Non-coding RNAs in acute ischemic stroke: from brain to periphery.

Acute ischemic stroke is a clinical emergency and a condition with high morbidity, mortality, and disability. Accurate predictive, diagnostic, and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined. With innovations in high-throughput gene sequencing analysis, many aberrantly expressed non-coding RNAs (ncRNAs) in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models. Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes, leading to neuroprotection or deterioration, thus ncRNAs can serve as therapeutic targets in acute ischemic stroke. Moreover, distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. In particular, ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke. In this review, we consolidate the latest progress of research into the roles of ncRNAs (microRNAs, long ncRNAs, and circular RNAs) in the pathological processes of acute ischemic stroke-induced brain damage, as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation.

Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer's disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3ß activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the "SD microbiota" replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3ß activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3ß activation in primary hippocampal neurons, suggesting that GSK-3ß, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3ß as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.

Glymphatic dysfunction mediates the influence of choroid plexus enlargement on information processing speed in patients with white matter hyperintensities.

Glymphatic dysfunction has been correlated with cognitive decline, with a higher choroid plexus volume (CPV) being linked to a slower glymphatic clearance rate. Nevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated. In this study, we performed neuropsychological assessment, T1-weighted three-dimensional (3D-T1) images, and diffusion tensor imaging (DTI) in a cohort of 206 WMHs subjects and 43 healthy controls (HCs) to further explore the relationship. The DTI analysis along the perivascular space (DTI-ALPS) index, as a measure of glymphatic function, was calculated based on DTI. Severe WMHs performed significantly worse in information processing speed (IPS) than other three groups, as well as in executive function than HCs and mild WMHs. Additionally, severe WMHs demonstrated lower DTI-ALPS index and higher CPV than HCs and mild WMHs. Moderate WMHs displayed higher CPV than HCs and mild WMHs. Mini-Mental State Examination, IPS, and executive function correlated negatively with CPV but positively with DTI-ALPS index in WMHs patients. Glymphatic function partially mediated the association between CPV and IPS, indicating a potential mechanism for WMHs-related cognitive impairment. CPV may act as a valuable prognostic marker and glymphatic system as a promising therapeutic target for WMHs-related cognitive impairment.

NOX1 triggers ferroptosis and ferritinophagy, contributes to Parkinson's disease.

The progressive loss of dopaminergic neurons in the midbrain is the hallmark of Parkinson's disease (PD). A newly emerging form of lytic cell death, ferroptosis, has been implicated in PD. However, it remains unclear in terms of PD-associated ferroptosis underlying causative genes and effective therapeutic approaches. This research explored the underlying mechanism of ferroptosis-related genes in PD. Here, Firstly, we found NOX1 associated with ferroptosis differently in PD patients by bioinformatics analysis. In vitro and in vivo models of PD were constructed to explore the underlying mechanism. qPCR, Western blot analysis, immunohistochemistry, immunofluorescence, Ferro orange, and BODIPY C11 were utilized to analyze the levels of ferroptosis. Transcriptomics sequencing was to investigate the downstream pathway and the analysis of immunoprecipitation to validate the upstream factor. In conclusion, NOX1 upregulation and activation of ferroptosis-related neurodegeneration, therefore, might be useful as a clinical therapeutic agent.

Detection of Candidatus Liberibacter asiaticus and five viruses in individual Asian citrus psyllid in China.

Introduction: Asian citrus psyllid (ACP, Diaphorina citri) is an important transmission vector of "Candidatus Liberibacter asiaticus" (CLas), the causal agent of Huanglongbing (HLB), the most destructive citrus disease in the world. As there are currently no HLB-resistant rootstocks or varieties, the control of ACP is an important way to prevent HLB. Some viruses of insect vectors can be used as genetically engineered materials to control insect vectors. Methods: To gain knowledge on viruses in ACP in China, the prevalence of five RNA and DNA viruses was successfully determined by optimizing reverse transcription polymerase chain reaction (RT-PCR) in individual adult ACPs. The five ACP-associated viruses were identified as follows: diaphorina citri bunyavirus 2, which was newly identified by high-throughput sequencing in our lab, diaphorina citri reovirus (DcRV), diaphorina citri picorna-like virus (DcPLV), diaphorina citri bunyavirus (DcBV), and diaphorina citri densovirus-like virus (DcDV). Results: DcPLV was the most prevalent and widespread ACP-associated virus, followed by DcBV, and it was detected in more than 50% of all samples tested. DcPLV was also demonstrated to propagate vertically and found more in salivary glands among different tissues. Approximately 60% of all adult insect samples were co-infected with more than one insect pathogen, including the five ACP-associated viruses and CLas. Discussion: This is the first time these viruses, including the newly identified ACP-associated virus, have been detected in individual adult ACPs from natural populations in China's five major citrus-producing provinces. These results provide valuable information about the prevalence of ACP-associated viruses in China, some of which have the potential to be used as biocontrol agents. In addition, analysis of the change in prevalence of pathogens in a single insect vector is the basis for understanding the interactions between CLas, ACP, and insect viruses.

