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Stroke ranks second as a leading cause of death and permanent disability globally. Microglia, innate immune cells in the brain, respond rapidly to ischemic injury, triggering a robust and persistent neuroinflammatory reaction throughout the disease’s progression. Neuroinflammation plays a critical role in the mechanism of secondary injury in ischemic stroke and is a significant controllable factor. Microglia activation takes on two general phenotypes: the pro-inflammatory M1 type and the anti-inflammatory M2 type, although the reality is more complex. The regulation of microglia phenotype is crucial to controlling the neuroinflammatory response. This review summarized the key molecules and mechanisms of microglia polarization, function, and phenotypic transformation following cerebral ischemia, with a focus on the influence of autophagy on microglia polarization. The goal is to provide a reference for the development of new targets for the treatment for ischemic stroke treatment based on the regulation of microglia polarization.

Phosphoinositide 3-kinase beta (PI3Kβ) plays an important role in platelet activation and thrombosis, but its role in stroke pathology remains unknown. In this study, we investigated whether inhibition of PI3Kβ protects against cerebral ischemia/reperfusion (I/R) injury by preventing circulating platelet activation and downstream microvascular thrombosis. We used a rat intraluminal filament model of transient middle cerebral artery occlusion (tMCAO) because the rapid restoration of cerebral blood flow to the ischemic area in both tMCAO and endovascular thrombectomy provides clinical relevance for this model. The results showed that TGX221, a selective PI3Kβ inhibitor, treatment immediately before the onset of reperfusion dose-dependently reduced infarct volume and improved neurological function. The protective effects were associated with blocking platelet activation and thrombotic response, thereby reducing downstream microvascular thrombosis, and maintaining reperfusion efficiency. These results suggest that PI3Kβ might be a promising target for treating downstream microvascular thrombosis induced by cerebral I/R injury and offer a novel adjunctive treatment to improve reperfusion therapy for acute ischemic stroke.

Collagen-type I alpha 1 chain (COL1A1) and COL1A2 are abnormally expressed in intracranial aneurysm (IA), but their mechanism of action remains unclear. This study was performed to investigate the mechanism of COL1A1 and COL1A2 affecting the occurrence and rupture of IA. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-miR-513b-5p, COL1A1, COL1A2, TNF-α, IL-6, MMP2, MMP3, MMP9 and TIMP4 in patients with ruptured IA (RA) (n = 100), patients with un-ruptured IA (UA) (n = 100), and controls (n = 100). Then, human vascular smooth muscle cells (HASMCs) were cultured, and dual luciferase reporter assay was performed to analyse the targeting relationship between miR-513b-5p and COL1A1 or COL1A2. The effects of the miR-513b-5p mimic and inhibitor on the proliferation, apoptosis, and death of HASMC and the RIP1-RIP3-MLKL and matrix metalloproteinase pathways were also explored. The effect of silencing and over-expression of COL1A1 and COL1A2 on the role of miR-513b-5p were also evaluated. Finally, the effects of TNF-α on miR-513b-5p targeting COL1A1 and COL1A2 were tested. Compared with those in the control group, the serum mRNA levels of miR-513b-5p, IL-6 and TIMP4 were significantly decreased in the RA and UA groups, but COL1A1, COL1A2, TNF-α, IL-1β, MMP2, MMP3 and MMP9 were significantly increased ( p  < 0.05). Compared with those in the UA group, the expression of COL1A1, COL1A2, TNF-α, IL-1β and MMP9 was significantly up-regulated in the RA group ( p  < 0.05). Results from the luciferase reporter assay showed that COL1A1 and COL1A were the direct targets of miR-513b-5p. Further studies demonstrated that miR-513b-5p targeted COL1A1/2 to regulate the RIP1-RIP3-MLKL and MMP pathways, thereby enhancing cell death and apoptosis. Over-expression of COL1A1 or COL1A2, rather than silencing COL1A1/2, could improve the inhibitory effect of miR-513b-5p on cell activity by regulating the RIP1-RIP3-MLKL and MMP pathways. Furthermore, over-expression of miR-513b-5p and/or silencing COL1A1/2 inhibited the TNF-α-induced cell proliferation and enhanced the TNF-α-induced cell death and apoptosis. The mechanism may be related to the inhibition of collagen I and TIMP4 expression and promotion of the expression of RIP1, p-RIP1, p-RIP3, p-MLKL, MMP2 and MMP9. MiR-513b-5p targeted the inhibition of COL1A1/2 expression and affected HASMC viability and extracellular mechanism remodelling by regulating the RIP1-RIP3-MLKL and MMP pathways. This process might be involved in the formation and rupture of IA.

