Naoxueshu Oral Liquid Accelerates Post-Craniotomy Hematoma Absorption in Patients: An Open-Label, Multicenter, and Randomized Controlled Trial.

OBJECTIVE: To investigate whether Naoxueshu Oral Liquid (NXS) could promote hematoma absorption in post-craniotomy hematoma (PCH) patients. METHODS: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18-80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS (10 mL thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage (ICH). RESULTS: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients (60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set (FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median (Q1, Q3): 85% (71%, 97%) vs. 76% (53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set (P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH (all P<0.05). CONCLUSIONS: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics. (Registration No. ChiCTR1800017981).

Serum IL-6 level trajectory for predicting the effectiveness and safety of tocilizumab in the treatment of refractory Takayasu arteritis.

AIM: To explore the value of serial monitoring of serum interleukin-6 (IL-6) levels for predicting treatment response and occurrence of adverse events during tocilizumab (TCZ) treatment in refractory Takayasu arteritis (TAK). METHODS: TAK patients receiving TCZ treatment were prospectively recruited and followed up at 1 month, 3 months and then every 3-6 months. Serum IL-6 levels were measured at each visit. Overall response was the combination of complete and partial response, requiring resolution of signs and symptoms, hsCRP and ESR level decreased at least by half, no progression on imaging and dose of glucocorticoid <15 mg/d. RESULTS: Thirty-five patients with a median follow up duration of 17 [9-44] months were included. The change of IL-6 after TCZ treatment for 6 months compared to the baseline was significantly lower in patients achieved overall response at 6, 12, 18 and 24 months. The ratio of IL-6 at 6 months to baseline could predict overall response at 12 and 24 months after TCZ treatment. With a cutoff value of 1.6, the sensitivity and specificity were 83.3 % and 87.5 % for 12 months, while 100 % and 88.9 % for 24 months. Patients with the ratio less than 1.6 were also 9 times more likely to achieve sustained improvement without treatment intensification. No correlation between IL-6 dynamics and occurrence of adverse events was found. CONCLUSIONS: The change of IL-6 levels after TCZ treatment for 6 months compared to the baseline can predict the overall treatment response at 12 months, 24 months and sustained improvement.

TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia.

BACKGROUND: White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor-2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. METHODS: Controlled cortical injury was induced in both wild-type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism-related genes, while western blot was conducted to validate the findings. RESULTS: TREM2 expressed highest at 3 days post-TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities. CONCLUSIONS: We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

Exosomal LncRNA TM7SF3-AU1 Aggravates White Matter Injury via MiR-702-3p/SARM1 Signaling After Subarachnoid Hemorrhage in Rats.

Subarachnoid hemorrhage (SAH) is a devastating disease associated with a high mortality and morbidity. Exosomes have been considered as a potential therapeutic target for SAH. However, the effect of exosomes in SAH remains to be elucidated. In this study, we focused on investigating the effect of plasma exosomal lncRNA TM7SF3-AU1 in white matter injury after SAH. The SAH model was established by means of endovascular perforation. Exosomes were extracted from rat plasma samples. The expression of RNAs in the exosomes was detected by the transcriptomic microarray. Differentially expressed circRNA, lncRNA, and mRNA were obtained. The ceRNA network showed that the lncRNA TM7SF3-AU1 and miR-702-3p were closely associated with SARM1. Knocking down TM7SF3-AU1 promoted the expression of miR-702-3p and suppressed the expression of SARM1, and knocking down TM7SF3-AU1 also attenuated white matter injury after SAH. In addition, knocking down TM7SF3-AU1 improved the neurological deficits in locomotion, anxiety, learning, memory, and electrophysiological activity after SAH. Mechanistically, TM7SF3-AU1 was able to absorb miR-702-3p, which directly bind the SARM1 mRNA. Furthermore, the white matter injury attenuated by knockdown of TM7SF3-AU1 was partially reversed by the miR-702-3p antagomir in SAH rats. Taken together, this study showed that TM7SF3-AU1 acts as a sponge for miR-702-3p, reducing the inhibitory effect of miR-702-3p on SARM1, resulting in increased SARM1 expression and thus leading to white matter injury after SAH. Our study provides new insights into exosome-associated white matter injury. It also highlights TM7SF3-AU1 as a potential therapeutic target for white matter injury after SAH.

