Microglia-mediated neuroinflammation and oxidative stress are pivotal drivers of secondary injury following traumatic brain injury (TBI). While neddylation governs essential cellular functions, its specific contribution to microglial activation and TBI pathology remains poorly understood. We integrated bulk microglial RNA sequencing profiles with single-cell RNA sequencing (scRNA-seq) datasets from TBI mouse brains. To assess therapeutic potential, we employed a controlled cortical impact mouse model and treated animals with the neddylation inhibitor MLN4924. The role of microglia was validated using microglia-depleted mice. Mechanistically, a combinatorial approach utilizing AlphaFold 3 molecular docking predictions, quantitative proteomics, and immunoprecipitation-mass spectrometry was performed to identify molecular targets. We revealed a specific and robust up-regulation of neddylation exclusively within microglial clusters. Pharmacological inhibition of neddylation using MLN4924 significantly ameliorated neurological deficits, attenuated brain edema, and preserved blood-brain barrier integrity. Crucially, these neuroprotective benefits were abrogated in microglia-depleted mice, pinpointing microglia as the primary cellular target. We identified the glutamate-cysteine ligase modifier subunit (GCLM) as a novel substrate of the CUL3–KLHL12 E3 ligase complex. MLN4924 inhibits CUL3 neddylation, thereby impeding the CUL3–KLHL12-mediated ubiquitination and degradation of GCLM. Consequently, GCLM stabilization restores intracellular glutathione synthesis, effectively scavenging reactive oxygen species and mitigating neuroinflammation. Our findings characterize the Neddylation-CUL3–KLHL12-GCLM axis as a critical regulator of microglial redox homeostasis and highlight this pathway as a promising therapeutic target for TBI intervention.

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding the function of the brain. Here, using single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters at single-cell resolution, involving over 4 million cells, as well as for 29,655 genes. We have identified cell clusters exhibiting preference for cortical subregions and explored their associations with brain-related diseases. Additionally, we pinpointed 155 genes with distinct regional expression patterns within the brainstem and unveiled 513 long non-coding RNAs showing region-enriched expression in the adult brain. Parcellation of brain regions based on spatial transcriptomic information revealed fine structure for several brain areas. Furthermore, we have uncovered 411 transcription factor regulons showing distinct spatiotemporal dynamics during neurodevelopment. Thus, we have constructed a single-cell-resolution spatial transcriptomic atlas of the mouse brain with genome-wide coverage.

Regeneration of the corticospinal tract (CST) is considered a therapeutic target to achieve improved recovery of motor function after spinal cord injury (SCI), which is an incurable CNS damage that affects millions of people. Exercise training is effective in improving multiple functions in spinal cord-injured patients. However, the effects of exercise training on axon regeneration have not been sufficiently reported. Osteopontin (OPN) has great potential application as a neuroprotective agent for the repair of the nervous system. Studies have shown that the extent of axon regeneration strongly correlates with the expression of OPN. Our previous studies demonstrated that treadmill exercise supplemented by OPN enhances motor function recovery, but axon regeneration is still limited. Extending the treadmill exercise for 12 weeks, we observed promoted axon regeneration, motor function improvement, and signaling pathway activation in mice with SCI after supplementing OPN. Axon regeneration was observed with an anterograde tracer, motor function recovery was evaluated by animal ethology and electrophysiology, and the levels of IGF-1R/Akt/mTOR signaling pathway were evaluated. The results showed that the CST of C5 crushed mice regenerated and formed synaptic connections with neurons after treadmill exercise supplemented by OPN, the horizontal ladder and cylinder rearing test of injured limbs were improved, motor evoked potential also suggested enhanced nerve conduction, and the expression of p-IR, p-Akt, and p-S6 were increased. And the improvements were more obvious than that of the exercise group. Collectively, our study found that treadmill exercise supplemented by OPN promote axon regeneration and motor function through the IGF-1R/Akt/mTOR signaling pathways, and these improvements can be inhibited by rapamycin and Methyl-beta-CD (M-B-CD).

