Publications by authors named "Heng Hu"

42 Publications

Author Correction: Blood substitution therapy rescues the brain of mice from ischemic damage.

Nat Commun 2021 May 13;12(1):2957. Epub 2021 May 13.

Department of Neuroscience, West Virginia University, Morgantown, WV, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22615-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119707PMC
May 2021

The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke.

Pharm Res 2021 May 12;38(5):803-817. Epub 2021 May 12.

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA.

Purpose: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results: NL-1 decreased hydrogen peroxide production with an IC of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion: As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11095-021-03046-4DOI Listing
May 2021

IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion.

Cells 2021 Apr 9;10(4). Epub 2021 Apr 9.

Department of Neuroscience, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10040855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069995PMC
April 2021

Intermittent Lipopolysaccharide Exposure Significantly Increases Cortical Infarct Size and Impairs Autophagy.

ASN Neuro 2021 Jan-Dec;13:1759091421991769

Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, United States.

Globally, stroke is a leading cause of death and disability. Traditional risk factors like hypertension, diabetes, and obesity do not fully account for all stroke cases. Recent infection is regarded as changes in systemic immune signaling, which can increase thrombosis formation and other stroke risk factors. We have previously shown that administration of lipopolysaccharide (LPS) 30-minutes prior to stroke increases in infarct volume. In the current study, we found that animals intermittently exposed to LPS have larger cortical infarcts when compared to saline controls. To elucidate the mechanism behind this phenomenon, several avenues were investigated. We observed significant upregulation of tumor necrosis factor-alpha (TNF-α) mRNA, especially in the ipsilateral hemisphere of both saline and LPS exposed groups compared to sham surgery animals. We also observed significant reductions in expression of genes involved in autophagy in the ipsilateral hemisphere of LPS stroke animals. In addition, we assessed DNA methylation of autophagy genes and observed a significant increase in the ipsilateral hemisphere of LPS stroke animals. Intermittent exposure to LPS increases cortical infarct volume, downregulates autophagy genes, and induces hypermethylation of the corresponding CpG islands. These data suggest that intermittent immune activation may deregulate epigenetic mechanisms and promote neuropathological outcomes after stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1759091421991769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020222PMC
February 2021

Fast detection of isocarbophos using bis-propargylcalix[4]arene stabilized silver nanoparticles.

Anal Sci 2021 Feb 12. Epub 2021 Feb 12.

Department of Forensic Medicine, Zhongnan Hospital of Wuhan University.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2116/analsci.20P372DOI Listing
February 2021

Blood substitution therapy rescues the brain of mice from ischemic damage.

Nat Commun 2020 08 25;11(1):4078. Epub 2020 Aug 25.

Department of Neuroscience, West Virginia University, Morgantown, West Virginia, 26506, USA.

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17930-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447645PMC
August 2020

MiR-34a Interacts with Cytochrome c and Shapes Stroke Outcomes.

Sci Rep 2020 02 24;10(1):3233. Epub 2020 Feb 24.

Neuroscience, Center for Basic and Translational Stroke Research; West Virginia University, Morgantown, West Virginia, 26506, USA.

Blood-brain barrier (BBB) dysfunction occurs in cerebrovascular diseases and neurodegenerative disorders such as stroke. Opening of the BBB during a stroke has a negative impact on acute outcomes. We have recently demonstrated that miR-34a regulates the BBB by targeting cytochrome c (CYC) in vitro. To investigate the role of miR-34a in a stroke, we purified primary cerebrovascular endothelial cells (pCECs) from mouse brains following 1 h transient middle cerebral artery occlusion (tMCAO) and measured real-time PCR to detect miR-34a levels. We demonstrate that the miR-34a levels are elevated in pCECs from tMCAO mice at the time point of BBB opening following 1 h tMCAO and reperfusion. Interestingly, knockout of miR-34a significantly reduces BBB permeability, alleviates disruption of tight junctions, and improves stroke outcomes compared to wild-type (WT) controls. CYC is decreased in the ischemic hemispheres and pCECs from WT but not in miR-34a mice following stroke reperfusion. We further confirmed CYC is a target of miR-34a by a dural luciferase reporter gene assay in vitro. Our study provides the first description of miR-34a affecting stroke outcomes and may lead to discovery of new mechanisms and treatments for cerebrovascular and neurodegenerative diseases such as stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59997-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040038PMC
February 2020

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection.

