Background and purpose
Cerebral small vessel disease (CSVD) is a clinical imaging syndrome with diverse etiology. Total homocysteine (HCY) level might increase the risk of myocardial and cerebral ...infarction by damaging the vascular endothelium. We aimed to explore the correlation between total HCY and CSVD imaging burden, based on Mendelian randomization methods.
Methods
A total of 1,023 participants of the Shunyi study, a population‐based cohort study, were included. Vascular risk factors, total HCY levels and methylenetetrahydrofolate reductase (MTHFR) gene mutations (C677T and A1298C) were examined. CSVD imaging markers, including lacunes, cerebral microbleeds, white matter hyperintensity, enlarged perivascular space and brain parenchymal fraction (BPF) were also assessed.
Results
Mutations of C677T were significantly correlated with increased total HCY levels (CC→TT: β = 0.28, p < 0.0001), while mutations of A1298C were correlated with decreased total HCY levels (AA→AC: β = −0.13, p < 0.0001; AA→CC: β = −0.25, p = 0.004). In the Mendelian randomization study, the C677T genotype was significantly associated with lacunes (CC→CT: odds ratio OR 2.76, p = 0.008; CC→TT: OR 2.50, p = 0.018), and the A1298C genotype was significantly correlated with BPF (AA→CC: β = 1.32, p = 0.015). Similarly, in multivariate regression analysis, total HCY levels were significantly correlated with lacunes (OR 2.14, p < 0.0001) and negatively correlated with BPF (β = −0.55, p = 0.004). Age, sex and vascular risk factors were adjusted for.
Conclusions
Total HCY level was correlated with imaging burden of CSVD, especially with lacunes and brain volume loss. For individuals with risk genetic predisposition, enhanced homocysteine‐lowering strategies might be necessary to reduce the risk and progress of CSVD.
The current Mendelian randomization study found the correlation of HCY with imaging burden of CSVD especially with lacunes and brain volumes loss, and genetic predisposition could facilitate or weaken the correlation. For individuals with risk genetic variants, enhanced HCY lowering strategies might be necessary to reduce the risk and progression of CSVD.
Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play an essential role in atherosclerosis. MicroRNAs (miRNAs) are a class of short non-coding ...RNAs, acting as posttranscriptional regulators of protein-coding genes involved in vascular cell biology. MiRNA-221 and miRNA-222 (miR-221/222) are known to be involved in the regulation of endothelial inflammation and angiogenesis. However, the function of miR-221/222 in ox-LDL-induced ECs apoptosis and atherosclerosis is still unknown. Here, we showed that miR-221/222 expression was markedly down-regulated in ox-LDL-induced apoptotic human umbilical cord vein endothelial cells. MiR-221/222 inhibition enhanced apoptosis in ECs, whereas over-expression of miR-221/222 could partly alleviate apoptotic cell death mediated by ox-LDL through suppression of Ets-1 and its downstream target p21. These findings suggest that manipulation of the miR-221/222-Ets-1-p21 pathway may offer a novel strategy for treatment of endothelial apoptosis and atherosclerosis.
Previous studies have found that ferroptosis plays an important role in a variety of neurological diseases. However, the precise role of ferroptosis in the multiple sclerosis patients remains ...uncertain. We defined and validated a computational metric of ferroptosis levels. The ferroptosis scores were computed using the AUCell method, which reflects the enrichment scores of ferroptosis‐related genes through gene ranking. The reliability of the ferroptosis score was assessed using various methods, involving cells induced to undergo ferroptosis by six different ferroptosis inducers. Through a comprehensive approach integrating snRNA‐seq, spatial transcriptomics, and spatial proteomics data, we explored the role of ferroptosis in multiple sclerosis. Our findings revealed that among seven sampling regions of different white matter lesions, the edges of active lesions exhibited the highest ferroptosis score, which was associated with activation of the phagocyte system. Remyelination lesions exhibit the lowest ferroptosis score. In the cortex, ferroptosis score were elevated in neurons, relevant to a variety of neurodegenerative disease‐related pathways. Spatial transcriptomics demonstrated a significant co‐localization among ferroptosis score, neurodegeneration and microglia, which was verified by spatial proteomics. Furthermore, we established a diagnostic model of multiple sclerosis based on 24 ferroptosis‐related genes in the peripheral blood. Ferroptosis might exhibits a dual role in the context of multiple sclerosis, relevant to both neuroimmunity and neurodegeneration, thereby presenting a promising and novel therapeutic target. Ferroptosis‐related genes in the blood that could potentially serve as diagnostic and prognostic markers for multiple sclerosis.
•DOCK2 silence protects against cerebral ischemia/reperfusion injury.•Loss of DOCK2 enhances M2 polarization and inhibits M1 polarization of microglia.•DOCK2 knockdown activates the STAT6 signaling ...pathway.
