Comparative transcriptome analysis explored the molecular mechanisms of a luxR-type regulator regulating intracellular survival of Aeromonas hydrophila.

Aeromonas hydrophila is not a traditional intracellular bacterium. However, previous studies revealed that pathogenic A. hydrophila B11 could temporarily survive for at least 24 h in fish phagocytes, and the regulation of intracellular survival in bacteria was associated with regulators of the LuxR-type. The mechanisms of luxR08110 on the A. hydrophila's survival in macrophages were investigated using comprehensive transcriptome analysis and biological phenotype analysis in this study. The results showed that after luxR08110 was silenced, the intracellular survival ability of bacteria was significantly diminished. Comparative transcriptome analysis revealed that luxR08110 was a critical regulator of A. hydrophila, which regulated the expression of over 1200 genes, involving in bacterial flagellar assembly and chemotaxis, ribosome, sulphur metabolism, glycerolipid metabolism, and other mechanisms. Further studies confirmed that after the inhibition of expression of luxR08110, the motility, chemotaxis and adhesion of A. hydrophila significantly decreased. Moreover, compared with the wild-type strain, the survival rates of silencing strain were all considerably reduced under both H2O2 and low pH stress conditions. According to both transcriptome analysis and phenotypic tests, the luxR08110 of A. hydrophila could act as global regulator in bacteria intracellular survival. This regulator regulated intracellular survival of A. hydrophila mainly through two ways. One way is to regulate bacterial flagellar synthesis and further affects the motility, chemotaxis and adhesion of bacteria. The other way is to regulate sulphur and glycerolipid metabolisms, thus affecting bacterial energy production and the ability to resist environmental stress.

Rigorous coupled-wave analysis of unilateral Smith-Purcell radiation from asymmetric resonators.

The Smith-Purcell radiation produced by electrons moving closely to a grating can be enhanced by resonances. Here, we show a method to manipulate the directionality of the resonance-enhanced radiation. Using the rigorous coupled-wave analysis method, we compare the radiation from symmetric and asymmetric gratings, showing that the enhanced Smith-Purcell radiation can become unilateral with a perturbation that breaks the structural symmetry. Our work provides an effective method for frequency-domain calculation of Smith-Purcell radiation and also an approach to realize more efficient use of the radiation.

Targeted sequencing identifies risk variants in 202 candidate genes for neurodevelopmental disorders.

With the continuous deepening of genetic research on neurodevelopmental disorders (NDDs), more patients have been identified the causal or candidate genes. However, it is still urgent needed to increase the sample size to confirm the associations between variants and clinical manifestations. We previously performed molecular inversion probe sequencing of autism spectrum disorder (ASD) candidate genes in 1543 ASD patients. In this study, we used the same method to detect de novo variants (DNVs) in 665 NDD patients with intellectual disability (ID) and/or epilepsy (EP) for genetic analysis and diagnosis. We compared findings from ID/EP and ASD patients to improve our understanding of different subgroups of NDDs. We identified 72 novel variants and 39 DNVs. A totally of 5.71 % (38/665) of the patients were genetically diagnosed by this sequencing strategy. ID/EP patients demonstrated a higher prevalence of likely gene disruptive DNVs in ASD genes than the healthy population. Regarding high-risk genes, SCN1A and CKDL5 were more frequently mutated in ID/EP patients than in ASD patients. Our data provide an overview of the mutation burden in ID/EP patients from the perspective of high risk ASD genes, indicating the differences and association of NDDs subgroups.

Interleukin-4 Modulates Neuroinflammation by Inducing Phenotypic Transformation of Microglia Following Subarachnoid Hemorrhage.

Neuroinflammation, a key pathological feature following subarachnoid hemorrhage (SAH), can be therapeutically targeted by inhibiting microglia M1 polarization and promoting phenotypic transformation to M2 microglia. Interleukin-4 (IL-4) is a pleiotropic cytokine known to its regulation of physiological functions of the central nervous system (CNS) and mediate neuroinflammatory processes. However, its specific role in neuroinflammation and microglia responses following SAH remains unexplored. In this investigation, we established both in vivo and in vitro SAH models and employed a comprehensive array of assessments, including ELISA, neurofunctional profiling, immunofluorescence staining, qRT-PCR, determination of phagocytic capacity, and RNA-Seq analyses. The findings demonstrate an elevated expression of IL-4 within cerebrospinal fluid (CSF) subsequent to SAH. Furthermore, exogenous administration of IL-4 ameliorates post-SAH neurofunctional deficits, attenuates cellular apoptosis, fosters M2 microglia phenotype conversion, and mitigates neuroinflammatory responses. The RNA-Seq analysis signifies that IL-4 governs the modulation of neuroinflammation in microglia within an in vitro SAH model through intricate cascades of signaling pathways, encompassing interactions between cytokines and cytokine receptors. These discoveries not only augment comprehension of the neuropathogenesis associated with post-SAH neuroinflammation but also present novel therapeutic targets for the management thereof.

