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• Research Paper Volume 13, Issue 16 pp 20149-20163

  25-Hydroxycholesterol protecting from cerebral ischemia-reperfusion injury through the inhibition of STING activity

  Relevance score: 21.637732

  Feihong Lin, Xinyu Yao, Chang Kong, Xia Liu, Zhangfan Zhao, Suhuan Rao, Lu Wang, Shan Li, Junlu Wang, Qinxue Dai

  Keywords: middle cerebral artery occlusion, 25-hydroxycholesterol, STING, autophagy, mTOR

  Published in Aging on August 18, 2021

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  Middle cerebral artery occlusion (MCAO) injury refers to impaired blood supply to the brain that is caused by a cerebrovascular disease, resulting in local brain tissue ischemia, hypoxic necrosis, and rapid neurological impairment. Nevertheless, the mechanisms involved are unclear, and pharmacological interventions are lacking. 25-Hydroxycholesterol (25-HC) was reported to be involved in cholesterol and lipid metabolism as an oxysterol molecule. This study aimed to determine whether 25-HC exerts a cerebral protective effect on MCAO injury and investigate its potential mechanism. 25-HC was administered prior to reperfusion in a mouse model of MCAO injury. 25-HC evidently decreased infarct size induced by MCAO and enhanced brain function. It reduced stimulator of interferon gene (STING) activity and regulated mTOR to inhibit autophagy and induce cerebral ischemia tolerance. Thus, 25-HC improved MCAO injury through the STING channel. As indicated in this preliminary study, 25-HC improved MCAO injury by inhibiting STING activity and autophagy as well as by reducing brain nerve cell apoptosis. Thus, it is a potential treatment drug for brain injury.

• Research Paper Volume 12, Issue 6 pp 5121-5139

  EMMPRIN/CD147 plays a detrimental role in clinical and experimental ischemic stroke

  Relevance score: 22.665646

  Anthony Patrizz, Sarah J. Doran, Anjali Chauhan, Hilda Ahnstedt, Meaghan Roy-O’Reilly, Yun-Ju Lai, Gillian Weston, Sami Tarabishy, Anita R. Patel, Rajkumar Verma, Ilene Staff, Julia K. Kofler, Jun Li, Fudong Liu, Rodney M. Ritzel, Louise D. McCullough

  Keywords: stroke, middle cerebral artery occlusion, CD147, EMMPRIN, aging

  Published in Aging on March 19, 2020

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  Background: Ischemic stroke is a devastating disease, often resulting in death or permanent neurological deficits. EMMPRIN/CD147 is a plasma membrane protein that induces the production of matrix metalloproteinases (MMPs), which contribute to secondary damage after stroke by disrupting the blood brain barrier (BBB) and facilitating peripheral leukocyte infiltration into the brain.

  Results: CD147 surface expression increased significantly after stroke on infiltrating leukocytes, astrocytes and endothelial cells, but not on resident microglia. Inhibition of CD147 reduced MMP levels, decreased ischemic damage, and improved functional, cognitive and histological outcomes after experimental ischemic stroke in both young and aged mice. In stroke patients, high levels of serum CD147 24 hours after stroke predicted poor functional outcome at 12 months. Brain CD147 levels were correlated with MMP-9 and secondary hemorrhage in post-mortem samples from stroke patients.

  Conclusions: Acute inhibition of CD147 decreases levels of MMP-9, limits tissue loss, and improves long-term cognitive outcomes following experimental stroke in aged mice. High serum CD147 correlates with poor outcomes in stroke patients. This study identifies CD147 as a novel, clinically relevant target in ischemic stroke.

  

  GFAP positive astrocytes co-localize with CD147. (A) Representative image of cresyl violet stained brain slice showing peri-infarct regions where imaging was performed. (B) Representative 20x IHC images of sham and stroke brain slices. CD147 co-localizes with GFAP positive astrocytes in the peri-infarct region. Pearson’s correlation coefficient <0.0001, SH 0.14±0.02 vs. ST 0.73±0.03, n=6.

  
  
  

  

  Lectin positive endothelial cells co-localize with CD147. (A) Representative 20x IHC images of sham and stroke brain slices indicating CD147 co-localizes with lectin positive endothelial cells. Pearson’s correlation coefficient <0.0001, SH 0.29±0.01 vs. ST 0.748±0.03, n=3 and 5 respectively. (B) 63x high magnification image of lectin with co-localization with CD 147 in stroke brain.

