Identification of a miRNA-mRNA regulatory network for post-stroke depression: a machine-learning approach.

Objective: The study aimed to explore the miRNA and mRNA biomarkers in post-stroke depression (PSD) and to develop a miRNA-mRNA regulatory network to reveal its potential pathogenesis. Methods: The transcriptomic expression profile was obtained from the GEO database using the accession numbers GSE117064 (miRNAs, stroke vs. control) and GSE76826 [mRNAs, late-onset major depressive disorder (MDD) vs. control]. Differentially expressed miRNAs (DE-miRNAs) were identified in blood samples collected from stroke patients vs. control using the Linear Models for Microarray Data (LIMMA) package, while the weighted correlation network analysis (WGCNA) revealed co-expressed gene modules correlated with the subject group. The intersection between DE-miRNAs and miRNAs identified by WGCNA was defined as stroke-related miRNAs, whose target mRNAs were stroke-related genes with the prediction based on three databases (miRDB, miRTarBase, and TargetScan). Using the GSE76826 dataset, the differentially expressed genes (DEGs) were identified. Overlapped DEGs between stroke-related genes and DEGs in late-onset MDD were retrieved, and these were potential mRNA biomarkers in PSD. With the overlapped DEGs, three machine-learning methods were employed to identify gene signatures for PSD, which were established with the intersection of gene sets identified by each algorithm. Based on the gene signatures, the upstream miRNAs were predicted, and a miRNA-mRNA network was constructed. Results: Using the GSE117064 dataset, we retrieved a total of 667 DE-miRNAs, which included 420 upregulated and 247 downregulated ones. Meanwhile, WGCNA identified two modules (blue and brown) that were significantly correlated with the subject group. A total of 117 stroke-related miRNAs were identified with the intersection of DE-miRNAs and WGCNA-related ones. Based on the miRNA-mRNA databases, we identified a list of 2,387 stroke-related genes, among which 99 DEGs in MDD were also embedded. Based on the 99 overlapped DEGs, we identified three gene signatures (SPATA2, ZNF208, and YTHDC1) using three machine-learning classifiers. Predictions of the three mRNAs highlight four miRNAs as follows: miR-6883-5p, miR-6873-3p, miR-4776-3p, and miR-6738-3p. Subsequently, a miRNA-mRNA network was developed. Conclusion: The study highlighted gene signatures for PSD with three genes (SPATA2, ZNF208, and YTHDC1) and four upstream miRNAs (miR-6883-5p, miR-6873-3p, miR-4776-3p, and miR-6738-3p). These biomarkers could further our understanding of the pathogenesis of PSD.

Downregulated Phosphoglycerate Kinase 1 Attenuates Cerebral Ischemia-Reperfusion Injury by Reversing Neuroinflammation and Oxidative Stress through the Nuclear Factor Erythroid 2 Related Factor 2/ARE Pathway.

Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and oxidative injury in cerebral ischemia-reperfusion injury (CIRI). In this study, we investigated the regulatory effects of phosphoglycerate kinase 1 (PGK1) on inflammation and oxidative response after CIRI in male adult Sprague-Dawley (SD) rats and using primary astrocytes obtained from neonatal SD rats, and explored its related mechanisms. We established a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R) by suture occlusion, and an oxygen-glucose deprivation/reoxygenation model of astrocytes using oxygen-free, glucose-free, and serum-free cultures. AAV8-PGK1-GFP was injected into the left ventricle 24 h before modeling. Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, co-immunoprecipitation (CoIP) assay, fluorescence in situ hybridization (FISH), and western blotting were used to elucidate the in-depth mechanisms of PGK1 in CIRI. PGK1 overexpression significantly exacerbated neurological deficits, increased cerebral infarct volume, and aggravated nerve cell injury in rats after MCAO/R. Using FISH and CoIP assays, we verified the localization of PGK1 and Nrf2 in primary astrocytes. Further rescue experiments showed that Nrf2 knockdown eliminated the protective effect of CBR-470-1 (a PGK1 inhibitor) on CIRI. Lastly, we confirmed that PGK1 aggravates CIRI by inhibiting the Nrf2/ARE pathway. In conclusion, our findings suggest that inhibiting PGK1 attenuates CIRI by reducing the release of inflammatory and oxidative factors from astrocytes by activating the Nrf2/ARE signaling pathway.

Traumatic oculomotor nerve palsy treated with transnasal endoscopic decompression through the optic strut.