Gene therapy of adeno-associated virus (AAV) vectors in preclinical models of ischemic stroke.

Stroke has been associated with devastating clinical outcomes, with current treatment strategies proving largely ineffective. Therefore, there is a need to explore alternative treatment options for addressing post-stroke functional deficits. Gene therapy utilizing adeno-associated viruses (AAVs) as a critical gene vector delivering genes to the central nervous system (CNS) gene delivery has emerged as a promising approach for treating various CNS diseases. This review aims to provide an overview of the biological characteristics of AAV vectors and the therapeutic advancements observed in preclinical models of ischemic stroke. The study further investigates the potential of manipulating AAV vectors in preclinical applications, emphasizing the challenges and prospects in the selection of viral vectors, drug delivery strategies, immune reactions, and clinical translation.

[Factors influencing the efficacy of initial adrenocorticotropic hormone therapy for infantile epileptic spasms syndrome]. / é¦–æ¬¡ä¿ƒè‚¾ä¸Šè ºçš®è´¨æ¿€ç´ æ²»ç–—å©´å„¿ç™«ç—«ç—‰æŒ›ç»¼åˆå¾ç–—æ•ˆçš„å½±å“å› ç´ åˆ†æž.

OBJECTIVES: To study the factors influencing the short-term (28 days) efficacy of initial adrenocorticotropic hormone (ACTH) therapy for infantile epileptic spasms syndrome (IESS), as well as the factors influencing recurrence and prognosis. METHODS: The clinical data were collected from the children with IESS who received ACTH therapy for the first time in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from April 2008 to January 2018 and were followed up for ≥2 years. The multivariate logistic regression analysis was used to evaluate the factors influencing the short-term efficacy of ACTH therapy, recurrence, and long-term prognosis. RESULTS: ACTH therapy achieved a control rate of seizures of 55.5% (111/200) on day 28 of treatment. Of the 111 children, 75 (67.6%) had no recurrence of seizures within 12 months of follow-up. The possibility of seizure control on day 28 of ACTH therapy in the children without focal seizures was 2.463 times that in those with focal seizures (P<0.05). The possibility of seizure control on day 28 of ACTH therapy in the children without hypsarrhythmia on electroencephalography on day 14 of ACTH therapy was 2.415 times that in those with hypsarrhythmia (P<0.05). The possibility of recurrence within 12 months after treatment was increased by 11.8% for every 1-month increase in the course of the disease (P<0.05). The possibility of moderate or severe developmental retardation or death in the children without seizure control after 28 days of ACTH therapy was 8.314 times that in those with seizure control (P<0.05). The possibility of moderate or severe developmental retardation or death in the children with structural etiology was 14.448 times that in those with unknown etiology (P<0.05). CONCLUSIONS: Presence or absence of focal seizures and whether hypsarrhythmia disappears after 14 days of treatment can be used as predictors for the short-term efficacy of ACTH therapy, while the course of disease before treatment can be used as the predictor for recurrence after seizure control by ACTH therapy. The prognosis of IESS children is associated with etiology, and early control of seizures after ACTH therapy can improve long-term prognosis.

Administration of intramuscular AAV-BDNF and intranasal AAV-TrkB promotes neurological recovery via enhancing corticospinal synaptic connections in stroke rats.