Cerebral ischemia/reperfusion is the major pathophysiological process in stroke and could lead to severe and permanent disability. The current study aimed to investigate the effects of dedicator of cytokinesis 2 (DOCK2) on cerebral ischemia/reperfusion-induced cerebral injury. We established a mouse middle cerebral artery occlusion (MCAO) model with suture-occluded method in vivo. Then, BV-2 cells were conducted to oxygen-glucose deprivation and re-oxygenation (OGD/R) in vitro. The results showed that DOCK2 was highly expressed in ischemic brain following MCAO and in BV-2 cells induced by OGD/R. DOCK2 depletion protected against MCAO-induced brain infarcts and neuron degeneration. DOCK2 downregulation improved long-term neurological function, which was assessed by the Morris water-maze test. Moreover, silencing of DOCK2 promoted M2 polarization (anti-inflammation) and repressed M1 polarization (pro-inflammation) of microglia both in vivo and in vitro. Subsequently, we found that the loss of DOCK2 upregulated the expression of p-STAT6. DOCK2 knockdown-induced microglial cell polarization towards M2 phenotype was partly abrogated by the STAT6 inhibitor AS1517499. In conclusion, DOCK2 downregulation protected against cerebral ischemia/reperfusion by modulating microglia polarization via the activation of the STAT6 signaling pathway.
Objectives
The association of C‐reactive protein (CRP) and serum 25‐hydroxyvitamin D 25(OH)D and cardiovascular disease (CVD) remains unknown.
Methods
We performed a cross‐sectional analysis on 3848 ...participants by using the data from the National Health and Nutrition Examination Surveys (2007 to 2008). CVD was defined as a compromise of stroke, myocardial infarction, heart failure, and coronary heart disease. High CRP was defined as ≥0.2 mg/dL, and vitamin D status were categorized as severe deficiency, <25 nmol/mL; deficiency, 25 to 49.9 nmol/mL; insufficiency, 50 to 74.9 nmol/mL; and normal, ≥75 nmol/mL. Statistical analysis was performed using logistic regression models.
Results
We found that both high CRP and low 25(OH)D levels were associated with CVD. Participants with high CRP levels and severe vitamin D deficiency had a higher likelihood of having CVD than those with neither risk factor (odds ratio = 2.69, 95% confidence interval = 1.45‐4.98, P = .0017). In stratified analysis, a significant positive association between vitamin D level and CVD was observed only in the high CRP group. However, in the absence of high CRP, even with severe vitamin D deficiency, no association was found with an increasing risk of CVD (P = .6416).
Conclusion
Within a cross‐sectional, nationally representative sample, these findings suggest that vitamin D status evaluation, or vitamin D supplement may be especially important for individuals with high CRP levels.
•A polysaccharide (PS-WNP) was purified from Polygonatum sibiricum.•Protective effect of PS-WNP against Aβ25–35-induced neurotoxicity in PC12 cells was examined.•PS-WNP pretreatment attenuated ...Aβ25–35-induced apoptosis in PC12 cells.•PS-WNP protected PC12 cells against Aβ25–35-induced apoptosis via PI3K/Akt signaling pathway.
One of the pathological hallmarks of Alzheimer's disease (AD) is the progressive accumulation of beta-amyloid (Aβ) in the form of senile plaques, and Aβ induced neurotoxicity has been identified as a major cause of the onset of AD. In this study, we investigated the protective effects of a polysaccharide (PS-WNP) from Polygonatum sibiricum against the Aβ25–35-induced neurotoxicity in PC12 cells and explored the underlying mechanism. The results showed that pretreatment with PS-WNP significantly attenuated cell death and the elevated Bax/Bcl-2 ratio evoked by Aβ25–35, and subsequently inhibited mitochondrial dysfunction and cytochrome c release into the cytosol. Moreover, PS-WNP significantly inhibited Aβ25–35 induced caspase-3 activation and enhanced the protein levels of phosphorylated Akt (p-Akt) in PC12 cells. Additionally, pretreatment with the PI3K inhibitor (LY294002) completely abolished the protective effects of PS-WNP against Aβ25–35-induced neuronal cell apoptosis. These observations unambiguously suggested that the protective effect of PS-WNP against Aβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of PI3K/Akt signaling pathway.
Medulloblastoma (MB) is a brain malignancy, which commonly occurs in children, but is rare in adults. The Surveillance, Epidemiology, and End Results (SEER) database was used to compare survival, ...clinical features, and prognostic factors of children and adults with MB from 1992 to 2013. Overall survival estimates were compared using the Kaplan-Meier method, and Cox Proportion Hazard Regression modeling was used to evaluate prognostic variables. We identified 616 children (63.8%) and 349 adults (36.2%) with diagnosis of MB. The estimated survival rates for children diagnosed with MB for 2, 5, and 10 years were 85.6%, 75.5%, and 67.9%, respectively; the corresponding estimates for adults were 84.9%, 74.2%, and 67.3%. Radiotherapy was the only identical prognostic factor observed in the two groups. Children MB patients were more likely to experience distal metastases that was associated with increased hazard of mortality, and be diagnosed after 2003. Among adult MB patients, gross total resection (GTR) was a favorable prognostic factor, while large cell/anaplastic (LC/A) histology was correlated with decreased survival. Our analysis highlighted that both groups had similar overall survival time, but the prognostic factors were not comparable, except radiotherapy which was associated with better survival.
