Differential epitranscriptome and proteome modulation in the brain of neonatal mice exposed to isoflurane or sevoflurane.

BACKGROUND: Repeated neonatal exposure to anesthetics may disturb neurodevelopment and cause neuropsychological disorders. The m6A modification participates in the gene regulation of neurodevelopment in mouse fetuses exposed to anesthetics. This study aims to explore the underlying molecular mechanisms of neurotoxicity after early-life anesthesia exposure. METHODS: Mice were exposed to isoflurane (1.5%) or sevoflurane (2.3%) for 2 h daily during postnatal days (PND) 7-9. Sociability, spatial working memory, and anxiety-like behavior were assessed on PND 30-35. Synaptogenesis, epitranscriptome m6A, and the proteome of brain regions were evaluated on PND 21. RESULTS: Both isoflurane and sevoflurane produced abnormal social behaviors at the juvenile age, with different sociality patterns in each group. Synaptogenesis in the hippocampal area CA3 was increased in the sevoflurane-exposed mice. Both anesthetics led to numerous persistent m6A-induced alterations in the brain, associated with critical metabolic, developmental, and immune functions. The proteins altered by isoflurane exposure were mainly associated with epilepsy, ataxia, and brain development. As for sevoflurane, the altered proteins were involved in social behavior. CONCLUSIONS: Social interaction, the modulation patterns of the m6A modification, and protein expression were altered in an isoflurane or sevoflurane-specific way. Possible molecular pathways involved in brain impairment were revealed, as well as the mechanism underlying behavioral deficits following repeated exposure to anesthetics in newborns.

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain.

Bone cancer pain (BCP) seriously affects the quality of life; however, due to its complex mechanism, the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factors (GEFs) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines. Intrathecal injection a P-Rex2-targeting RNAi lentivirus relieved BCP and reduced the expression of P-Rex2, p-Rac1, p-GluR1, and number of spines in the BCP mice. Meanwhile, P-Rex2 knockdown reversed BCP-enhanced AMPA receptor (AMPAR)-induced current in dorsal horn neurons. In summary, this study suggested that P-Rex2 regulated GluR1-containing AMPAR trafficking and spine morphology via Rac1/pGluR1 pathway is a fundamental pathogenesis of BCP. Our findings provide a better understanding of the function of P-Rex2 as a possible therapeutic target for relieving BCP.

Thrombospondin 4, a mediator and candidate indicator of pain.

Pain is the most common symptom for which patients seek medical attention. Existing treatments for pain control are largely ineffective due to the lack of an accurate way to objectively measure pain intensity and a poor understanding of the etiology of pain. Thrombospondin 4(TSP4), a member of the thrombospondin gene family, is expressed in neurons and astrocytes and induces pain by interacting with the calcium channel alpha-2-delta-1 subunit (Cavα2δ1). In the present study we show that TSP4 expression level correlates positively with pain intensity, suggesting that TSP4 could be a novel candidate of pain indicator. Using RNAi-lentivirus (RNAi-LV) to knock down TSP4 both in vivo and in vitro, together with electrophysiological experiments involving paired patch-clamp recordings of evoked action potentials and post-synaptic currents in cultured neurons, we found that TSP4 contributes to the development of bone cancer pain, neuropathic pain, and inflammatory pain. This effect is mediated by regulation of neuron excitability via inhibition of synapsin I (Syn I) and modulation of excitatory and inhibitory presynaptic transmission via regulation of vesicular glutamate transporter 2(Vglut2), vesicular GABA transporter (VGAT), and glutamate decarboxylase (GAD) expression. The present study provides a replicable, predictive, valid indicator of pain and demonstrated the underlying molecular and electrophysiological mechanisms by which TSP4 contributes to pain.

The global burden, trends, and inequalities of individuals with developmental and intellectual disabilities attributable to iodine deficiency from 1990 to 2019 and its prediction up to 2030.

Objective: The objective of this study was to assess the global burden of disease for developmental and intellectual disabilities caused by iodine deficiency from 1990 to 2019. Methods: Using data from the global burden of disease (GBD) 2019, we conducted a cross-country inequity analysis to examine the worldwide burden of developmental and intellectual disabilities caused by the issue of iodine deficiency from 1990 to 2019. Absolute and relative inequality were assessed by the slope index of inequality and the concentration index, respectively. After summarising the latest evidence, we also projected the age-standardized prevalence and years lived with disability (YLD) rates up to 2030 using the BAPC and INLA packages in R statistical software. Results: In 2019, the global age-standardized prevalence and YLD rates for developmental and intellectual disabilities due to iodine deficiency were 22.54 per 100,000 population (95% UI 14.47 to 29.23) and 4.12 per 100,000 population (95% UI 2.25 to 6.4), respectively. From 1990 to 2019, the age-standardized prevalence and YLD rates of developmental and intellectual disabilities due to iodine deficiency decreased significantly. Geographic distribution showed that areas with lower socio-demographic indices (SDI) were the most affected. The correlation between higher SDI and lower prevalence highlights the role of economic and social factors in the prevalence of the disease. Cross-national inequity analysis shows that disparities persist despite improvements in health inequalities. In addition, projections suggest that the disease burden may decline until 2030. Conclusion: This research underscores the necessity for targeted interventions, such as enhancing iodine supplementation and nutritional education, especially in areas with lower SDI. We aim to provide a foundation for policymakers further to research effective preventative and potential alternative treatment strategies.