Immun Inflamm Dis 2019 12 5;7(4):326-341. Epub 2019 Nov 5.

Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia.

Introduction: Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multifactorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that focal ischemic stroke induction results in functional defects of lymphocytes in the spleen, thymus, and peripheral blood, leading to spontaneous bacterial infection in the lungs without inoculation. However, how ischemic stroke alters immune cell niche and the expression of cytokines and chemokines in the lungs has not been fully characterized.

Methods: Ischemic stroke was induced in mice by tMCAO. Immune cell profiles in the brain and the lungs at 24- and 72-hour time points were compared by flow cytometric analysis. Cytokine and chemokine expression in the lungs were determined by multiplex bead arrays. Tissue damage and bacterial burden in the lungs following tMCAO were evaluated.

Results: Ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b dendritic cells, but reduces the percentage of CD4 T cells, CD8 T cells, B cells, natural killer cells, and eosinophils in the lungs. The alteration of immune cell niche in the lungs coincides with a significant reduction in the levels of multiple chemokines in the lungs, including CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. Spontaneous bacterial infection and tissue damage following tMCAO, however, were not observed.

Conclusion: This is the first report to demonstrate a significant reduction of lymphocytes and multiple proinflammatory chemokines in the lungs following ischemic stroke in mice. These findings suggest that ischemic stroke directly impacts pulmonary immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/iid3.277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842816PMC
December 2019

[Responses of soil organic carbon and microbial community structure to different tillage patterns and straw returning for multiple years.]

Ying Yong Sheng Tai Xue Bao 2019 Sep;30(9):3183-3194

Shandong Province Key Laboratory of Soil and Water Conservation and Environmental Conservation, College of Resources and Environment, Linyi University, Linyi 276000, Shandong, China.

Soil organic carbon is essential for maintaining terrestrial ecosystem function and mitigating soil degradation. Soil microorganisms participate in soil carbon cycling. They are affected by tillage methods and straw returning. A split-plot design was adopted in this experiment. The whole-plot treatment had two tillage methods, subsoil tillage (ST) and rotary tillage (RT). The split-plot treatment included full straw returning (F) and no straw returning (0). The microbial community structure and carbon sequestration genes were assessed by Illumina sequencing technique. Soil organic carbon contents were measured during 2012-2017. The results showed that 1) subsoil tillage and straw returning significantly increased pH, microbial biomass carbon, total nitrogen, silt content, and clay content, while significantly decreased sand content; 2) during the test period (2012-2017), soil organic carbon (SOC) content under all treatments showed an increasing trend, but the increment for average SOC content under straw returning and subsoiling treatments was significantly higher than that of no straw returning and rotary tillage by 33.2 % and 30.6%, respectively; 3) Proteobacteria was the most abundant type of bacteria in the soil, followed by Acidobacteria and Gemmatadanetes; 4) STF treatment maintained high microbial diversity; 5) Excepted for soil sand content, soil pH, microbial biomass carbon, total nitrogen, silt content and clay content all caused the variation of soil microbial community structure under the STF treatment in the direction of SOC accumulation; 6) in addition to the gene abundance in the di- and oligosaccharides metabolic pathway, the gene abundance in the metabolic pathways for CO fixation, central carbohydrate metabolism, fermentation, one-carbon metabolism, organic acids, sugar alcohols and glycoside hydrolases showed that subsoil tillage was significantly higher than rotary tillage, with posi-tively correlation with soil organic carbon content. Therefore, the combination of subsoil tillage and straw returning could improve basic soil properties, affect soil microbial community structure, and increase the capacity of soil carbon fixation, thus providing a realistic basis for solving soil degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.13287/j.1001-9332.201909.039DOI Listing
September 2019

Gradual common carotid artery occlusion as a novel model for cerebrovascular Hypoperfusion.

Metab Brain Dis 2018 12 28;33(6):2039-2044. Epub 2018 Sep 28.

One Medical Center Drive, West Virginia University, Morgantown, WV, 26506, USA.

