77 pubs · 2,338 cites · h-index 26
BACKGROUND: Subarachnoid hemorrhage (SAH) results in the accumulation of blood in the subarachnoid space, which can trigger inflammatory responses and oxidative damage, thereby exacerbating secondary brain injury. Microglia play a critical role in clearing hematomas and cellular debris during pathological recovery. This study aimed to investigate the regulatory role of SIRT2 in phagocytic function and its potential mechanisms. METHODS: The SAH model of endovascular perforation in Sprague-Dawley (SD) rats and in vitro model of primary microglia culture with Oxygenated hemoglobin (OxyHb) stimulation were used. Flow cytometry, Western blot, immunofluorescence, ELISA were used to detect the microglial phagocytic ability, expressions of SRIT2 and LC3-associated phagocytosis (LAP)-related proteins. Molecular docking, and immunoprecipitation were used to explore the underlying mechanism of the SIRT2/NRF2/CD36 signaling pathway. Behavioral experiments were conducted to evaluate changes in neurological function. RESULTS: Within 24 h after SAH, the expression of SIRT2 in brain and microglia was significantly increased, while the phagocytic ability and the expression of LAP-related proteins Rubicon, NOX2 were decreased. After inhibiting SIRT2, microglial LAP function was enhanced and the phagocytic index was increased. Mechanistically, SIRT2 inhibited NRF2 nuclear translocation by deacetylation, thereby downregulating CD36 expression and suppressing microglia LAP. ML385 reversed the enhancement of LAP and the improvement in neurological function induced by SIRT2 inhibition. CONCLUSION: SIRT2 suppresses microglial LAP by deacetylating NRF2, thereby impairing its nuclear translocation and reducing transcriptional expression of CD36 subsequently. Inhibiting SIRT2 may effectively enhance microglial LAP function via activating NRF2/CD36 pathway, promoting blood clearance and improving neurological prognosis after SAH.
Supplementary analysis shows R-2HG reduces proliferation in IDH1 wild-type glioma cells, indicating its potential impact.
Supplementary figure shows the impact of UBE2T on nucleolar function in IDH1/TP53-mutant glioma, suggesting significant implications for tumor progression.
Bioinformatics and in vivo models reveal UBE2T's role in glioma progression, suggesting new therapy targets.
Investigating UBE2T interactions with E3 ubiquitin ligases in glioma, suggesting enhanced nucleolar activity.
Analysis shows how UBE2T-mediated ubiquitination impacts nucleolar function in glioma, indicating its role in tumor progression.
Analysis reveals UBE2T impacts nucleolar function in IDH1/TP53-mutant glioma, suggesting potential therapeutic targets.
UBE2T promotes growth and stem-like properties in glioma cells, indicating its role in tumor progression.
Supplementary details reveal how UBE2T enhances nucleolar function, promoting cancer progression through IDH1 and TP53 mutations.
Prospective cohort analysis reveals hemodynamic differences in moyamoya disease patients, suggesting varying outcomes with bypass techniques.
Prospective cohort study evaluates safety and efficacy of side-to-side bypass for moyamoya disease, suggesting individual approaches based on outcomes.
Preclinical study reveals that UBE2T promotes tumor progression in IDH1 and TP53-mutant glioma, suggesting targeted inhibition by APR-246 as a potential therapeutic strategy.
Long recognized as a significant integrated task in major English proficiency tests, reading-to-write tasks have been researched from dimensions mainly concerning its testing validity. A further exploration into the process is essential for a better understanding of the construct and instructions of the integrated task in different cultural and educational contexts. The present study investigated the process of a response writing task by collecting data of interviews and reflective journals from 36 Chinese learners. These data were analyzed qualitatively to identify the main phases and sub-stages occurring in the reading-to-write process. The results disclosed three main phases: pre-reading, reading for writing, and writing from reading. Besides, among a set of sub-stages, planning and rereading recurred and were embedded with each other in the main phases, and therefore, bridged reading and writing. The purposes of the occurrence of the main phases and recurring sub-stages presented the dynamic agency that learners exercise. Accordingly, a new model was constructed to account for the nuanced processes as well as their connection and interaction in a reading-to-write task, providing new insight into the recursive and reciprocal nature of reading-to-write tasks for learners in the Chinese context and furthermore, into the construct of integrated academic tasks. Pedagogical suggestions for L2 learners were provided in the end.
