Inhibition of phospholipase D promotes neurological function recovery and reduces neuroinflammation after spinal cord injury in mice.

Introduction: Spinal cord injury (SCI) is a severely disabling disease. Hyperactivation of neuroinflammation is one of the main pathophysiological features of secondary SCI, with phospholipid metabolism playing an important role in regulating inflammation. Phospholipase D (PLD), a critical lipid-signaling molecule, is known to be involved in various physiological processes, including the regulation of inflammation. Despite this knowledge, the specific role of PLD in SCI remains unclear. Methods: In this study, we constructed mouse models of SCI and administered PLD inhibitor (FIPI) treatment to investigate the efficacy of PLD. Additionally, transcriptome sequencing and protein microarray analysis of spinal cord tissues were conducted to further elucidate its mechanism of action. Results: The results showed that PLD expression increased after SCI, and inhibition of PLD significantly improved the locomotor ability, reduced glial scarring, and decreased the damage of spinal cord tissues in mice with SCI. Transcriptome sequencing analysis showed that inhibition of PLD altered gene expression in inflammation regulation. Subsequently, the protein microarray analysis of spinal cord tissues revealed variations in numerous inflammatory factors. Biosignature analysis pointed to an association with immunity, thus confirming the results obtained from transcriptome sequencing. Discussion: Collectively, these observations furnish compelling evidence supporting the anti-inflammatory effect of FIPI in the context of SCI, while also offering important insights into the PLD function which may be a potential therapeutic target for SCI.

Impact of inflammation and Treg cell regulation on neuropathic pain in spinal cord injury: mechanisms and therapeutic prospects.

Spinal cord injury is a severe neurological trauma that can frequently lead to neuropathic pain. During the initial stages following spinal cord injury, inflammation plays a critical role; however, excessive inflammation can exacerbate pain. Regulatory T cells (Treg cells) have a crucial function in regulating inflammation and alleviating neuropathic pain. Treg cells release suppressor cytokines and modulate the function of other immune cells to suppress the inflammatory response. Simultaneously, inflammation impedes Treg cell activity, further intensifying neuropathic pain. Therefore, suppressing the inflammatory response while enhancing Treg cell regulatory function may provide novel therapeutic avenues for treating neuropathic pain resulting from spinal cord injury. This review comprehensively describes the mechanisms underlying the inflammatory response and Treg cell regulation subsequent to spinal cord injury, with a specific focus on exploring the potential mechanisms through which Treg cells regulate neuropathic pain following spinal cord injury. The insights gained from this review aim to provide new concepts and a rationale for the therapeutic prospects and direction of cell therapy in spinal cord injury-related conditions.

Changing Patterns of Injury Mortality Among the Elderly Population in Urban and Rural Areas - China, 1987-2021.

What is already known about this topic?: Injury is a significant public health issue, particularly among the elderly population. However, the extent of this problem varies significantly based on age, gender, and geographic location. What is added by this report?: This study aims to examine the changing patterns of injury mortality rates in China over a 35-year period and assess the age-period-cohort effects on mortality trends. What are the implications for public health practice?: This study examines the evolving patterns of injury mortality in the elderly population and identifies potential high-risk groups. The findings offer valuable insights for informing injury prevention policies.

The identification of new roles for nicotinamide mononucleotide after spinal cord injury in mice: an RNA-seq and global gene expression study.

