to explore epigenetic mechanisms and potential treatments for OGD/R-related diseases.

Association between red blood cell folate and Trichomonas vaginalis infection among women.

BACKGROUND: Increased folic acid has been found to be latently protective against gynecological infection, including several kinds of vaginosis. In this study, we laid emphasis on whether RBC (Red Blood Cell) folate was associated with the infectious ratio of Trichomonas vaginalis, a kind of anaerobic parasitic protozoan. METHODS: We set RBC folate as the exposure variable and Trichomonas vaginalis as the outcome variable. Other subsidiary variables were regarded as covariates that may work as potential effect modifiers. The cross-sectional study was conducted with two merged waves of the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2004, and a sample of 1274 eligible women (1212 negative and 62 positive in Trichomonas vaginalis infection) was integrated for the exploration of the association between RBC folate and Trichomonas vaginalis infection. Multivariate regression analyses, subgroup analyses, and subsequent smooth curve fittings were conducted to estimate the relationship between RBC folate and Trichomonas vaginalis in women. RESULTS: In the multivariable logistic regression analyses, a negative association was observed between stratified RBC folate status and Trichomonas vaginalis infection with all confounders adjusted. Referencing the lowest RBC folate concentration quartile, the higher concentration quartiles reported a relatively lower infection ratio, while there was a weak correlation between total RBC folate concentration and T. vaginalis (Trichomonas vaginalis) infection. In subgroup analyses stratified by BMI and age, this association was only found significant in high age and BMI groups. CONCLUSIONS: The cross-sectional study indicated a negative association between RBC folic acid and Trichomonas vaginalis infection, and latent effects of BMI and age on the association were also found.

Identification of Differentially Expressed Proteins in Rats with Early Subacute Spinal Cord Injury using an iTRAQ-based Quantitative Analysis.

BACKGROUND: Injuries to the central nervous system (CNS), such as spinal cord injury (SCI), may devastate families and society. Subacute SCI may majorly impact secondary damage during the transitional period between the acute and subacute phases. A range of CNS illnesses has been linked to changes in the level of protein expression. However, the importance of proteins during the early subacute stage of SCI remains unknown. The role of proteins in the early subacute phase of SCI has not been established yet. METHODS: SCI-induced damage in rats was studied using isobaric tagging for relative and absolute protein quantification (iTRAQ) to identify proteins that differed in expression 3 days after the injury, as well as proteins that did not alter in expression. Differentially expressed proteins (DEPs) were analyzed employing Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to discover the biological processes, cell components, and molecular functions of the proteins. We also performed Gene Set Enrichment Analysis (GSEA) software BP pathway and KEGG analysis on all proteins to further identify their functions. In addition, the first 15 key nodes of a protein-protein interaction (PPI) system were found. RESULTS: During the early subacute stage of SCI, we identified 176 DEPs in total between the control and damage groups, with 114 (64.77%) being up-regulated and 62 (35.23%) being downregulated. As a result of this study, we discovered the most important cellular components and molecular activities, as well as biological processes and pathways, in the early subacute phase of SCI. The top 15 high-degree core nodes were Alb, Plg, F2, Serpina1, Fgg, Apoa1, Vim, Hpx, Apoe, Agt, Ambp, Pcna, Gc, F12, and Gfap. CONCLUSION: Our study could provide new views on regulating the pathogenesis of proteins in the early subacute phase after SCI, which provides a theoretical basis for exploring more effective therapeutic targets for SCI in the future.

Identification and characterization of aging/senescence-induced genes in osteosarcoma and predicting clinical prognosis.

Background: Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction. Methods: Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM. Results: Three molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score. Conclusion: Aging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.

Mendelian randomization study indicates lack of causal associations between iron status and lung cancer.