  
  
  

  

  CD147 is expressed on brain infiltrating monocytes. (A) Representative dot plot of sham and stroke (72hr) brain shows microglia and infiltrating myeloid cells. Representative dot plot of 72hr stroke brain, gated on myeloid cells, shows Ly6C^hi monocytes, Ly6C^lo monocytes, and Ly6G neutrophils. (B) Absolute cell counts at 72hr in stroke brain (and sham microglia). (C) Quantified % CD147 positive cells in brain. Representative histogram showing expression of CD147 on microglia (sham and stroke; gray= microglia-specific FMO). Representative histogram showing expression of CD147 on brain-infiltrating myeloid cells after stroke. (D) Quantified CD147⁺ cell counts from brain, n=6. (E) Quantified %CD147 positive blood cells. Representative histogram showing expression of CD147 on blood cells after stroke. (F) Quantified expression level of MMP-9 on brain-infiltrating myeloid cells (and sham microglia). Representative histogram showing expression of MMP-9 on brain-infiltrating myeloid cells (and sham microglia).

  
  
  

  

  Matrix metalloproteinase-9 (MMP-9) protein concentrations and infarct volumes decrease following anti-CD147 antibody administration. (A) Timeline depicting the dosing strategy of CD147. (B) Representative western blots of MMP-9 protein concentrations in 72-hour post stroke mice following IgG control or anti-CD147 antibody administration, quantified in (C) p<0.01, n=4, * indicates statistical significance. (D) Representative TTC images of 72 hour post stroke brain slices of IgG control or ant-CD147 antibody. Red color details healthy brain tissue while white is indicative of infarcted tissue. (E) Quantification of percent infarct volume of cortex, striatum or total hemisphere relative to contralateral regions, p<0.05 for each region, n=4.

  
  
  

  

  Histological and Cognitive outcomes are improved following anti-CD147 antibody administration. (A) Quantification of percent atrophy of brain slices 14 days following MCAO, p<0.05, n=9. (B) Representative cresyl violet images of IgG or anti-CD147 antibody administered slices, region of interest highlighted by red oval. (C) Neurological deficit scores were obtained at four time points over 14 days beginning with one-hour post onset of MCAO. Day 3 post MCAO anti-CD147 administered mice displayed improved NDS, p<0.05. By day 14 NDS were the same between both groups. (D) Corner testing revealed an effect of antibody treatment across two time points; day 3 and day 14, p<0.05. (E) Barnes maze testing highlighted improvement in spatial learning and memory in antibody treated mice compared to IgG control on day 14, p=0.03.

  
  
  

  

  CD147 expression in the aged brain. (A) Representative dot plot of aged sham and stroke (72hr) brain; shows microglia and infiltrating myeloid cells. Representative dot plot of 72hr stroke brain; gated on myeloid cells, shows Ly6C^hi monocytes, Ly6C^lo monocytes, and Ly6G neutrophils. (B) Quantified counts at 72hr in stroke brain and sham microglia. (C) Quantified % CD147 positive cells in brain. (D) Absolute counts of CD147⁺ cells in brain, n=6. (E) Quantified %CD147 postive cells from blood. (F) Quantified expression level of MMP-9 on brain-infiltrating myeloid cells (and sham microglia).

  
  
  

  

  CD147 blocking antibody reduced infarct volume and improved cognitive outcomes in aged male mice. (A) CD147 blocking antibody administration reduced the amount of atrophy witnessed in the aged brain following stroke compared to IgG control at day 14. (B) Representative cresyl violet stained brain slices. (C) Neurological deficit scores showed improvement at day 3 and day 14 following stroke. (D) Cognitive impairment, as measured by escape time on the Barnes Maze, was prevented in stroke mice that received CD147 blocking antibody. (E) Levels of pro-MMP-9 were reduced in stroke mice receiving blocking antibody. (F) Brain hemoglobin, a reflection of blood brain barrier breakdown and hemorrhagic transformation was decreased in blocking antibody treated mice.

  
  
  

  

  CD147 is expressed on human astrocytes and levels of CD147 correlate with poor outcomes. (A) Serum levels of human CD147 24 hours post stroke. (B) Representative immunohistochemical staining patterns of CD147 in human brain tissues from age-matched control and ischemic stroke subjects (Top, scale bar = 50 μm). Immunofluorescence (IF) staining in human brain tissues (Bottom, scale bar = 100 μm). Simple IF with DAPI (blue), CD147 (green), and GFAP (red). Double IF with CD147 (green) and GFAP (red). (C) Quantification of levels of CD147 and GFAP expressing CD147 in human brain tissue.

  
  
  

• Research Paper Volume 8, Issue 5 pp 1049-1063

  Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice

  Relevance score: 23.76626

  Joshua Crapser, Rodney Ritzel, Rajkumar Verna, Venugopal R. Venna, Fudong Liu, Anjali Chauhan, Edward Koellhoffer, Anita Patel, Austin Ricker, Kendra Maas, Joerg Graf, Louise D. McCullough

  Keywords: aging, inflammation, infection, experimental stroke, middle cerebral artery occlusion

  Published in Aging on April 25, 2016

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  Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke.

