Therapeutic Potential of Natural Compounds in Subarachnoid Haemorrhage.

Subarachnoid hemorrhage (SAH) is a common and fatal cerebrovascular disease with high morbidity, mortality and very poor prognosis worldwide. SAH can induce a complex series of pathophysiological processes, and the main factors affecting its prognosis are early brain injury (EBI) and delayed cerebral ischemia (DCI). The pathophysiological features of EBI mainly include intense neuroinflammation, oxidative stress, neuronal cell death, mitochondrial dysfunction and brain edema, while DCI is characterized by delayed onset ischemic neurological deficits and cerebral vasospasm (CVS). Despite much exploration in people to improve the prognostic outcome of SAH, effective treatment strategies are still lacking. In recent years, numerous studies have shown that natural compounds of plant origin have unique neuro- and vascular protective effects in EBI and DCI after SAH and long-term neurological deficits, which mainly include inhibition of inflammatory response, reduction of oxidative stress, anti-apoptosis, and improvement of blood-brain barrier and cerebral vasospasm. The aim of this paper is to systematically explore the processes of neuroinflammation, oxidative stress, and apoptosis in SAH, and to summarize natural compounds as potential targets for improving the prognosis of SAH and their related mechanisms of action for future therapies.

Impinging Flow Mediates Vascular Endothelial Cell Injury through the PKCα/ERK/PPARγ Pathway in vitro.

INTRODUCTION: This study aimed to elucidate the mechanisms underlying endothelial injury in the context of intracranial aneurysm formation and development, which are associated with vascular endothelial injury caused by hemodynamic abnormalities. Specifically, we focus on the involvement of PKCα, an intracellular signaling transmitter closely linked to vascular diseases, and its role in activating MAPK. Additionally, we investigate the protective effects of PPARγ, a vasculoprotective factor known to attenuate vascular injury by mitigating the inflammatory response in the vessel wall. METHODS: The study employs a modified T-chamber to replicate fluid flow conditions at the artery bifurcation, allowing us to assess wall shear stress effects on human umbilical vein endothelial cells in vitro. Through experimental manipulations involving PKCα knockdown and Ca2+ and MAPK inhibitors, we evaluated the phosphorylation status of PKCα, NF-κB, ERK5, ERK1/2, JNK1/2/3, and P38, as well as the expression levels of PPARγ, NF-κB, and MMP2 via Western blot analysis. The cellular localization of phosphorylated NF-κB was determined using immunofluorescence. RESULTS: Our results showed that impinging flow resulted in the activation of PKCα, followed by the phosphorylation of ERK5, ERK1/2, and JNK1/2/3, leading to a decrease in PPARγ expression, an increase in the expression of NF-κB and MMP2, and the induction of apoptotic injury. Inhibition of PKCα activation or knockdown of PKCα using shRNA leads to a suppression of ERK5, ERK1/2, JNK1/2/3, and P38 phosphorylation, an elevation in PPARγ expression, and a reduction in NF-κB and MMP2 expression, alleviated apoptotic injury. Furthermore, we observe that the regulation of PPARγ, NF-κB, and MMP2 expression is influenced by ERK5 and ERK1/2 phosphorylation, and activation of PPARγ effectively counteracts the elevated expression of NF-κB and MMP2. CONCLUSION: Our findings suggest that the PKCα/ERK/PPARγ pathway plays a crucial role in mediating endothelial injury under conditions of impinging flow, with potential implications for vascular diseases and intracranial aneurysm development.

HMGB1 induced oxidative stress and Inflammation in endothelial cells exposed to Impinging Flow.

BACKGROUND: Oxidative stress and inflammation contribute to many aspects of the pathological processes involved in intracranial aneurysm (IA). However, the underlying mechanism for inducing oxidative stress and inflammation under impinging flow remains unclear. Accumulating evidence has shown that High mobility group box-1 (HMGB1) is associated with oxidative stress-related chronic diseases and inflammatory responses. Therefore, we aimed to investigate whether HMGB1 is involved in oxidative stress and inflammatory responses in endothelial cells (ECs) exposed to impinging flow. METHODS: We used a modified T-chamber to simulate the in vitro situation of human umbilical vein endothelial cells (HUVECs) subjected to impinging flow at the arterial bifurcation in order to analyze the effect of wall shear stress (WSS) on the ECs. To investigate the role of HMGB1 in this process, we transfected ECs with shRNA before conducting impinging flow experiments. Intracellular reactive oxygen species (ROS) were measured by flow cytometry, and malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels were measured to assess oxidative stress. Inflammation was assessed by measuring the mRNA expression levels of IL-1ß, IL-6 and IL-8 using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We also examined the cellular localisation of HMGB1 by immunofluorescence. RESULTS: Exposure of HUVECs to WSS can increase the level of oxidative stress and inflammatory response. WSS increased the expression of HMGB1 in ECs and promoted the translocation of HMGB1 from cytosol to cytoplasm. When we knocked down HMGB1, the level of oxidative stress and inflammatory response caused by WSS in ECs decreased, suggesting that HMGB1 can mediate the oxidative stress and inflammatory response in HUVECs exposed to WSS. Conclusions：HMGB1 induced oxidative stress and inflammatory response in ECs exposed to Impinging Flow.

