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Vascular dementia (VaD) causes progressive cognitive decline in the elderly population, but there is short of available therapeutic measures. Microglia-mediated neuroinflammation is vigorously involved in the pathogenesis of VaD, but the traditional classification of microglial M1/M2 phenotypes remains restrictive and controversial. This study aims to investigate whether microglia transform into novel subtypes in VaD. Chronic cerebral hypoperfusion (CCH) rat model was constructed to mimic VaD. Microglia were isolated via magnetic-activated cell sorting and analyzed by single-cell RNA sequencing (scRNA-seq) and bioinformatics. The findings inferred from scRNA-seq and bioinformatics were further validated through in vivo experiments. In this study, microglia were divided into eight clusters. The proportion of MG5 cluster was significantly increased in the white matter of the CCH group compared with the Sham group and was named chronic ischemia-associated microglia (CIAM). Immunity- and inflammation-related genes, including RT1-Db1, RT1-Da, RT1-Ba, Cd74, Spp1, C3, and Cd68, were markedly upregulated in CIAM. Enrichment analysis illustrated that CIAM possessed the function of evoking neuroinflammation. Further studies unveiled that Cd74 is associated with the most abundant GO terms involved in inflammation as well as cell proliferation and differentiation. In addition, microglia-specific Cd74 knockdown mediated by adeno-associated virus decreased the abundance of CIAM in the white matter, thereby mitigating inflammatory cytokine levels, alleviating white matter lesions, and improving cognitive impairment for CCH rats. These findings indicate that Cd74 is the core molecule of CIAM to trigger neuroinflammation and induce microglial differentiation to CIAM, suggesting that Cd74 may be a potential therapeutic target for VaD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroinflammation is assumed as the critical pathophysiologic mechanism of white matter lesions (WMLs), and infiltrated peripheral monocyte-derived macrophages are implicated in the development of neuroinflammation. This study sought to explore the blood molecules that promote the migration of peripheral monocytes to the sites of WMLs. The serum protein expression profiles of patients and Sprague-Dawley rat models with WMLs were detected by data-independent acquisition (DIA) proteomics technique. Compared with corresponding control groups, we acquired 62 and 41 differentially expressed proteins (DEPs) in the serum of patients and model rats with WMLs respectively. Bioinformatics investigations demonstrated that these DEPs were linked to various Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms involved in neuroinflammation. Afterward, we identified thrombin-activatable fibrinolysis inhibitor (TAFI) as a shared and overexpressed protein in clinical and animal serum samples, which was further verified by enzyme-linked immunosorbent assay. Additionally, an upregulation of TAFI was also observed in the white matter of rat models, and the inhibition of TAFI impeded the migration of peripheral monocytes to the area of WMLs. In vitro experiments suggested that TAFI could enhance the migration ability of RAW264.7 cells and increase the expression of Ccr2. Our study demonstrates that neuroinflammatory signals can be detected in the peripheral blood of WMLs patients and model rats. TAFI may serve as a potential protein that promotes the migration of peripheral monocytes to WMLs regions, thereby providing a novel molecular target for further investigation into the interaction between the central and peripheral immune systems., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1β, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to explore the role of mesenchymal stromal cells (MSCs)-derived exosomes (MSCs-Exo) in the cerebral ischemia-reperfusion (I/R) injury., Methods: Exosomes were isolated from MSCs of adult C57BL/6J mice by the gradient centrifugation method. The expression of miR-26a-5p and CDK6 in MSCs-Exo and mice brain tissues were evaluated by qRT-PCR and western blot. miR-26a-5p mimics and miR-NC were transfected into MSCs, and exosomes were isolated from the MSCs stably expressing miR-26a-5p. Then MSCs-Exo-miR-26a-5p mimics or MSCs-Exo-miR-NC was injected into mice through the tail vein, or added into medium to stimulate BV-2 cells. Cell viability was evaluated by CCK-8 assay. Cell apoptosis was detected by flow cytometry. The apoptosis in brain tissues was evaluated by TUNEL staining assay. Bioinformatics analysis and luciferase reporter assay were performed to determine the binding relationship between miR-26a-5p and CDK6., Results: miR-26a-5p was downregulated and CDK6 was upregulated in MSCs-Exo of MCAO-mice and OGD-induced MSCs. MSCs-Exo-miR-26a-5p mimics significantly reduced cell apoptosis of OGD-injured BV-2 cells. MSCs-Exo-miR-26a-5p mimics significantly reduced the infarct volume of MCAO-induced mice. Luciferase reporter assay revealed that CDK-6 was a target of miR-26a-5p. In addition, MSCs-Exo-miR-26a-5p mimics significantly decreased the expression of CDK6 in both OGD-induced BV-2 cells and the brain tissues of MCAO-treated mice., Conclusion: Our results indicated that MSCs‑Exo attenuated I/R injury in mice by inhibiting microglia apoptosis might via exosomal miR-26a-5p mediated suppression of CDK6. Our study shed light on the application of MSC-Exo as a potential therapeutic tool for cerebral I/R injury.