Chronic cerebrovascular hypoperfusion results in vascular dementia and increases predisposition to lacunar infarcts. However, there are no suitable animal models. In this study, we developed a novel model for chronic irreversible cerebral hypoperfusion in mice. Briefly, an ameroid constrictor was placed on the right carotid artery to gradually occlude the vessel, while a microcoil was placed on the left carotid artery to prevent compensation of the blood flow. This procedure resulted in a gradual hypoperfusion developing over a period of 34 days with no cerebral blood flow recovery. Histological analysis of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and the corpus callosum. Overall, our paradigm is a viable model to study brain pathology resulting from gradual cerebrovascular hypoperfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11011-018-0312-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342504PMC
December 2018

A Multiscale Analysis on the Superelasticity Behavior of Architected Shape Memory Alloy Materials.

Materials (Basel) 2018 Sep 17;11(9). Epub 2018 Sep 17.

Laboratory of Excellence on Design of Alloy Metals for Low-Mass Structure (Labex-DAMAS), Université de Lorraine, 57070 Metz, France.

In this paper, the superelasticity effects of architected shape memory alloys (SMAs) are focused on by using a multiscale approach. Firstly, a parametric analysis at the cellular level with a series of representative volume elements (RVEs) is carried out to predict the relations between the void fraction, the total stiffness, the hysteresis effect and the mass of the SMAs. The superelasticity effects of the architected SMAs are modeled by the thermomechanical constitutive model proposed by Chemisky et al. 2011. Secondly, the structural responses of the architected SMAs are studied by the multilevel finite element method (FE 2 ), which uses the effective constitutive behavior of the RVE to represent the behavior of the macroscopic structure. This approach can truly couple the responses of both the RVE level and structural level by the real-time information interactions between two levels. Through a three point bending test, it is observed that the structure inherits the strong nonlinear responses-both the hysteresis effect and the superelasticity-of the architected SMAs at the cellular level. Furthermore, the influence of the void fraction at the RVE level to the materials' structural responses can be more specifically and directly described, instead of using an RVE to predict at the microscopic level. Thus, this work could be referred to for optimizing the stiffness, the hysteresis effect and the mass of architected SMA structures and extended for possible advanced applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma11091746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163616PMC
September 2018

Effect of Varying Chain Length and Content of Poly(dimethylsiloxane) on Dynamic Dewetting Performance of NP-GLIDE Polyurethane Coatings.

Langmuir 2018 08 13;34(34):10102-10113. Epub 2018 Aug 13.

Department of Chemistry , Queen's University , 90 Bader Lane , Kingston , Ontario , Canada K7L 3N6.

Polyurethane coatings containing nanopools of a grafted lubricating liquid ingredient for dewetting enablement (NP-GLIDE) are prepared by curing a commercial polyol P0, a hexamethylene diisocyanate trimer, and P1- g-PDMS, which is a graft copolymer consisting of a polyol backbone P1 bearing poly(dimethylsiloxane) (PDMS) side chains. These materials are known as NP-GLIDE because most test liquids have no problem to cleanly glide off them and because segregated nanopools of the grafted lubricating ingredient (PDMS) for dewetting enablement are dispersed throughout the coating matrix. To optimize the dewetting performance of the NP-GLIDE coatings, the molecular weights of the PDMS side chains in the P1- g-PDMS samples were increased from 1.0 kDa (1k) to 5.0 kDa (5k) and 10.0 kDa (10k). A comparative study of the coatings containing three different P1- g-PDMS samples at a constant PDMS mass fraction of either 6.0 or 2.00% (m/m) showed that P1- g-PDMS-based coatings exhibited the best dewetting properties. These properties included the lowest sliding angles for test liquids that were incompatible with PDMS and the fastest and most effective contraction of marker ink traces and a paint. Coatings containing 0.50 and 1.00% (m/m) of PDMS were also prepared from P1- g-PDMS and compared with those containing 2.00 and 6.0% (m/m) of PDMS. The coatings were shown to retain their dewetting properties with the PDMS contents as low as 1.00% (m/m). Although the results of this study provided valuable insight into the design of future practical NP-GLIDE coatings, a model has also been proposed for the surface structure of the coatings to justify our observations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.8b01965DOI Listing
August 2018

Uncoupling of the Electron Transport Chain Compromises Mitochondrial Oxidative Phosphorylation and Exacerbates Stroke Outcomes.

J Neuroinfect Dis 2018 31;9(4). Epub 2018 Dec 31.

Department of Neuroscience, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, USA.