Observational studies provided conflicting results on the association between iron status and the risk of lung cancer. The aim of our study was to investigate the effect of genetically determined iron status on lung cancer risk using a mendelian randomization (MR) approach. Single-nucleotide polymorphisms for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for risk of lung cancer were derived from a Genome-Wide Association Study (GWAS) summary performed by the International Lung Cancer Consortium. The inverse-variance weighted method was used for the main analyses and sensitivity analyses. MR analysis demonstrated that increased genetically-predicted iron status did not causally increase risk of lung cancer. The odds ratios were 1.11 (95% CI, 0.92, 1.34; P = .26), 0.76 (95% CI, 0.52, 1.12; P = .17), 1.09 (95% CI, 0.86, 1.38; P = .47), and 0.91 (95% CI, 0.81, 1.02; P = .11) per 1 standard deviation increment of serum iron, ferritin, transferrin saturation, and transferrin levels, respectively. No observed indication of heterogeneity (P for Q > 0.05) or pleiotropy (P for intercept > 0.05) were found from the sensitivity analysis. The MR study indicated that genetic iron status was not causally associated with the risk of lung cancer, the causal relationship between iron status and lung cancer needs to be further elucidated by additional studies that strictly control for confounding factors.

Regulating DNA methylation could reduce neuronal ischemia response and apoptosis after ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is an important pathophysiological condition that can cause cell injury and large-scale tissue injury in the nervous system. Previous studies have shown that epigenetic regulation may play a role in the pathogenesis of IRI. METHODS: In this study, we isolated mouse cortical neurons and constructed an oxygen-glucose deprivation/reoxygenation (OGD) model to explore the change in DNA methylation and its effect on the expression of corresponding genes. RESULTS: We found that DNA methylation in neurons increased with hypoxia duration and that hypermethylation of numerous promoters and 3'-untranslated regions increased. We performed Gene Ontology enrichment analysis to study gene function and Kyoto Encyclopedia of Genes and Genomes pathway analysis to identify the pathways associated with gene regulation. The results showed that hypermethylation-related genes expressed after OGD were related to physiological pathways such as neuronal projection, ion transport, growth and development, while hypomethylation-related genes were related to pathological pathways such as the external apoptosis signaling pathway, neuronal death regulation, and regulation of oxidative stress. However, the changes in DNA methylation were specific for certain genes and may have been related to OGD-induced neuronal damage. Importantly, we integrated transcription and DNA methylation data to identify several candidate target genes, including hypomethylated Apoe, Pax6, Bmp4, and Ptch1 and hypermethylated Adora2a, Crhr1, Stxbp1, and Tac1. This study further indicated the effect of DNA methylation on gene function in brain IRI from the perspective of epigenetics, and the identified genes may become new targets for achieving neuroprotection in the brain after IRI.

Clinical features and burden of osteoporotic fractures among the elderly in the USA from 2016 to 2018.

This study provides a national estimate of the incidence of hospitalizations and assesses the clinical features and outcomes during inpatient admission due to osteoporotic fractures diagnosed by ICD-10-CM/PCS among the elderly in the USA, using the US Nationwide Inpatient Sample, 2016-2018. PURPOSE: To provide a national estimate of the incidence of hospitalizations and assess the clinical features and outcomes during inpatient admission due to osteoporotic fractures (OFs) among the elderly in the USA. METHODS: The study included all inpatients aged 65 years and older who participated in the US Nationwide Inpatient Sample (NIS). We conducted a retrospective analysis of hospitalizations with OFs diagnosed by the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS), using the US NIS, 2016-2018. Trends in epidemiological characteristics and outcomes were calculated by annual percentage change (APC). RESULTS: From 2016 to 2018, there were an estimated 0.16 million hospitalizations for OFs, and the estimated annual incidence rate changed from 995 cases per 1 million persons in 2016 to 1114 cases per 1 million persons in 2018 (APC, 5.8% [95% CI, 0.0 to 12.0]; P > 0.05). Over two-thirds of the patients (68.2%) were age-related osteoporosis with current pathological fracture, and OFs were more likely to occur in vertebra (51.7%) and femur (34.7%). During the hospitalization, the average length of stay (LOS) was 5.83 days, the average cost reached $60,901.04, and the overall mortality was 2.3%. All outcomes including LOS, average cost and mortality did not change significantly in 2016-2018 (all P values for trend were over 0.05). CONCLUSION: Between 2016 and 2018, the incidence rate of OFs remained relatively stable, but the total number of cases was huge. OFs was predominantly age-related, mostly in vertebrae and femurs, with relatively stable cost and mortality during hospitalization.