Seawater intrusion, a common geological process along the coastal zones, changes the groundwater properties, which are potentially associated with the groundwater copper (Cu) levels. However, there are no studies on the details of groundwater Cu levels affected by seawater intrusion. The groundwater in the seawater intrusion area of Buzhuang Town was sampled to detect the effect of seawater intrusion on groundwater Cu levels. The Cu levels in the local groundwater range between 0.92 and 4.99 μg L-1, which averages about 5 times than those in the non-intrusion area. The Cu deviations (ΔCu) are positive, and increase with more intrusion of seawater. Simulation experiments also confirm that more Cu leaches from sediments when more seawater or brine water is mixed in. The groundwater Cu levels are positively correlated with TDS, Cl-, Br-, SO42-, HCO3-, Na+, K+ and Mg2+. The Cu-bearing minerals in the local groundwater are under-saturated. The CEC of the sediment for the simulated experiments decreases with more mixture of seawater or brine water. CuCO03, Cu(OH)02, CuHCO3+, Cu(CO3)22-, CuCl2-, Cu2+ species in the local groundwater are obviously higher than those in the non-intrusion area, and the levels of CuCl2-, Cu+, CuCO3, Cu2+, CuSO4, CuOH+, CuCl+, Cu2(OH)22+ are positively correlated with the degree of seawater intrusion, indicating the important role of Cl-, HCO3-, OH- complexation on groundwater Cu levels. Thus, ion competition and complexation are the important dynamics of groundwater Cu enrichment along the coastal zones. A new enrichment model of groundwater Cu in the seawater intrusion area is presented. Seawater intrusion should be taken into consideration when the enrichment mechanisms of groundwater Cu are discussed.

BACKGROUND Different responses to identical trauma may be related to the genetic background of individuals, but the molecular mechanism is unclear. In this study we investigated the heterogeneity of trauma in mice and the potential biological explanations for the differences. MATERIAL AND METHODS Compared with other organs, the pathological response of the lung after injury is the earliest and most serious. We used C57BL/6 and BALB/C mice to explore the genetic background of different responses to trauma in the lung. We measured mortality rate, pulmonary microvascular permeability, and Cxcl15 gene expression in BALB/C and C57BL/6 mice before and after blast-wave injury. Microvascular permeability was measured using a fluorescent tracer, and Cxcl15 gene expression level and expression distribution were measured using fluorogenic probe quantitative polymerase chain reaction and northern blot. RESULTS C57BL/6 mice showed lower mortality rates and pulmonary microvascular permeability than BALB/C mice after blast-wave injury; there was no significant difference in the permeability before blast-wave injury. The Cxcl15 gene was expressed specifically in the lung tissue of mice. The level of Cxcl15 expression in BALB/C mice was higher than in C57BL/6 mice before and after injury, and the variation trend of Cxcl15 expression level after injury was significantly different between BALB/C and C57BL/6 mice. CONCLUSIONS Our results indicated that BALB/C and C57BL/6 mice had significant heterogeneity in posttraumatic response in terms of mortality and degree of lung damage. The differences in genetic factors such as Cxcl15 may have played a role in this heterogeneity.