Purpose: This study primarily elucidating the specific mechanism of SIRT2 on neuroinflammation and microglial pyroptosis in a mouse model of SAH. Patients and Methods: CSF were collected from 57 SAH patients and 11 healthy individuals. C57BL/6 mouse SAH model was established using prechiasmatic cistern blood injection and the in vitro hemoglobin (Hb) stimulation microglia model. Lentivirus was used as a vector for RNA interference technology to knock down the SIRT2 gene expression. Small interfering RNA was used to knockdown the expression of FOXO3a. The tools included measurements of brain water content, neurological scores, Western blot, PCR, ELISA, TEM, immunofluorescence, LDH assay, modified Garcia score, and balance beam tests to evaluate changes in pyroptosis and neuroinflammatory responses. Results: In CSF samples from SAH patients, elevated levels of SIRT2 and GSDMD were observed, with SIRT2 demonstrating particular diagnostic value for predicting prognosis at the 3-month follow-up. SIRT2 upregulation exacerbated neurological deficits, brain edema, and blood-brain barrier disruption in mice following SAH. SIRT2 increased GSDMD, caspase-1, and IL-1β/IL-18 expression, and amplified GSDMD-positive microglia. FOXO3a was also upregulated post-SAH. siRNA-mediated SIRT2 knockdown ameliorated microglial pyroptosis after SAH. FOXO3a siRNA reduced NLRP3 inflammasome activation and microglial pyroptosis severity, along with neuroinflammation post-SAH. Conclusion: In summary, SIRT2 promoted microglial pyroptosis, primarily by increasing the expression and activity of Foxo3a, thereby exacerbating neuroinflammatory damage following subarachnoid hemorrhage.
Background Neuroinflammation participates in the pathogenesis of subarachnoid haemorrhage (SAH); however, no effective treatments exist. MicroRNAs regulate several aspects of neuronal dysfunction. In a previous study, we found that exosomal miR-486-3p is involved in the pathophysiology of SAH. Targeted delivery of miR-486-3p without blood-brain barrier (BBB) restriction to alleviate SAH is a promising neuroinflammation approach. Methods In this study, we modified exosomes (Exo) to form an RVG-miR-486-3p-Exo (Exo/miR) to achieve targeted delivery of miR-486-3p to the brain. Neurological scores, brain water content, BBB damage, flow cytometry and FJC staining were used to determine the effect of miR-486-3p on SAH. Western blot analysis, ELISA and RT-qPCR were used to measure relevant protein and mRNA levels. Immunofluorescence staining and laser confocal detection were used to measure the expression of mitochondria, lysosomes and autophagosomes, and transmission electron microscopy was used to observe the level of mitophagy in the brain tissue of mice after SAH. Results Tail vein injection of Exo/miR improved targeting of miR-486-3p to the brains of SAH mice. The injection reduced levels of neuroinflammation-related factors by changing the phenotype switching of microglia, inhibiting the expression of sirtuin 2 (SIRT2) and enhancing mitophagy. miR-486-3p treatment alleviated neurobehavioral disorders, brain oedema, BBB damage and neurodegeneration. Further research found that the mechanism was achieved by regulating the acetylation level of peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α) after SIRT2 enters the nucleus. Conclusion Exo/miR treatment attenuates neuroinflammation after SAH by inhibiting SIRT2 expression and stimulating mitophagy, suggesting potential clinical applications.