Circulating neutrophil extracellular traps (NETs) resistant to t‐PA have not been studied completely although NETs in thrombi may contribute to tissue plasminogen activator (t‐PA) resistance. This ...research intended to elucidate whether circulating NETs are associated with t‐PA resistance and the underlying mechanism. The levels of NETs were detected in the circulating neutrophils, ischemic brain tissue of acute ischemic stroke (AIS) patients, and transient middle cerebral artery occlusion (tMCAO) models. NET formation in blood, thrombi, and ischemic brain tissue of mice were analyzed by immunofluorescence. Exposed phosphatidylserine (PS) was assessed using flow cytometry and confocal microscopy. Procoagulant activity (PCA) was evaluated using fibrin formation assays, thrombin, and purified coagulation complex. The plasma levels of NETs in AIS patients were significantly higher than those in healthy individuals. After thrombolysis, a significant increase was noted in NET markers in no‐improvement patients, while the changes in improvement patients were not significant. Importantly, NETs were decorated with von Willebrand factor (vWF) and plasminogen activator inhibitor‐1 (PAI‐1) in the blood and thrombi, which could reverse the fibrinolytic effects. In addition, NETs activated platelets (PLTs) and endothelial cells (ECs), stimulating a procoagulant phenotype and facilitating vWF and PAI‐1 release. DNase I, activated protein C (APC), and sivelestat markedly inhibited these effects. Furthermore, targeting NETs protected mice from tMCAO‐induced cerebral ischemia, possibly by regulating vWF and PAI‐1. In summary, NETs may contribute to t‐PA resistance in AIS through activation of PLTs and ECs. Strategies against NETs may present a promising therapeutic approach to improve the thrombolysis efficiency of t‐PA in AIS patients.
Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a poor prognosis. Cross-talk between competitive endogenous RNAs (ceRNAs) plays a critical role in tumor development ...and physiology. In this study, we present a multi-step computational approach to construct a functional GBM long non-coding RNA (lncRNA)-mediated ceRNA network (LMCN) by integrating genome-wide lncRNA and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. LncRNAs in the LMCN exhibited specific topological features consistent with a regulatory association with coding mRNAs across GBM pathology. We determined that the lncRNA MCM3AP-AS was involved in RNA processing and cell cycle-related functions, and was correlated with patient survival. MCM3AP-AS and MIR17HG acted synergistically to regulate mRNAs in a network module of the competitive LMCN. By integrating the expression profile of this module into a risk model, we stratified GBM patients in both the The Cancer Genome Atlas and an independent GBM dataset into distinct risk groups. Finally, survival analyses demonstrated that the lncRNAs and network module are potential prognostic biomarkers for GBM. Thus, ceRNAs could accelerate biomarker discovery and therapeutic development in GBM.
Microglia are rapidly activated following ischaemic stroke and participate in the induction of neuroinflammation, which exacerbates the injury of ischaemic stroke. However, the mechanisms regulating ...ischaemic microglia remain unclear. In the present study, middle cerebral artery occlusion and oxygen and glucose deprivation models were established for in vivo and vitro monitoring of experimental stroke. We applied recombinant human thioredoxin‐1 (rhTrx‐1) and Necrostatin‐1 (Nec‐1, inhibitor of RIPK1) to examine the role of receptor‐interacting protein kinase 1 (RIPK1) in the development of inflammation in ischaemic microglia via explored the inflammatory responses and the associated mechanisms. Molecular docking results indicated that rhTrx‐1 could directly bind to RIPK1. In vivo and vitro data revealed that rhTrx‐1 reduced necroptosis, mitochondrial membrane potential damage, reactive oxygen species accumulation and NLR Family, pyrin domain‐containing 3 protein (NLRP3) inflammasome activation and regulated the microglial M1/M2 phenotypic changes by inhibiting RIPK1 expression in ischaemic microglia. Consistent with these findings, further in vivo experiments revealed that rhTrx‐1 treatment attenuated cerebral ischaemic injury by inhibiting the inflammatory response. Our data demonstrated the role of RIPK1 in microglia‐induced neuroinflammation following cerebral ischaemia. Administration of rhTrx‐1 provides neuroprotection in ischaemic stroke‐induced microglial neuroinflammation by inhibiting RIPK1 expression.
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