Background: Some studies have indicated that a local injection of Botulinum Toxin Type A (BTX-A) is a promising therapy for trigeminal neuralgia (TN). However, BTX-A treatment is still ineffective for approximately 10-43% of patients. We therefore investigated which factors are associated with the therapeutic effect in BTX-A treatment of medically refractory, classical TN., Methods: We performed a retrospective cohort study with a total of 104 patients who were receiving BTX-A injection for medically refractory classical TN between August 2013 and October 2016. A VAS score, pain attack frequency per day as well as patients' overall response to treatment and side effects were evaluated in 104 patients with TN who were receiving BTX-A., Results: A total of 87 patients reported successful results; 41 stated that their pain was completely controlled while 46 reported adequate pain relief, totaling 83.7%. Our study suggests that treatment success was higher in patients 50 or older (OR=3.66, 95% CI: 1.231-10.885). Univariate and multivariate analyses demonstrated that the patient's age was independently associated with treatment outcome (OR=1.72, 95% CI: 1.063-2.282), with ≥50 years being a significant predictor of pain relief ( P =0.020 and P =0.033, respectively). Seventeen patients (16.3%) reported mild side effects., Conclusion: A local injection of BTX-A may be a safe and efficient treatment for classical TN which lasts for several months. BTX-A is a novel strategy which is particularly worth trying for particularly middle-aged and elderly patients who cannot tolerate drug side effects and may be afraid of serious complications from microvascular decompression., Competing Interests: The authors report no conflicts of interest in this work.

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood-brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.

Background and Purpose: The symptom of headache and neck pain is common in patients with cervicocerebral artery dissection (CAD). We attempt to screen ischemic stroke patients with CAD based on the characteristics of the pain., Methods: Eighty-one consecutive ischemic stroke patients with CAD from 2010 to 2017 and 84 consecutive ischemic stroke patients with large artery atherosclerosis (LAA) were registered prospectively and observed in Zhengzhou, China. Those ischemic stroke patients complained of headache and neck pain were categorized into 2 groups. By analyzing the difference of headache and neck pain in 2 groups, we summarized characteristics of the pain secondary to CAD., Results: There were 34 patients in CAD group and 19 patients in LAA group. As for patients in CAD group, the pain could be located in the ipsilateral (41.9%), bilateral (41.9%), or contralateral (16.1%) side of the dissected artery, but in LAA group the pain was often in both sides (68.4%). When the dissected artery was involved in anterior circulation, 55.6% of CAD patients had pain in temporal and when involved in posterior circulation, 65.2% of CAD patients had pain in the occipital and neck. Patients with CAD had a higher prevalence of throbbing pain (30.0%), while pulsating pain (43.8%) was more common in LAA group. Patients often presented with severe pain (46.9%) in CAD group, while less frequently (11.8%) in LAA group, with a significant difference (P = .003). And there was a significant difference between the length (≥20 mm) of the involved artery and severity of the pain (P = .028) in CAD group., Conclusions: Ischemic stroke patients caused by CAD tend to suffer from headache and neck pain, which may be severe and throbbing, compared with those resulting from LAA. The anterior circulation dissection has a higher prevalence of temporal pain while posterior circulation dissection is typically more associated with occipital and neck pain., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To analyze the characteristics and relative factors of headache and neck pain due to cervicocerebral artery dissection (CAD)., Methods: A total of 146 consecutive patients with CAD in Zhengzhou, China (2010-2017) were observed and registered prospectively. There were 60 (60/146) cases who complained of headache and neck pain, and we analyzed the characteristics of pain according to their clinical features. For the 130 (130/146) patients with complete clinical laboratory data, they were divided into two groups according to pain, and the relative factors of pain were analyzed., Results: The headache and neck pain in 60 CAD patients was mostly acute onset (98.3%), 70.6% (12/17) of patients with anterior circulation dissection and 88.4% (38/43) of patients with posterior circulation dissection complained of moderate to severe pain. 41.2% (7/17) of patients with anterior circulation dissection had temporal pain, while 46.5% (20/43) of the patients with posterior circulation dissection had occipital pain. There were 23.5% (4/17) and 32.6% (14/43) of patients with anterior and posterior circulation dissection complained of throbbing pain, respectively, 23.5% (4/17) and 20.9% (9/43) of patients with anterior and posterior circulation dissection complained of pulsating pain. The pain could occur in the ipsilateral (40.0%), bilateral (52.7%), or contralateral (7.3%) sites of the dissection. In the 130 patients, there were 56 cases (43.1%) in the pain group, and 74 cases (56.9%) in the non-pain group. Multivariate logistic regression analysis showed that female gender (OR 4.01, 95% CI 1.63-9.85, P = 0.002), posterior circulation (OR 3.18, 95% CI 1.39-7.28, P = 0.006), history of headache (OR 4.72, 95% CI 1.08-20.52, P = 0.039), and low-density lipoprotein less than 1.8 mmol/L (OR 2.90, 95% CI 1.15-7.34, P = 0.025) were risk factors of the occurrence of the pain related to CAD., Conclusion: The headache and neck pain caused by CAD is a moderate to severe pain occurring suddenly. The pain nature may be diverse but mostly like throbbing and pulsating. When the dissected artery is located in the posterior circulation, the pain is mostly in the occipital region, and mostly in the temporal region when the dissected artery is located in the anterior circulation. The pain can occur in ipsilateral, bilateral, or contralateral of the dissection. In addition, several factors might contribute to the occurrence of headache and neck pain.