Circular RNA PTP4A2 regulates microglial polarization through STAT3 to promote neuroinflammation in ischemic stroke.

OBJECTIVE: Microglial polarization plays a critical role in neuroinflammation and may be a potential therapeutic target for ischemic stroke. This study was to explore the role and underlying molecular mechanism of Circular RNA PTP4A2 (circPTP4A2) in microglial polarization after ischemic stroke. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO), while primary mouse microglia and BV2 microglial cells experienced oxygen glucose deprivation/reperfusion (OGD/R) to mimic ischemic conditions. CircPTP4A2 shRNA lentivirus and Colivelin were used to knock down circPTP4A2 and upregulate signal transducer and activator of transcription 3 (STAT3) phosphorylation, respectively. Microglial polarization was assessed using immunofluorescence staining and Western blot. RNA pull-down and RNA binding protein immunoprecipitation (RIP) were applied to detect the binding between circPTP4A2 and STAT3. RESULTS: The levels of circPTP4A2 were significantly increased in plasma and peri-infarct cortex in tMCAO mice. CircPTP4A2 knockdown reduced infarct volume, increased cortical cerebral blood flow (CBF), and attenuated neurological deficits. It also decreased pro-inflammatory factors levels in peri-infarct cortex and plasma, and increased anti-inflammatory factors concentrations 24 h post-stroke. In addition, circPTP4A2 knockdown suppressed M1 microglial polarization and promoted M2 microglial polarization in both tMCAO mice and OGD/R-induced BV2 microglial cells. Moreover, circPTP4A2 knockdown inhibited the phosphorylation of STAT3 induced by oxygen-glucose deprivation. In contrast, increased phosphorylation of STAT3 partly counteracted the effects of circPTP4A2 knockdown. RNA pull-down and RIP assays further certified the binding between circPTP4A2 and STAT3. CONCLUSION: These results revealed regulatory mechanisms of circPTP4A2 that stimulated neuroinflammation by driving STAT3-dependent microglial polarization in ischemic brain injury. CircPTP4A2 knockdown reduced cerebral ischemic injury and promoted microglial M2 polarization, which could be a novel therapeutic target for ischemic stroke.

Significance of Cuproptosis-related genes in immunological characterization, diagnosis and clusters classification in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder that affects millions of people throughout the world. Cuproptosis is a newly discovered form of programmed cell death linked to several neurological disorders. Nevertheless, the precise mechanisms of Cuproptosis-related genes (CRGs) in PD remain unknown. This study investigated immune infiltration and CRG expression profiling in patients with Parkinson's disease and healthy controls. Subsequently, we construct a predictive model based on 5 significant CRGs. The performance of the predictive model was validated by nomograms and external datasets. Additionally, we classified PD patients into two clusters based on CRGs and three gene clusters based on differentially expressed genes (DEG) of CRGs clusters. We further evaluated immunological characterization between the different clusters and created the CRGs scores to quantify CRGs patterns. Finally, we investigate the prediction of CRGs drugs and the ceRNA network, providing new insights into the pathogenesis and management of PD.

Identification and Experimental Validation of Parkinson's Disease with Major Depressive Disorder Common Genes.