Stroke causes long-term disability in survivors. BDNF/TrkB plays an important role in synaptic plasticity and synaptic transmission in the central nervous system (CNS), promoting neurological recovery. In this study, we performed non-invasive treatment methods focused on intramuscular injection into stroke-injured forelimb muscles, or intranasal administration using adeno-associated virus (AAV) vectors carrying genes encoding BDNF or TrkB. In a permanent rat middle cerebral artery occlusion (MCAO) model, we assessed the effects of combination therapy with AAV-BDNF and AAV-TrkB on motor functional recovery and synaptic plasticity of the corticospinal connections. Our results showed that BDNF or TrkB gene transduced in the spinal anterior horn neurons and cerebral cortical neurons. Compared to AAV vector treatment alone, behavioral and electrophysiological results showed that the combination therapy significantly improved upper limb motor functional recovery and neurotransmission efficiency after stroke. BDA tracing, immunofluorescence staining, qRT-PCR, and transmission electron microscopy of synaptic ultrastructure results revealed that the combination therapy not only potently increased the expression of Synapsin I, PSD-95, and GAP-43, but also promoted the axonal remodeling and restoration of abnormal synaptic structures. These findings provide a new strategy for enhancing neural plasticity and a potential means to treat stroke clinically.

NT157 inhibits cell proliferation and sensitizes glioma cells to TRAIL-induced apoptosis by up-regulating DR5 expression.

NT157, a small-molecule tyrosine kinase inhibitor, exhibits broad-spectrum anti-tumor activity. However, NT157-mediated inhibition against glioma has not been explored yet. Herein, the anticancer effects and underlying mechanism of NT157 against human giloma growth were evaluated. The results showed that NT157 alone significantly inhibited glioma cells growth in vitro by lunching cell cycle arrest through up-regulating p21 and p27, and down-regulating cell cycle-related factors. NT157 alone also induced significant glioma cells apoptosis, followed by PARP cleavage and caspase-3 activation. Our findings further revealed that NT157 triggered significant DNA damage and dysfunction of PI3K/AKT, MAPKs and EGFR-STAT3 signaling pathways. Addition of several kinases inhibitors effectively abrogated NT157-induced DR5 up-regulation, which further confirmed the significant role of DR5 pathway. Moreover, combined treatment of NT157 and TRAIL showed enhanced apoptosis against U251 and U87 cells. However, Knockdown of DR5 expression significantly attenuated combined treatment-induced PARP cleavage and caspase-3 activation. Importantly, combined administration of NT157 and TRAIL in vivo effectively inhibited glioma xenograft growth of nude mice by inhibiting cell proliferation and angiogenesis, and inducing DNA damage and apoptosis. Taken together, our findings validated the rational design that combined strategy of NT157 and TRAIL to trigger DNA damage and apoptosis by up-regulating DR5 could be a high efficient way to combat human glioma.

Novel HCN1 Mutations Associated With Epilepsy and Impacts on Neuronal Excitability.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel plays a critical role in regulating the resting membrane potential and integrating synaptic transmission. Variants of HCN1 have been recognized as causes of epilepsy, and mutant HCN1 channels could act with loss-of-function (LOF), loss- and gain-of-function (LOF and GOF) and gain-of-function (GOF) mechanisms. However, phenotypes and pathogenesis of HCN1-related epilepsy are still poorly understood. This study enrolled five epileptic cases carrying five different HCN1 variants: two pathogenic variants (I380F and S710Rfs*71), two likely pathogenic variants (E240G and A395G), and a paternally inherited variant (V572A). Four variants were novel. Electrophysiological experiments revealed impaired biophysical properties of the identified mutants, including current densities and activation/deactivation kinetics. Moreover, three variants exerted effects on the biophysical properties of wild-type HCN1 channels in heterozygous conditions. Immunofluorescence experiments showed that two variants reduced the protein expression of HCN1channels in neurons. Neurons expressing E240G (GOF) variant showed increased input resistance. However, the variant of I380F (LOF) increased the neuronal firing rate, thus leading to neuronal hyperexcitability. In conclusion, the present study expands the genotypic and phenotypic spectrum of patients with HCN1-related epilepsy and clarifies the underlying mechanisms. We reported five new cases including four unreported likely/pathogenic variants. We provided assessments of biophysical function for each variant, which could help patients to receive individual therapy in the future. We confirmed that HCN1 variants contributed to neuronal hyperexcitability by regulating input resistance and the action potential firing rate, and we have shown that they can affect protein expression in neurons for the first time.

Enhancement of Smith-Purcell radiation from cylindrical gratings by quasi-bound states in the continuum.