OBJECTIVES: Rheumatic and musculoskeletal diseases (RMD) may exhibit different immune responses to novel coronavirus (COVID-19) infection compared to healthy individuals. While previous studies have primarily investigated changes in COVID-19-related antibodies post-vaccination for RMD patients, this study sought to explore the dynamics of SARS-CoV-2 IgG antibodies and neutralising antibodies (NAb) in RMD patients after COVID-19 infection. METHODS: In this longitudinal study, we monitored the SARS-CoV-2 IgG antibodies and NAb levels in RMD patients and healthy controls (HC) at 60 and 90 days post-COVID-19 infection. Chemiluminescent immunoassay was used to detect the levels of novel coronavirus-specific IgG (anti-S1/S2 IgG) antibodies and NAb. RESULTS: A total of 292 RMD patients and 104 HC were enrolled in the study. At both the 60-day and 90-day post-COVID-19 infection, RMD patients exhibited significantly lower levels of anti-S1/S2 IgG and NAb than those in the HC group (p<0.001). The anti-S1/S2 IgG antibody levels remained relatively stable, while the NAb levels in RMD patients could vary greatly between the 60th and 90th days. A logistic regression analysis revealed that the prior administration of glucocorticoids (GC), immunosuppressants, and b/tsDMARDs stood out as independent risk factors associated with reduced anti-S1/S2 IgG and NAb levels, irrespective of the specific RMD subtypes. CONCLUSIONS: GC and anti-rheumatic medications can potentially alter the production of specific antibodies, especially NAb, in RMD patients post-COVID-19 infection. These findings emphasise the importance of continuous monitoring for NAb fluctuations in RMD patients following a COVID-19 infection.
BACKGROUND: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia. METHODS: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms. RESULTS: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP. CONCLUSION: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract.
Objective. The search for methods by which to predict the risks of cerebral hyperperfusion syn-drome (CHS) in adults with moyamoya disease (MMD), including those utilizing new biomarkers, still deserves further research. The objective of this study was to investigate the association between the hemodynamics of parasylvian cortical arteries (PSCAs) and postoperative CHS. Methods. A consecutive number of adults with MMD who had undergone direct bypass between September 2020 and December 2022 were recruited. Intraoperative microvascular doppler ultrasonography (MDU) was performed to evaluate the hemodynamics of PSCAs. The intraoperative flow direction, mean value of velocity (MVV) of recipient artery (RA) and bypass graft were recorded. According to flow direction after bypass, RA was divided into entering sylvian (RA.ES) and leaving sylvian (RA.LS) subtypes. Univariate, multivariate, and ROC analyses of the risk factors for postoperative CHS were performed. Results. A total of 16 (15.09%) cases in 106 consecutive hemispheres (101 patients) sat-isfied the postoperative CHS criteria. According to univariate analysis, advanced Suzuki stage, MVV of RA before bypass, and fold increase of MVV in RA.ES after bypass were significantly associated with postoperative CHS (p < 0.05). Multivariate analysis indicated that left-operated hemisphere (OR (95%CI), 4.58 (1.05–19.97), p = 0.043), advanced Suzuki stage (OR (95%CI), 5.47 (1.99–15.05), p = 0.017), and fold increase of MVV in RA.ES (OR (95%CI), 1.17 (1.06–1.30), p = 0.003) were statistically significantly associated with the occurrence of CHS. The cut-off value of fold increase of MVV in RA.ES was 2.7-fold (p < 0.05). Conclusions. Left-operated hemisphere, advanced Suzuki stage, and postoperative fold increase of MVV in RA.ES were potential risk factors for postoperative CHS. Intraoperative MDU was useful for evaluating hemodynamics and predicting CHS.
Identifies risk factors for cerebral hyperperfusion syndrome in adults with moyamoya disease, indicating prompt treatment preserves clinical prognosis.
The presence of aneurysmal subarachnoid hemorrhage (aSAH) is usually accompanied by excessive inflammatory response leading to damage of the central nervous system, and the sialic acid-binding Ig-like lectin 10 (Siglec-10) is a recognized factor being able to modify the inflammatory reaction. To investigate the potential role of Siglec-10 in aSAH, we collected the cerebrospinal fluid (CSF) of control ( n = 11 ) and aSAH ( n = 14 ) patients at separate times and measured the Siglec-10 concentration utilizing the enzyme-linked immunosorbent assay (ELISA) and evaluated the alterations of GOS and GCS during the disease process. In accordance with the STROBE statement, results showed that Siglec-10 in CSF rose quickly in response aSAH attack and then fell back to a slightly higher range above baseline, while it remained at relative high concentration and last longer in several severely injured patients. In general, higher Siglec-10 expression over a longer period usually indicated a better clinical prognosis. This prospective cohort study suggested that Siglec-10 could possibly be used as a biomarker for predicting prognosis of aSAH due to its ability to balance aSAH-induced nonsterile inflammation. Additionally, these findings might provide novel therapeutic perspectives for aSAH and other inflammation-related diseases.