Parkinson's disease (PD) is the second most common neurodegenerative disease that affects about 10 million people worldwide. Non-motor and motor symptoms usually accompany PD. Major depressive disorder (MDD) is one of the non-motor manifestations of PD it remains unrecognized and undertreated effectively. MDD in PD has complicated pathophysiologies and remains unclear. The study aimed to explore the candidate genes and molecular mechanisms of PD with MDD. PD (GSE6613) and MDD (GSE98793) gene expression profiles were downloaded from Gene Expression Omnibus (GEO). Above all, the data of the two datasets were standardized separately, and differentially expressed genes (DEGs) were obtained by using the Limma package of R. Take the intersection of the two differential genes and remove the genes with inconsistent expression trends. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were investigated to explore the function of the common DEGs. Additionally, the construction of the protein-protein interaction (PPI) network was to search the hub genes, and then the least absolute shrinkage and selection operator (LASSO) regression was used to further identify the key genes. GSE99039 for PD and GSE201332 for MDD were performed to validate the hub genes by the violin plot and receiver operating characteristic (ROC) curve. Last but not least, immune cell dysregulation in PD was investigated by immune cell infiltration. As a result, a total of 45 common genes with the same trend. Functional analysis revealed that they were enriched in neutrophil degranulation, secretory granule membrane, and leukocyte activation. LASSO was performed on 8 candidate hub genes after CytoHubba filtered 14 node genes. Finally, AQP9, SPI1, and RPH3A were validated by GSE99039 and GSE201332. Additionally, the three genes were also detected by the qPCR in vivo model and all increased compared to the control. The co-occurrence of PD and MDD can be attributed to AQP9, SPI1, and RPH3A genes. Neutrophils and monocyte infiltration play important roles in the development of PD and MDD. Novel insights may be gained from the findings for the study of mechanisms.

A review of studies on gut microbiota and levodopa metabolism.

Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Levodopa (L-dopa) has been the cornerstone for treating Parkinson's since the 1960s. However, complications such as "wearing-off" and dyskinesia inevitably appear with disease progression. With the further development of microbiomics in recent years, It has been recognized that gut microbiota plays a crucial role in Parkinson's disease pathogenesis. However, Little is known about the impact of gut microbiota in PD treatment, especially in levodopa metabolism. This review examines the possible mechanisms of gut microbiota, such as Helicobacter pylori, Enterobacter faecalis, and Clostridium sporogenes, affecting L-dopa absorption. Furthermore, we review the current status of gut microbiota intervention strategies, providing new insights into the treatment of PD.

Neuroinflammation and peripheral immunity: Focus on ischemic stroke.

Ischemic stroke (IS) produces a powerful inflammatory cascade in the brain, resulting in the occurrence of neuroinflammation. Neuroinflammation is triggered not only by resident immune cells, but also by neutrophils, macrophages, and T lymphocytes infiltrating the peripheral immune system. The disruption of the blood-brain barrier appears to exacerbate inflammatory infiltrates after IS. In turn, IS also has effects on peripheral immunity, manifested as peripheral immunosuppression syndrome, which increases the risk of stroke-associated infections such as pneumonia. Moreover, strokes also damage peripheral organs such as the heart, lungs, spleen, and kidneys. The purpose of this review is to provide an overview of central neuroinflammation and stroke-induced immunosuppression in the context of IS.

Association of platelet-to-neutrophil ratios with 1-year outcome and mortality in patients with acute ischemic stroke.

BACKGROUND: Platelet-neutrophil crosstalk is being increasingly recognized as a driver of inflammation and thrombosis in patients with ischemic stroke. The aim of this study was to investigate the potential of PNR value in predicting the long-term prognosis and evaluate whether or not an available and routine blood cell biomarker could help predict the long-term neurological function and mortality in AIS patients. METHODS: A total of 718 patients with suspected acute ischemic stroke were involved and followed up for 1 year by standard telephone interview or reexamination. Kaplan-Meier curve, Univariate and Multivariate Cox Regression were analyzed using Statistical Packages for Social Sciences. RESULTS: ROC curve for PNR to evaluate 1-year outcomes was analyzed and the area under the curve (AUC) was 0.659 (P < 0.001). The cutoff point was observed at 38.30, with a sensitivity of 53.09 % and a specificity of 71.25 %. Moreover, patients in PNR ≤ 38.30 were more likely to have more serious NIHSS on admission, 1-year mRS and higher 1-year mortality (P < 0.001, respectively). The 1-year mortality in the low PNR group was significantly higher than that of the high PNR group (log-rank tests: P < 0.0001). Age, NIHSS, RBC and PNR were combined into model B which significantly increased the AUC value from 0.736 to 0.888 compared to model A (including Age, NIHSS and RBC). CONCLUSION: PNR may serve as a readily assessable biomarker for early predicting neurological deterioration and the long-term prognosis of AIS. The nomogram that included age, NIHSS, PNR and RBC may be a useful predictive tool for 1-year mortality.