Alteration of mRNA 5-Methylcytosine Modification in Neurons After OGD/R and Potential Roles in Cell Stress Response and Apoptosis.

Epigenetic modifications play an important role in central nervous system disorders. As a widespread posttranscriptional RNA modification, the role of the m5C modification in cerebral ischemia-reperfusion injury (IRI) remains poorly defined. Here, we successfully constructed a neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) model and obtained an overview of the transcriptome-wide m5C profiles using RNA-BS-seq. We discovered that the distribution of neuronal m5C modifications was highly conserved, significantly enriched in CG-rich regions and concentrated in the mRNA translation initiation regions. After OGD/R, modification level of m5C increased, whereas the number of methylated mRNA genes decreased. The amount of overlap of m5C sites with the binding sites of most RNA-binding proteins increased significantly, except for that of the RBM3-binding protein. Moreover, hypermethylated genes in neurons were significantly enriched in pathological processes, and the hub hypermethylated genes RPL8 and RPS9 identified by the protein-protein interaction network were significantly related to cerebral injury. Furthermore, the upregulated transcripts with hypermethylated modification were enriched in the processes involved in response to stress and regulation of apoptosis, and these processes were not identified in hypomethylated transcripts. In final, we verified that OGD/R induced neuronal apoptosis in vitro using TUNEL and western blot assays. Our study identified novel m5C mRNAs associated with ischemia-reperfusion in neurons, providing valuable perspectives for future studies on the role of the RNA methylation in cerebral IRI.

Isobaric Tagging for Relative and Absolute Protein Quantification (iTRAQ)-Based Quantitative Proteomics Analysis of Differentially Expressed Proteins 1 Week After Spinal Cord Injury in a Rat Model.

BACKGROUND Spinal cord injury (SCI) is a devastating trauma of the central nervous system (CNS), with high levels of morbidity, disability, and mortality. One week after SCI may be a critical time for treatment. Changes in protein expression have crucial functions in nervous system diseases, although the effects of changes occurring 1 week after SCI on patient outcomes are unclear. MATERIAL AND METHODS Protein expression was examined in a rat contusive SCI model 1 week after SCI. Differentially expressed proteins (DEPs) were identified by isobaric tagging for relative and absolute protein quantification (iTRAQ)-coupled liquid chromatography tandem-mass spectrometry (LC-MS/MS) proteomics analysis. Gene Ontology (GO) analysis was performed to identify the biological processes, molecular functions, and cellular component terms of the identified DEPs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to identify key enriched pathways. Protein-protein interaction (PPI) networks were analyzed to identify the top 10 high-degree core proteins. RESULTS Of the 295 DEPs identified, 204 (69.15%) were upregulated and 91 (30.85%) were downregulated 1 week after injury. The main cellular components, molecular functions, biological processes, and pathways identified may be crucial mechanisms involved in SCI. The top 10 high-degree core proteins were complement component C3 (C3), alpha-2-HS-glycoprotein (Ahsg), T-kininogen 1 (Kng1), Serpinc1 protein (Serpinc1), apolipoprotein A-I (Apoa1), serum albumin (Alb), disulfide-isomerase protein (P4hb), transport protein Sec61 subunit alpha isoform 1 (Sec61a1), serotransferrin (Tf), and 60S ribosomal protein L15 (Rpl15). CONCLUSIONS The proteins identified in this study may provide potential targets for diagnosis and treatment 1 week after SCI.

PTEN modulates neurites outgrowth and neuron apoptosis involving the PI3K/Akt/mTOR signaling pathway.