Smith-Purcell radiation (SPR) is an important means of generating terahertz waves, and the enhancement of SPR is an attractive topic nowadays. Inspired by the phenomenon of special SPR, where the enhancement is achieved by using a high-duty-cycle grating, we describe a new, to the best of our knowledge, but more effective approach to this challenging problem. By deriving a simple analytical solution for the SPR from an annular electron beam passing through a cylindrical metallic grating, we show that the inverse structure, a low-duty-cycle grating can exhibit rather high SPR efficiencies in the presence of quasi-bound states in the continuum (quasi-BICs). The analytical prediction is supported by particle-in-cell simulations, which show that the quasi-BICs can enhance the superradiant SPR generated by a train of electron bunches by orders of magnitude. These results present an interesting mechanism for enhancing the SPR from metallic gratings, and may find applications in terahertz free-electron lasers.

A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome.

FASTKD2 encodes an RNA-binding protein, which is a key post-transcriptional regulator of mitochondrial gene expression. Mutations in FASTKD2 have recently been found in mitochondrial encephalomyopathy, which is characterized by a deficiency in mitochondrial function. To date, seven patients have been reported. Six patients were identified with nonsense or frameshift mutations in the FASTKD2 gene, and only one patient harbored a missense mutation and a nonsense mutation. Here, we identified a novel FASTKD2 homozygous mutation, c.911 T > C, in a patient diagnosed with Lennox-Gastaut syndrome. We observed that the expression of FASTKD2 and the levels of mitochondrial 16 S rRNA were lower in the patient than in the unaffected controls. In conclusion, the missense mutation c.911 T > C caused loss of function in FASTKD2, which was associated with a new phenotype, Lennox-Gastaut syndrome.

Edaravone Dexborneol Treatment Attenuates Neuronal Apoptosis and Improves Neurological Function by Suppressing 4-HNE-Associated Oxidative Stress After Subarachnoid Hemorrhage.

Edaravone dexborneol is a novel neuroprotective drug that comprises edaravone and (+)-borneol in a 4:1 ratio. Phase II and III studies have demonstrated that Chinese patients treated with edaravone dexborneol within 48 h of AIS onset have better functional outcomes than those treated with edaravone alone. However, the effect of edaravone dexborneol on subarachnoid hemorrhage (SAH) has not yet been elucidated. This study aimed to investigate the therapeutic effects of edaravone dexborneol on SAH-induced brain injury and long-term behavioral deficits and to explore the possible mechanisms. The experimental rat SAH model was induced by an intraluminal puncture of the left middle cerebral artery (MCA). Edaravone dexborneol or edaravone at a clinical dose was infused into the tail vein for 3 days post-SAH surgery. Behavioral outcomes were assessed by a modified Garcia scoring system and rotarod, foot-fault, and corner tests. Immunofluorescence, Western blot, and ELISA methods were used to evaluate neuronal damage and oxidative stress. Our results showed that a post-SAH therapeutic regimen with edaravone dexborneol helped improve neurological function up to 21 days after SAH surgery and demonstrated a greater beneficial effect than edaravone alone, accompanied by an obvious inhibition of neuronal apoptosis in the CA1 hippocampus and basal cortex regions. Mechanistically, edaravone dexborneol not only suppressed the lipid peroxidation product malondialdehyde (MDA) but also improved the total antioxidant capability (TAC) 3 days after SAH. Notably, edaravone dexborneol treatment significantly inhibited the expression of another lipid peroxidation product, 4-hydroxynonenal (4-HNE), in the CA1 hippocampus and basal cortex, which are vital participants in the process of neuronal oxidative damage and death after SAH because of their acute cytotoxicity. Together, our results demonstrate that edaravone dexborneol confers neuroprotection and stabilizes long-term behavioral ability after SAH injury, possibly by suppressing 4-HNE-associated oxidative stress. These results may help develop new clinical strategies for SAH treatment.

Etiologic Classification of 541 Infantile Spasms Cases: A Cohort Study.

