Severe Central Nervous System Injury Research Articles

Machine Learning and Experiments Revealed Key Genes Related to PANoptosis Linked to Drug Prediction and Immune Landscape in Spinal Cord Injury.

Spinal cord injury (SCI) is a severe central nervous system injury without effective therapies. PANoptosis is involved in the development of many diseases, including brain and spinal cord injuries. However, the biological functions and molecular mechanisms of PANoptosis-related genes in spinal cord injury remain unclear. In the bioinformatics analysis of public data of SCI, the differentially expressed genes (DEGs) identified by GSE151371 were hybridized with PANoptosis-related genes (PRGs) to obtain differentially expressed PANoptosis-related genes (DE-PRGs). Through three machine learning algorithms, we obtained the hub genes. Then, we constructed functional analysis, drug prediction, regulatory network construction, and immune infiltrating cell analysis. Finally, the expression of the hub gene was verified in GSE93561, GSE45376, and qRT-PCR analysis. Through the above analysis, 14 DE-PRGs were obtained by intersecting 3582 DEGs with 46 PRGs. Five key hub genes, CASP4, GSDMB, NAIP, NLRC4, and NLRP3, were obtained by 3 machine learning algorithms. All five hub genes were enriched in phagocytosis mediated by FC GAMMA R. The 11 immune cells were significantly different between spinal cord injury (SCI) group and human control (HC) group, such as mast cell and gamma delta T cell. The transcription factor (TF)-hub gene network contained 10-nodes (4 hub genes and 6 TFs) and 8-edges. The miRNA-hub gene network consisting of 5-nodes (3 hub genes and 2 miRNAs) and 3-edges was constructed. Moreover, the CASP4 predicted 1 small molecule drug and NLRP3 predicted 9 small molecule drugs. Finally, the expression of 5 hub genes were significantly different in GSE45376 and GSE93561 (SCI vs. HC) and mice SCI model (Sham vs. SCI). Collectively, we identified 5 hub genes (CASP4, GSDMB, NAIP, NLRC4, and NLRP3) associated with PANoptosis, providing potential directions for treating spinal cord injury.

Severe central nervous system injury in 9 children with COVID-19

PurposeTo investigate the clinical features and prognosis of severe central nervous system (CNS) injury in children caused by coronavirus disease 2019 (COVID-19).MethodWe retrospectively studied confirmed pediatric cases of COVID-19 complicated with CNS injury.ResultsNine patients diagnosed with COVID-19 complicated with severe CNS injury were admitted to the pediatric intensive care unit of the Affiliated Hospital of Jining University from December 1, 2022 to January 12, 2023. Of the nine patients, seven were male (77.78%). Five children were aged ≥ 10 years, and the others were 1–2 years old. All children had fever, eight had convulsions, seven had progressed to multiple organ failure, and all suffered varying degrees of coma. Most of the children had elevated interleukin-6 (100%), lactic acid (100%), alanine transaminase (87.5%), aspartate transaminase (87.5%), creatine kinase MB (87.5%), and lactate dehydrogenase (85.7%) levels. Four children had cerebrospinal fluid proteinnacell separation. The cranial imaging results of five children were abnormal. One child had lost his vital signs when admitted to hospital, and the remaining eight received hormonal shock, human immunoglobulin transfusion, antinainfection, cranial pressure reduction, and tracheal intubation, among others, during hospitalization. Ultimately, eight children died, and the remaining child has serious neurological sequelae and is undergoing rehabilitation.ConclusionsSevere CNS injury caused by COVID-19 has an acute onset, rapid progression, high disability rate, and high fatality rate. A low cerebrospinal fluid protein level may be a protective factor for children with severe nervous system injury caused by COVID-19.

A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury.