Objective: Mitochondrial dysfunction is known to be implicated in stroke, but the complex mechanisms of stroke have led to few stroke therapies. The present study to disrupted mitochondrial oxidative phosphorylation through a known electron transport chain (ETC) uncoupler, Carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP). Analyzing the resulting neurological deficits as well as infarct volume could help determine the role of mitochondria in stroke outcome and determine whether uncoupling the ETC could potentially be a strategy for new stroke therapies. The objective of this study was to determine the effects of uncoupling electron flow on mitochondrial oxidative phosphorylation and stroke infarction.

Methods: Cerebral endovascular cells (CECs) were treated with various concentrations of FCCP, and bioenergetics were measured. For the stroke mouse model, FCCP (1 mg/kg, i.p) or vehicle was administered followed by 1-hour transient middle cerebral artery occlusion (tMCAO). Infarct volume was measured after a 23-hour reperfusion, and triphenyl tetrazolium chloride (TTC) staining was used to assess infarct volume.

Results: FCCP significantly decreased basal respiration, ATP turnover, maximal respiration, and spare capacity when the concentration of FCCP was greater than 1000 nM. The mice pretreated with FCCP had a significantly increased infarct volume within the cortex, striatum, and total hemisphere. Mice receiving FCCP had a significantly increased neurological deficit score compared to the vehicle.

Conclusions: FCCP compromised mitochondrial oxidative phosphorylation in CECs in a dose-dependent manner. Uncoupling the electron transport chain with FCCP prior to tMCAO exacerbated stroke infarction in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/2314-7326.1000283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059652PMC
December 2018

UV-Curable Antismudge Coatings.

ACS Appl Mater Interfaces 2017 Aug 21;9(30):25623-25630. Epub 2017 Jul 21.

Department of Chemistry, Queen's University , 90 Bader Lane, Kingston, Ontario Canada K7L 3N6.

Current antismudge coatings that bear nano-pools of a grafted liquid ingredient for dewetting enablement (NP-GLIDE) are cured at high temperatures, which are undesirable for application on heat-sensitive substrates. Reported herein is the development of a NP-GLIDE coating that can be photocured at room temperature. Of the various formulations that have been tested, robust coatings were obtained from one recipe consisting of a photoinitiator, a trifunctional monomer that bears three double bonds, and a graft copolymer. The last bears pendent double bonds and a poly(dimethylsiloxane) (PDMS) side chain as the antismudge agent. Coatings were prepared by casting films from a solution containing these three components and then photolyzing the resultant films. A systematic study revealed that the liquid sliding property developed on the coating at a lower cross-linking density than that required for ink to contract. Further, retaining the ability to contract ink traces after many writing and erasing cycles was the most demanding of the three antismudge tests. For our optimized formulation, only 5 min of irradiation was required to yield a transparent coating with superior antismudge properties. Moreover, irradiating selected regions and then removing, with a solvent, reagents in the nonirradiated regions can yield a surface with patterned wettability. These advantageous properties of the new photocurable coating facilitate its applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.7b05732DOI Listing
August 2017

Silicone-Infused Antismudge Nanocoatings.

ACS Appl Mater Interfaces 2017 Mar 2;9(10):9029-9037. Epub 2017 Mar 2.

Department of Chemistry, Queen's University , 90 Bader Lane, Kingston, Ontario, Canada K7L 3N6.

A polyurethane-based NP-GLIDE coating that bears on its surface and in its interior nano-pools of a grafted liquid ingredient for dewetting enablement is obtained from casting and curing a film comprising a triisocyanate, a polyol (P1), and a graft (g) copolymer of P1 and poly(dimethylsiloxane) (P1-g-PDMS). A silicone-infused NP-GLIDE (SINP-GLIDE) PU coating is obtained from cocasting the NP-GLIDE precursors with a free silicone oil (SO) or SO mixture (SOs). This paper reports the preparation of the novel SINP-GLIDE coatings and discusses the effect of changing the amount and type of the infused SO as well as the coating formation conditions on their optical clarity. Also reported are the contact and sliding angles of various test liquids on the NP-GLIDE and SINP-GLIDE coatings, and the data variation trends are rationalized using existing theories. Further, the stable water sliding performance of the SINP-GLIDE coatings under simulated raining and other conditions is demonstrated. The improved and stable water sliding performance of the SINP-GLIDE coatings facilitates their practical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.7b00126DOI Listing
March 2017

Evaluation of Bioenergetic Function in Cerebral Vascular Endothelial Cells.