  

  The effects of age on stroke outcome and the effects of stroke on gut permeability. (A) There was a significant effect of age on mortality 72 hours after 90 minute MCAO as analyzed by Mantel-Cox test of Kaplan-Meier survival curves (p<0.05, n=26-28/group). (B) Aged mice had significantly worse NDS than young 72 hours after 90 minute MCAO as measured by Mann-Whitney U test (p=0.05, n=18-21/group). (C) There was a significant effect of stroke (F[1,33]=p<0.05, n=9-10/group), but not aging, on intestinal permeability to NaF (MW 376 Da) 72 hours after 90 minute MCAO as measured by 2-way ANOVA. (D) The extent of gut permeability to NaF correlated positively with neurological deficit score at this timepoint (r=0.89, p<0.0001, n=18). (E) Permeability to the higher molecular weight FITC-Dextran (MW 4 kDa) significantly increased 24 hours after 90 minute MCAO in aged mice in plasma collected 2 hours after gavage (p<0.05, n=4/group). Values in (B) are expressed as box plots and values in (C, E) are expressed as mean ± SEM. Abbreviations: NaF, sodium fluorescein; NDS, neurological deficit score." *, p≤0.05.

  
  
  

  

  The effects of stroke and age on bacterial translocation 72 hours after 90 minute MCAO and on MLN bacterial burden 7 days after 60 minute MCAO. (A) Representative image of intestinal and MLN fluorescence in a non-GFP transfected aged sham ("Control") and in an aged stroke (90min MCAO, 72hr reperfusion) mouse transplanted with GFP+ E. coli ("GFP+ ve"). Average fluorescence of controls was subtracted as background from GFP+ aged sham and stroke values. (B) While there was no difference in intestinal fluorescence 72 hours after 90 minute stroke or sham surgery (p=0.51, n=4/group) there was a (C) significant increase in aged MLN fluorescence following stroke compared to sham values (p<0.01, n=4/group). (D) Species of Staphylococcus and Enterococcus colonized organs from both young and aged mice 72 hours after 90 minute MCAO, bacteria of the genera Escherichia and Enterobacter were only found in organs from young and aged mice, respectively (n=12-16/group). (E) There was a significant effect of age on MLN bacterial burden a week after 60 minute MCAO or sham surgery as measured by a 2-way ANOVA performed on the logarithmically transformed CFU/mL data (F[1,19]=p<0.01, n=4-7/group). Aged mice had significantly greater MLN bacterial burden compared to young at this timepoint following stroke (p<0.05). Data are presented as raw untransformed CFU/mL values. (F) Representative image of CFUs grown on blood agar from young and aged stroke MLN homogenates. Values in (D) are expressed as the percentage of the total number of successfully identified bacteria that were matched with a particular genus and values in (B, C, and E) are expressed as mean ± SEM. Abbreviations: MLN, mesenteric lymph node; CFU, colony-forming unit; GFP+ ve, microbiome transplanted with GFP-tagged E. coli; ASH,aged sham; AST, aged stroke; n.s., not significant; a.u., arbitrary units. *, p≤0.05; **, p<0.01.

  
  
  

  

  The effects of age and stroke on body temperature, body weight, IL-6 and LBP levels. (A) There was a significant effect of stroke (F[1,40]=p<0.0001) and aging (F[1,40]=p<0.05) on body temperature 72 hours after 90 minute MCAO as well as an interaction between stroke and aging (F[1,40]=p<0.01, n=11/group) as measured by 2-way ANOVA. Body temperature decreased significantly after stroke in young (p<0.05) and aged (p<0.0001) mice, but aged mice had more severe hypothermia (p<0.01). (B) Young mice lost a significantly greater proportion of their initial body weight compared to aged 72 hours after 90 minute MCAO (p<0.05, n=15-19/group), however aged mice sustained significantly more weight loss than young at 7 days after 60 minute MCAO (p<0.05, n=4-7/group), as young mice largely recovered their initial weight by this time. (C) There was a significant effect of stroke on IL-6 levels measured 6 hours after 90 minute MCAO in both young (p<0.001) and aged (p<0.0001) mice, returning to sham levels by 24 hours in young mice but remaining elevated in aged at this timepoint (p<0.05) with a similar trend at 72 hours in aged mice (n=5-8/group). (D) Both stroke (F[1,36]=p<0.0001) and aging (F[1,36]=p<0.05) had a significant effect on serum LBP levels 72 hours after 90 minute MCAO as analyzed by 2-way ANOVA (n=8-15/group). Values are expressed as mean ± SEM. Abbreviations: IL-6, interleukin-6; A/YSH, aged/young sham; A/YST, aged/young stroke; LBP, lipopolysaccharide-binding protein. *, p≤0.05; **, p<0.01; ***, p<0.001.