Why severe injury to the central nervous system (CNS) triggers the development of large neurogenic heterotopic ossifications (NHOs) within periarticular muscles remains unknown. We report that spinal cord injury (SCI) triggers a rapid corticosterone spike in mice, which is causal for NHO development because treatments with corticosterone or the synthetic glucocorticoid (GC) receptor (GR) agonist dexamethasone are sufficient to trigger heterotopic ossification and upregulate the expression of osteoinductive and osteogenic differentiation genes in injured muscles even without SCI. The central role for GR signaling in causing NHO is further demonstrated in mice deleted for the GR gene (Nr3c1), which no longer develop NHO after SCI. Furthermore, administration of clinical GR antagonists inhibits NHO development in mice with SCI. This study identifies endogenous GC as causing pathological NHO after CNS injury and suggests that GR antagonists may be of prophylactic use to prevent NHO development in victims of severe CNS injuries.

ARL11 knockdown alleviates spinal cord injury by inhibiting neuroinflammation and M1 activation of microglia in mice

Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1β and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo. Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro. ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.

EEG Motor Imagery Classification: Tangent Space with Gate-Generated Weight Classifier.

Individuals grappling with severe central nervous system injuries often face significant challenges related to sensorimotor function and communication abilities. In response, brain-computer interface (BCI) technology has emerged as a promising solution by offering innovative interaction methods and intelligent rehabilitation training. By leveraging electroencephalographic (EEG) signals, BCIs unlock intriguing possibilities in patient care and neurological rehabilitation. Recent research has utilized covariance matrices as signal descriptors. In this study, we introduce two methodologies for covariance matrix analysis: multiple tangent space projections (M-TSPs) and Cholesky decomposition. Both approaches incorporate a classifier that integrates linear and nonlinear features, resulting in a significant enhancement in classification accuracy, as evidenced by meticulous experimental evaluations. The M-TSP method demonstrates superior performance with an average accuracy improvement of 6.79% over Cholesky decomposition. Additionally, a gender-based analysis reveals a preference for men in the obtained results, with an average improvement of 9.16% over women. These findings underscore the potential of our methodologies to improve BCI performance and highlight gender-specific performance differences to be examined further in our future studies.

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-β (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Neurogenic heterotopic ossification: A review. Part 1

BACKGROUND: Heterotopic ossification is the formation of bone tissues in the soft tissues of the body. A distinct form of heterotopic ossification is neurogenic, that is, resulting from severe injury to the brain or spinal cord of different genesis. Neurogenic heterotopic ossification is a complex multifactorial process of differentiated bone formation in the paraarticular soft tissues of large joints. Heterotopic ossification leads to the formation of persistent contractures and ankylosis, which cause severe disability and complicate rehabilitation.
 AIM: To analyze publications dealing with various aspects of neurogenic heterotopic ossification.
 MATERIALS AND METHODS: In the first part of our review, we present the results of the literature analysis on the epidemiology, risk factors, pathogenesis, and clinic and laboratory diagnosis of neurogenic heterotopic ossification. Scientific literature databases PubMed, Google Scholar, Cochrane Library, Crossref, and eLibrary were searched for without language limitations.
 RESULTS: Current literature data on heterotopic ossification in patients with central nervous system pathologies are presented. Topical questions of etiology, risk factors, pathogenesis, and clinic and laboratory diagnostics of this pathological process are highlighted.
 CONCLUSIONS: Understanding the risk factors of heterotopic ossification development and their prevention in the context of the modern knowledge of heterotopic ossification pathogenesis may help reduce the incidence of heterotopic ossification in patients with severe central nervous system injury.

The pathogenesis of DLD-mediated cuproptosis induced spinal cord injury and its regulation on immune microenvironment.