Acute and chronic exposure to high altitude causes multiple negative neurological consequences. Further research has shown the efficacy of targeted drugs after acute hypoxia. However, the effects and mechanisms of physical therapy like exercise, on after exposed-induced myelin repair and functional improvements have remained unclear. Here, we explored the efficacy of treadmill training at different intensities on recovery in a rat model of acute hypobaric hypoxia (HH) injury. A 4-week treadmill training scheme was used at 30

Regulatory T (Treg) cells contribute to white matter repair following ischemic stroke, but their limited availability in circulation restricts their therapeutic potential. Exercise, as a non-invasive and effective rehabilitation method, has been shown to restore Treg balance in diseases. This study explores the effects of treadmill training on Treg upregulation and its influence on myelin repair and functional recovery in rats with middle cerebral artery occlusion (MCAO). After four weeks of treadmill training, we analyzed the proportion of Treg cells (Tregs), FOXP3 expression, and oligodendrocyte-related protein levels using flow cytometry, immunofluorescence, and Western blotting. Myelin structure was examined with transmission electron microscopy (TEM), while motor coordination and balance were assessed using the fatigue rotarod and CatWalk analysis systems. To further explore the role of Tregs, the FOXP3 inhibitor P60 was used to inhibit Treg activity. The findings of our study indicate that training on a treadmill supports the maturation of oligodendrocytes, leads to an increase in myelin-associated proteins and the thickness of myelin, and promotes the recovery of motor function. Inhibition of Treg activity diminished these benefits, highlighting Tregs’ key role in exercise-induced remyelination. These findings suggest that treadmill training facilitates myelin regeneration and functional recovery by upregulating Tregs, offering potential new strategies for stroke treatment.

Objective To determine the effects of treadmill training on the structure of hippocampal myelin and cognitive function in rats exposed to acute plateau hypoxia. Methods With 30 SPF-grade female SD rats (aged 6-8 weeks, weighing 200-220 g), 6 of them were used for observation of myelin structure after injury, and the remaining 24 rats were randomly divided into control group, hypobaric hypoxia group and treadmill training group (n=8). The rats in above experimental groups were placed in a low-pressure oxygen chamber at an altitude of 6 000 m for 7 consecutive days, and the rats of the control group were placed in the confined chamber for the same period without hypoxia. Then, the rats of the treadmill training group received a 4-week treadmill training scheme since the day after hypoxia. Finally, all the rats were tested for cognitive function with open field test (OFT) and Morris water maze (MWM). Transmission electron microscopy (TEM) was used to observe the changes of demyelination in the hippocampus. The expression of oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP) in the hippocampal CA1 and CA3 regions was measured by immunofluorescence staining and Western blotting. Results Behavioral tests showed that the number into the central area, total distance, distance ratio in OFT and the number of platform crossings and distance to the target area in MWM were reduced in the hypobaric hypoxia group than the control group (P < 0.05), while these indexes were increased in the treadmill training group than in the hypobaric hypoxia group (P < 0.05). Immunofluorescence staining indicated that the number of Olig2 positive cells per unit area and the mean fluorescence intensity of MBP in the CA1 and CA3 regions were significantly lessen in the hypobaric hypoxia group than the control group (P < 0.05), while these indicators were higher in the treadmill training group than the hypobaric hypoxia group (P < 0.05). Western blotting displayed that the expression levels of Olig2 and MBP in the hippocampus were obviously lower in the hypobaric hypoxia group than the control group (P < 0.01), while the levels were increased in the treadmill training group than the hypobaric hypoxia group (P < 0.01). Conclusion Treadmill training promotes the number of the oligodendrocyte spectrum cells in CA1 and CA3 regions, enhances the expression of myelin-related proteins and improves myelin repair in hippocampus of hypobaric hypoxia rats, and thereby ameliorates hypoxia-induced anxiety-like behaviors and memory dysfunction.