Spinal cord injury: global burden from 1990 to 2019 and projections up to 2030 using Bayesian age-period-cohort analysis.

Background: Spinal cord injuries, often resulting from spine fractures, can lead to severe lifelong symptoms such as paraplegia and even mortality. Over the past few decades, there has been a concerning increase in the annual incidence and mortality rates of spinal cord injuries, which has also placed a growing financial strain on healthcare systems. This review aims to offer a comprehensive overview of spinal cord injuries by estimating their global incidence, prevalence, and the impact in terms of years lived with disability, using data obtained from the 2019 Global Burden of Disease Study. Method: In this study, we utilized data from the 2019 Global Burden of Disease Study, a widely recognized source for global health data. Our methodology involved estimating the global incidence and prevalence of spinal cord injuries while also assessing the impact on years lived with a disability. We analyzed this data comprehensively to identify patterns and trends and made predictions. Finding: This research delved into the evolving trends in the global burden of spinal cord injuries, identified key risk factors, and examined variations in incidence and disability across different Socio-demographic Index (SDI) levels and age groups. Briefly, in 2019, the global incidence and burden of YLDs of SCI significantly increased compared to 1990. While males had higher incidence rates compared to females. Falls were identified as the primary cause of SCI. Trend projections up to 2030 revealed a slight decrease in ASIR for males, an upward trend in age-specific incidence rates for both sexes and a similar pattern in age-standardized YLD rates. Additionally, our findings provided crucial groundwork for shaping future policies and healthcare initiatives, with the goal of mitigating the burden of spinal cord injuries, enhancing patient outcomes, and fortifying prevention efforts. Interpretation: Understanding the global burden of spinal cord injuries is essential for designing effective healthcare policies and prevention strategies. With the alarming increase in prevalence rates and their significant impact on individuals and healthcare systems, this research contributes vital insights to guide future efforts in reducing the incidence of spinal cord injuries, improving the quality of life for affected individuals, and reducing the economic burden on healthcare systems worldwide.

Schnurri-2 Promotes the Expression of Excitatory Glutamate Receptors and Contributes to Neuropathic Pain.

Neuropathic pain is a type of chronic pain with complex mechanisms, and current treatments have shown limited success in treating patients suffering from chronic pain. Accumulating evidence has shown that the pathogenesis of neuropathic pain is mediated by the plasticity of excitatory neurons in the dorsal horn of the spinal cord, which provides insights into the treatment of hyperalgesia. In this study, we found that Schnurri-2 (Shn2) was significantly upregulated in the L4-L6 segments of the spinal cord of C57 mice with spared nerve injury, which was accompanied by an increase in GluN2D subunit and glutamate receptor subunit 1 (GluR1) levels. Knocking down the expression of Shn2 using a lentivirus in the spinal cord decreased the GluN2D subunit and GluR1 levels in spared nerve injury mice and eventually alleviated mechanical allodynia. In summary, Shn2 regulates neuropathic pain, promotes the upregulation of GluN2D in glutamatergic neurons and increases the accumulation of GluR1 in excitatory neurons. Taken together, our study provides a new underlying mechanism for the development of neuropathic pain.

NWD1 facilitates synaptic transmission and contributes to neuropathic pain.

Neuropathic pain is the most common symptom for which patients seek medical attention. Existing treatments to control pain are largely ineffective because of poor understanding the underlying mechanisms. Synaptic plasticity is fundamental to the spinal sensitivity of neuropathic pain. In the present study, we showed that SNL induced significant allodynia and hyperalgesia as well as upregulation of Nwd1 and GluN2B, which were reversed by knockdown of NWD1. Electrophysiological experiments demonstrated that SNL enhanced synaptic transmission, which was prevented by knockdown of NWD1. In vitro experiments showed that knockdown of NWD1 inhibited dendritic growth and synaptogenesis. Taken together, our results suggest that NWD1 enhances synaptic transmission and contributes to the development of neuropathic pain by enhancing GluN2B synaptic expression and anchor and promoting excitatory synaptogenesis.

CXCL12 promotes spinal nerve regeneration and functional recovery after spinal cord injury.

Spinal cord injury (SCI) leads to permanent loss of motor and sensory function due to the complex mechanisms of the external microenvironment and internal neurobiochemistry that restrict neuronal plasticity and axonal regeneration. Chemokine CXCL12 was verified in regulating the development of central nervous system (CNS) and repairing of CNS disease. In the present study, CXCL12 was downregulated in the spinal cord after SCI. SCI also induced gliosis and loss of synapse. Intrathecal treatment of CXCL12 promoted the functional recovery of SCI by inducing the formation of neuronal connections and suppressing glia scar. To confirm whether CXCL12 promoted synapse formation and functional neuronal connections, the primary cortical neurons were treated with CXCL12 peptide, the synapse was examined using Immunofluorescence staining and the function of synapse was tested using a whole-cell patch clamp. The results indicated that CXCL12 peptide promoted axonal elongation, branche formation, dendrite generation and synaptogenesis. The electrophysiological results showed that CXCL12 peptide increased functional connections among neurons. Taken together, the present study illustrated an underlying mechanism of the development of SCI and indicated a potential approach to facilitate functional recovery of spinal cord after SCI.