Spinal cord injury (SCI) is a severe central nervous system injury that leads to significant sensory and motor impairment. Copper, an essential trace element in the human body, plays a vital role in various biological functions and is strictly regulated by copper chaperones and transporters. Cuproptosis, a novel type of metal ion-induced cell death, is distinct from iron deprivation. Copper deprivation is closely associated with mitochondrial metabolism and mediated by protein fatty acid acylation. In this study, we investigated the effects of cuproptosis-related genes (CRGs) on disease progression and the immune microenvironment in acute spinal cord injury (ASCI) patients. We obtained the gene expression profiles of peripheral blood leukocytes from ASCI patients using the Gene Expression Omnibus (GEO) database. We performed differential gene analysis, constructed protein-protein interaction networks, conducted weighted gene co-expression network analysis (WGCNA), and built a risk model. Our analysis revealed that dihydrolipoamide dehydrogenase (DLD), a regulator of copper toxicity, was significantly associated with ASCI, and DLD expression was significantly upregulated after ASCI. Furthermore, gene ontology (GO) enrichment analysis and gene set variation analysis (GSVA) showed abnormal activation of metabolism-related processes. Immune infiltration analysis indicated a significant decrease in T cell numbers in ASCI patients, while M2 macrophage numbers were significantly increased and positively correlated with DLD expression. In summary, our study demonstrated that DLD affects the ASCI immune microenvironment by promoting copper toxicity, leading to increased peripheral M2 macrophage polarization and systemic immunosuppression. Thus, DLD has potential as a promising biomarker for ASCI, providing a foundation for future clinical interventions.

Basic fibroblast growth factor-loaded methacrylate gelatin hydrogel microspheres for spinal nerve regeneration.

Spinal cord injury is a severe central nervous system injury, and developing appropriate drug delivery platforms for spinal nerve regeneration is highly anticipated. Here, we propose a basic fibroblast growth factor (bFGF)-loaded methacrylate gelatin (GelMA) hydrogel microsphere with ideal performances for spinal cord injury repair. Benefitting from the precise droplet manipulation capability of the microfluidic technology, the GelMA microspheres possess uniform and satisfactory size and good stability. More importantly, by taking advantage of the porous structures and facile chemical modification of the GelMA microspheres, bFGF could be easily loaded and gradually released. By co-culturing with neural stem cells, it is validated that the bFGF-loaded GelMA microspheres could effectively promote the proliferation and differentiation of neural stem cells. We also confirm the effective role of the bFGF-loaded GelMA microspheres in nerve repair of spinal cord injury in rats. Our results demonstrate the potential value of the microspheres for applications in repairing central nervous system injuries.

Potential benefits of spinal cord stimulation treatment on quality of life for paralyzed patients with spinal cord injury.

Spinal cord injury (SCI) is a severe central nervous system injury that can cause sensory or motor dysfunction. Although mortality rates for people with spinal cord injuries have dropped dramatically with advances in medicine, chronic long-term sequelae after SCI persist. The most bothersome problems reported by patients include pain, spasticity, urinary dysfunction, and loss of motor function. Thus, quality of life (QoL) is an essential issue in chronic SCI. Spinal cord stimulation (SCS) applies an adjustable, nondamaging electrical pulse that can reduce uncomfortable comorbidities and improve mobility, thus enhancing the QoL of patients with SCI. This review summarizes pivotal breakthroughs from SCS for individual clinical impairment from SCI. We conclude that careful evaluation of SCS can help improve neuropathic pain, spasms, motor symptoms, and voiding dysfunction in patients with SCI, thus improving QoL.