Background: Nicotinamide mononucleotide (NMN), an important transforming precursor of nicotinamide adenine dinucleotide (NAD+). Numerous studies have confirmed the neuroprotective effects of NMN in nervous system diseases. However, its role in spinal cord injury (SCI) and the molecular mechanisms involved have yet to be fully elucidated. Methods: We established a moderate-to-severe model of SCI by contusion (70 kdyn) using a spinal cord impactor. The drug was administered immediately after surgery, and mice were intraperitoneally injected with either NMN (500 mg NMN/kg body weight per day) or an equivalent volume of saline for seven days. The central area of the spinal cord was harvested seven days after injury for the systematic analysis of global gene expression by RNA Sequencing (RNA-seq) and finally validated using qRT-PCR. Results: NMN supplementation restored NAD+ levels after SCI, promoted motor function recovery, and alleviated pain. This could potentially be associated with alterations in NAD+ dependent enzyme levels. RNA sequencing (RNA-seq) revealed that NMN can inhibit inflammation and potentially regulate signaling pathways, including interleukin-17 (IL-17), tumor necrosis factor (TNF), toll-like receptor, nod-like receptor, and chemokine signaling pathways. In addition, the construction of a protein-protein interaction (PPI) network and the screening of core genes showed that interleukin 1ß (IL-1ß), interferon regulatory factor 7 (IRF 7), C-X-C motif chemokine ligand 10 (Cxcl10), and other inflammationrelated factors, changed significantly after NMN treatment. qRT-PCR confirmed the inhibitory effect of NMN on inflammatory factors (IL-1ß, TNF-α, IL-17A, IRF7) and chemokines (chemokine ligand 3, Cxcl10) in mice following SCI. Conclusion: The reduction of NAD+ levels after SCI can be compensated by NMN supplementation, which can significantly restore motor function and relieve pain in a mouse model. RNA-seq and qRT-PCR systematically revealed that NMN affected inflammation-related signaling pathways, including the IL-17, TNF, Toll-like receptor, NOD-like receptor and chemokine signaling pathways, by down-regulating the expression of inflammatory factors and chemokines.

Epidemiological Shifts in Infectious Diseases in China: Implications and Policy Recommendations.

In recent decades, China has experienced significant alterations in its landscape of infectious diseases, with noteworthy reductions in historically prevalent illnesses such as tuberculosis and viral hepatitis. At the same time, emerging pathogens like severe acute respiratory syndrome (SARS), Influenza A virus subtype H7N9 (H7N9), and SARS coronavirus 2 (SARS-CoV-2) pose new challenges. These epidemiological shifts, fueled by fast economic development, urbanization, modifications in the healthcare system, and an aging population, present considerable obstacles to the country's public health infrastructure and policy frameworks. This article provides a comprehensive review of these changes, underscoring the driving forces behind them and the resultant impact on health policy and infrastructure. It stresses the challenges and calls for an intensification of surveillance efforts, the establishment of collaborative partnerships both nationally and internationally, the encouragement of worldwide cooperation, and the reinforcement of public health education as pivotal strategies for managing China's changing spectrum of infectious diseases.

Changing Patterns of Mortality in Viral Hepatitis - China, 1987-2021.

What is already known about this topic?: Viral hepatitis continues to present a major global public health challenge, with China shouldering the heaviest burden of this disease worldwide. What is added by this report?: This study examined evolving trends and assessed the impacts of age, period, and cohort on viral hepatitis mortality from 1987 to 2021 in both urban and rural settings across China. What are the implications for public health practice?: This research provides critical insights, enabling policymakers to develop precise and effective intervention strategies that are specifically tailored to address the needs of high-risk older adults.

The Effect of Glycine and N-Acetylcysteine on Oxidative Stress in the Spinal Cord and Skeletal Muscle After Spinal Cord Injury.