Genome-wide identification of long non-coding RNAs and their potential functions in radish response to salt stress.

Long non-coding RNAs (lncRNAs) are increasingly recognized as cis- and trans-acting regulators of protein-coding genes in plants, particularly in response to abiotic stressors. Among these stressors, high soil salinity poses a significant challenge to crop productivity. Radish (Raphanus sativus L.) is a prominent root vegetable crop that exhibits moderate susceptibility to salt stress, particularly during the seedling stage. Nevertheless, the precise regulatory mechanisms through which lncRNAs contribute to salt response in radish remain largely unexplored. In this study, we performed genome-wide identification of lncRNAs using strand-specific RNA sequencing on radish fleshy root samples subjected to varying time points of salinity treatment. A total of 7,709 novel lncRNAs were identified, with 363 of them displaying significant differential expression in response to salt application. Furthermore, through target gene prediction, 5,006 cis- and 5,983 trans-target genes were obtained for the differentially expressed lncRNAs. The predicted target genes of these salt-responsive lncRNAs exhibited strong associations with various plant defense mechanisms, including signal perception and transduction, transcription regulation, ion homeostasis, osmoregulation, reactive oxygen species scavenging, photosynthesis, phytohormone regulation, and kinase activity. Notably, this study represents the first comprehensive genome-wide analysis of salt-responsive lncRNAs in radish, to the best of our knowledge. These findings provide a basis for future functional analysis of lncRNAs implicated in the defense response of radish against high salinity, which will aid in further understanding the regulatory mechanisms underlying radish response to salt stress.

Inhibition of GPR17/ID2 Axis Improve Remyelination and Cognitive Recovery after SAH by Mediating OPC Differentiation in Rat Model.

Myelin sheath injury contributes to cognitive deficits following subarachnoid hemorrhage (SAH). G protein-coupled receptor 17 (GPR17), a membrane receptor, negatively regulates oligodendrocyte precursor cell (OPC) differentiation in both developmental and pathological contexts. Nonetheless, GPR17's role in modulating OPC differentiation, facilitating remyelination post SAH, and its interaction with downstream molecules remain elusive. In a rat SAH model induced by arterial puncture, OPCs expressing GPR17 proliferated prominently by day 14 post-onset, coinciding with compromised myelin sheath integrity and cognitive deficits. Selective Gpr17 knockdown in oligodendrocytes (OLs) via adeno-associated virus (AAV) administration revealed that reduced GPR17 levels promoted OPC differentiation, restored myelin sheath integrity, and improved cognitive deficits by day 14 post-SAH. Moreover, GPR17 knockdown attenuated the elevated expression of the inhibitor of DNA binding 2 (ID2) post-SAH, suggesting a GPR17-ID2 regulatory axis. Bi-directional modulation of ID2 expression in OLs using AAV unveiled that elevated ID2 counteracted the restorative effects of GPR17 knockdown. This resulted in hindered differentiation, exacerbated myelin sheath impairment, and worsened cognitive deficits. These findings highlight the pivotal roles of GPR17 and ID2 in governing OPC differentiation and axonal remyelination post-SAH. This study positions GPR17 as a potential therapeutic target for SAH intervention. The interplay between GPR17 and ID2 introduces a novel avenue for ameliorating cognitive deficits post-SAH.

National Brain Tumour Registry of China (NBTRC) statistical report of primary brain tumours diagnosed in China in years 2019-2020.