J Vis Exp 2016 11 19(117). Epub 2016 Nov 19.

Department of Physiology and Pharmacology, West Virginia University; Experimental Stroke Core, West Virginia University; Center for Basic and Translational Stroke Research, West Virginia University;

The integrity of the blood-brain-barrier (BBB) is critical to prevent brain injury. Cerebral vascular endothelial (CVE) cells are one of the cell types that comprise the BBB; these cells have a very high-energy demand, which requires optimal mitochondrial function. In the case of disease or injury, the mitochondrial function in these cells can be altered, resulting in disease or the opening of the BBB. In this manuscript, we introduce a method to measure mitochondrial function in CVE cells by using whole, intact cells and a bioanalyzer. A mito-stress assay is used to challenge the cells that have been perturbed, either physically or chemically, and evaluate their bioenergetic function. Additionally, this method also provides a useful way to screen new therapeutics that have direct effects on mitochondrial function. We have optimized the cell density necessary to yield oxygen consumption rates that allow for the calculation of a variety of mitochondrial parameters, including ATP production, maximal respiration, and spare capacity. We also show the sensitivity of the assay by demonstrating that the introduction of the microRNA, miR-34a, leads to a pronounced and detectable decrease in mitochondrial activity. While the data shown in this paper is optimized for the bEnd.3 cell line, we have also optimized the protocol for primary CVE cells, further suggesting the utility in preclinical and clinical models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/54847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226249PMC
November 2016

Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition.

J Toxicol Environ Health A 2016 19;79(11):447-52. Epub 2016 Apr 19.

a Department of Physiology and Pharmacology , West Virginia University , Morgantown , West Virginia , USA.

It is generally accepted that gestational xenobiotic exposures result in systemic consequences in the adult F1 generation. However, data on detailed behavioral and cognitive consequences remain limited. Using our whole-body nanoparticle inhalation facility, pregnant Sprague-Dawley rats (gestational day [GD] 7) were exposed 4 d/wk to either filtered air (control) or nano-titanium dioxide aerosols (nano-TiO2; count median aerodynamic diameter of 170.9 ± 6.4 nm, 10.4 ± 0.4 mg/m(3), 5 h/d) for 7.8 ± 0.5 d of the remaining gestational period. All rats received their final exposure on GD 20 prior to delivery. The calculated daily maternal deposition was 13.9 ± 0.5 µg. Subsequently, at 5 mo of age, behavior and cognitive functions of these pups were evaluated employing a standard battery of locomotion, learning, and anxiety tests. These assessments revealed significant working impairments, especially under maximal mnemonic challenge, and possible deficits in initial motivation in male F1 adults. Evidence indicates that maternal engineered nanomaterial exposure during gestation produces psychological deficits that persist into adulthood in male rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15287394.2016.1164101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899177PMC
May 2017

Tert-butylhydroquinone compromises survival in murine experimental stroke.

Neurotoxicol Teratol 2016 Mar-Apr;54:15-21. Epub 2016 Jan 28.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, United States.. Electronic address:

Tert-butylhydroquinone (tBHQ), an Nrf2 signaling pathway inducer that is widely used as a food additive in the U.S., prevents oxidative stress-induced cytotoxicity in neurons. This study assesses the effects of tBHQ on ischemic stroke outcomes in mice. We measured infarct size, neurological deficits, and brain volume after tBHQ treatments in murine permanent middle cerebral artery occlusion (pMCAO) model in vivo. Further, we evaluated the regulation of tBHQ on mitochondrial function in cerebrovascular endothelial cells in vitro, which is critical to the blood-brain barrier (BBB) permeability. Our results demonstrated that tBHQ increased post-stroke mortality and worsened stroke outcomes. Mitochondrial function was suppressed by tBHQ treatment of cerebrovascular endothelial cells, and this suppression was potentiated by co-treatment with lipopolysaccharide (LPS), the bacterial mimic. These data indicate that tBHQ-exacerbated stroke damage might due to the compromised BBB permeability in permanent stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ntt.2016.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789102PMC
December 2016

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity.