Oxidative stress is a frequently occurring pathophysiological feature of spinal cord injury (SCI) and can result in secondary injury to the spinal cord and skeletal muscle atrophy. Studies have reported that glycine and N-acetylcysteine (GlyNAC) have anti-aging and anti-oxidative stress properties; however, to date, no study has assessed the effect of GlyNAC in the treatment of SCI. In the present work, we established a rat model of SCI and then administered GlyNAC to the animals by gavage at a dose of 200 mg/kg for four consecutive weeks. The BBB scores of the rats were significantly elevated from the first to the eighth week after GlyNAC intervention, suggesting that GlyNAC promoted the recovery of motor function; it also promoted the significant recovery of body weight of the rats. Meanwhile, the 4-week heat pain results also suggested that GlyNAC intervention could promote the recovery of sensory function in rats to some extent. Additionally, after 4 weeks, the levels of glutathione and superoxide dismutase in spinal cord tissues were significantly elevated, whereas that of malondialdehyde was significantly decreased in GlyNAC-treated animals. The gastrocnemius wet weight ratio and total antioxidant capacity were also significantly increased. After 8 weeks, the malondialdehyde level had decreased significantly in spinal cord tissue, while reactive oxygen species accumulation in skeletal muscle had decreased. These findings suggested that GlyNAC can protect spinal cord tissue, delay skeletal muscle atrophy, and promote functional recovery in rats after SCI.

Glycine and N-Acetylcysteine (GlyNAC) Combined with Body Weight Support Treadmill Training Improved Spinal Cord and Skeletal Muscle Structure and Function in Rats with Spinal Cord Injury.

Skeletal muscle atrophy is a frequent complication after spinal cord injury (SCI) and can influence the recovery of motor function and metabolism in affected patients. Delaying skeletal muscle atrophy can promote functional recovery in SCI rats. In the present study, we investigated whether a combination of body weight support treadmill training (BWSTT) and glycine and N-acetylcysteine (GlyNAC) could exert neuroprotective effects, promote motor function recovery, and delay skeletal muscle atrophy in rats with SCI, and we assessed the therapeutic effects of the double intervention from both a structural and functional viewpoint. We found that, after SCI, rats given GlyNAC alone showed an improvement in Basso-Beattie-Bresnahan (BBB) scores, gait symmetry, and results in the open field test, indicative of improved motor function, while GlyNAC combined with BWSTT was more effective than either treatment alone at ameliorating voluntary motor function in injured rats. Meanwhile, the results of the skeletal muscle myofiber cross-sectional area (CSA), hindlimb grip strength, and acetylcholinesterase (AChE) immunostaining analysis demonstrated that GlyNAC improved the structure and function of the skeletal muscle in rats with SCI and delayed the atrophication of skeletal muscle.

Melodic intonation therapy for non-fluent aphasia after stroke: A clinical pilot study on behavioral and DTI findings.

Music-based melodic intonation therapy (MIT) has shown promise as a treatment for non-fluent aphasia after stroke. This trial compared the efficacy of music-based MIT and speech therapy (ST) in aphasia, focusing on arcuate fasciculus connectivity in brain structural and language ability scores. A total of 62 patients were enrolled, of whom 40 completed the trial. The experimental group received MIT for 30 min/d, five days per week for four weeks, while the control group received ST with the same dose. The BDAE and fMRI-DTI were performed at T0 and T1. The music-based MIT group demonstrated better language levels. DTI showed that FA, FN, and path length of the MIT group in the right hemisphere were significantly increased. Music-based MIT had positive effects on reorganization and activation of arcuate fasciculus in aphasia after stroke. This research is funded by NSFC No. T2341003 and No.2020CZ-10. Clinical Trials ChiCTR2000037871. Ethics approval number: 2020-013-1.

Mechanism of skeletal muscle atrophy after spinal cord injury: A narrative review.

Spinal cord injury leads to loss of innervation of skeletal muscle, decreased motor function, and significantly reduced load on skeletal muscle, resulting in atrophy. Factors such as braking, hormone level fluctuation, inflammation, and oxidative stress damage accelerate skeletal muscle atrophy. The atrophy process can result in skeletal muscle cell apoptosis, protein degradation, fat deposition, and other pathophysiological changes. Skeletal muscle atrophy not only hinders the recovery of motor function but is also closely related to many systemic dysfunctions, affecting the prognosis of patients with spinal cord injury. Extensive research on the mechanism of skeletal muscle atrophy and intervention at the molecular level has shown that inflammation and oxidative stress injury are the main mechanisms of skeletal muscle atrophy after spinal cord injury and that multiple pathways are involved. These may become targets of future clinical intervention. However, most of the experimental studies are still at the basic research stage and still have some limitations in clinical application, and most of the clinical treatments are focused on rehabilitation training, so how to develop more efficient interventions in clinical treatment still needs to be further explored. Therefore, this review focuses mainly on the mechanisms of skeletal muscle atrophy after spinal cord injury and summarizes the cytokines and signaling pathways associated with skeletal muscle atrophy in recent studies, hoping to provide new therapeutic ideas for future clinical work.