Objective: To explore the etiology of infantile spasms (IS) in a large Chinese cohort based on the United States National Infantile Spasms Consortium (NISC) classification. Methods: In the present study, we recruited IS patients diagnosed at a single center (Xiangya Hospital, Central South University) between Jan 2010 and Aug 2019. Thereafter, we collected their clinical and genetic information retrospectively. Their underlying etiologies were classified according to the NISC classification and then compared in different scenarios to understand their distribution. Results: A total of 541 patients with IS from 18 provinces were included in this study. The underlying etiology was identified in 53.2% of the cases: structural-acquired, 25.3%; genetic, 12.9%; genetic-structural, 7.2%; structural-congenital, 5.0%; metabolic, 2.4%; infections, 0.4% and immune, 0%. Whole-exome sequencing (WES) provided the highest diagnostic yield (26.9%). In structural-acquired IS, the proportion of hypoglycemic brain injuries was significant, second only to hypoxic-ischemic encephalopathy. There was no patient discovered to have Down syndrome. STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1 were the most frequently implicated genes. Genetic causes were found to be the most common cause of IS in the early onset group, while structural-acquired etiologies were common in males and preterm babies. Patients with pre-spasm seizures were associated with a higher proportion of identified causes than those without. Non-acquired structural etiologies were more common in patients without hypsarrhythmia than in those with hypsarrhythmia. Significance: The most prevalent cause of IS was structural acquired followed by genetic causes. When brain MRI fails to detect the etiology, we propose WES as the next step. Structural-acquired IS and cases with genetic disorders are characteristic of the Chinese cohort, however, the etiology differs with the patient's age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia.

Hormonal Therapy for Infantile Spasms: A Systematic Review and Meta-Analysis.

OBJECTIVE: The limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs. METHODS: EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs). RESULTS: A total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41-1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60-1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08-2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05-1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH. CONCLUSION: Our analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

Bioinformatics Analyses Reveal the Prognostic Value and Biological Roles of SEPHS2 in Various Cancers.

PURPOSE: Selenophosphate synthetase 2 (SEPHS2) has been shown to regulate selenoprotein biosynthesis by catalyzing the synthesis of active selenium donor selenophosphate. SEPHS2 influences the survival of tumor cells. However, few studies have explored the expression level and prognostic of SEPHS2 in various cancers. METHODS: The expression of SEPHS2 in human tumor tissues and normal adjacent tissues was analyzed in The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), and UALCAN databases. Cox regression analysis and Kaplan-Meier curve analysis were performed to analyze the association of SEPHS2 expression with the prognosis of cancer patients. The expression and prognosis of SEPHS2 in gliomas were further verified using the Chinese Glioma Genome Atlas (CGGA) dataset. The relationship between SEPHS2 and immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens was comprehensively explored using a TCGA cohort. The mechanism by which SEPHS2 regulates tumor progression was explored by using the STRING database. A nomogram was constructed using the R software to predict the overall survival (OS) of patients with brain lower grade glioma (LGG). RESULTS: SEPHS2 was highly expressed in many cancers including LGG. Its high expression was significantly associated with poor OS, disease-free survival (DFS), and progression-free survival (PFS). Univariate and multivariate Cox analyses showed that SEPHS2 was an independent prognostic factor for LGG. Concordance index and calibration curves revealed that the nomogram had good predictive performance (concordance index: 0.791; 95% CI: 0.732-1). A significant correlation was found between SEPHS2 and immune infiltration, TMB, MSI, and tumor neoantigens across diverse cancers. Enrichment analysis showed that SEPHS2 may regulate the PPAR signaling pathway. CONCLUSION: SEPHS2 expression regulates tumor development and it is a potential treatment target and prognostic biomarker, especially for lower grade glioma.

[Recurrence factors for myelin oligodendrocyte glycoprotein antibody disease in children and the effect of recurrence prevention regimens].

OBJECTIVE: To study the clinical features and recurrence factors of myelin oligodendrocyte glycoprotein (MOG) antibody disease in children and the effect of recurrence prevention regimens. METHODS: A retrospective analysis was performed on the medical data of 41 children with MOG antibody disease who were hospitalized in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from December 2014 to September 2020. According to the presence or absence of recurrence, they were divided into a monophasic course group (n=19) and a recurrence group (n=22). According to whether preventive treatment for recurrence was given, the children with recurrence were further divided into a preventive treatment group and a non-preventive treatment group. The clinical features were analyzed for all groups, and the annualized relapse rate (ARR) was compared before and after treatment with prevention regimens. RESULTS: For these 41 children, acute disseminated encephalomyelitis was the most common initial manifestation and was observed in 23 children (56%). Of the 41 children, 22 (54%) experienced recurrence, with 57 recurrence events in total, among which optic neuritis was the most common event (17/57, 30%). The proportion of children in the recurrence group who were treated with corticosteroids for less than 3 months in the acute phase was higher than that in the monophasic course group (64% vs 32%; P < 0.05). There was no significant difference in the ARR between the preventive treatment and non-preventive treatment groups (P > 0.05). The assessment of preventive treatment regimens for 32 cases showed that the children treated with rituximab or azathioprine had a significant reduction in the ARR during treatment (P < 0.05). CONCLUSIONS: More than half of the children with MOG antibody disease may experience recurrence. Most children with recurrence are treated with corticosteroids for less than 3 months in the acute phase. Rituximab and azathioprine may reduce the risk of recurrence.