Objective: To present a surgical treatment regimen of transnasal endoscopic decompression through the optic strut for traumatic oculomotor nerve palsy based on the anatomical study of the superior orbital fissure and the oculomotor nerve fissure segment. Methods: The bone structure of the oculomotor nerve fissure segment and the important bone anatomical landmarks of the lateral wall of the sphenoidal sinus were identified on a dried skull and a cadaveric head, respectively, using a nasal endoscope, and a surgical plan was determined. Decompression was conducted on the orbital apex, the superior orbital fissure, the optic canal and the optic strut of the two patients in sequence, after which the degree and range of decompression were identified by three-dimensional (3D) computed tomography (CT). Results: The oculomotor nerve had a close correlation with the lateral surface of the optic strut. The transnasal endoscope was employed to identify the lateral optic-carotid recess (LOCR), as well as the positions of the optic nerve, internal carotid artery (ICA), and superior orbital fissure, collectively called the "optic strut triangle". The surgical plans for decompression of the orbital apex, superior orbital fissure, optic canal, and optic strut and the necessity of optic strut drilling were determined, and the surgical procedures for safe drilling of the optic strut were elaborated. After surgery, the two patients had significantly improved symptoms, without complications. In addition, their postoperative CT showed that the medial margin of the superior orbital fissure was fully decompressed. Conclusion: The optic strut triangle is a crucial anatomical landmark in the decompression of the oculomotor nerve, and optic strut drilling is necessary for such decompression. For patients with traumatic oculomotor nerve palsy and fractures of the medial wall of the superior orbital fissure on CT, the oculomotor nerve fissure segment can be decompressed in an effective, complete and safe manner as per the surgical plan of decompressing the orbital apex, superior orbital fissure, optic canal and optic strut in turn under a transnasal endoscope, conducive to the recovery of neurological function of patients.

Serum calprotectin as a prognostic predictor in severe traumatic brain injury.

BACKGROUND: Calprotectin plays an important role during inflammation. We intended to explore the prognostic value of serum calprotectin levels in patients with severe traumatic brain injury (sTBI). METHODS: In this prospective cohort study of 149 sTBI patients, we determined the relationship between serum calprotectin levels and 90-day overall survival plus poor outcome (Glasgow outcome scale score of 1-3) after sTBI, and analyzed its associations with Rotterdam computerized tomography (CT) scores, Glasgow coma scale (GCS) scores and two markers of inflammatory reaction including serum C-reactive protein levels and blood leucocyte count. RESULTS: Serum calprotectin levels were significantly correlated with Rotterdam CT scores, GCS scores, serum C-reactive protein levels and blood leucocyte count. Patients with poor outcome at 90 days displayed higher serum calprotectin levels than the other remainders. Serum calprotectin appeared as an independent predictor for 90-day overall survival and poor outcome. Under receiver operating characteristic curve, serum calprotectin levels exhibited an efficient discrimination capacity for 90-day poor outcome. CONCLUSIONS: Serum calprotectin levels are significantly correlated with inflammation, trauma severity and poor outcome at 90 days in sTBI patients, suggesting that serum calprotectin may be a biomarker for providing complementary prognostic information to identify patients at risk of poor outcome after sTBI.

A novel prognosis prediction model, including cytotoxic T lymphocyte-associated antigen-4, ischemia-modified albumin, lipoprotein-associated phospholipase A2, glial fibrillary acidic protein, and homocysteine, for ischemic stroke in the Chinese hypertensive population.

BACKGROUND: There is still a lack of tools to assess the prognosis of ischemic stroke patients induced by hypertension. In this study, we built a novel prognostic assessment model for ischemic stroke in the Chinese hypertensive population. METHODS: Mass spectrometry technique was used to analyze the changes in serum protein profiles of hypertensive patients with ischemic stroke. A total of 314 hypertensive patients were divided into the testing group (206 patients) and the validation group (108 patients). RESULTS: Compared with hypertensive patients without ischemic stroke, serum cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), ischemia-modified albumin (IMA), lipoprotein-associated phospholipase A2 (Lp-PLA2), glial fibrillary acidic protein (GFAP), and homocysteine (HCY) levels were significantly increased among hypertensive patients with ischemic stroke (p < 0.05). Then, we built a novel prognostic assessment model for hypertensive patients with ischemic stroke [Logit(P) = 29.172-1.088*CTLA-4-0.952*IMA-0.537*Lp-PLA2 -0.066*GFAP -0.149*HCY]. It showed higher efficiency (AUC = 0.981, sensitivity = 95.5%, specificity = 93.8%) than any single marker. The estimated probability was 0.739, which means if higher than 0.739, it was classified into poor prognosis. Compared with the estimated probability ≤0.739 group, the survival rate of hypertensive patients with ischemic stroke in the estimated probability >0.739 group was significantly decreased (χ2  = 40.001, p < 0.001). In the validation group, our novel prognostic assessment model still showed good efficiency (AUC = 0.969, sensitivity = 89.4%, specificity = 92.5%; χ2  = 47.551, p < 0.001). CONCLUSION: Current novel prognostic assessment model we have built is of great value in the prognostic evaluation for ischemic stroke in the Chinese hypertensive population.