Clinical features of 86 cases of acute diquat poisoning

To explore the clinical features of acute diquat (DQ) poisoning, and further improve the awareness of acute DQ poisoning. A retrospective analysis was performed on the clinical data of patients with acute DQ poisoning diagnosed in the emergency department of the Second Hospital of Hebei Medical University from January 1, 2019 to December 31, 2021. The clinical data included age, gender, exposure routes, presence of pesticides (drugs) mixture poisoning, dosage of poison, the time from taking poisoning to admitting in the emergency department, clinical manifestations, laboratory data, treatment, hospital days, prognosis and survival days. The number of cases who firstly complained of acute DQ poisoning in the past three years were 19 cases in 2019, 28 cases in 2020, and 51 cases in 2021. A total of 12 patients were excluded due to being diagnosed paraquat (PQ) poisoning by toxicology detection. Finally, 86 cases of acute DQ poisoning were included, including 80 cases of oral DQ poisoning, 1 case of intramuscular injection, 1 case of binocular contact and 4 cases of dermal exposure. In 80 cases of oral DQ poisoning, there were 70 cases of diquat poisoning alone (42 cases survived, 28 cases died) and 10 cases of pesticide mixture poisoning (6 cases survived, 4 cases died). The time from oral poisoning to admitting in the emergency department was 0.5-96.0 hours, with an average of (8.6±5.8) hours. The time of intramuscular injection poisoning to admitting in the emergency department was 3 hours. The time of dermal exposure to admitting in the emergency department was relatively long, with an average of 66.1 hours. The time from oral simple DQ poisoning to death was 12.0-108.0 hours, and the time from oral mixed DQ poisoning to death was 24.0-576.0 hours. A total of 70 patients with oral diquat poisoning alone presented various degrees of multiple organ injuries. All patients presented gastrointestinal symptoms such as nausea and vomiting. Renal injury and central nervous system injury were the most significant and closely related to the prognosis. Acute oral DQ poisoning can cause to multiple organ injuries, and the clinical manifestations are related to the dose of the poison. In severe cases, acute renal failure and refractory circulatory failure occur within 24 hours after poisoning, and severe central nervous system injury with disturbance of consciousness as the primary manifestation occurs within 36 hours, followed by multiple organ failure until death.

Intestinal Mucosal Barrier Is Regulated by Intestinal Tract Neuro-Immune Interplay.

Inflammatory bowel disease, irritable bowel syndrome and severe central nervous system injury can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases. Hence, repairing the intestinal barrier represents a potential therapeutic target for many diseases. Enteral afferent nerves, efferent nerves and the intrinsic enteric nervous system (ENS) play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors. In addition, intestinal microorganisms and their metabolites play a regulatory role in the intestinal mucosal barrier. This paper primarily discusses the interactions between norepinephrine and β-adrenergic receptors, cholinergic anti-inflammatory pathways, nociceptive receptors, complex ENS networks, gut microbes and various immune cells with their secreted cytokines to summarize the key roles in regulating intestinal inflammation and improving mucosal barrier function.

Therapeutic Strategies to Protect the Central Nervous System against Shiga Toxin from Enterohemorrhagic Escherichia coli.

Infection with Shiga toxin-producing Escherichia coli (STEC) may cause hemorrhagic colitis, hemolytic uremic syndrome (HUS) and encephalopathy. The mortality rate derived from HUS adds up to 5% of the cases, and up to 40% when the central nervous system (CNS) is involved. In addition to the well-known deleterious effect of Stx, the gram-negative STEC releases lipopolysaccharides (LPS) and may induce a variety of inflammatory responses when released in the gut. Common clinical signs of severe CNS injury include sensorimotor, cognitive, emotional and/or autonomic alterations. In the last few years, a number of drugs have been experimentally employed to establish the pathogenesis of, prevent or treat CNS injury by STEC. The strategies in these approaches focus on: 1) inhibition of Stx production and release by STEC, 2) inhibition of Stx bloodstream transport, 3) inhibition of Stx entry into the CNS parenchyma, 4) blockade of deleterious Stx action in neural cells, and 5) inhibition of immune system activation and CNS inflammation. Fast diagnosis of STEC infection, as well as the establishment of early CNS biomarkers of damage, may be determinants of adequate neuropharmacological treatment in time.

Evaluation of the effect of myelotomy on nerve function in rats with spinal cord injury by diffusion tensor imaging.