MicroRNAs in spinal cord injury: A narrative review.

Spinal cord injury (SCI) is a global medical problem with high disability and mortality rates. At present, the diagnosis and treatment of SCI are still lacking. Spinal cord injury has a complex etiology, lack of diagnostic methods, poor treatment effect and other problems, which lead to the difficulty of spinal cord regeneration and repair, and poor functional recovery. Recent studies have shown that gene expression plays an important role in the regulation of SCI repair. MicroRNAs (miRNAs) are non-coding RNA molecules that target mRNA expression in order to silence, translate, or interfere with protein synthesis. Secondary damage, such as oxidative stress, apoptosis, autophagy, and inflammation, occurs after SCI, and differentially expressed miRNAs contribute to these events. This article reviews the pathophysiological mechanism of miRNAs in secondary injury after SCI, focusing on the mechanism of miRNAs in secondary neuroinflammation after SCI, so as to provide new ideas and basis for the clinical diagnosis and treatment of miRNAs in SCI. The mechanisms of miRNAs in neurological diseases may also make them potential biomarkers and therapeutic targets for spinal cord injuries.

Association between brain N-acetylaspartate levels and sensory and motor dysfunction in patients who have spinal cord injury with spasticity: an observational case-control study.

Spinal cord injury is a severe and devastating disease, and spasticity is a common and severe complication that is notoriously refractory to treatment. However, the pathophysiological mechanisms underlying spasticity and its development remain largely unknown. The goal of the present study was to find differences, if any, in metabolites of the left precentral gyrus and basal ganglia of patients who have spinal cord injury with or without spasticity, and to explore the relationship between the brain metabolite concentrations and clinical status. Thirty-six participants were recruited for magnetic resonance spectroscopic examination: 23 with spinal cord injury (12 with spasticity and 11 without spasticity) and 13 healthy controls. We acquired localized proton spectra from the precentral gyrus and basal ganglia via 10 mm3 voxels. Notably, univariate linear regression analysis demonstrated that the lower that the N-acetylaspartate concentration (a marker for neuronal loss) was in the precentral gyrus of the patients, the lower their ASIA (American Spinal Injury Association) light-touch scores, pinprick scores, and motor scores. Additionally, longer durations of injury were associated with higher N-acetylaspartate levels in the precentral gyrus. Compared with the healthy participants and patients without spasticity, N-acetylaspartate levels in the patients with spasticity were significantly lower in both the precentral gyrus and basal ganglia. Lower N-acetylaspartate levels also correlated with greater sensory and motor dysfunction in the patients who had spinal cord injury with spasticity.

In vivo astrocyte-to-neuron reprogramming for central nervous system regeneration: a narrative review.

The inability of damaged neurons to regenerate within the mature central nervous system (CNS) is a significant neuroscientific challenge. Astrocytes are an essential component of the CNS and participate in many physiological processes including blood-brain barrier formation, axon growth regulation, neuronal support, and higher cognitive functions such as memory. Recent reprogramming studies have confirmed that astrocytes in the mature CNS can be transformed into functional neurons. Building on in vitro work, many studies have demonstrated that astrocytes can be transformed into neurons in different disease models to replace damaged or lost cells. However, many findings in this field are controversial, as the source of new neurons has been questioned. This review summarizes progress in reprogramming astrocytes into neurons in vivo in animal models of spinal cord injury, brain injury, Huntington's disease, Parkinson's disease, Alzheimer's disease, and other neurodegenerative conditions.