Objective To investigate the effects of treadmill training on the repair of myelin structure of dorsal corticospinal tract (dCST) in mice with T10 spinal cord mild contusion. Methods Twelve adult C57/BL female mice were used to construct and verify the model of spinal cord mild contusion, and another 30 mice were randomly divided into 3 groups (n=10): sham group, spinal cord injury (SCI) group, and treadmill training group.The mice of SCI and treadmill training groups were given unilateral (left) spinal cord contusion, while the sham group was given laminectomy only.A 4-week training scheme was conducted for the treadmill training group 1 week after SCI surgery (parameters: 12 m/min, 30 min/session, 1 time/day, 5 d/week).The primary motor cortex (M1) of mice in each group was injected with biotinylated dextran amine (BDA) to trace dCST 2 weeks before sampling, followed by the collection of tissue samples when the 4-week training finished.Then the expression levels of platelet-derived growth factor receptor α(PDGFRα), Ki67 protein, oligodendrocyte transcription factor 2(Olig2), adenomatous polyposis coli protein (APC/CC1) and myelin basic protein (MBP) were detected by immunofluorescence assay.Transmission electron microscopy (TEM) was also used to observe the myelination in the left dCST area.Moreover, Basso Mouse Scale (BMS) was performed in each group to evaluate the motor function of left hindlimb before injury, 1 week after injury and 1, 2, and 4 weeks after training. Results Immunofluorescent labeling showed that the ratio of PDGFRα/Ki67 double positive cells to the total number of PDGFRα positive cells, the ratio of Olig2/APC/CC1 double positive cells to the total number of Olig2 positive cells, as well as the mean fluorescence intensity of MBP in the left dCST area of the SCI group were significantly lower than those of the sham group (P < 0.01), while these indexes were higher in the treadmill training group than in the SCI group (P < 0.01).TEM results indicated that the G-ratio of the left dCST area was elevated in the SCI group (P < 0.01), but was reduced greatly in the treadmill training group (P < 0.01).Finally, the BMS scores were improved in the treadmill group at each detection time point after injury, but there was no significant difference as compared with the SCI group (P>0.05). Conclusion Treadmill training can facilitate the proliferation and differentiation of oligodendrocytes precursor cells (OPCs), improve the maturation of oligodendrocytes (OLs) in the left dCST region, and increase the expression of myelin related proteins, thus promoting the repair of myelin structure after SCI in adult mice.

Previous studies reported that the codeletion of PTEN and SOCS3 can greatly enhance the capacity of axon regeneration after central nervous system (CNS) injury. Moreover, the promotion of functional recovery can be improved by rehabilitative training under a use-dependent plasticity mechanism after CNS injury. However, few studies have reported the interaction between these mechanisms after spinal cord injury (SCI). Therefore, we investigated the combined effects of PTEN/SOCS3 coinhibition and rehabilitative training on axon regeneration and upper extremity motor functional improvement after cervical SCI in mice. In this study, we used RNA interference viruses to coinhibit PTEN and SOCS3 and induced a C5 crush injury on the side of preference. The injured upper extremity was trained by single pellet grasping for 4 weeks. We found that the coinjection of viruses significantly increased the expression of p-S6 and p-STAT in the cortex, reduced the dieback pattern of injured axons and promoted traced axon regeneration. More importantly, combination therapy further enhanced axon regeneration compared with PTEN/SOCS3 coinhibition alone. In behavioral tests, the motor performance of the mice in the PTEN/SOCS3 + Training group was better than that of the mice in the other groups. These results indicate that combining task-based rehabilitative training with PTEN/SOCS3 coinhibition further promotes axon regeneration and significant improvement in forelimb skilled motor function after cervical SCI. Our findings provide new therapeutic insights into SCI treatment.

