Hypoxia-Preconditioned Bone Marrow Mesenchymal Stem Cells Improved Cerebral Collateral Circulation and Stroke Outcome in Mice.

BACKGROUND: Adequate collateral circulation can remarkably improve patient prognoses for patients experiencing ischemic stroke. Hypoxic preconditioning enhances the regenerative properties of bone marrow mesenchymal stem cells (BMSCs). Rabep2 (RAB GTPase binding effector protein 2) is a key protein in collateral remodeling. We investigated whether BMSCs and hypoxia-preconditioned BMSCs (H-BMSCs) augment collateral circulation poststroke, particularly through Rabep2 regulation. METHODS: BMSCs or H-BMSCs (1×106) were delivered intranasally in ischemic mice with distal middle cerebral artery occlusion at 6 hours poststroke. Two-photon microscopic imaging and vessel painting methods were used to analyze collateral remodeling. Blood flow, vascular density, infarct volume, and gait analysis were assessed to evaluate poststroke outcomes. Expressions of proangiogenic marker VEGF (vascular endothelial growth factor) and Rabep2 were determined by Western blotting. Western blot, EdU (5-ethynyl-2'-deoxyuridine) incorporation, and tube formation assays were conducted on cultured endothelial cells treated with BMSCs. RESULTS: BMSCs were more effectively transplanted in the ischemic brain after hypoxic preconditioning. The ipsilateral collateral diameter was increased by BMSCs and strengthened by H-BMSCs (P<0.05). BMSCs increased peri-infarct blood flow and vascular density and reduced infarct volume, gait deficits (P<0.05), and furthermore by H-BMSCs (P<0.05). VEGF and Rabep2 protein expression was increased by BMSCs (P<0.05), which was enhanced by preconditioning (P<0.01). Additionally, BMSCs increased Rabep2 expression, proliferation, and tube formation of endothelial cells in vitro (P<0.05). H-BMSCs enhanced these effects (P<0.05), which were annulled by Rabep2 knockdown. CONCLUSIONS: BMSCs increased collateral circulation and improved poststroke outcomes, through the upregulation of Rabep2. These effects were enhanced by hypoxic preconditioning.

m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation.

Recent evidence have indicated that ferroptosis, a novel iron-dependent form of non-apoptotic cell death, plays a critical role in human cancers. Besides, emerging literatures have revealed the ovel function of N6-methyladenosine (m6A) in bladder cancer physiological. However, the underlying mechanism of m6A on bladder cancer is still unclear. Here, present work revealed that m6A methyltransferase ('writer') WTAP up-regulated in bladder cancer tissue and cells, indicating the poor prognosis of bladder cancer patients. Functionally, gain/loss-of-functional experiments illustrated that WTAP promoted the viability of bladder cancer cells and inhibited the erastin-induced ferroptosis. Mechanistically, there was a remarkable m6A modification site on 3'-UTR of endogenous antioxidant factor NRF2 RNA and WTAP could install its methylation. Moreover, m6A reader YTHDF1 recognized the m6A site on NRF2 mRNA and enhanced its mRNA stability. Therefore, these findings demonstrated potential therapeutic strategyies for bladder cancer via m6A-dependent manner.

Endovascular treatment with or without intravenous alteplase for acute ischaemic stroke due to basilar artery occlusion.

BACKGROUND AND PURPOSE: It remains controversial if endovascular treatment (EVT) can improve the outcome of patients with acute basilar artery occlusion (BAO). This study aims to compare the functional outcomes between EVT with and without intravenous thrombolysis (IVT) first in patients who had acute ischaemic stroke (AIS) due to BAO. METHODS: Patients who had AIS with BAO who underwent EVT within 24 hours of onset were enrolled in this multicentre cohort study, and the efficacy and safety were compared between IVT+EVT and direct EVT. The primary outcome was 90-day functional independence. All outcomes were assessed with adjusted OR (aOR) from the multivariable logistic regression. In addition, a meta-analysis was performed on all recently published pivotal studies on functional independence after EVT in patients with BAO. RESULTS: Of 310 enrolled patients with BAO, 241 (78%) were treated with direct EVT and 69 (22%) with IVT+EVT. Direct EVT was associated with a worse functional outcome (aOR, 0.46 (95% CI 0.24 to 0.85), p=0.01). IVT+EVT was associated with a lower percentage of patients who needed ≥3 passes of stent retriever (10.14% vs 20.75%). The meta-analysis regression revealed a potential positive correlation between bridging with IVT first and functional independence (r=0.14 (95% CI 0.05 to 0.24), p<0.01). CONCLUSIONS: This study showed that compared with direct EVT, EVT with IVT first was associated with better functional outcomes in patients with BAO treated within 24 hours of onset. The meta-analysis demonstrated similar favourable efficacy of IVT first followed by EVT in patients with BAO.

Matrix metallopeptidase 9 and placental growth factor may correlate with collateral status based on whole-brain perfusion combined with multiphase computed tomography angiography.

OBJECTIVE: The aim of this study was to find out the relationship between serum biomarkers and cerebral collateral status in acute ischemic stroke with cerebral large artery atherosclerosis. METHODS: We enrolled patients with ischemic stroke due to large artery atherosclerosis within 7 days of symptom onset, age 18-80 years, from August 2016 to December 2017. Twelve biomarkers representing different pathophysiological mechanisms were tested after admission. Whole-brain perfusion combined with multiphase computed tomography angiography was performed to assess cerebral collateral structure and function. RESULTS: Fifty-two patients completed the test of candidate biomarkers and recruited in this study. The mean age was 55.0 (11.1) years, 42 (80.8%) patients were male, 20 (38.5%) had poor collateral, 36 (69.2%) patients had anterior circulation stenosis or occlusion. Compared with poor collateral group, the level of MMP-9 (135,475.00 pg/ml vs. 103,612.00 pg/ml, p = 0.040) and PGF (5.75 pg/ml vs. 3.46 pg/ml, p = 0.046) was significantly higher in good collateral group. The adjusted OR (95%CI) of MMP-9 and PGF were 5.533 (1.10-27.74, p = 0.038), 7.73 (1.41-42.39, p = 0.018), respectively. sTie-2 level had a positive correlation with proportion of Tmax 4-6 (r = 0.302, p = 0.033) and HMW-KGN had negative correlation with proportion of Tmax 6-8 (r = -0.338, p = 0.02). After adjustment, the correlation of sTie-2 level and proportion of Tmax 4-6 was statistically significant (p = 0.003), and correlation of HMW-KGN and Tmax6-8 was not statistically significant (p = 0.056). DISCUSSION: Serum PGF and MMP-9 levels may correlate with collateral status based on MP-CTA in acute ischemic stroke patients with cerebral large artery atherosclerosis. Higher PGF and MMP-9 concentration associated with good collateral status.