HELLPAR/RRM2 axis related to HMMR as novel prognostic biomarker in gliomas.

BACKGROUND: Gliomas are the most frequent type of central nervous system tumor, accounting for more than 70% of all malignant CNS tumors. Recent research suggests that the hyaluronan-mediated motility receptor (HMMR) could be a novel potential tumor prognostic marker. Furthermore, mounting data has highlighted the important role of ceRNA regulatory networks in a variety of human malignancies. The complexity and behavioural characteristics of HMMR and the ceRNA network in gliomas, on the other hand, remained unknown. METHODS: Transcriptomic expression data were collected from TCGA, GTEx, GEO, and CGGA database.The relationship between clinical variables and HMMR was analyzed with the univariate and multivariate Cox regression. Kaplan-Meier method was used to assess OS. TCGA data are analyzed and processed, and the correlation results obtained were used to perform GO, GSEA, and ssGSEA. Potentially interacting miRNAs and lncRNAs were predicted by miRWalk and StarBase. RESULTS: HMMR was substantially expressed in gliomas tissues compared to normal tissues. Multivariate analysis revealed that high HMMR expression was an independent predictive predictor of OS in TCGA and CGGA. Functional enrichment analysis found that HMMR expression was associated with nuclear division and cell cycle. Base on ssGSEA analysis, The levels of HMMR expression in various types of immune cells differed significantly. Bioinformatics investigation revealed the HEELPAR-hsa-let-7i-5p-RRM2 ceRNA network, which was linked to gliomas prognosis. And through multiple analysis, the good predictive performance of HELLPAR/RRM2 axis for gliomas patients was confirmed. CONCLUSION: This study provides multi-layered and multifaceted evidence for the importance of HMMR and establishes a HMMR-related ceRNA (HEELPAR-hsa-let-7i-5p-RRM2) overexpressed network related to the prognosis of gliomas.

The efficacy and safety of quinagolide in hyperprolactinemia treatment: A systematic review and meta-analysis.

Purpose: Three dopamine agonists [bromocriptine, cabergoline, and quinagolide (CV)] have been used for hyperprolactinemia treatment for decades. Several studies have reviewed the efficacy and safety of bromocriptine and cabergoline. However, no systematic review or meta-analysis has discussed the efficacy and safety of CV in hyperprolactinemia and prolactinoma treatment. Methods: Five medical databases (PubMed, Web of Science, Embase, Scopus, and Cochrane Library) were searched up to 9 May 2022 to identify studies related to CV and hyperprolactinemia. A meta-analysis was implemented by using a forest plot, funnel plot, sensitivity analysis, meta-regression, and Egger's test via software R 4.0 and STATA 12. Results: A total of 1,211 studies were retrieved from the five medical databases, and 33 studies consisting of 827 patients were finally included in the analysis. The pooled proportions of patients with prolactin concentration normalization and tumor reduction (>50%) under CV treatment were 69% and 20%, respectively, with 95% confidence intervals of 61%-76% and 15%-28%, respectively. The pooled proportion of adverse effects was 13%, with a 95% confidence interval of 11%-16%. Conclusion: Our study showed that CV is not less effective than cabergoline and bromocriptine in treating hyperprolactinemia, and the side effects were not significant. Hence, this drug could be considered an alternative first-line or rescue treatment in treating hyperprolactinemia in the future. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022347750.

A novel prognostic signature of cuproptosis-related genes and the prognostic value of FDX1 in gliomas.