Growing evidence has proven the efficacy of physical exercise in remyelination and motor function performance after spinal cord injury (SCI). However, the molecular mechanisms of treadmill training on myelin repair and functional recovery after SCI have not yet been fully studied. Here, we explored the effect of treadmill training on upregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α)-mediated myelin repair and functional recovery in a mouse model of thoracic T10 contusion injury. A 4-week treadmill training scheme was conducted on mice with SCI. The expression levels of oligodendrogenesis-related protein and PGC1α were detected by immunofluorescence, RNA fluorescence in situ hybridization and western blotting. Transmission electron microscopy (TEM) was used to observe myelin structure. The Basso Mouse Scale (BMS) and CatWalk automated gait analysis system were used for motor function recovery evaluation. Motor evoked potentials (MEPs) were also identified. In addition, adeno-associated virus (AAV)-mediated PGC1α knockdown in OLs was used to further unravel the role of PGC1α in exercise-induced remyelination. We found that treadmill training boosts oligodendrocyte precursor cells (OPCs) proliferation, potentiates oligodendrocytes (OLs) maturation, and increases myelin-related protein and myelin sheath thickness, thus impelling myelin repair and hindlimb functional performance as well as the speed and amplitude of nerve conduction after SCI. Additionally, downregulating PGC1α through AAV attenuated these positive effects of treadmill training. Collectively, our results suggest that treadmill training enhances remyelination and functional recovery by upregulating PGC1α, which should provide a step forward in the understanding of the effects of physical exercise on myelin repair.

This study aims to investigate the effect of insulin-like growth factor 1 (IGF-1) combined with osteopontin (OPN) on the protein expression levels and growth of neuronal axons and its possible mechanism. In this study, IGF-1 combined with OPN promoted neuronal axon growth through the IGF-1R/Akt/mTOR signaling pathway in lipid rafts, and the effect was better than that of either agent alone. This effect was suppressed when given the mTOR inhibitor rapamycin or the lipid raft cholesterol extraction agent methyl-β-cyclodextrin (M-β-CD). Rapamycin could inhibit the expression of phosphorylated ribosomal S6 protein (p-S6) and phosphorylated protein kinase B (p-Akt) and limit axon growth. In addition to the above effects, M-β-CD significantly downregulated the expression of phosphorylated insulin-like growth factor 1 receptor (p-IR). To further investigate the changes in lipid rafts when stimulated by different recombinant proteins, membrane lipid rafts were isolated to observe the changes by western blot. The expression levels of insulin-like growth factor 1 receptor (IR) and P-IR in the IGF-1 combined with OPN group were the highest. When M-β-CD was administered to the lipid rafts of neurons, the enrichment of IR by IGF-1 combined with OPN was weakened, and the p-IR was decreased. Our study found that IGF-1 combined with OPN could promote axon growth by activating the IGF-1R/Akt/mTOR signaling pathway in neuronal lipid rafts.

In this study, we examined the combined impact of osteopontin (OPN) and treadmill training on mice with spinal cord injury (SCI). OPN was overexpressed by injecting AAV9-SPP1-GFP into the sensorimotor cortex, followed by a left incomplete C5 crush injury two weeks later. Mice (Ex or Ex + OPN group) were trained at 50% maximum running speed for 8 weeks. To analyze the effects, we used biotinylated dextran amine (BDA) for tracing the corticospinal tract (CST) and performed Western blotting and immunohistochemical methods to assess the activation of the mammalian target of rapamycin (mTOR). We also examined axonal regeneration and conducted behavioral tests to measure functional recovery. The results demonstrated that treadmill training promoted the expression of neurotrophic factors such as brain-derived neurotrophic factor (BNDF) and insulin-like growth factor I (IGF-1) and activated mTOR signaling. OPN amplified the effect of treadmill training on activating mTOR signaling indicated by upregulated phosphorylation of ribosomal protein S6 kinase (S6). The combination of OPN and exercise further promoted functional recovery and facilitated limited CST axonal regeneration which did not occur with treadmill training and OPN treatment alone. These findings indicate that OPN enhances the effects of treadmill training in the treatment of SCI and offer new therapeutic insights for spinal cord injury.