Carbonyl Reductase 1 Attenuates Ischemic Brain Injury by Reducing Oxidative Stress and Neuroinflammation.

Oxidative stress and neuroinflammatory response after the ischemic injury are important pathophysiologic mechanisms that cause brain tissue loss and neurological deficit. This study aims to observe the expression and role of carbonyl reductase 1 (CBR1), an NADPH-dependent oxidoreductase with specificity for carbonyl compounds such as 4-hydroxynonenal (4-HNE), in the brain after ischemic injury and to investigate the influence of CBR1 on ischemia-induced neuroinflammation. CBR1 expresses in the neurons, astrocyte, and microglia in the normal brain. The expression of CBR1 decreased in the ischemic regions following cerebral ischemia, and also reduced in primary neurons after OGD (oxygen-glucose deprivation); however, the expression of CBR1 significantly increased in microglia in the ischemic penumbra. Furthermore, TAT-CBR1 fusion protein played neuroprotective effects in reducing the infarct volume and improving neurological outcomes after ischemic injury. Mechanistically, CBR1 decreased the levels of 4-HNE in the brain after stroke; it also modulated microglial polarization toward the M2 phenotype, which was well-known to confer neuroprotection after ischemic injury. Our results demonstrate that CBR1 provides neuroprotection against ischemic injury by reducing oxidative stress and neuroinflammation, making a promising agent for cerebral ischemia treatment.

Low-Dose IL-2 Treatment Affords Protection against Subarachnoid Hemorrhage Injury by Expanding Peripheral Regulatory T Cells.

Subarachnoid hemorrhage (SAH) is considered a devastating disease, leaving survivors with lifelong neurological impairment. With increased knowledge that regulatory T cells (Tregs) provide protection against stroke, novel agents which could expand Treg populations have been assessed in terms of the potential clinical neuroprotection effect. Using a rat SAH model, we investigated the number variation of Tregs induced by SAH and the protective effect of low-dose interleukin-2 (IL-2) treatment on the SAH model. We observed that the number of peripheral Tregs significantly decreased soon after SAH, accompanying with reactivity recovery after 3 days. Our results also revealed that low-dose IL-2 treatment not only elevated Tregs numbers but significantly reduced neuronal injury and improved neurological functions up to 21 days (d) after SAH. Furthermore, compared with PBS-treatment group, cerebral proinflammatory factors and peripheral neutrophils were significantly suppressed by low-dose IL-2 after SAH. Therefore, the results suggest that low-dose IL-2 treatment is a novel and clinically feasible immunotherapy to improve long-term outcomes after SAH, perhaps via up-regulating Treg population to suppress neuroinflammation induced by SAH.

Ethyl pyruvate improves white matter remodeling in rats after traumatic brain injury.

BACKGROUND: Severe traumatic brain injury (TBI) results in long-term neurological deficits associated with white matter injury (WMI). Ethyl pyruvate (EP) is a simple derivative of the endogenous energy substrate pyruvate with neuroprotective properties, but its role in recovery from WMI has not been explored. AIMS: This study examines the effect of EP treatment on rats following TBI using behavioral tests and white matter histological analysis up to 28 days post-injury. MATERIALS AND METHODS: Anaesthetised adult rats were subjected to TBI by controlled cortical impact. After surgery, EP or Ringers solution (RS) was administrated intraperitoneally at 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Sensorimotor deficits were evaluated up to day 21 after TBI by four independent tests. Immunofluorescence and transmission electron microscopy (TEM) were performed to assess white matter injury. Microglia activation and related inflammatory molecules were examined up to day 14 after TBI by immunohistochemistry or real-time PCR. RESULTS: Here, we demonstrate that EP improves sensorimotor function following TBI as well as improves white matter outcomes up to 28 d after TBI, as shown by reduced myelin loss. Furthermore, EP administration during the acute phase of TBI recovery shifted microglia polarization toward the anti-inflammatoryM2 phenotype, modulating the release of inflammatory-related factors. CONCLUSION: EP treatment may protect TBI-induced WMI via modulating microglia polarization toward M2.