Combined selective peripheral neurotomy in the treatment of spastic lower limbs of spinal cord injury patients.

OBJECTIVE: To explore the therapeutic effect of combined selective peripheral neurotomy (cSPN) on the spasm of the lower limbs after spinal cord injury. METHODS: A prospective intervention (before-after trial) with an observational design was conducted in 14 spinal cord injury patients with severe lower limbs spasticity by cSPN. Given the severe spasm of hip adductor, triceps surae, and hamstring muscles in these patients, a total of 26 obturator nerve branches, 26 tibia nerve branches, and 4 sciatic nerve branches partial neurotomy were performed. The modified Ashworth scale, composite spasticity scale, surface electromyography, gait analysis, functional ambulation category, spinal cord independence measure, and modified spinal cord injury-spasticity evaluation tool were used before and after surgery. RESULTS: Compared with preoperative, the spasm of the hip adductor, triceps surae, and hamstrings of the lower limbs in the postoperative patients decreased significantly. The abnormal gait of knee flexion and varus in the standing stage were significantly reduced. The grading of walking ability and activities of daily living were significantly improved. CONCLUSIONS: Combined selective peripheral neurotomy can significantly reduce the spasm of lower limbs post spinal cord injury, improve abnormal gait, and improve motor function and activities of daily living. TRIAL REGISTRATION: ChiCTR1800019003 (2018-10-20).

The Overexpression of Insulin-Like Growth Factor-1 and Neurotrophin-3 Promote Functional Recovery and Alleviate Spasticity After Spinal Cord Injury.

Objective: This study was conducted to investigate the effects of the exogenous overexpression of nerve growth factors NT-3 and IGF-1 on the recovery of nerve function after spinal cord injury (SCI) and identify the potential mechanism involved. Methods: Sixty-four female SD rats were randomly divided into four groups: an SCI group, an adeno-associated viral (AAV)-RFP and AAV-GFP injection group, an AAV-IGF-1 and AAV-NT-3 injection group, and a Sham group. After grouping, the rats were subjected to a 10-week electrophysiological and behavioral evaluation to comprehensively evaluate the effects of the intervention on motor function, spasticity, mechanical pain, and thermal pain. Ten weeks later, samples were taken for immunofluorescence (IF) staining and Western blot (WB) detection, focusing on the expression of KCC2, 5-HT2A, and 5-HT2C receptors in motor neurons and the spinal cord. Results: Electrophysiological and behavioral data indicated that the AAV-IGF-1 and AAV-NT-3 groups showed better recovery of motor function (P < 0.05 from D14 compared with the AAV-RFP + AAV-GFP group; P < 0.05 from D42 compared with SCI group) and less spasticity (4-10 weeks, at 5 Hz all P < 0.05 compared with SCI group and AAV- RFP + AAV-GFP group) but with a trend for more pain sensitivity. Compared with the SCI group, the von Frey value result of the AAV-IGF-1 and AAV-NT-3 groups showed a lower pain threshold (P < 0.05 at 4-8 weeks), and shorter thermal pain threshold (P < 0.05 at 8-10 weeks). IF staining further suggested that compared with the SCI group, the overexpression of NT-3 and IGF-1 in the SCI-R + G group led to increased levels of KCC2 (p < 0.05), 5-HT2A (p < 0.05), and 5-HT2C (p < 0.001) in motor neurons. WB results showed that compared with the SCI group, the SCI-R + G group exhibited higher expression levels of CHAT (p < 0.01), 5-HT2A (p < 0.05), and 5-HT2C (p < 0.05) proteins in the L2-L6 lumbar enlargement. Conclusion: Data analysis showed that the overexpression of NT-3 and IGF-1 may improve motor function after SCI and alleviate spasms in a rat model; however, these animals were more sensitive to mechanical pain and thermal pain. These behavioral changes may be related to increased numbers of KCC2, 5-HT2A, and 5-HT2C receptors in the spinal cord tissue. The results of this study may provide a new theoretical basis for the clinical treatment of SCI.