Intestinal dysbiosis mediates cognitive impairment via the intestine and brain NLRP3 inflammasome activation in chronic sleep deprivation.

Growing evidence suggests the involvement of the microbiota-gut-brain axis in cognitive impairment induced by sleep deprivation (SD), however how the microbiota-gut-brain axis work remains elusive. Here, we discovered that chronic SD induced intestinal dysbiosis, activated NLRP3 inflammasome in the colon and brain, destructed intestinal/blood-brain barrier, and impaired cognitive function in mice. Transplantation of "SD microbiota" could almost mimic the pathological and behavioral changes caused by chronic SD. Furthermore, all the behavioral and pathological abnormalities were practically reversed in chronic sleep-deprived NLRP3-/- mice. Regional knockdown NLRP3 expression in the gut and hippocampus, respectively. We observed that down-regulation of NLRP3 in the hippocampus inhibited neuroinflammation, and ameliorated synaptic dysfunction and cognitive impairment induced by chronic SD. More intriguingly, the down-regulation of NLRP3 in the gut protected the intestinal barrier, attenuated the levels of peripheral inflammatory factors, down-regulated the expression of NLRP3 in the brain, and improved cognitive function in chronic SD mice. Our results identified gut microbiota as a driver in chronic SD and highlighted the NLRP3 inflammasome as a key regulator within the microbiota-gut-brain axis.

Application Value of Serum Metabolic Markers for Cognitive Prediction in Elderly Epilepsy.

Background and Study Aims: Elderly epilepsy is the third most common chronic disease that affects metabolism either alone or through antiepileptic drugs (AEDs). Here, we focus on whether neurocognitive profiles in elderly epilepsy and its treatment are linked to metabolic conditions. Patients and Methods: Elderly patients with epilepsy without cognitive impairment (n = 78) and with cognitive impairment (n = 75) were enrolled. C-reactive protein (CRP) and metabolic markers (triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), albumin, fasting glucose (Glu) and glycosylated hemoglobin (HbA1c)) were measured. Serum markers were modeled using logistic regression analysis. Results: TG, TC, fasting glucose, HbA1c and CRP were significantly increased (p < 0.05, 0.05, 0.001, 0.001, 0.01, respectively) in elderly epilepsy, whereas HDL-c, LDL-c and serum albumin were decreased (p < 0.001, 0.001, 0.001) in elderly epilepsy. TG, TC, fasting Glu, HbA1c and CRP were significantly elevated (p < 0.05, 0.001, 0.001, 0.001, 0.001, respectively) in epilepsy with cognitive impairment, whereas HDL-c, LDL-c and serum albumin were decreased (p < 0.001, 0.001, 0.001). The abnormal glycolipid profile was predominated in AED-treated patients. The regression model combined with TG, LDL-c, HDL-c and albumin performed better (area under the ROC curve was 0.824) in AED-treated patients. Conclusion: The relevant relationship between glycolipid profile and cognitive impairment with epilepsy was described, and the logistic regression model based on serum TG, LDL-c, HDL-c and albumin is reported and may serve as promising diagnostic markers for elderly epilepsy with cognitive impairment. Additionally, a specific emphasis on the complex role of altered lipid metabolism and AEDs is made.

Exploration of the potential mechanism of Pushen capsule in the treatment of vascular dementia based on network pharmacology and experimental verification.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Pushen capsule is a traditional Chinese medicine compound functioning as 'stimulating blood circulation to remove blood stasis', which widely used to treat hyperlipidemia. Recent clinical research showed that Pushen capsule ameliorated cognitive function in patients with vascular mild cognitive impairment. AIM OF THE STUDY: Explore the potential mechanism of Pushen capsule in vascular dementia (VaD) using network pharmacology analysis and experimental verification. MATERIALS AND METHODS: Active ingredients and their related targets of Pushen capsule, and VaD-related targets were searched in public databases. Core targets, potential functions and mechanisms of Pushen capsule on VaD were predicted by protein-protein interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. In vivo experiments were conducted to demonstrate the potential mechanisms of Pushen capsule in the treatment of VaD. RESULTS: In total, 155 active ingredients, 273 related targets of Pushen capsule, and 1035 VaD-related targets were selected from the public databases. 147 common targets of Pushen capsule against VaD were obtained. The PPI network, GO and KEGG enrichment analyses revealed that some core targets and signaling pathways are related to inflammation. The experimental results showed that Pushen capsule treatment largely alleviated hippocampal glial activation, accelerated the polarization of activated microglia from the M1 to the M2 phenotype and reduced associated inflammatory factor expression to protect against VaD-induced neuronal loss, synaptic protein reduction and cognitive defects in a dose-dependent manner. Moreover, Pushen capsule reduced the mRNA expression of NF-κB p65; and STAT1. CONCLUSION: Our study demonstrates that Pushen capsule alleviates hippocampal neuroinflammation to protect against VaD-induced cognitive impairment in a dose-dependent manner. The neuroprotective effect of Pushen capsule on VaD might be regulated by the NF-κB; and JAK-STAT pathway.