Fine particulate matter (PM2.5) pollution remains a prominent environmental problem worldwide, posing great threats to human health. The adverse effects of PM2.5 on the respiratory and cardiovascular systems have been extensively studied, while its detrimental effects on the central nervous system (CNS), specifically neurodegenerative disorders, are less investigated. Neurodegenerative disorders are characterized by reduced neurogenesis, activated microglia, and neuroinflammation. A variety of studies involving postmortem examinations, epidemiological investigations, animal experiments, and in vitro cell models have shown that PM2.5 exposure results in neuroinflammation, oxidative stress, mitochondrial dysfunction, neuronal apoptosis, and ultimately neurodegenerative disorders, which are strongly associated with the activation of microglia. Microglia are the major innate immune cells of the brain, surveilling and maintaining the homeostasis of CNS. Upon activation by environmental and endogenous insults, such as PM exposure, microglia can enter an overactivated state that is featured by amoeboid morphology, the over-production of reactive oxygen species, and pro-inflammatory mediators. This review summarizes the evidence of microglial activation and oxidative stress and neurodegenerative disorders following PM2.5 exposure. Moreover, the possible mechanisms underlying PM2.5-induced microglial activation and neurodegenerative disorders are discussed. This knowledge provides certain clues for the development of therapies that may slow or halt the progression of neurodegenerative disorders induced by ambient PM.

Treadmill exercise is widely considered an effective strategy for restoration of skilled motor function after spinal cord injury (SCI). However, the specific exercise intensity that optimizes recovery and the underlying mechanistic basis of this recovery remain unclear. To that end, we sought to investigate the effect of different treadmill exercise intensities on cortical mTOR activity, a key regulator of functional recovery following CNS trauma, in an animal model of C5 crush spinal cord injury (SCI). Following injury, animals were subjected to treadmill exercise for 4 consecutive weeks at three different intensities (low intensity [LEI]; moderate intensity [MEI]; and high intensity [HEI]). Motor function recovery was assessed by horizontal ladder test, cylinder rearing test, and electrophysiology, while neurotrophic factors and cortical mechanistic target of rapamycin (mTOR) pathway–related proteins were assessed by Western blotting. The activation of the cortical mTOR pathway and axonal sprouting was evaluated by immunofluorescence and the changes of plasticity in motor cortex neurons were assessed by Golgi staining. In keeping with previous studies, we found that 4 weeks of treadmill training resulted in improved skilled motor function, enhanced nerve conduction capability, increased neuroplasticity, and axonal sprouting. Importantly, we also demonstrated that when compared with the LEI group, MEI and HEI groups demonstrated elevated expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), phosphorylated ribosomal S6 protein (p-S6), and protein kinase B (p-Akt), consistent with an intensity-dependent activation of the mTOR pathway and neurotrophic factor expression in the motor cortex. We also observed impaired exercise endurance and higher mortality during training in the HEI group than in the LEI and MEI groups. Collectively, our findings suggest that treadmill exercise following SCI is an effective means of promoting recovery and highlight the importance of the cortical mTOR pathway and neurotrophic factors as mediators of this effect. Importantly, our findings also demonstrate that excessive exercise can be detrimental, suggesting that moderation may be the optimal strategy. These findings provide an important foundation for further investigation of treadmill training as a modality for recovery following spinal cord injury and of the underlying mechanisms.

We focus on providing the first comprehensive national dataset on the incidence, injury aetiology and mortality of TSCI in China. A multi-stage stratified cluster sampling method was used. We included TSCI cases from all hospitals in three regions, nine provinces and 27 cities in China via search of electronic medical records and retrospectively analysed the characteristics of TSCI in China from 2009 to 2018. We estimated the incidence of TSCI in the total population and subgroups. There were 5954 actual cases in 2009, corresponding to a total estimated TSCI incidence of 45.1 cases per million population (95% CI, 44.0–46.3). There were 10,074 actual cases in 2018, corresponding to a total estimated TSCI incidence of 66.5 cases per million population (95% CI, 65.2–67.8) (P < 0.001; annual average percentage change (AAPC), 4.4%). From 2009 to 2018, the incidence of almost all sex/age groups showed an increasing trend over time (P < 0.001; AAPC, 0.7–8.8%). The elderly population (aged 65–74) displayed the highest incidence of TSCI (with an average annual incidence of 127.1 cases per million [95% CI, 119.8–134.3]). The TSCI incidence increased significantly from 2009 to 2018. The incidence in the elderly populations was consistently high and continues to increase over time. The mortality of TSCI patients in hospitals is relatively low and continues to decrease each year, but elderly individuals remain at a high risk of hospital death.