Aging Dis 2016 Jan 2;7(1):14-27. Epub 2016 Jan 2.

1 Department of Physiology and Pharmacology,; 2 Experimental Stroke Core, Center for Basic and Translational Stroke Research.

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14336/AD.2015.0906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723230PMC
January 2016

MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

J Cereb Blood Flow Metab 2016 Feb 30;36(2):387-92. Epub 2015 Sep 30.

Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia, USA Experimental Stroke Core, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia, USA

The blood-brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood-brain barrier integrity. We report for the first time a novel mechanism underlying blood-brain barrier integrity: miR-34a mediated regulation of blood-brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests miR-34a targets several mitochondria-associated gene candidates. We demonstrated that miR-34a triggers the breakdown of blood-brain barrier in cerebrovascular endothelial cell monolayer in vitro, paralleled by reduction of mitochondrial oxidative phosphorylation and adenosine triphosphate production, and decreased cytochrome c levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0271678X15606147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759667PMC
February 2016

Lipopolysaccharide exacerbates infarct size and results in worsened post-stroke behavioral outcomes.

Behav Brain Funct 2015 Oct 13;11(1):32. Epub 2015 Oct 13.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV, 26506-9229, USA.

Background: A third of ischemic stroke cases have no traditional underlying causes such as hypertension, diabetes, atherosclerosis, obesity, or age. Moreover, thirty to forty percent of strokes occur during or acutely after an active infection and the incidence of stroke increases during flu season. We and others have shown that the combination of a minor bacterial infection mimic, 100 μg/kg of lipopolysaccharide (LPS) prior to a minor stroke-30 min transient middle cerebral artery occlusion (tMCAO)-exacerbates infarct volume in a mouse model. Thus, experimental and epidemiological data strongly suggest that infection and/or inflammation play a role in stroke occurrence and severity. However, to date, long-term outcomes of stroke during an active infection has not been studied.

Methods: 3-4 month old C57Bl6/J mice were treated with saline or LPS 30 min prior to a 30 min tMCAO or sham surgery. A behavioral battery was administered to assess health status/sickness behavior, neurological deficits, motor, cognitive, and affective behaviors.

Results: We show for the first time that exposure to a low dose of LPS prior to a mild stroke significantly worsens neurological deficits and sickness scores. Motor, cognitive, and affective behaviors were assessed post-stroke and while stroke significantly affected motor behavior on rotarod, LPS did not increase the motor deficits. We did not observe any effects of stroke or LPS on cognitive and affective behaviors.

Conclusions: Our observations of the association between infection, stroke, and worse sickness and neurological outcomes identify (1) a clinical need to aggressively treat infections in people with risk factors for stroke and (2) the need to understand the mechanism(s) of the association between infections and stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12993-015-0077-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604642PMC
October 2015

Stable Encapsulated Air Nanobubbles in Water.

Angew Chem Int Ed Engl 2015 Nov 6;54(48):14291-4. Epub 2015 Oct 6.

Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, Ontario, K7L 3N6 (Canada).

The dispersion into water of nanocapsules bearing a highly hydrophobic fluorinated internal lining yielded encapsulated air nanobubbles. These bubbles, like their micrometer-sized counterparts (microbubbles), effectively reflected ultrasound. More importantly, the nanobubbles survived under ultrasonication 100-times longer than a commercial microbubble sample that is currently in clinical use. We justify this unprecedented stability theoretically. These nanobubbles, owing to their small size and potential ability to permeate the capillary networks of tissues, may expand the applications of microbubbles in diagnostic ultrasonography and find new applications in ultrasound-regulated drug delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201505817DOI Listing
November 2015

Fluorine-Free Anti-Smudge Polyurethane Coatings.

Angew Chem Int Ed Engl 2015 Oct 28;54(43):12722-7. Epub 2015 Aug 28.

Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, Ontario, K7L 3N6 (Canada).

Conventionally, low-surface-tension fluorinated reagents are incorporated into anti-smudge (oil- and water-repellent) coatings for oil repellency. However, fluorinated compounds are expensive and an environmental concern because of their high stability and bioaccumulation. These factors limit their widespread application. We report herein the development of fluorine-free anti-smudge polyurethane coatings that are clear at thicknesses up to tens of micrometers and are able to sustain extensive surface damage. We demonstrate that these coatings can be applied readily onto a diverse range of substrates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201504892DOI Listing
October 2015

Lower serum soluble-EGFR is a potential biomarker for metastasis of HCC demonstrated by N-glycoproteomic analysis.