Background: The lack of a well-designed brain tumour registry with standardized pathological diagnoses in underdeveloped countries hinders the ability to compare epidemiologic data across the globe. The National Brain Tumour Registry of China (NBTRC), created in January 2018, is the first multi-hospital-based brain tumour registry in China. Patient data reported to the NBTRC in years 2019-2020 were assessed. Methods: Tumour pathology was based on the 2016 World Health Organization (WHO) classification of tumours of the central nervous system and ICD-O-3. The anatomical site was coded per the Surveillance, Epidemiology, and End Results (SEER) solid tumour module (version of July 2019). The cases were tabulated by histology and anatomical site. Categorical variables were reported as numbers (percentages). The distribution of tumours by age (0-14, 15-19, 20-39, 40-64, and 65+ years) was analysed. Findings: There were a total of 25,537 brain tumours, foremost among them meningioma (23.63%), followed by tumours of the pituitary (23.42%), and nerve sheath tumours (9.09%). Glioblastoma, the most common and lethal form of primary brain cancer in adults, represented 8.56% of all cases. Of note, 6.48% of the malignant tumours were located in the brain stem. The percentage of malignant brain tumours decreased with increasing age, 24.08% in adults (40+ years), 30.25% in young adults (20-39 years), 35.27% in adolescents (15-19 years), and 49.83% in children (0-14 years). Among the 2107 paediatric patients, the most common sites were ventricle (17.19%), brainstem (14.03%), pituitary and craniopharyngeal duct (13.4%), and cerebellum (12.3%), a distribution that differed from that of the entire cohort. The histology distribution was also unique in children, with glioblastoma much less incident compared to the whole cohort (3% vs. 8.47%, p < 0.01). 58.80% of all patients chose higher-level neurosurgical hospitals outside of their province of residence. The median in-hospital length of stay (LOS) for the various pathologies ranged from 11 to 19 days. Interpretation: The histological and anatomical site distribution of brain tumours in the NBTRC was statistically different in the subgroup of children (0-14 years). Patient choice of pursuing trans-provincial treatment was common and the in-hospital LOS was longer compared to that reported in similar European and American patient populations, which merits further attention. Funding: The National Key Research and Development Program of China (2015BAI12B04, 2013BAI09B03, 2014BAI04B01, and 2021YFF1201104) and Chinese National Natural Science Foundation of China (81971668).

Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF-κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.

Incidence and risk factors of tuberculosis in systemic lupus erythematosus patients: a multi-center prospective cohort study.

Objectives: Both burdens of tuberculosis (TB) and systemic lupus erythematosus (SLE) in China are ranked as top three in the world. SLE patients are at high risk for TB, but so far, there are no guidelines for TB prevention and management targeting this population in China. This study aims to investigate the incidence of active tuberculosis (ATB) and to explore the risk factors for developing ATB in SLE patients, and to provide evidence for TB prevention and management for SLE patients in China. Methods: A multi-center prospective cohort study was conducted. SLE patients were enrolled from clinics and wards of 13 tertiary hospitals in Eastern, Middle, and Western China from September 2014 to March 2016. Baseline demographic features, TB infection status, clinical information, and laboratory data were collected. ATB development was examined during follow-up visits. Kaplan-Meier method was applied to plot survival curves, and Log-rank test was used to evaluate differences. Cox proportional-hazards model was used to explore the risk factors for ATB development. Results: With a median follow-up time of 58 months [interquartile range (IQR): 55-62], 16 out of 1361 SLE patients developed ATB. The 1-year incidence of ATB was 368 [95% confidence interval (CI): 46-691] per 100,000. Over a 5-year period, the cumulative incidence of ATB was 1141 [95% CI: 564-1718] per 100,000, and the incidence density was 245 per 100,000 person-years. Cox regression models were constructed with maximum daily dose of glucocorticoids (GCs) as a continuous variable and a categorical variable, respectively. In model 1, maximum daily dose of GCs (pills per day) [adjusted hazard ratio (aHR)=1.16, 95%CI: 1.04-1.30, p=0.010] and TB infection (aHR=8.52, 95%CI: 3.17-22.92, p<0.001) were independent risk factors for ATB development. In model 2, maximum daily dose of GCs≥30 mg/d (aHR =4.81, 95%CI: 1.09-22.21, P=0.038) and TB infection (aHR=8.55, 95%CI: 3.18-23.00, p<0.001] were independent risk factors for ATB development. Conclusions: SLE patients had a higher incidence of ATB compared to the general population. The risk of developing ATB was even higher with increased daily dose of GCs or in a status of TB infection, in which case TB preventive treatment should be considered.

Spatio-Temporal Analysis of Marine Water Quality Data Based on Cross-Recurrence Plot (CRP) and Cross-Recurrence Quantitative Analysis (CRQA).