Construction of circRNA-Mediated Immune-Related ceRNA Network and Identification of Circulating circRNAs as Diagnostic Biomarkers in Acute Ischemic Stroke.

Background and Purpose: Accumulating evidence suggests that circular RNAs (circRNAs) are involved in immune and inflammatory processes after acute ischemic stroke (AIS). However, the roles of circRNA-mediated competing endogenous RNA (ceRNA) in modulating immune inflammation of AIS have not yet been determined. This study aimed to construct a circRNA-mediated immune-related ceRNA network and identify novel circRNAs in AIS. Methods: Microarray data were downloaded from the GEO database and further analysed by R software. Then, we constructed a circRNA-mediated ceRNA network based on interaction information from the bioinformatics database. A topological property analysis of the ceRNA network was conducted to screen novel circRNAs. Finally, we further applied quantitative real-time polymerase chain reaction (qRT-PCR) to two independent sets. Results: We constructed an AIS immune-related ceRNA (AISIRC) network containing immune-related genes (IRGs), miRNAs, and circRNAs. Additionally, we extracted the subnetwork from the AISIRC network and screened six immune-related circRNAs. After identification and validation, we finally confirmed that plasma levels of circPTP4A2 and circTLK2 were significantly increased in AIS patients compared with both healthy control subjects (HCs) and transient ischemic attack (TIA) patients. Logistic regression and receiver-operating characteristic (ROC) curve analyses demonstrated that these two circRNAs may function as predictive and discriminative biomarkers for AIS. We also confirmed that plasma levels of circPTP4A2 were elevated in TIA patients compared with HCs and might be an independent risk factor for predicting TIA. Longitudinal analysis of circRNA expression up to 90 days after AIS indicated that the ability of circPTP4A2 and circTLK2 to monitor AIS dynamics was highly desirable. Conclusion: In summary, the circRNA-mediated immune-related ceRNA network was successfully constructed, and two circulating circRNAs (circPTP4A2 and circTLK2) improved sensitivity for the diagnosis of AIS and could be considered diagnostic biomarkers.

SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression.

BACKGROUND: Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression. METHODS: We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches. RESULTS: The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice. CONCLUSIONS: This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691 .

Down-regulation of circular RNA CDC14A peripherally ameliorates brain injury in acute phase of ischemic stroke.

BACKGROUND: Inflammation is integral to the pathophysiology of ischemic stroke and a prime target for the development of new stroke therapies. The aim of the present study is to seek out the regulatory mechanism of circCDC14A in neuroinflammatory injury in tMCAO mice. METHODS: The expression level of circCDC14A in peri-infarct cortex and plasma of mice were detected by qPCR. The localization of circCDC14A in peripheral blood cells and peri-infarct cortex of tMCAO mice were explored by in situ hybridization and immunofluorescence colocalization staining. Lentivirus were microinjected into lateral ventricular of brain or injected into tail vein to interfere with the expression of circCDC14A, thus their effects on behavior, morphology, and molecular biology of tMCAO mice were analyzed. RESULTS: The expression of circCDC14A in plasma and peri-infarct cortex of tMCAO mice significantly increased, and circCDC14A was mainly localized in neutrophils peripherally while in astrocytes in peri-infarct cortex centrally. Tail vein injection of lentivirus to interfere with the expression of circCDC14A significantly reduced the infarct volume (P < 0.01) at 72 h after reperfusion and density of activated astrocytes in peri-infarct cortex at 3 days, 5 days and 7 days after tMCAO modeling (all P < 0.0001). Moreover, mNSS (P < 0.0001) and survival rate (P < 0.001) were significantly improved within 7 days in si-circCDC14A group compared to circCon group. Additionally, morphology analysis showed the volume and surface area of each activated astrocytes significantly decreased (P < 0.0001). Quantification analysis measured the percentage of N2 phenotype among infiltrated neutrophils in brain sections and found N2 ratio was significantly higher in si-circCDC14A group compared to circCon group (P < 0.001). CONCLUSION: Knocking down the expression of circCDC14A in peripheral blood cells relieved astrocytes activation in peri-infarct cortex, thereby relieved brain damage in the acute phase of ischemic stroke.