Background: Cervicocerebral artery dissection (CAD) is a major cause of ischemic stroke in young adults. There are many existing studies on determinants for CAD; however, they are still not totally defined. We conduct the study to further investigate the determinants for CAD based on ischemic stroke patients., Methods: 81 ischemic stroke patients with CAD were enrolled in the CAD stroke group and 84 ischemic stroke patients without CAD were enrolled in the non-CAD stroke group. Their clinical data, such as age, gender, vascular risk factors, headache and neck pain and clinical laboratory data, were collected to analyze the differences between the two groups., Results: A total of 165 ischemic stroke patients were included. The mean age of CAD stroke group was (51.6 ± 12.4) years, and (55.5 ± 8.1) years in non-CAD stroke group, with a statistically significant difference (P = 0.017). The average level of triglycerides in CAD stroke group was (1.3 ± 0.7) mmol/L, and (1.7 ± 1.1) mmol/L in non-CAD stroke group, with a statistically significant difference (P = 0.012). There were 42.0% (34/81) of headache and neck pain in CAD stroke group and 22.6% (19/84) in non-CAD stroke group, with a statistically significant difference (P = 0.008). The key findings with significant difference were stratified and multivariate logistic regression analysis showed that age < 50 years old (OR 2.98, 95% CI 1.43-6.21, P = 0.004), triglycerides < 1.6 mmol/L (OR 3.51, 95% CI 1.69-7.27, P = 0.001) and headache and neck pain (OR 2.94, 95% CI 1.39-6.20, P = 0.005) showed a positive correlation with CAD., Conclusion: In the process of diagnosis and treatment of ischemic stroke, for patients with age < 50 years old, headache and neck pain and triglycerides < 1.6 mmol/L, the cervicocerebral artery dissection should be considered, and vascular imaging examination needs to be performed in time.

In this study, a numerical simulation using computational fluid dynamics (CFD) was used to investigate the hydrodynamic characteristics of circular ponds with three different impellers (hydrofoil, four-pitched-blade turbine, and grid plate). The reliability of the CFD model was validated by particle image velocimetry (PIV). Hydrodynamic analyses were conducted to evaluate the average velocity magnitude along the light direction (Uz), turbulence properties, average shear stress, pressure loss and the volume percentage of dead zone inside circular ponds. The simulation results showed that Uz value of hydrofoil was 58.9, 40.3, and 28.8% higher than those of grid plate with single arm, grid plate with double arms and four-pitched blade turbines in small-scale circular ponds, respectively. In addition, hydrofoil impeller with down-flow operation had outstanding mixing characteristics. Lastly, the results of Chlorella pyrenoidosa cultivation experiments indicated that the biomass concentration of hydrofoil impeller with down-flow operation was 65.2 and 88.8% higher than those of grid plate with double arms and four-pitched-blade turbine, respectively. Therefore, the optimal circular pond mixing system for microalgae cultivation involved a hydrofoil impeller with down-flow operation.

A new method is proposed to calculate the Stark shift induced by surface dielectric effect in colloidal nanocrystals. The effective mass approximation model is revised according to quantum confined dielectric effect. LUMO (the lowest unoccupied molecular orbital), HOMO (the highest occupied molecular orbital), band gap and Stark shift are calculated in CdSe and PbSe nanocrystals that bear significantly different physical properties. The calculated results fit well with the experimental data. The calculation of dielectric effect-induced Stark shift indicates that the quantum confined dielectric effect in PbSe and CdSe nanocrystals is size- and temperature-dependent, which is more notable in PbSe nanocrystals with a narrower band gap and results in the gentle variation of quantum confinement energy with particle size.