Neurons and glial cells in the central nervous system (CNS) are generated from neuroepithelial cells in the ventricular zone that surrounds the embryonic neural tube. The proliferation and distinct differentiation of neural precursors occurs at certain stages and are regulated by a series of transcription factors leading to the generation of neuronal and glial cell subtypes. In this manuscript, we review the effects of the Olig family, namely, members Olig1, Olig2 and Olig3, on the distinct differentiation of glial and neuronal cells in the developing spinal cord and injured neural tissue.

An increasing number of studies connect neuronal activity with developmental myelination but how neuronal activity regulates remyelination has not been clarified. In this study, we induced the demyelination of the dorsal corticospinal tract (dCST) by a mild contusion spinal cord injury (SCI) on the T10 segment, and manipulated the neuronal activity of the primary motor cortex (M1) using chemogenetic viruses to induce activity and to suppress it. We found that oligodendrocyte precursor cell (OPC) proliferation and oligodendrocyte maturity following remyelination was strengthened after 4-week of neuronal activity stimulation. Furthermore, hindlimb motor function was also found to be improved. Vice versa, suppression of neuronal activity attenuated these effects. These results indicate that bidirectional regulation of neuronal activity can effectively modulate the development of oligodendrocyte lineage cells and the remyelination process. Neuronal activity supports the proliferation of OPCs, improves oligodendrocyte maturation and amplifies the axonal remyelination process, even though leads to better motor function recovery. Manipulation of neuronal activity in a non-invasive manner is therefore a promising avenue for exploration towards the treatment of central nervous system (CNS) demyelination diseases.

Transplantation of neural stem cells (NSCs) may be a potential strategy for traumatic brain injury treatment (TBI) due to their intrinsic advantages, such as cell replacement, secretion of neurotrophins and formation of functional synapses with host. However the underlying effects of transplanted NSCs on host micro-environment still need to be further elucidated. In this manuscript the effects of NSCs on release of neurotransmitter, survival of hippocampal neurons, reactivity of astrocytes and recovery of cognitive function after TBI were observed. The NSCs were isolated from cortex of neonatal Sprague-Dawley rat and then transplanted into injured brain regions caused by free-weight drop. The proliferation of astrocytes around injured sites were examined by GFAP immunofluorescent staining on 3, 7, 14 days after injury. The survival of neurons at CA1 regions of hippocampus toward contused regions was observed by HE staining on 3 and 14 days post-injury. The content of glutamic acid (Glu) and GABA in hippocampal tissues was examined on 1, 3, 7, 14, 28 days after injury by ELISA. On third day post-injury, hippocampal-dependent spatial memory was measured for 5 days without intermittent. NSCs in culture have the ability to proliferate and differentiate into different phenotypes of neural cells. After transplantation of NSCs, the proliferation of astrocytes around injured site was significantly inhibited compared to the injured group. At the same time the survival of neurons in hippocampal CA1 region were much more than those in injured group on 14 days post-injury. Meanwhile, the cognitive functions in NSC transplanted group was remarkably improved compared with injured group (p < 0.05). Furthermore, NSCs transplantation dramatically inhibited the release of Glu and maintained the content of GABA in injured hippocampal tissues on 1, 3, 7, 14, 28 days post-injury, which was of difference in statistics (p < 0.05). NSCs transplantation can effectively alleviate the formation of glial scar, enhance the survival of hippocampal neurons and improve cognitive function defects in rats with TBI. The underlying mechanism may be related to their effects on inhibiting the release of Glu and maintaining the content of GABA, so as to down-regulate excitotoxicity of neurotransmitter and improve the micro-environment in injured sites.

