Glioma is the most common malignant brain tumor and has high lethality. This tumor generated a robust inflammatory response that results in the deterioration of the disease. However, the prognostic role of systemic cellular inflammatory indicators in gliomas remains controversial. This meta‐analysis aimed to assess the prognostic significance of preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), red cell distribution width (RDW), and prognostic nutritional index (PNI) in patients with gliomas. Databases of PubMed, EMBASE, Web of Science, and The Cochrane Library were systematically searched for all studies published up to January 2019. Study screening and data extraction followed established Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The Newcastle–Ottawa Scale was used to assess the quality of studies. Eighteen studies containing 3,261 patients were included. The analyses showed an increased NLR or RDW was found to be an independent predictor of worse survival in patients with gliomas (hazard ratio (HR): 1.38; 95% confidence interval (CI): 1.09–1.74; P = 0.008; and HR: 1.40; 95% CI: 1.13–1.74; P = 0.002, respectively). Furthermore, a higher PNI indicates a better overall survival (OS; HR: 0.57; 95% CI: 0.42–0.77; P = 0.0002). For the evaluation of PLR and LMR, none of these variables correlated with OS (P = 0.91 and P = 0.21, respectively). Our meta‐analysis indicates the NLR, RDW, and PNI rather than PLR and LMR are the independent index for predicting the OS of gliomas. Pre‐operative NLR, RDW, and PNI can help to evaluate disease progression, optimize treatment, and follow‐up in patients with gliomas.

Chronic cerebral ischemia is a complex form of stress, of which the most common hemodynamic characteristic is chronic cerebral hypoperfusion (CCH). Lasting endoplasmic reticulum (ER) stress can drive neurological disorders. Targeting ER stress shows potential neuroprotective effects against stroke. However, the role of ER stress in CCH pathological processes and the effects of targeting ER stress on brain ischemia are unclear. Here, a CCH rat model was established by bilateral common carotid artery occlusion. Rats were treated with 4-PBA, URB597, or both for 4 weeks. Neuronal morphological damage was detected using hematoxylin–eosin staining. The expression levels of the ER stress–ASK1 cascade-related proteins GRP78, IRE1α, TRAF2, CHOP, Caspase-12, ASK1, p-ASK1, JNK, and p-JNK were assessed by Western blot. The mRNA levels of TNF-α, IL-1β, and iNOS were assessed by RT-PCR. For oxygen–glucose deprivation experiments, mouse hippocampal HT22 neurons were used. Apoptosis of the hippocampus and HT22 cells was detected by TUNEL staining and Annexin V-FITC analysis, respectively. CCH evoked ER stress with increased expression of GRP78, IRE1α, TRAF2, CHOP, and Caspase-12. Co-immunoprecipitation experiments confirmed the interaction between TRAF2 and ASK1. ASK1/JNK signaling, inflammatory cytokines, and neuronal apoptosis were enhanced, accompanied by persistent ER stress; these were reversed by 4-PBA and URB597. Furthermore, the ASK1 inhibitor GS4997 and 4-PBA displayed synergistic anti-apoptotic effects in cells with oxygen–glucose deprivation. In summary, ER stress-induced apoptosis in CCH is associated with the IRE1α/TRAF2/ASK1/JNK signaling pathway. Targeting the ER stress–ASK1 cascade could be a novel therapeutic approach for ischemic cerebrovascular diseases.

Ischemic stroke, a cerebrovascular disease worldwide, triggers a cascade of pathophysiological events, including blood‐brain barrier (BBB) breakdown. Brain microvascular endothelial cells (BMECs) play a vital role in maintaining BBB function. The injury of BMECs may worsen neurovascular dysfunction and patients’ prognosis. Therefore, uncover the principal molecular mechanisms involved in BBB disruption in stroke becomes pressing. The endocannabinoid system (ECS) has been implicated in increasingly physiological functions, both in neurometabolism and cerebrovascular regulation. Modulating its activities by the fatty acid amide hydrolase (FAAH) shows anti‐inflammatory characteristics. Andrographolide (AG), one Chinese herbal ingredient, has also attracted attention for its role in immunomodulatory and as a therapeutic target in BBB disorders. Recently, the FAAH inhibitor URB597 and AG have important regulatory effects on neuronal and vascular cells in ischemia. However, the effects of URB597 and AG on BMEC permeability and apoptosis in oxygen‐glucose deprivation (OGD) and the underlying mechanisms remain unclear. To address these issues, cultured BMECs (bEnd.3 cells) were exposed to OGD. The cell viability, permeability, tube formation, and apoptosis were assessed following treatment with URB597, AG, and cotreatment. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), proinflammatory factors, tight junction (TJ) proteins, and oxidative stress‐mediated Nrf2 signaling were also investigated. Results revealed that OGD broke the endothelial barrier, cell viability, MMP, and tube formation, which was reversed by URB597 and AG. OGD‐induced enhancement of ROS, MDA, and apoptosis was reduced after drug interventions. URB597 and AG exhibited antioxidant/anti‐inflammatory and mitochondrial protective effects by activating Nrf2 signaling. These findings indicated that URB597 and AG protect BMECs against OGD‐induced endothelial permeability impairment and apoptosis by reducing mitochondrial oxidative stress and inflammation associated with activation of Nrf2 signaling. URB597 and AG showing the vascular protection may have therapeutic potential for the BBB damage in ischemic cerebrovascular diseases.

Introduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen–glucose deprivation (OGD). Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed. Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes. Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.