Endovascular Treatment With and Without Intravenous Thrombolysis in Large Vessel Occlusions Stroke: A Systematic Review and Meta-Analysis.

Background: Previous studies have shown conflicting results about the benefits of pretreatment with intravenous thrombolysis before endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) with large vessel occlusions (LVOs). This study aimed to investigate the clinical efficacy and safety of EVT alone vs. bridging therapy (BT) in patients with AIS with LVOs. Methods: A systematic review with meta-analysis of all available studies comparing clinical outcomes between BT and EVT alone was conducted by searching the National Center for Biotechnology Information/National Library of Medicine PubMed and Web of Science databases for relevant literature from database inception to October 20, 2020. Results: A total of 93 studies enrolling 45,190 patients were included in the present analysis. In both unadjusted and adjusted analyses, BT was associated with a higher likelihood of 90-day good outcome (crude odds ratio [cOR] 1.361, 95% confidence interval [CI] 1.234-1.502 and adjusted OR [aOR] 1.369, 95% CI 1.217-1.540) and successful reperfusion (cOR 1.271, 95% CI 1.149-1.406 and aOR 1.267, 95% CI 1.095-1.465) and lower odds of 90-day mortality (cOR 0.619, 95% CI 0.560-0.684 and aOR 0.718, 95% CI 0.594-0.868) than EVT alone. The two groups did not differ in the occurrence of symptomatic intracranial hemorrhage (sICH) (cOR 1.062, 95% CI 0.915-1.232 and aOR 1.20, 95% CI 0.95-1.47), 24-h early recovery (cOR 1.306, 95% CI 0.906-1.881 and aOR 1.46, 95% CI 0.46-2.19), and number of thrombectomy device passes ≤ 2 (aOR 1.466, 95% CI 0.983-2.185) after sensitivity analyses and adjustment for publication bias. Conclusions: BT provides more benefits than EVT alone in terms of clinical functional outcomes without compromising safety in AIS patients with LVOs.

FBXO22, ubiquitination degradation of PHLPP1, ameliorates rotenone induced neurotoxicity by activating AKT pathway.

Parkinson's disease (PD) is a neurodegenerative disease caused by the lacking of dopaminergic neurons. Many reports have illustrated that rotenone is applied to establish the experimental model of PD, which simulates PD-like symptoms. FBXO22 is a poorly understood protein that may be involved in neurological disorders. However, little is known about FBXO22 in PD. In this study, first, SH-SY5Y cells were treated with rotenone to construct PD model in vitro. It was discovered that the FBXO22 expression was down-regulated following rotenone treatment. Additionally, overexpression of FBXO22 reduced rotenone treatment-mediated cell apoptosis in SH-SY5Y cells. In view of the ubiquitination effect of FBXO22, our study uncovered that FBXO22 bound with and degraded PHLPP1 by ubiquitination. Next, the effects of PHLPP1 on AKT pathway in PD were further explored. It was demonstrated that PHLPP1 inactivated AKT pathway through down-regulating the pAKT/AKT and pmTOR/mTOR levels. Through rescue assays, the results showed that PHLPP1 overexpression partially reversed the reduction of rotenone induced neurotoxicity caused by FBXO22 overexpression. Finally, we found that overexpression of FBXO22 alleviated rotenone-induced PD symptoms in rat model. Moreover, it was discovered that l-dopa treatment could not affect the FBXO22 expression in PD. In conclusion, findings from our work proved that FBXO22 degraded PHLPP1 by ubiquitination to ameliorate rotenone induced neurotoxicity, which attributed to activate AKT pathway. This work suggested that FBXO22 may be an effective biological marker for PD treatment.