  
  
  

  

  The effects of age and stroke on peripheral lymphocytes 72 hours after 90 minute MCAO. (A) There was an effect of stroke (F[1,46]=p<0.0001) on the ratio of circulating lymphocytes to myeloid cells, a measure of lymphopenia, as analyzed by 2-way ANOVA (n=10-15/group). This ratio was significantly reduced in young (p<0.05) and aged (p<0.0001) mice following stroke. (B) There was a significant effect of stroke (F[1,14]=p<0.005, n=3-6/group) but not age on the proportion of circulating CD69+ CD4+ T cells as analyzed by 2-way ANOVA. (C) The proportion of circulating CD8+ T cells expressing CD69 was affected by both stroke (F[1,14]=p=0.05) and age (F[1,14]=p<0.05) via 2-way ANOVA (n=3-6/group). Values are expressed as mean ± SEM. *, p≤0.05; ***, p<0.001.

  
  
  

  

  The effects of age and stroke on post-stroke lymphocyte infiltration into the brain. (A) A significantly larger proportion of T cells infiltrating into the ischemic hemisphere 72 hours after 90 minute MCAO were BrdU-positive in aged mice compared to young (pB) There was a significant effect of age (F(1,16)=p) on the number of T cells infiltrating into the brain 72 hours after 90 minute MCAO as measured by 2-way ANOVA, with significantly less T cells infiltrating into the aged ischemic hemisphere 7 days after 60 minute MCAO as assessed by Student's t test (pC) There was an effect of age (F(1,16)=phi cells in the brain) 72 hours after 90 minute MCAO as measured by 2-way ANOVA, with T cells making up a significantly greater proportion of infiltrating leukocytes in aged mice 7 days after 60 minute MCAO as assessed by Student's t test (p=0.05, n=4-10/group). Values are expressed as mean ± SEM. *, p≤0.05; **, p

  
  
  

• Research Paper pp undefined-undefined

  JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models

  Relevance score: 18.354044

  Geun-Hyoung Ha, Eun Ji Kim, Jee Soo Park, Ji Eun Kim, Hyun Nam, Je Young Yeon, Sun-Ho Lee, Kyunghoon Lee, Chung Kwon Kim, Kyeung Min Joo

  Keywords: adult human neural stem cells, middle cerebral artery occlusion, stoke, neuroprotection, pro-angiogenic effects

  Published in Aging on Invalid Date

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  Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10⁵ ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.

• Research Paper pp undefined-undefined

  Suppression of cerebral ischemia injury induced blood brain barrier breakdown by dexmedetomidine via promoting CCN1

  Relevance score: 19.04641

  Shuangmei Liu, Xuepeng Jia, Bo Liu, Yue Liu, Hong Yin

  Keywords: dexmedetomidine, cerebral ischemia injury, blood brain barrier, CCN1, middle cerebral artery occlusion

  Published in Aging on Invalid Date

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  Background: Blood-brain barrier (BBB) could aggravate cerebral ischemia injury. Dexmedetomidine (Dex) has been believed to play a protective role in cerebral ischemia injury-induced BBB injury.

  Methods: Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) models were established to simulate cerebral ischemia injury. Animal experiments included 4 groups, Sham, MCAO, MCAO+Dex, MCAO+Dex+sh-CCN1. Generally applicable gene set enrichment analysis was performed to analyze gene expression difference. Total collagen content and Evans blue staining were performed to measure infarct ratio and BBB breakdown, respectively. The cell apoptosis, mRNA and protein expression were measured through flow cytometry, PCR, and western blotting, respectively. The levels of IL-1β, TNF-α, and IL-6 in serum were measured with commercial ELISA kits.

  Results: Dex greatly promoted the expression level of CCN1. Dex suppressed cerebral ischemia injury, increased tight junction protein expression, improved the memory ability and neurological function of MCAO rats through targeting CCN1. The significant increase of inflammatory factors in the serum of MCAO rats were suppressed by Dex. Dex suppressed OGD induced increase of HRP permeability and promoting tight junction protein expression in vitro through regulating CCN1. The neurological function evaluation was performed with Neurological Severity Score (NSS) and Longa Score Scale.

  Conclusions: Dex could remarkably alleviate cerebral ischemia injury by inhibiting BBB breakdown, inflammatory response, and promoting neurological function and tight junction protein expression via up-regulating CCN1. This study might provide a novel therapeutic target for the prevention and treatment of cerebral ischemia injury-induced BBB.