Discov Med 2015 May;19(106):333-41

Department of Anatomy, Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai, 200032, China.

Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world due to its high metastatic potential. By using the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative N-glycoproteomic analysis, 26 differentially expressed serum glycoproteins derived from defined stages in orthotopic xenograft tumor model were identified. Among them, expression level of soluble EGFR (sEGFR) was verified in HCC cell lines. We found that non-metastasis HCC cell lines express significantly more sEGFR than HCC cell lines with metastasis potential both in cell lysates and culture media. Serum samples from 28 non-metastatic HCC patients and 28 metastatic HCC patients were assayed. Compared with the non-metastatic HCC group, serum level of sEGFR in metastatic HCC group was statistically lower (p<0.01). All these results provide evidence that sEGFR is a potential candidate for metastasis-associated biomarkers of HCC. The related molecular mechanism deserves to be further explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2015

Chemokines and their receptors play important roles in the development of hepatocellular carcinoma.

World J Hepatol 2015 Jun;7(10):1390-402

Chun-Min Liang, Long Chen, Heng Hu, Hui-Ying Ma, Ling-Ling Gao, Jie Qin, Cui-Ping Zhong, Lab of Tumor Immunology, Department of Anatomy and Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai 200032, China.

The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v7.i10.1390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450202PMC
June 2015

Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.

Stroke 2015 Jun 28;46(6):1681-9. Epub 2015 Apr 28.

From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.

Background And Purpose: The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and the central nervous system. BBB disruption is a consequence of ischemic stroke and BBB permeability can be altered by infection/inflammation, but the complex cellular and molecular changes that result in this BBB alteration need to be elucidated to determine mechanisms.

Methods: Infection mimic (lipopolysaccharide) challenge on infarct volume, BBB permeability, infiltrated neutrophils, and functional outcomes after murine transient middle cerebral artery occlusion in vivo; mitochondrial evaluation of cerebrovascular endothelial cells challenged by lipopolysaccharide in vitro; pharmacological inhibition of mitochondria on BBB permeability in vitro and in vivo; the effects of mitochondrial inhibitor on BBB permeability, infarct volume, and functional outcomes after transient middle cerebral artery occlusion.

Results: We report here that lipopolysaccharide worsens ischemic stroke outcome and increases BBB permeability after transient middle cerebral artery occlusion in mice. Furthermore, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: lipopolysaccharide-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in cerebrovascular endothelial cells, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in cerebrovascular endothelial cells in vitro and in an in vivo animal model, and worsened stroke outcomes in transient middle cerebral artery occlusion mice after inhibition of mitochondrial function.

Conclusions: We concluded that mitochondria are key players in BBB permeability. These novel findings suggest a potential new therapeutic strategy for ischemic stroke by endothelial cell mitochondrial regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.115.009099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418219PMC
June 2015

Tunable ultrathin membranes with nonvolatile pore shape memory.

ACS Appl Mater Interfaces 2015 May 7;7(19):10401-6. Epub 2015 May 7.

†Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, New York 13699, United States.

The concept of a responsive nanoporous thin-film gel membranes whose pores could be tuned to a desired size by a specific "molecular signal" and whose pore geometry becomes "memorized" by the gel is reported. The ∼100 nm thick membranes were prepared by dip-coating from a solution mixture of a random copolymer comprising responsive and photo-cross-linkable units and monodisperse latex nanoparticles used as a sacrificial colloidal template. After stabilization of the films by photo-cross-linking the latex template was removed, yielding nanoporous structures with a narrow pore size distribution and a high porosity. The thin-film membranes could be transferred onto porous supports to serve as tunable size-selective barriers in various colloids separation applications. The pore dimensions and hence the membrane's colloidal-particle-size cutoff were reversibly regulated by swelling-shrinking of the polymer network with a specially selected low-molar-mass compound. The attained pore shape was "memorized" in aqueous media and "erased" by treatment in special solvents reverting the membrane to the original state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.5b01416DOI Listing
May 2015

[Clinical analysis of early esophageal varices bleeding after endoscopic varices ligation in advanced schistosomiasis patients].

Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2014 Oct;26(5):577-8

Objective: To study the clinical characteristics of early esophageal varices bleeding after endoscopic varices ligation (EVL) in advanced schistosomiasis patients.

Methods: The data of 206 advanced schistosomiasis patients who received VEL were collected and studied retrospectively.

Results: There were 17 cases of early esophageal varices bleeding after EVL including 1 died case, the early hemorrhage rate was 8.25%, and the mortality rate was 0.5%. The early bleeding occurred from the 4th to 12th day, and 76% occurred from the 7th to 9th day postoperatively. The direct cause of hemorrhagic was ligation ring falling off, and the inducements were the improper diet (10 cases, 58.8%) and increased abdominal pressure (6 cases, 35%). All the cases of early esophageal varices bleeding occurred in the patients whose liver function being Child-Pugh C.

Conclusions: The incidence and mortality of EVL early postoperative hemorrhage are both low, and mostly occur from the 7th to 9th day postoperatively. We should pay attention to the diet and nursing, and the patients with Child-Pugh C liver function are the high risk group.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2014

NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke.

Exp Neurol 2015 Jan 2;263:17-27. Epub 2014 Oct 2.

Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA; Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. Electronic address:

Chronic stroke is the phase of brain recovery and repair generally beginning 3 months after stroke onset. No pharmaceutical approach is currently available to enhance brain repair in chronic stroke. We have previously determined the therapeutic effects of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) alone or in combination (SCF+G-CSF) in an animal model of chronic stroke and demonstrated that only SCF+G-CSF induces long-term functional recovery. However, the mechanism underlying the SCF+G-CSF-induced brain repair in chronic stroke remains largely elusive. In the present study, we determined the role of nuclear factor-kappa B (NF-κB) in neurovascular network remodeling and motor function improvement by SCF+G-CSF treatment in chronic stroke. SCF+G-CSF was subcutaneously administered for 7 days beginning 17 weeks after induction of experimental stroke. To inhibit NF-κB activation, NF-κB inhibitor was infused into the brain before SCF+G-CSF treatment. We observed that NF-κB inhibitor abolished the SCF+G-CSF-induced axonal sprouting, synaptogenesis and angiogenesis in the ipsilesional somatosensorimotor cortex. In addition, blockage of NF-κB activation resulted in elimination of the SCF+G-CSF-induced motor functional restoration in chronic stroke. These data suggest that NF-κB is required for the SCF+G-CSF-induced neuron-vascular network remodeling in the ipsilesional somatosensorimotor cortex and motor functional recovery in chronic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2014.08.026DOI Listing
January 2015

[Serum glycoprotein profiling by lectin affinity microarray to distinguish the various stages of primary liver carcinogenesis].

Zhonghua Gan Zang Bing Za Zhi 2014 May;22(5):358-63

The Affiliatde Tumor Hospital of Guangxi Medical university, Nanning 530021, China.

Objective: To identify specific serum glycoprotein profiles that correspond to the carcinogenic process of primary liver cancer (PLC) by analyzing a population with high-incidence of PLC using lectin affinity microarray.

Methods: Serum samples were collected from individuals classified as high risk for PLC (including patients with liver cirrhosis and hepatitis B) and development of PLC was recorded. Healthy individuals served as normal controls. The serum samples were subjected to glycoprotein profling by using lectin microarrays and the results were confirmed by lectin blot. Between-group differences were statistically analyzed.

Results: PLC carcinogenesis was found to be correlated with enhanced affinity for AAL, ACL, ConA, LCA, MPL, NML, PHA-E, PHA-L, PSA, RCA-I, STL, VAL,WGA, and SNA (P less than 0.05). These data implied that changes in specific glycan structures, such as aFuc, GlcNAc, GalNAc, mannose, bisecting GlcNAc and terminal beta1-4 Gal, may be involved in PLC carcinogenesis . The PLC group showed significantly different results for all detected lectins, except SNA (P less than 0.05). However, among the PLC group, the SNA affinity was not significantly different for the hepatitis B group (P =0.443, P more than 0.05).

Conclusion: Glycans may be associated with the carcinogenic process of PLC and may be developed as diagnostic and prognostic biomarkers of PLC in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3760/cma.j.issn.1007-3418.2014.05.008DOI Listing
May 2014