In the central nervous system, the primary immune cells, the microglia, prevent pathogenic invasion as the first line of defense. Microglial energy consumption is dependent on their degree of activity. Microglia express transporters for the three primary energy substrates (glucose, fatty acids, glutamine) and regulate diabetic encephalopathy via microglia-neuron interactions. Microglia may play a sentry role for rapid protection or even ablation of impaired neurons. Neurons exhibit hyperactivity in response to hyperglycemia, hyperlipidemia, and neurotoxic factors and release potential microglial activators. Microglial activation is also regulated by proinflammatory factors, caspase-3 activity, P2X7 receptor, interferon regulatory factor-8, and glucocorticoids. Modulation of microglia in diabetic encephalopathy may involve CX3CL1, p38 MAPK, purinergic, and CD200/CD200R signaling pathways, and pattern recognition receptors. The microglia-neuron interactions play an important role in diabetic encephalopathy, and modulation of microglial activation may be a therapeutic target for diabetic encephalopathy.

BACKGROUND:Traumatic brain injury (TBI) can be complicated by TBI-triggered acute lung injury (ALI), in which inflammation plays a central role. It has been reported that an Erythropoietin-derived peptide (pHBSP) was able to ameliorate TBI; however, its function in TBI-caused ALI has not been reported yet.METHODS:In this study, we studied the effect of pHBSP on TBI-caused ALI by using a weight-drop induced TBI model. At 8 h and 24 h post-TBI, pulmonary edema (PE) and bronchoalveolar lavage fluid (BALF) proteins were measured, and haematoxylin and eosin (H&E) staining of lung sections was carried out. At 24 h following TBI, the lungs were harvested for immunofluorescence staining and qRT-PCR analysis.RESULTS:At 8 h and 24 h post-TBI, pHBSP treatment significantly decreased wet/dry ratios, decreased total BALF protein, and attenuated the histological signs of pulmonary injury. At 24 h post-TBI, pHBSP treatment decreased the accumulation of CD68+ macrophages in the lung and reduced the mRNA levels of TNF-α, IL-6, IL-1β and iNOS in the lung.CONCLUSIONS:We identified the protective role that pHBSP played in TBI-caused ALI, suggesting that pHBSP is a potent candidate for systemic therapy in TBI patients.

Spinal cord ischemia and reperfusion (SCIR) injury can lead to neurologic dysfunction and paraplegia, which are serious complications after shock or thoracoabdominal aortic surgery. Autophagy is a fundamental cellular process in eukaryotes, and homeostasis of autophagic activities in the cytoplasm is critical for the maintenance of neuronal function. To date, no studies have addressed the involvement of autophagy in the regulation of motor neurons in the ventral horn of the spinal cord area following SCIR-induced spastic paralysis or the underlying mechanisms of this process. In this study, we investigated spastic paralysis in rats following SCIR injury. The number of autophagosomes increased 3 h following the injury, and subsequently decreased slowly to near-normal levels in the sham group as indicated by the autophagy markers microtubule-associated protein 1 light chain 3 (LC3), beclin-1, and p62. Furthermore, after treatment with the autophagy inhibitor 3-Methyladenine (3-MA) and autophagy activator rapamycin following SCIR, autophagy in the SCIR-3-MA group decreased significantly, while that in the SCIR-Rap group increased, compared with SCIR-DMSO controls group. Moreover, the assessment of motor neurons function, using Reuter's score and motor evoked potentials (MEP) and somatosensory evoked potentials (SEP), indicated that promoting autophagy reduced scores compared with SCIR controls, while inhibiting autophagy increased the scores, and hence motor neurons function. Autophagy in the SCIR model protected motor neurons function and morphology. These results would provide more evidences for better understanding function of autophagy in motor neurons degeneration and mechanisms underlying spastic paralysis. Autophagy would be a novel target for prevention and therapy in SCIR damage.