The main challenge for the advancement of current high-speed automotives is aerodynamic heating. In this study, the application of lateral jet for thermal protection of the high-speed automotives is extensively studied. The simulation of the lateral coolant jet is done via Computational fluid dynamic at high-velocity condition. Finding optimum jet configuration for reduction of the aerodynamic heating is the main goal of this research. Two different coolant jets (Helium and Carbon dioxide) are investigated as coolant jet and flow study and fuel penetration mechanism are fully presented. In addition, the thermal load on the main body of nose cone is compared for different configurations. Our results specify that the injection of lateral jet near the tip of spike is effective for thermal protection of main body via deflection of bow shock. Also, Carbon dioxide jet with lower diffusivity is more effective for the protection of forebody with multi-row disk from sever aerodynamic heating.

Neuroinflammation is a feature common to neurodegenerative diseases, such as Parkinson’s disease (PD), which might be responsive to therapeutic intervention. Rotenone has been widely used to establish PD models by inducing mitochondrial dysfunction and inflammation. Our previous studies have reported that pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor, could prevent mitochondrial dysfunction in rotenone induced PD models by regulating mitochondrial functions. In the present study, we aimed to investigate the effect of PQQ on neuroinflammation and the mechanism involved. BV2 microglia cells were pre-treated with PQQ followed by rotenone incubation. The data showed that PQQ did not affect the cell viability of BV2 cells treated with rotenone, while the conditioned medium (CM) of BV2 cells pre-treated with PQQ significantly increased cell viability of SH-SY5Y cells. In rotenone-treated BV2 cells, PQQ dose-dependently decreased lactate dehydrogenase (LDH) release and suppressed the up-regulation of pro-inflammation factors, such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in the cultured media, as well as nitric oxide (NO) release induced by rotenone. PQQ pretreatment also increased the ratio of LC3-II/LC3-I and expression of Atg5 in BV2 cells stimulated with rotenone. Additionally, the autophagosome observed by transmission electron microscopy (TEM) and co-localization of mitochondria with lysosomes indicated that mitophagy was induced by PQQ in rotenone-injured BV2 cells, and the PINK1/parkin mediated mitophagy pathway was regulated by PQQ. Further, autophagy inhibitor, 3-methyladenine (3-MA), partially abolished the neuroprotective effect of PQQ and attenuated the inhibition of inflammation with PQQ pretreatment. Taken together, our data extend our understanding of the neuroprotective effect of PQQ against rotenone-induced injury and provide evidence that autophagy enhancement might be a novel therapeutic strategy for PD treatment.

Background APOBEC-1 complementation factor (A1CF) and Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-1 (APOBEC-1) constitute the minimal proteins necessary for the editing of apolipoprotein B (apoB) mRNA in vitro. Unlike APOBEC-1 and apoB mRNA, the ubiquitous expression of A1CF in human tissues suggests its unique biological significance, with various factors such as protein kinase C, thyroid hormones, and insulin regulating the activity and expression of A1CF. Nevertheless, few studies have provided an overview of this topic. Objective We conducted a literature review to describe the molecular mechanisms of A1CF and its relevance to human diseases. Method In the PubMed database, we used the keywords ‘A1CF’ and ‘APOBEC-1 complementation factor’ to collect peer-reviewed articles published in English from 2000 to 2023. Two authors independently reviewed the articles and reached the consensus. Result After reviewing 127 articles, a total of 61 articles that met the inclusion criteria were included in the present review. Studies revealed that A1CF is involved in epigenetic regulation of reproductive cells affecting embryonic development, and that it is closely associated with the occurrence of gout due to its editing properties on apoB. A1CF can also affect the process of epithelial-mesenchymal transition in renal tubular epithelial cells and promote liver regeneration by controlling the stability of IL-6 mRNA, but no influence on cardiac function was found. Furthermore, increasing evidence suggests that A1CF may promote the occurrence and development of breast cancer, lung cancer, renal cell carcinoma, hepatocellular carcinoma, endometrial cancer, and glioma. Conclusion This review clarifies the association between A1CF and other complementary factors and their impact on the development of human diseases, aiming to provide guidance for further research on A1CF, which can help treat human diseases and promote health.