In recent years, with the frequency of marine disasters, water quality has become an important environmental problem for researchers, and much effort has been put into the prediction of marine water quality. The temporal and spatial correlation of marine water quality parameters directly determines whether the marine time-series data prediction task can be completed efficiently. However, existing research has only focused on the correlation analysis of marine data in a certain area and has ignored the temporal and spatial characteristics of marine data in complex and changeable marine environments. Therefore, we constructed a spatio-temporal dynamic analysis model of marine water quality based on a cross-recurrence plot (CRP) and cross-recurrence quantitative analysis (CRQA). The time-series data of marine water quality were first mapped to high-dimensional space through phase space reconstruction, and then the dynamic relationship among various factors affecting water quality was visually displayed through CRP. Finally, their correlation was quantitatively explained by CRQA. The experimental results showed that our scheme demonstrated well the dynamic correlation of various factors affecting water quality in different locations, providing important data support for the spatio-temporal prediction of marine water quality.

Effects of apolipoprotein E polymorphism on cerebral oxygen saturation, cerebral perfusion, and early prognosis after traumatic brain injury.

OBJECTIVE: To investigate the effects of the apolipoprotein E (APOE) gene on oxygen saturation and cerebral perfusion in the early stages of traumatic brain injury (TBI). METHODS: This study included 136 consecutive TBI patients and 51 healthy individuals. The APOE genotypes of all subjects were determined using quantitative fluorescence polymerase chain reaction (QF-PCR). Regional cerebral oxygen saturation (rScO2) of patients with TBI and normal subjects was monitored using near-infrared spectroscopy (NIRS). Computed tomography (CT) perfusion was used to obtain cerebral perfusion in patients with TBI and normal subjects. RESULTS: In the TBI group, the rScO2 of APOEε4 carriers (53.06 ± 6.87%) was significantly lower than that of non-carriers (58.19 ± 5.83%, p < 0.05). Meanwhile, the MTT of APOEε4 carriers (6.75 ± 1.30 s) was significantly longer than that of non-carriers (5.87 ± 1.00 s, p < 0.05). Furthermore, correlation analysis showed a negative correlation between rSCO2 and MTT in patients with TBI. Both the univariate and multifactorial logistic regression analyses revealed that APOE ε4, hypoxia, MTT >5.75 s, Marshall CT Class, and GCS were independent risk factors for early poor prognosis in patients with TBI. CONCLUSION: Both cerebral perfusion and cerebral oxygen were significantly impaired after TBI, and low cerebral perfusion and hypoxia were related to poor prognosis of patients with TBI. Compared with APOE ε4 non-carriers, APOE ε4 carriers not only had poorer cerebral perfusion and cerebral oxygen metabolism but also worse prognosis in the early stages of TBI. Furthermore, a negative correlation was observed between the rSCO2 and MTT levels. In addition, both CT perfusion scanning (CTP) and NIRS are reliable for monitoring the condition of patients with TBI in the neurological intensive care unit (NICU).

System analysis based on the migration- and invasion-related gene sets identifies the infiltration-related genes of glioma.

The current database has no information on the infiltration of glioma samples. Here, we assessed the glioma samples' infiltration in The Cancer Gene Atlas (TCGA) through the single-sample Gene Set Enrichment Analysis (ssGSEA) with migration and invasion gene sets. The Weighted Gene Co-expression Network Analysis (WGCNA) and the differentially expressed genes (DEGs) were used to identify the genes most associated with infiltration. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the major biological processes and pathways. Protein-protein interaction (PPI) network analysis and the least absolute shrinkage and selection operator (LASSO) were used to screen the key genes. Furthermore, the nomograms and receiver operating characteristic (ROC) curve were used to evaluate the prognostic and predictive accuracy of this clinical model in patients in TCGA and the Chinese Glioma Genome Atlas (CGGA). The results showed that turquoise was selected as the hub module, and with the intersection of DEGs, we screened 104 common genes. Through LASSO regression, TIMP1, EMP3, IGFBP2, and the other nine genes were screened mostly in correlation with infiltration and prognosis. EMP3 was selected to be verified in vitro. These findings could help researchers better understand the infiltration of gliomas and provide novel therapeutic targets for the treatment of gliomas.

Targeting GPR133 via miR-106a-5p inhibits the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of glioma cells.