The present study aimed to explore the role of the PTEN/Akt/mTOR signaling pathway in the neurite outgrowth and apoptosis of cortical neurons. Cortical neurons were seeded on or adjacent to chondroitin sulfate proteoglycans. The length, number and crossing behavior of the neurites were calculated. Immunohistochemical staining and TUNEL data were analyzed. Neurites treated with PTEN inhibitor exhibited significant enhancements in elongation, initiation and crossing abilities when they encountered chondroitin sulfate proteoglycans in vitro. These effects disappeared when the PTEN/Akt/mTOR signaling pathway was blocked. Neurons exhibited significant enhancements in survival ability following PTEN inhibition. The present study demonstrated that PTEN inhibition can promote axonal elongation and initiation in cerebral cortical neurons, as well as the ability to cross the chondroitin sulfate proteoglycan border. In addition, PTEN inhibition is useful for protecting the neuron from apoptosis. The PTEN/Akt/mTOR signaling pathway is an important signaling pathway.

Erratum: Angiopoietin-2 induces the neuronal differentiation of mouse embryonic NSCs via phosphatidylinositol 3 kinase-Akt pathway-mediated phosphorylation of mTOR.

[This corrects the article on p. 1895 in vol. 11, PMID: 30972213.].

Angiopoietin-2 induces the neuronal differentiation of mouse embryonic NSCs via phosphatidylinositol 3 kinase-Akt pathway-mediated phosphorylation of mTOR.

The fate of neural stem cells (NSCs) is decided by numerous growth factors. Among these factors, the well-known angiogenic factor angiopoietin-2 (Ang-2) has been revealed to participate in neurogenesis separate from its role in angiogenesis. However, the effect of Ang-2 on the fate determination of mouse embryonic NSCs and the underlying mechanism remain unclear. This result of this study indicated that treatment of mouse embryonic NSCs with 200 ng/ml Ang-2 significantly promoted neuronal differentiation without affecting glial differentiation, and mammalian target of rapamycin (mTOR) was phosphorylated in a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner during this process. Rapamycin, a specific mTOR inhibitor, suppressed the increase in neuronal differentiation stimulated by Ang-2, and this suppression did not result from an effect of Ang-2 or rapamycin on the apoptosis of differentiated NSCs. Collectively, our research demonstrates that PI3K/Akt pathway-mediated mTOR phosphorylation plays an important role in the Ang-2-enhanced neuronal differentiation of mouse embryonic NSCs.

Identification of differentially expressed proteins in rats with spinal cord injury during the transitional phase using an iTRAQ-based quantitative analysis.

BACKGROUND: Spinal cord injury (SCI) is a disease associated with high disability and mortality rates. The transitional phase from subacute phase to intermediate phase may play a major role in the process of secondary injury. Changes in protein expression levels have been shown to play key roles in many central nervous system (CNS) diseases. Nevertheless, the roles of proteins in the transitional phase of SCI are not clear. METHODS: We examined protein expression in a rat model 2 weeks after SCI and identified differentially expressed proteins (DEPs) using isobaric tagging for relative and absolute protein quantification (iTRAQ). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEPs were performed. Furthermore, we constructed a protein-protein interaction (PPI) network, and the top 10 high-degree core nodes were identified. Meanwhile, we validated protein level changes of five high-degree core regulated proteins using Western blots. RESULTS: A total of 162 DEPs were identified between the injury group and the control, of which 101 (62.35%) were up-regulated and 61 (37.65%) were down-regulated in the transitional phase of SCI. Key molecular function, cellular components, biological process terms and pathways were identified and may be important mechanisms in the transitional phase of SCI. Alb, Calm1, Vim, Apoe, Syp, P4hb, Cd68, Eef1a2, Rab3a and Lgals3 were the top 10 high-degree core nodes. Western blot analysis performed on five of these proteins showed the same trend as iTRAQ results. CONCLUSION: The current study may provide novel insights into how proteins regulate the pathogenesis of the transitional phase after SCI.