Exercise or sport activities for patients with cancer: A protocol for overview of systematic reviews and meta-analyses.

OBJECTIVE: We plan to review all published systematic reviews (SRs) and meta-analyses (MAs) of exercise or sport activities for patients with cancer. The aim of this study is to combine and reanalyze related data and to provide more comprehensive and higher-level evidence. METHODS: We plan to search four English databases and four Chinese databases from inception to June 2019. Patients who were treated by all of exercise or sport activities such as running, gymnastics, taichi, and qigong, will be included. The following information will be extracted from each included SR: first author, year of publication, country of origin, number of primary study; the number of patients enrolled, participant characteristics, duration of cancer diagnosis, cancer types. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and A Measurements Tool to Assess Systematic Reviews 2 (AMSTAR-2) will be used to assess the reporting and methodological quality of SRs/MAs. The characteristics of included SRs/MAs and their quality will be descriptively summarized using systematically structured tables. The network MA approach and narrative synthesis will be used to examine data when applicable. Odds ratio and (standardized) mean difference with their 95% confidence intervals will be used as summary statistics. Stata 13.0 software will be used to analyze and pool data. RESULTS: The results of the overview will be submitted to a peer-reviewed journal for publication. ETHICS AND DISSEMINATION: The study is not a clinical study, and we will search and evaluate existing sources of literature. So, ethical approval is not required.

MiRNA-574-3p inhibits cell progression by directly targeting CCND2 in colorectal cancer.

Colorectal cancer (CRC) remains the candidate for one of the typical types of malignant tumors of in gastrointestinal tract all around the world, which leads to tremendous death and ranks as the top leading death of cancer. Recently, microRNAs have emerged as double-edged sword in numerous cancers. This investigation aims to discuss the regulative role of microRNA-574-3p (miR-574-3p), elucidating its molecular mechanism and clinical significance in CRC. Herein, it revealed to us that miR-574-3p was lowly expressed in CRC tissues in comparison with the matched paracarcinoma tissues. In addition, transfection of SW480 and HT29 cells with miR-574-3p mimics prohibited the post-transcriptional expression of Cyclin D2 (CCND2), which then significantly blocked cell growth and cell migration, yet triggered cell apoptosis. Also, dual-luciferase reporter assays proved the role of CCND2 as the targeted gene for miR-574-3p. miR-574-3p overexpression prohibited the activity of CCND2 in SW480 and HT29 cells. Silencing of CCND2 in SW480 and HT29 CRC cell lines leading to reduced cell proliferative and migrative rates, and enhanced apoptotic rate. The suppressive effects of elevation of miR-574-3p on the proliferation of the human CRC cells and promotive effects on cell apoptosis by targeting CCND2 were further illustrated in the in vitro studies. Thus, we hypothesize that miR-574-3p may be served as a prospective therapeutic candidate for CRC.

Association between CD14 rs2569190 C>T polymorphism and ischemic stroke susceptibility: a meta-analysis based on 5,277 subjects.

INTRODUCTION: Previous epidemiological studies have suggested that CD14 rs2569190 C>T polymorphism plays an important role in ischemic stroke (IS) risk, but the results were inconsistent. Therefore, we conducted a meta-analysis to determine the association between CD14 rs2569190 C>T polymorphism and IS susceptibility. METHODS: Online databases were searched from inception up to July 1, 2018, for studies concerning CD14 rs2569190 C>T polymorphism and its association with IS susceptibility. ORs and corresponding 95% CIs were calculated in the genetic models of each polymorphism locus with Stata Version 14.0. Furthermore, heterogeneity, meta-regression, accumulative analyses, sensitivity analyses, and publication bias were examined. RESULTS: Overall, 10 observed studies involving 5,277 subjects were included in this meta-analysis on CD14 rs2569190 C>T polymorphism. Generally, no significant associations were found between CD14 rs2569190 C>T polymorphism and IS risk (allele contrast of T vs C: OR =1.03, 95% CI =0.96-1.12, P=0.41, I2=27.8%; co-dominant models of CT vs CC: OR =1.01, 95% CI =0.81-1.25, P=0.95, I2=51.9%; co-dominant models of TT vs CC: OR =1.04, 95% CI =0.89-1.22, P=0.62, I2=25.1%; dominant model of CT + TT vs CC: OR =1.02, 95% CI =0.84-1.25, P=0.82, I2=51.4%; recessive model of TT vs CC + CT: OR =1.07, 95% CI =0.95-1.22, P=0.28, I2=0%), similar to the results in the subgroup analysis. CONCLUSION: The current evidence indicated that CD14 rs2569190 C>T polymorphism was not a critical risk factor for IS development.