Background: Gliomas are the most common malignant tumors of the central nervous system, with extremely bad prognoses. Cuproptosis is a novel form of regulated cell death. The impact of cuproptosis-related genes on glioma development has not been reported. Methods: The TCGA, GTEx, and CGGA databases were used to retrieve transcriptomic expression data. We employed Cox's regressions to determine the associations between clinical factors and cuproptosis-related gene expression. Overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) were evaluated using the Kaplan-Meier method. We also used the least absolute shrinkage and selection operator (LASSO) regression technique. Results: The expression levels of all 10 CRGs varied considerably between glioma tumors and healthy tissues. In glioma patients, the levels of CDKN2A, FDX1, DLD, DLAT, LIAS, LIPT1, and PDHA1 were significantly associated with the OS, disease-specific survival, and progression-free interval. We used LASSO Cox's regression to create a prognostic model; the risk score was (0.882340) *FDX1 expression + (0.141089) *DLD expression + (-0.333875) *LIAS expression + (0.356469) *LIPT1 expression + (-0.123851) *PDHA1 expression. A high-risk score/signature was associated with poor OS (hazard ratio = 3.50, 95% confidence interval 2, -4.55, log-rank p < 0.001). Cox's regression revealed that the FDX1 level independently predicted prognosis; FDX1 may control immune cell infiltration of the tumor microenvironment. Conclusion: The CRG signature may be prognostic in glioma patients, and the FDX1 level may independently predict glioma prognosis. These data may afford new insights into treatment.

Bioinformatics analysis constructs potential ferroptosis-related ceRNA network involved in the formation of intracranial aneurysm.

Background: Intracranial aneurysm (IA) causes more than 80% of nontraumatic subarachnoid hemorrhages (SAHs). The mechanism of ferroptosis involved in IA formation remains unclear. The roles played by competitive endogenous RNA (ceRNA) regulation networks in many diseases are becoming clearer. The goal of this study was to understand more fully the ferroptosis-related ceRNA regulation network in IA. Materials and methods: To identify differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially expressed lncRNAs (DELs) across IA and control samples, the GEO datasets GSE122897 and GSE66239 were downloaded and analyzed with the aid of R. Ferroptosis DEGs were discovered by exploring the DEGs of ferroptosis-related genes of the ferroptosis database. Potentially interacting miRNAs and lncRNAs were predicted using miRWalk and StarBase. Enrichment analysis was also performed. We utilized the STRING database and Cytoscape software to identify protein-protein interactions and networks. DAB-enhanced Prussian blue staining was used to detect iron in IA tissues. Results: Iron deposition was evident in IA tissue. In all, 30 ferroptosis DEGs, 5 key DEMs, and 17 key DELs were screened out for constructing a triple regulatory network. According to expression regulation of DELs, DEMs, and DEGs, a hub triple regulatory network was built. As the functions of lncRNAs are determined by their cellular location, PVT1-hsa-miR-4644-SLC39A14 ceRNA and DUXAP8-hsa-miR-378e/378f-SLC2A3 ceRNA networks were constructed. Conclusion: CeRNA (PVT1-hsa-miR-4644-SLC39A14 and DUXAP8-hsa-miR-378e/378f-SLC2A3) overexpression networks associated with ferroptosis in IA were established.

The Association of Morphological Differences of Middle Cerebral Artery Bifurcation and Aneurysm Formation: A Systematic Review and Meta-Analysis.

OBJECTIVE: We explored the relationships between morphological parameters of middle cerebral artery (MCA) bifurcations based on imaging and the development of middle cerebral aneurysms. Artery bifurcations can form disordered hemodynamics which can promote the development of aneurysms, whereas the hemodynamic environment at the bifurcation tip is highly reliant on the bifurcation's geometry. METHODS: We searched 3 electronic databases for all relevant, publicly available publications as of March 18, 2022. Through the screening of abstracts and full texts, a meta-analysis was performed to compare the daughter-to-daughter angle, the inclination angle (γ), and the parent vessel diameter of MCA bifurcations between patients in MCA aneurysm and non-aneurysm controls. RESULTS: Ten articles describing 1012 patients with MCA aneurysms and 1106 control individuals without aneurysms were included in the analysis. The aneurysm group showed a larger daughter-to-daughter branch angle at MCA bifurcations than the non-aneurysm group (weighted mean difference [WMD] = 42.00; 95% confidence interval [CI], 33.77 to 50.23; P < 0.00001). The daughter-to-daughter angle was also larger in the MCA aneurysm group with than without an aneurysm side branch (WMD = 37.03; 95% CI, 26.57 to 47.50; P < 0.00001), and in the MCA aneurysm group than in the non-aneurysm control group (WMD = 41.87; 95% CI, 29.19 to 54.54; P < 0.00001). The aneurysm group had a larger inclination angle than the control group (WMD = 28.73; 95% CI, 18.78 to 38.69; P < 0.00001). In patients with a MCA aneurysm, the parent vessel of the branch with the MCA aneurysm tended to be smaller in diameter than the contralateral branch without the aneurysm (WMD = -0.12; 95% CI, -0.24 to 0.00; P = 0.05). CONCLUSIONS: A larger daughter-to-daughter angle and larger inclination angle at MCA bifurcations are closely related to MCA bifurcation aneurysms. The parent vessel diameter is negatively related to MCA bifurcation aneurysms.

Increased ASF1B Expression Correlates With Poor Prognosis in Patients With Gliomas.