Spinal cord injury (SCI) is a severe central nervous system injury that can generally induce different degrees of sensory and motor dysfunction. To clarify the changes of diffusion tensor imaging (DTI) parameters after spinal cord myelotomy in rats with SCI. Eighteen Sprague Dawley (SD) rats were randomly divided into the Sham group (n=6), SCI group (n=6), and Mye group (n=6), respectively. The DTI values at 1, 3, 7, and 21 days after modeling were collected by magnetic resonance imaging (MRI). The spinal specimen at the injury site was collected on the 21st day for Nissl's staining to assess the changes in neurons. The fractional anisotropy (FA) values in both the SCI group and Mye group significantly decreased. In addition, the FA values between the two groups were statistically significant (P < 0.001). The apparent diffusion coefficient (ADC), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values all decreased and then increased (P < 0.001). Pearson correlation test showed that the ADC, MD, and AD values were positively correlated with the Basso Beattie Bresnahan (BBB) score. Nissl's staining showed a higher number of Nissl's bodies, and deep staining of Nissl's bodies in the Mye group, while the morphology of neurons was relatively good. The number of neurons in the Mye group was significantly higher after myelotomy compared to the SCI group (P < 0.001). The DTI parameters, especially ADC values, could non-invasively and quantifiably evaluate the efficacy of myelotomy for rats with SCI.

When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification.

Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-β1-mediated pathways. This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients.

Taxonomic dysbiosis of gut microbiota and serum biomarkers reflect severity of central nervous system injury

The term “chronic critical illness” (CCI) refers to patients with prolonged dependence on intensive care. In most patients, CCI is triggered by severe brain injury. Ever more studies researching the microbiota in pathologic conditions are published every year, but a lot is yet to be elucidated about the composition of the gut microbiota in CCI. The aim of this study was to investigate possible correlations between changes in the taxonomic abundance of the gut microbiota, levels of proinflammatory and neurological serum biomarkers and the severity of central nervous system injury in patients with CCI. Our prospective observational pilot study included 29 patients with CCI. Using real-time PCR allowed us to detected changes in the taxonomic abundance of the gut microbiota. The correlation analysis of serum biomarkers and the taxonomic composition of the gut microbiota revealed statistically significant correlations between cortisol levels and the abundance of F. prausnitzii (r = ‒0.62; p &lt; 0.05) and B. thetaiotaomicron (r = ‒0.57; p &lt; 0.05) in vegetative state patients; between the CRP/albumin ratio and the abundance of S. aureus (r = 0.72; p &lt; 0.05); between the abundance of B. fragilis group/F. prausnitzii and S100 levels (r = 0.45; p &lt;0.05) in conscious patients; between Glasgow coma scale scores and the abundance of Enterococcus spp. (r = ‒0.77; p &lt;0.05) in both groups. Thus, the association between the changes in the taxonomic composition of the gut microbiota and the severity of neurologic deficit can be evaluated using PCR-based diagnostic techniques and blood serum biomarkers. This approach will help to optimize antibacterial treatment regimens and/or develop alternative strategies to minimize the aggressive effect of antibiotics on the gut microbiota.

Catastrophic Central Nervous System Injury Rating

Abstract We present a case involving a catastrophic injury that resulted from a completely obstructed airway when an examinee choked on food. She had cardiopulmonary arrest and developed a hypoxic-ischemic encephalopathy associated with profound neurological losses. The evaluation of the consequences of severe central nervous system injury necessitates evaluation and rating of all the sequelae of that injury. The first step is clinical assessment, followed by thoughtful application of these data to the processes and criteria provided in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides). The approaches discussed in the fifth and sixth editions of the AMA Guides are similar.

Drug development in targeting ion channels for brain edema.

Cerebral edema is a pathological hallmark of various central nervous system (CNS) insults, including traumatic brain injury (TBI) and excitotoxic injury such as stroke. Due to the rigidity of the skull, edema-induced increase of intracranial fluid significantly complicates severe CNS injuries by raising intracranial pressure and compromising perfusion. Mortality due to cerebral edema is high. With mortality rates up to 80% in severe cases of stroke, it is the leading cause of death within the first week. Similarly, cerebral edema is devastating for patients of TBI, accounting for up to 50% mortality. Currently, the available treatments for cerebral edema include hypothermia, osmotherapy, and surgery. However, these treatments only address the symptoms and often elicit adverse side effects, potentially in part due to non-specificity. There is an urgent need to identify effective pharmacological treatments for cerebral edema. Currently, ion channels represent the third-largest target class for drug development, but their roles in cerebral edema remain ill-defined. The present review aims to provide an overview of the proposed roles of ion channels and transporters (including aquaporins, SUR1-TRPM4, chloride channels, glucose transporters, and proton-sensitive channels) in mediating cerebral edema in acute ischemic stroke and TBI. We also focus on the pharmacological inhibitors for each target and potential therapeutic strategies that may be further pursued for the treatment of cerebral edema.