The natural compound curcumin (Cur) can regulate growth inhibition and apoptosis in various cancer cell lines, although its clinical applications are restricted by extreme water insolubility and instability. To overcome these hurdles, we fabricated a Cur-coordinated reactive oxygen species (ROS)-responsive nanoparticle using the interaction between boronic acid and Cur. We synthesized a highly biocompatible 4-(hydroxymethyl) phenylboronic acid (HPBA)-modified poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) polymer (PPH) and fabricated a Cur-coordinated ROS-responsive nanoparticle (denoted by PPHC) based on the interaction between boronic acid and Cur. The mean diameter of the Cur-coordinated PPHC nanoparticle was 163.8 nm and its zeta potential was -0.31 mV. The Cur-coordinated PPHC nanoparticle improved Cur stability in physiological environment and could timely release Cur in response to hydrogen peroxide (H O ). PPHC nanoparticles demonstrated potent antiproliferative effect in vitro in A549 cancer cells. Furthermore, the viability of cells treated with PPHC nanoparticles was significantly increased in the presence of -acetyl-cysteine (NAC), which blocks Cur release through ROS inhibition. Simultaneously, the ROS level measured in A549 cells after incubation with PPHC nanoparticles exhibited an obvious downregulation, which further proved that ROS depression indeed influenced the therapeutic effect of Cur in PPHC nanoparticles. Moreover, pretreatment with phosphate-buffered saline (PBS) significantly impaired the cytotoxic effect of Cur in A549 cells in vitro while causing less damage to the activity of Cur in PPHC nanoparticle. The Cur-coordinated nanoparticles developed in this study improved Cur stability, which could further release Cur in a ROS-dependent manner in cancer cells.

To identify the effectiveness of remimazolam at the end of tonsillectomy and adenoidectomy for preventing emergence delirium in children under sevoflurane anesthesia. One hundred and four patients aged 3-7 years scheduled for tonsillectomy and adenoidectomy under sevoflurane anesthesia were recruited. Patients were randomly assigned to receive either remimazolam 0.2 mg kg (intervention, n=52) or 0.9% normal saline (control, n=52) at the end of the procedure. The primary outcome was the incidence of emergence delirium, defined as a Pediatric Anesthesia Emergence Delirium (PAED) score ≥10. Secondary outcomes were peak PAED score, emergence time, postoperative pain intensity, length of postanesthesia care unit (PACU) stay, parental satisfaction, and postoperative behavior changes three days postoperatively. Emergence delirium occurred in 6 of 51 (12%) patients receiving remimazolam versus 22 of 50 (44%) patients receiving saline (risk difference 32% [95% confidence interval, 16% to 49%], relative risk 0.27 [95% confidence interval, 0.12 to 0.60]; <0.001). The peak PAED scores (median [interquartile range]) were lower in the remimazolam group than in the saline group (7 [6-8] versus 9 [8-11], <0.001). Likewise, parental satisfaction was improved in the remimazolam group compared with the saline group (9 [8-10] versus 8 [7-8], <0.001). There was no difference between groups concerning postoperative pain scores, length of PACU stay, or postoperative behavior changes. In children undergoing tonsillectomy and adenoidectomy, administration of remimazolam 0.2 mg kg at the end of the surgery, compared with 0.9% saline, resulted in a significantly lower likelihood of emergence delirium after sevoflurane anesthesia.

We aimed to investigate potential synergistic antiplatelet effects of extract (GBE50) in combination with aspirin using in vitro models. Arachidonic acid (AA), platelet activating factor (PAF), adenosine 5'-diphosphate (ADP) and collagen were used as inducers. The antiplatelet effects of GBE50, aspirin and 1:1 combination of GBE50 and aspirin were detected by microplate method using rabbit platelets. Synergy finder 2.0 was used to analyze the synergistic antiplatelet effect. The compounds in GBE50 were identified by UPLC-Q/TOF-MS analysis and the candidate compounds were screened by TCMSP database. The targets of candidate compounds and aspirin were obtained in TCMSP, CCGs, Swiss target prediction database and drugbank. Targets involving platelet aggregation were obtained from GenCLiP database. Compound-target network was constructed and GO and KEGG enrichment analyses were performed to identify the critical biological processes and signaling pathways. The levels of thromboxane B2 (TXB2), cyclic adenosine monophosphate (cAMP) and PAF receptor (PAFR) were detected by ELISA to determine the effects of GBE50, aspirin and their combination on these pathways. GBE50 combined with aspirin inhibited platelet aggregation more effectively. The combination displayed synergistic antiplatelet effects in AA-induced platelet aggregation, and additive antiplatelet effects occurred in PAF, ADP and collagen induced platelet aggregation. Seven compounds were identified as candidate compounds in GBE50. Enrichment analyses revealed that GBE50 could interfere with platelet aggregation via cAMP pathway, AA metabolism and calcium signaling pathway, and aspirin could regulate platelet aggregation through AA metabolism and platelet activation. ELISA experiments showed that GBE50 combined with aspirin could increase cAMP levels in resting platelets, and decreased the levels of TXB2 and PAFR. Our study indicated that GBE50 combined with aspirin could enhance the antiplatelet effects. They exerted both synergistic and additive effects in restraining platelet aggregation. The study highlighted the potential application of GBE50 as a supplementary therapy to treat thrombosis-related diseases.