Background: Several studies have suggested that anti-silencing function 1 B (ASF1B) can serve as a good potential marker for predicting tumor prognosis. But the values of ASF1B in gliomas have not been elucidated and further confirmation is needed. Methods: Transcriptomic and clinical data were downloaded from The Cancer Genome Atlas database (TCGA), genotypic tissue expression (GTEx), and the Chinese Gliomas Genome Atlas database (CGGA). Univariate and multivariate Cox regression analyses were used to investigate the link between clinical variables and ASF1B. Survival analysis was used to assess the association between ASF1B expression and overall survival (OS). The relationship between ASF1B expression and OS was studied using survival analysis. To investigate the probable function and immunological infiltration, researchers used gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA). Results: In glioma tissues, ASF1B expression was considerably higher than in normal tissues. The survival analysis found that increased ASF1B expression was linked with a poor prognosis in glioma patients. ASF1B demonstrated a high diagnostic value in glioma patients, according to a Receiver Operating Characteristic (ROC) analysis. ASF1B was found to be an independent predictive factor for OS in a Cox regression study (HR = 1.573, 95% CI: 1.053-2.350, p = 0.027). GO, KEGG, and GSEA functional enrichment analysis revealed that ASF1B was associated with nuclear division, cell cycle, m-phase, and cell cycle checkpoints. Immuno-infiltration analysis revealed that ASF1B was positively related to Th2 cells, macrophages, and aDC and was negatively related to pDC, TFH, and NK CD56 bright cells. Conclusion: A high level of ASF1B mRNA expression was correlated with a poor prognosis in glioma patients in this study, implying that it could be a reliable prognostic biomarker for glioma patients.

Impinging Flow Induces Expression of Monocyte Chemoattractant Protein-1 in Endothelial Cells Through Activation of the c-Jun N-terminal Kinase/c-Jun/p38/c-Fos Pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is an important regulator of the formation and development of intracranial aneurysms. This study explored the molecular mechanisms underlying the induction of MCP-1 and related inflammatory factors in human umbilical vein endothelial cells (HUVECs) under hemodynamic conditions. METHODS: A modified T chamber was used to simulate fluid flow at the bifurcation of the artery and wall shear stress on HUVECs in vitro. Changes in HUVECs were analyzed in response to impinging flow. And HUVECs without impinging flow were used as the control group. Protein expression levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, activator protein-1, and MCP-1 were detected by Western blot, and the messenger RNA expression levels of MCP-1, interleukin (IL)-1ß, and IL-6 were determined by quantitative reverse transcription polymerase chain reaction. RESULTS: Under impinging flow, the phosphorylation levels of ERK, JNK, and p38, as well as the protein levels of MCP-1, c-Jun, and c-Fos, increased. The messenger RNA expression of MCP-1, IL-1ß, and IL-6 also increased in HUVECs. Pretreatment of the HUVECs with inhibitors of JNK and p38 significantly attenuated the increased expression of MCP-1, IL-1ß, and IL-6, while ERK inhibitors had no obvious effect. CONCLUSIONS: Under impinging flow, MCP-1 and inflammatory factors are regulated through the JNK/c-Jun/p38/c-Fos pathway and participate in EC inflammation.

Potential Role of the Chemotaxis System in Formation and Progression of Intracranial Aneurysms Through Weighted Gene Co-Expression Network Analysis.

BACKGROUND: Intracranial aneurysm (IA) is the most common and is the main cause of spontaneous subarachnoid hemorrhage (SAH). The underlying molecular mechanisms for preventing IA progression have not been fully identified. Our research aimed to identify the key genes and critical pathways of IA through gene co-expression networks. METHODS: Gene Expression Omnibus (GEO) datasets GSE13353, GSE54083 and GSE75436 were used in the study. The genetic data were analyzed by weighted gene co-expression network analysis (WGCNA). Then the clinically significant modules were identified and the differentially expressed genes (DEGs) with the genes were intersected in these modules. GO (gene ontology) and KEGG (Kyoto Gene and Genomic Encyclopedia) were used for gene enrichment analysis to determine the function or pathway. In addition, the composition of immune cells was analyzed by CIBERSORT algorithm. Finally, the hub genes and key genes were identified by GSE122897. RESULTS: A total of 266 DEGs and two modules with clinical significance were identified. The inflammatory response and immune response were identified by GO and KEGG. CCR5, CCL4, CCL20, and FPR3 were the key genes in the module correlated with IA. The proportions of infiltrating immune cells in IA and normal tissues were different, especially in terms of macrophages and mast cells. CONCLUSION: The chemotactic system has been identified as a key pathway of IA, and interacting macrophages may regulate this pathological process.