Background: Glioma is the most common malignant brain tumor. GPR133 is a key factor in the progression of glioma. However, the role of GPR133 in glioma invasion and EMT and the microRNAs (miRNAs) associated with this pathway are still poorly understood.Objective: This study aims to elucidate the biological function of miR-106a-5p and GPR133 in glioma as well as the molecular mechanism of their interaction.Methods: The mRNA expression of miR-106a-5p and GPR133 in glioma specimens and cells was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The protein level of GPR133 and the levels of invasion- and EMT-related proteins were measured by western blotting. miR-106a-5p and GPR133 function in glioma cells was determined through cell counting kit-8 (CCK-8), transwell, wound healing, colony formation assays in vitro and xenograft assays in vivo. To determine the targeting relationship between miR-106a-5p and GPR133, a dual-luciferase reporter assay was conducted.Results: A marked reduction in miR-106a-5p expression was observed in glioma cells and specimens. Patients with high expression of miR-106a-5p had a good prognosis, while patients with high expression of GPR133 had a shorter OS. Additionally, overexpression of miR-106a-5p or downregulation of GPR133 inhibited the progression of glioma cells. Furthermore, miR-106a-5p negatively regulated GPR133 expression by binding to its 3'-UTR, and restrained the invasion, migration, proliferation and EMT of glioma cells by targeting GPR133.Conclusions: miR-106a-5p is a tumor suppressor that negatively regulates GPR133. The miR-106a-5p/GPR133 axis could potentially serve as a therapeutic target for glioma.

Electroacupuncture alleviates early brain injury via modulating microglia polarization and suppressing neuroinflammation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage refers to an uncommon but severe subtype of stroke leading to high mortality and disability rates. Electroacupuncture, a traditional Chinese medical therapy combined with modern technology, shows evident curative effects on cerebral vascular diseases. This study attempts to investigate the possible treatment effects and mechanisms of EA on early brain injury after SAH. Data were gathered among sham group, SAH-induced group, and EA-treated group of male SD rats, concerning mortality rates, weight loss, rotarod latencies, cerebral blood flow, cell apoptosis, pro-inflammatory cytokines releasing, apoptotic protein level, microglia activation and related signal pathway. All results were collected 24-72 h after SAH induction. EA treatment demonstrated significant improvement on motor function 24 h after SAH without significant changes in mortality rate, weight loss, and cerebral blood flow. Another important finding was that EA regulated Bax and Bcl-2 imbalance and reduced cleaved casepase-3 caused by SAH. Additionally, levels of TNF-α, IL-1ß, IL-6 were suppressed. The neuron apoptosis was suppressed by EA. The M1 polarization of activated microglia decreased while M2 polarized phenotype increased after EA treatment. Furthermore, pSTAT3-NOX2 signal axis, the M1 phenotype related activation pathway, was depressed after EA treatment. These findings suggested that EA improved motor deficits and ameliorated early brain injury after SAH probably via decreasing neuron apoptosis and anti-inflammation, which may involve modulation of microglia polarization. Taken together, EA may be a potential therapy for SAH treatment.

Role of LDL-C level alteration in increased mortality risks in spontaneous intracerebral hemorrhage patients: Systematic review and meta-analysis.

Background: Current studies indicate a contradictory relationship between decreased mortality risks of spontaneous intracerebral hemorrhage (sICH) and elevated low-density lipoprotein cholesterol (LDL-C) levels. Thus, this meta-analysis was designed to examine the involvement of high LDL-C levels in a lower mortality risk of sICH patients. Methods: PubMed, Cochrane, and Embase databases were searched up to the date of August 3rd, 2022. Pooled odds ratio (OR) with a 95% confidence interval (CI) was estimated for the higher vs. lower serum LDL-C level groups. Subgroup and sensitivity analyses were also carried out. Egger's test was applied to detect any potential publication bias. Results: Of 629 citations reviewed, 8 eligible cohort studies involving 83,013 patients were enrolled in this meta-analysis. Compared with lower serum LDL-C levels containing patients, higher serum LDL-C patients exhibited significantly decreased risks of 3-month mortality (OR: 0.51; 95%CI: 0.33-0.78; I2 = 47.8%); however, the LDL-C level change wasn't significantly associated with in-hospital mortality risks (OR: 0.92; 95%CI: 0.63-1.33; I2 = 91.4%) among sICH subjects. All studies included were classified as high-quality investigations. Conclusions: This meta-analysis suggests a higher LDL-C level may decrease the mortality risk in sICH patients. LDL-C level increase is inversely associated with the 3-month mortality risks in these patients but not significantly correlated with the in-hospital mortality risks. Further well-designed prospective studies with extended follow-up periods are needed to confirm these findings and explore underlying cross-talks. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022318318, identifier: PROSPERO 2022 CRD42022318318.