EphA2, vascular endothelial growth factor, and vascular endothelial growth factor correlate with adverse outcomes and poor survival in patients with glioma.

PURPOSE: To assess expression levels of Ephrin type-A receptor 2 (EphA2), vascular endothelial growth factor (VEGF), and von Willebrand factor (vWF), and assess their potentials as prognostic biomarkers to predict the risk of poor survival in patients with primary lower grade glioma. METHOD: The study included75 patients with histopathologically confirmed primary glioma (World Health Organization Grade IV). All patients underwent combined surgery and postoperative radiotherapy for the management of primary glioma. Immuno-histochemical analysis was performed to evaluate expression levels ofEphA2 and VEGF. Evaluation of tumor microvessel density was also performed at angiogenesis hot spots due to tumor growth. Main outcomes of the study were the prognostic efficiencies of EphA2, VEGF, and vWF in primary low-grade glioma, as well as whether their expression levels were associated with cancer progression. RESULTS: Of the patients with glioma, 67% had very strong expression of EphA2. Overall survival was inversely correlated with the expression of EphA2. Regarding VEGF expression, 38 patients (51%) had strong expression, 29 patients (39%) had weak expression, and 8 patients (11%) had no expression. Strong VEGF expression was associated with poor prognosis and poor survival. CONCLUSION: EphA2, VEGF, and vWF could be considered prognostic markers for assessment of primary glioma.

Prognostic evaluation of serum long non-coding RNA H19 for endoscopic keyhole surgery or craniotomy in glioma.

BACKGROUND: Our study aims to explore the effect of serum long non-coding RNA (lncRNA) H19 level on the long-term prognosis of endoscopic keyhole surgery or craniotomy for glioma. METHODS: A total of 264 glioma patients were selected. Patients were randomly divided into the Craniotomy-high H19 group, the Craniotomy-low H19 group, the Endoscopic keyhole surgery-high H19 group and the Endoscopic keyhole surgery-low H19 group. RESULTS: Compared with adjacent tissues (5.19 ± 1.42), H19 level in cancer tissues (7.45 ± 1.60) and serum (6.44 ± 1.57) was significantly increased (P < 0.05). Compared with serum, H19 level in cancer tissues was significantly increased (P < 0.05). Pearson correlation analysis found that the relative expression level of serum H19 in glioma patients was positively correlated with cancer tissues (rPearson = 0.547, P < 0.001), but had no significant correlation with adjacent tissues (rPearson = 0.126, P = 0.207). The expression of H19 in serum was significantly related to WHO grade (rPearson = 0.514, P < 0.001). Compared with the Endoscopic keyhole surgery-high H19 group and the Endoscopic keyhole surgery-low H19 group, the survival rate of patients in the Craniotomy-high H19 group (χ2 = 17.115 and log-rank P < 0.001; χ2 = 18.406 and log-rank P < 0.001) and the Craniotomy-low H19 group was significantly reduced (χ2 = 15.007 and log-rank P < 0.001; χ2 = 16.121 and log-rank P < 0.001). Cox regression results showed that serum H19 level, craniotomy and WHO grade were risk factors for glioma. When H19 level was lower than 6.28, the 30-month survival rate of patients with the endoscopic keyhole surgery was 100%. CONCLUSION: For patients with low H19 level (<5.36), both endoscopic keyhole surgery and craniotomy are available, otherwise, endoscopic keyhole surgery is more recommended.

miR-22 inhibits the proliferation, motility, and invasion of human glioblastoma cells by directly targeting SIRT1.

Recently, microRNAs (miRNAs), a kind of small and non-coding RNA, can target the downstream molecules. Increasing evidence demonstrates that miRNAs meditate the onset and progression of a variety of tumors. In the present study, we carried out gene transfection, western blot, and reverse transcription PCR (RT-PCR) to explore the role of miR-22 in glioblastoma tissues and cell lines. Here, we verified that the expression of miR-22 was downregulated in glioblastoma tissues and cells rather than matched non-tumor tissues and normal human astrocyte (NHA) cells (p < 0.001). By contrast, SIRT1 messenger RNA (mRNA) and protein were upregulated in glioblastoma tissues and cells (p < 0.001). In vitro miR-22 mimics interfered with cell proliferation, migration, and invasion of U87 and U251 cells. Mechanically, the 3'-untranslated regions (3'-UTRs) of SIRT1 were a direct target of miR-22, leading to the decreased expression of SIRT1 protein in U87 and U251 cells. Meanwhile, miR-22 mimics also inhibited the expression of epidermal growth factor receptor (EGFR) and matrix metallopeptidase 9 (MMP9). In conclusion, miR-22 inhibited cell proliferation, migration, and invasion via targeting the 3'-UTR of SIRT1 in the progression of glioblastoma and miR-22-SIRT1 pathway can be recommended as a potential target for treatment of glioblastoma.