The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology.

The balance of ion concentrations inside and outside the cell is an essential homeostatic mechanism in neurons and serves as the basis for a variety of physiological activities. In the central nervous system, NKCC1 and KCC2, members of the SLC12 cation-chloride co-transporter (CCC) family, participate in physiological and pathophysiological processes by regulating intracellular and extracellular chloride ion concentrations, which can further regulate the GABAergic system. Over recent years, studies have shown that NKCC1 and KCC2 are essential for the maintenance of Cl- homeostasis in neural cells. NKCC1 transports Cl- into cells while KCC2 transports Cl- out of cells, thereby regulating chloride balance and neuronal excitability. An imbalance of NKCC1 and KCC2 after spinal cord injury will disrupt CI- homeostasis, resulting in the transformation of GABA neurons from an inhibitory state into an excitatory state, which subsequently alters the spinal cord neural network and leads to conditions such as spasticity and neuropathic pain, among others. Meanwhile, studies have shown that KCC2 is also an essential target for motor function reconstruction after spinal cord injury. This review mainly introduces the physiological structure and function of NKCC1 and KCC2 and discusses their pathophysiological roles after spinal cord injury.

Inhibition by rno-circRNA-013017 of the apoptosis of motor neurons in anterior horn and descending axonal degeneration in rats after traumatic spinal cord injury.

Introduction: Spinal cord injury (SCI) often causes continuous neurological damage to clinical patients. Circular RNAs (circRNAs) are related to a lot of diseases, including SCI. We previously found five candidate circRNAs which were likely to regulate the secondary pathophysiological changes in rat model after traumatic SCI. Methods: In this study, we first selected and overexpressed target circRNA in rats. We then explored its functional roles using various functional assays in a rat model after SCI. Results: We found that rno-circRNA-013017-the selected target circRNA-reduced neuron apoptosis, preserved the survival and activity of motor neurons, and regulated apoptosis-related proteins at 3 days post-SCI using western blot, immunofluorescence and polymerase chain reaction. Additionally, we found that rno-circRNA-013017 inhibited descending axonal degeneration and preserved motor neurons and descending axons at 6 weeks post-SCI using immunofluorescence, biotin dextran amine diffusion tensor imaging. Finally, the overexpression of rno-circRNA-013017 promoted the locomotor function of rats after SCI using open-field test and gait analysis. Conclusion: Focusing on the functions of rno-circRNA-013017, this study provides new options for future studies exploring therapeutic targets and molecular mechanisms for SCI.

Correction: Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model.

Surgical decompression after spinal cord injury (SCI) is a conventional treatment. Although it has been proven to have clinical effects, there are certain limitations, such as the surgical conditions that must be met and the invasive nature of the treatment. Therefore, there is an urgent need to develop a simple and maneuverable therapy for the emergency treatment of patients with SCI before surgery. Rapamycin (RAPA) has been reported to have potential as a therapeutic agent for SCI. In this study, we observed the therapeutic effects of rapamycin and surgical decompression, in combination or separately, on the histopathology in rabbits with SCI. After combination therapy, intramedullary pressure (IMP) decreased significantly, autophagic flux increased, and apoptosis and demyelination were significantly reduced. Compared with RAPA/surgical decompression alone, the combination therapy had a significantly better effect. In addition, we evaluated the effects of mechanical pressure on autophagy after SCI by assessing changes in autophagic initiation, degradation, and flux. Increased IMP after SCI inhibited autophagic degradation and impaired autophagic flux. Decompression improved autophagic flux after SCI. Our findings provide novel evidence of a promising strategy for the treatment of SCI in the future. The combination therapy may effectively improve emergency treatment after SCI and promote the therapeutic effect of decompression. This study also contributes to a better understanding of the effects of mechanical pressure on autophagy after neurotrauma.