CCL26 in primary biliary cholangitis - Is it a novel disease mediator?

AIM: To verify the role of CX3C chemokine ligand 1 - CX3C chemokine receptor 1 (CX3CL1-CX3CR1) pathway in the pathogenesis of primary biliary cholangitis (PBC). To explore whether CCL26, a novel functional ligand to CX3CR1, participates in the immunological mechanism of PBC. METHODS: Fifty-nine PBC patients and 54 healthy controls were recruited. Enzyme-linked immunosorbent assay and flow cytometry were used to measure CX3CL1 and CCL26 concentrations in plasma and CX3CR1 expression on peripheral lymphocytes, respectively. Chemotactic effects of CX3CL1 and CCL26 toward lymphocytes were detected by Transwell cell migration assays. CX3CL1 and CCL26 expressions in liver were assessed by immunohistochemical staining. Effects of CX3CL1 and CCL26 on stimulating cytokine production from lymphocytes were evaluated using intracellular flow cytometry. RESULTS: Significantly elevated CX3CL1 and CCL26 plasma concentration and CX3CR1 expression on CD4+ and CD8+ T cells were noted in PBC patients. CX3CL1 exhibited chemotactic activity toward CD8+ T, natural killer (NK) and NKT cells in a dose-dependent manner while such chemotactic effects were not detected for CCL26. In PBC patients, CX3CL1 and CCL26 were both increasingly expressed in biliary tracts and a concentration gradient of CCL26 in hepatocytes around portal areas was observed. Immobilized CX3CL1 could enhance interferon-γ production from T and NK cells while such effect was not exhibited by soluble CX3CL1 or CCL26. CONCLUSIONS: CCL26 expression is significantly elevated in plasma and biliary duct of PBC patients, yet does not appear to attract CX3CR1-expressing immune cells. CX3CL1-CX3CR1 pathway promotes the infiltration of T, NK and NKT cells into bile ducts and forms a positive feedback loop with T-helper 1 type cytokines in PBC.

Neuroblasts migration under control of reactive astrocyte-derived BDNF: a promising therapy in late neurogenesis after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a disease with high mortality and morbidity, which leads to severe neurological dysfunction. Neurogenesis has provided therapeutic options for treating TBI. Brain derived neurotrophic factor (BDNF) plays a key role in neuroblasts migration. We aimed to investigate to the key regulating principle of BDNF in endogenous neuroblasts migration in a mouse TBI model. METHODS: In this study, controlled cortical impact (CCI) mice (C57BL/6J) model was established to mimic TBI. The sham mice served as control. Immunofluorescence staining and enzyme-linked immunosorbent assay were performed on the CCI groups (day 1, 3, 7, 14 and 21 after CCI) and the sham group. All the data were analyzed with Student's t-test or one-way or two-way analysis of variance followed by Tukey's post hoc test. RESULTS: Our results revealed that neuroblasts migration initiated as early as day 1, peaking at day 7, and persisted till day 21. The spatiotemporal profile of BDNF expression was similar to that of neuroblasts migration, and BDNF level following CCI was consistently higher in injured cortex than in subventricular zone (SVZ). Reactive astrocytes account for the major resource of BDNF along the migrating path, localized with neuroblasts in proximity. Moreover, injection of exogenous CC chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, at random sites promoted neuroblasts migration and astrocytic BDNF expression in both normal and CCI mice (day 28). These provoked neuroblasts can also differentiate into mature neurons. CC chemokine ligand receptor 2 antagonist can restrain the neuroblasts migration after TBI. CONCLUSIONS: Neuroblasts migrated along the activated astrocytic tunnel, directed by BDNF gradient between SVZ and injured cortex after TBI. CCL2 might be a key regulator in the above endogenous neuroblasts migration. Moreover, delayed CCL2 administration may provide a promising therapeutic strategy for late neurogenesis post-trauma.

The Association of LDH Expression and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: Possible Involvement of Cerebral Blood Perfusion.