Rosmarinic acid exerts a neuroprotective effect on spinal cord injury by suppressing oxidative stress and inflammation via modulating the Nrf2/HO-1 and TLR4/NF-κB pathways

Spinal cord injury (SCI) is a severe central nervous system injury for which few efficacious drugs are available. Rosmarinic acid (RA), a water-soluble polyphenolic phytochemical, has antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the effect of RA on SCI is unclear. We investigated the therapeutic effect and underlying mechanism of RA on SCI. Using a rat model of SCI, we showed that RA improved locomotor recovery after SCI and significantly mitigated neurological deficit, increased neuronal preservation, and reduced apoptosis. Also, RA inhibited activation of microglia and the release of TNF-α, IL-6, and IL-1β and MDA. Moreover, proteomics analyses identified the Nrf2 and NF-κB pathways as targets of RA. Pretreatment with RA increased levels of Nrf2 and HO-1 and reduced those of TLR4 and MyD88 as well as phosphorylation of IκB and subsequent nuclear translocation of NF-κB-p65. Using H2O2– and LPS-induced PC12 cells, we found that RA ameliorated the H2O2-induced decrease in viability and increase in apoptosis and oxidative injury by activating the Nrf2/HO-1 pathway. Also, LPS-induced cytotoxicity and increased apoptosis and inflammatory injury in PC-12 cells were mitigated by RA by inhibiting the TLR4/NF-κB pathway. The Nrf2 inhibitor ML385 weakened the effect of RA on oxidant stress, inflammation and apoptosis in SCI rats, and significantly increased the nuclear translocation of NF-κB. Therefore, the neuroprotective effect on SCI of RA may be due to its antioxidant and anti-inflammatory properties, which are mediated by modulation of the Nrf2/HO-1 and TLR4/NF-κB pathways. Moreover, RA activated Nrf2/HO-1, which amplified its inhibition of the NF-κB pathway.

The Etiology of Neonatal Intensive Care Unit Death in Extremely Low Birth Weight Infants: A Multicenter Survey in China.

The aim of this study is to identify causes of neonatal intensive care unit (NICU) death in extremely low birth weight (ELBW) infants less than 1,000 g admitted in Chinese tertiary NICUs. We retrospectively collected data on 607 ELBW infants from 39 level III NICUs from July 2016 to June 2019. The primary causes of death were compared among different gestation age, postnatal age groups, and areas with variable economic status. Among all 607 ELBW NICU deaths, 47.1% were multiple gestation with high rate of in vitro fertilization (IVF) (43.3%); 53.4 and 34.1% received any or full course of antenatal corticosteroid (ACS). The most common causes of ELBW NICU death were respiratory distress syndrome-related neonatal respiratory failure (RDS-NRF, 43.5%), severe infection (19.1%), necrotizing enterocolitis or bowel perforation (9.4%), severe central nervous system injury (8.4%), and bronchopulmonary dysplasia-related respiratory failure (BPD-NRF, 7.7%). Causes of ELBW NICU death varied across postnatal age groups. RDS-NRF was the leading cause of early neonatal death, while severe infection in late neonatal death and BPD in postneonatal EBLW NICU death. RDS-NRF, severe brain injury, and asphyxia were most likely to die at early neonatal age (median age [interquartile range], 2 [0-5], 6 [3-9], and 3 [1-6] days, respectively) while severe infection and necrotizing enterocolitis (NEC) at late neonatal age, BPD-NRF at postneonatal age. In Chinese tertiary NICUs, the major causes of death in extremely low birth weight infants were RDS, infection, NEC, brain injury and BPD, and they varied with postnatal age. Developing specific prevention strategies for identified causes of death in ELBW NICU may potentially improve ELBW survival.