Nanjing Neuropsychiatry Clinic Medical Center
Nanjing Neuropsychiatry Clinic Medical Center
Chen Y.,Nanjing University |
Han L.,Nanjing University |
Li J.,Nanjing University |
Li J.,Jiangsu University |
And 8 more authors.
PLoS ONE | Year: 2015
Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in postischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the18 F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way. © 2015 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Meng H.-L.,Nanjing University |
Li X.-X.,Nanjing University |
Chen Y.-T.,Nanjing University |
Chen Y.-T.,Nanjing Medical University |
And 13 more authors.
CNS Neuroscience and Therapeutics | Year: 2016
Aims: This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes. Methods: In vivo, middle cerebral artery occlusion (MCAO) was induced in both FasL-mutant (gld) and wild-type (wt) mice. In vitro, primary cortical neuron or microglia or coculture from wt/gld mice was subjected to oxygen glucose deprivation (OGD). sFasL level in the supernatant was evaluated by ELISA. Neuronal-conditioned medium (NCM) or exogenous sFasL was applied to primary microglia with or without FasL neutralizing antibody. Protein expression of JAK2/STAT3 and NF-κB pathways were determined by Western blot. The effect of microglia phenotype from wt/gld mice on the fate of ischemic neurons was further elucidated. Results: In vivo, compared with wild-type mice, M1 markers (CD16, CD32 and iNOS) were attenuated in gld mice after MCAO. In vitro, post-OGD neuron released more sFasL. Both post-OGD NCM and exogenous sFasL could trigger M1-microglial polarization. However, this M1 phenotype shift was partially blocked by utilization of FasL neutralizing antibody or gld NCM. Consistently, JAK2/STAT3 and NF-κB signal pathways were both activated in microglia after exogenous sFasL treatment. Compared with wild-type mice, M1-conditioned medium prepared from gld mice protected neuron against OGD injury. Conclusions: Ischemic neurons release sFasL, which contributes to M1-microglial polarization. The underlying mechanisms may involve the activation of JAK2/STAT3 and NF-κB signaling pathways. © 2016 John Wiley & Sons Ltd
Liu A.-H.,Nanjing Medical University |
Niu F.-N.,Nanjing Medical University |
Chang L.-L.,Nanjing Medical University |
Zhang B.,Nanjing Medical University |
And 6 more authors.
CNS Neuroscience and Therapeutics | Year: 2014
Aims: The purpose of this study was to evaluate the energy metabolism and mitochondrial function in skeletal muscle from patients with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or chronic progressive external ophthalmoplegia (CPEO) using phosphorus magnetic resonance spectroscopy (31P-MRS), to determine whether abnormally increasing cytochrome c oxidase (COX), as detected in muscle biopsy, could be a cause for MELAS. Methods: 31P-MRS was performed on the quadriceps femoris muscle of 12 healthy volunteers and 11 patients diagnosed as MELAS or CPEO by muscle biopsy and genetic analysis. All subjects experienced a state of rest, 5-min exercise, and 5-min recovery protocol in a supine position. Results: Compared to CPEO, MELAS patients typically exhibited COX-positive ragged-red fibers (RRFs) as well as strongly SDH-positive blood vessels (SSVs). However, based on 31P-MRS results, MELAS showed a higher inorganic phosphate (Pi)/phosphocreatine (PCr) ratio and lower ATP/PCr ratio during exercise and delayed Pi/PCr and ATP/PCr recovery to normal. Conclusions: This study suggests that high COX expression contributes to severe skeletal energy failure by 31P-MRS spectroscopy in MELAS. © 2014 John Wiley & Sons Ltd.
Cheng Q.,Nanjing Medical University |
Zhang Z.,Nanjing Medical University |
Zhang Z.,Jiangsu Province Stroke Center for Diagnosis and Therapy |
Zhang S.,Nanjing Medical University |
And 16 more authors.
Brain Research | Year: 2015
Current treatments for ischemic stroke are limited, stem cell transplantation offers great potential as a therapeutic strategy. The present study was undertaken to determine whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could improve brain injury after middle cerebral artery occlusion (MCAO) through modulating peripheral immunoinflammation. The study showed that neurological deficit was ameliorated and brain edema, infarct volume was significantly decreased from 72 h to 1 week post-MCAO with hUC-MSCs treatment via tail vein injection within 30 mins after stroke; hUC-MSCs attenuated the levels of inflammatory factors including IL-1, TNF-α, IL-23, IL-17 and IL-10 in peripheral blood serum and ischemia hemisphere after stroke; hUC-MSCs significantly decreased the level of Th17 cells at 24 h and increased the level of Tregs at 72 h post-MCAO in peripheral immune system; the level of TGF-β in blood serum was enhanced by hUC-MSCs. In conclusion, our findings suggested that hUC-MSCs had neuroprotection in MCAO mice by TGF-β modulating peripheral immune and hUC-MSCs may be as a potential therapy for ischemic stroke. © 2014 Elsevier B.V. All rights reserved.