BACKGROUND AND PURPOSE: Several pieces of evidence suggest that serum lactate hydrogenase (LDH) level is associated with the pathological process of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). This research aimed to investigate the associations of serum LDH level with the occurrence of DCI in aSAH patients. METHODS: A total of 122 patients diagnosed with aSAH within 72h of onset were retrospectively enrolled. The serum levels of LDH between 7:00-8:00 am on day 1, day 3 and day 7, patients' demographics, and clinical features were collected. Computed tomography perfusion was performed within 7 days after aSAH. The occurrence of DCI was recorded during the hospitalization. RESULTS: Among all the enrolled patients, 43 (35.2%) developed DCI during hospitalization. Patients occurred DCI were always accompanied by more serious clinical features and found with higher serum LDH levels. LDH levels on day 3 and day 7 after onset were independently associated with the occurrence of DCI and showed high predictive value according to the receiver operating characteristic (ROC) curve. Moreover, there was a strong correlation between LDH and mean cerebral blood flow, transit time, and mean time to peak. CONCLUSION: Serum LDH level on day 3 and day 7 may be a valuable, convenient, and rapid predictive indicator for the occurrence of DCI in aSAH patients.

Electroacupuncture promotes remyelination and alleviates cognitive deficit via promoting OPC differentiation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating cerebral vascular disease which causes neurological deficits including long-term cognitive deficit. Demyelination of white matter is correlated with cognitive deficit in SAH. Electroacupuncture (EA) is a traditional Chinese medical treatment which protects against cognitive deficit in varies of neurological diseases. However, whether EA exerts protective effect on cognitive function in SAH has not been investigated. The underlying mechanism of remyelination regulated by EA remains unclear. This study aimed to investigate the protective effects of EA on cognitive deficit in a rat model of SAH. SAH was induced in SD rats (n = 72) by endovascular perforation. Rats in EA group received EA treatment (10 min per day) under isoflurane anesthesia after SAH. Rats in SAH and sham groups received the same isoflurane anesthesia with no treatment. The mortality rate, neurological score, cognitive function, cerebral blood flow (CBF), and remyelination in sham, SAH and EA groups were assessed at 21 d after SAH.EA treatment alleviated cognitive deficits and myelin injury of rats compared with that in SAH group. Moreover, EA treatment enhanced remyelination in white matter and promoted the differentiation of OPCs after SAH. EA treatment inhibited the expression of Id2 and promoted the expression of SOX10 in oligodendrocyte cells. Additionally, the cerebral blood flow (CBF) of rats was increased by EA compared with that in SAH group. EA treatment exerts protective effect against cognitive deficit in the late phase of SAH. The underlying mechanisms involve promoting oligodendrocyte progenitor cell (OPC) differentiation and remyelination in white matter via regulating the expression of Id2 and SOX10. The improvement of CBF may also account for the protective effect of EA on cognitive function. EA treatment is a potential therapy for the treatment of cognitive deficit after SAH.

EphA4/EphrinB2 signaling mediates pericyte-induced transient glia limitans formation as a secondary protective barrier after subarachnoid hemorrhage in mice.

BACKGROUND: Most patients with subarachnoid hemorrhage (SAH) do not exhibit brain parenchymal injury upon imaging but present significant blood-brain barrier (BBB) disruption and secondary neurological deficits. The aim of this study was to investigate whether stressed astrocytes act as a secondary barrier to exert a protective effect after SAH and to investigate the mechanism of glial limitan formation. METHODS: A total of 204 adult male C57BL/6 mice and an endovascular perforation SAH model were employed. The spatiotemporal characteristics of glial limitan formation after SAH were determined by immunofluorescence staining and transmission electron microscopy. The molecular mechanisms by which pericytes regulate glia limitans formation were analyzed using polymerase chain reaction, Western blotting, immunofluorescence staining and ELISA in a pericyte-astrocyte contact coculture system. The findings were validated ex vivo and in vivo using lentiviruses and inhibitors. Finally, pericytes were targeted to regulate glial limitan formation, and the effect of the glia limitans on secondary brain injury after SAH was evaluated by flow cytometry and analysis of neurological function. RESULTS: Stress-induced glial limitan formation occurred 1 day after SAH and markedly subsided 3 days after ictus. Pericytes regulated astrocyte glia limitan formation via EphA4/EphrinB2 signaling, inhibited inflammatory cell infiltration and altered neurological function. CONCLUSIONS: Astrocyte-derived glia limitans serve as a secondary protective barrier following BBB disruption after SAH in mice, and pericytes can regulate glial limitan formation and alter neurological function via EphA4/EphrinB2 signaling. Strategies for maintaining this secondary protective barrier may be novel treatment approaches for alleviating early brain injury after SAH.