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      Melatonin alleviates lipopolysaccharide‐compromised integrity of blood–brain barrier through activating AMP‐activated protein kinase in old mice

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          Blood–brain barrier ( BBB) dysfunction is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients, and this could occur in old people even when facing common stress. However, the mechanism remains to be defined. In this study, we tested the hypothesis that decreased melatonin levels may account for the BBB disruption in old mice challenged with lipopolysaccharide ( LPS), which mimicked the common stress of sepsis. Mice (24–28 months of age) received melatonin (10 mg kg −1 day −1, intraperitoneally, i.p.) or saline for one week before exposing to LPS (1 mg kg −1, i.p.). Evan's blue dye ( EB) and immunoglobulin G (IgG) leakage were used to assess BBB permeability. Immunostaining and Western blot were used to detect protein expression and distribution. Our results showed that LPS significantly increased BBB permeability in old mice accompanied by the degradation of tight junction proteins occludin and claudin‐5, suppressed AMP‐activated protein kinase ( AMPK) activation, and elevated gp91 phox protein expression. Interestingly, administration of melatonin for one week significantly decreased LPS‐induced BBB disruption, AMPK suppression, and gp91 phox upregualtion. Moreover, activation of AMPK with metformin significantly inhibited LPS‐induced gp91 phox upregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS‐induced BBB disruption through activating AMPK and inhibiting gp91 phox upregulation in old mice.

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          The effect of age on the development and outcome of adult sepsis.

          Sepsis is an increasingly common and lethal medical condition that occurs in people of all ages. The influence of age on sepsis risk and outcome is incompletely understood. We sought to determine the independent effect of age on the incidence, severity, and outcome of adult sepsis. Longitudinal observational study using national hospital discharge data. Approximately 500 geographically separated nonfederal acute care hospitals in the United States. Patients were 10,422,301 adult sepsis patients hospitalized over 24 yrs, from 1979 to 2002. None. Incident sepsis cases were age adjusted and characterized by demographics, sources and types of infection, comorbid medical conditions, and hospital discharge status. Elderly patients (> or = 65 yrs of age) accounted for 12% of the U.S. population and 64.9% of sepsis cases, yielding a relative risk of 13.1 compared with younger patients (95% confidence interval, 12.6-13.6). Elderly patients were more likely to have Gram-negative infections, particularly in association with pneumonia (relative risk, 1.66; 95% confidence interval, 1.63-1.69) and to have comorbid medical conditions (relative risk, 1.99; 95% confidence interval, 1.92-2.06). Case-fatality rates increased linearly by age; age was an independent predictor of mortality in an adjusted multivariable regression (odds ratio, 2.26; 95% confidence interval, 2.17-2.36). Elderly sepsis patients died earlier during hospitalization, and elderly survivors were more likely to be discharged to a nonacute health care facility. The incidence of sepsis is disproportionately increased in elderly adults, and age is an independent predictor of mortality. Compared with younger sepsis patients, elderly nonsurvivors of sepsis die earlier during hospitalization and elderly survivors more frequently require skilled nursing or rehabilitative care after hospitalization. These findings have implications for patient care and health care resource prioritization and provide insights for expanded scientific investigations and potential patient interventions.
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            AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes.

            AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established. The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function. The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 to -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of nuclear factor (NF)-kappaB (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPKalpha2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPKalpha2(-/-) mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPKalpha2(-/-) mice. Analysis of aortic endothelial cells from AMPKalpha2(-/-) mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPKalpha2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 and -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of NF-kappaB (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPKalpha2 in low-density lipoprotein receptor knockout (LDLr(-/-)) strain markedly increased 26S proteasome activity, IkappaB degradation, NF-kappaB transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor. We conclude that AMPKalpha2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells.
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              NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke.

              Cerebral ischemia/reperfusion is associated with reactive oxygen species (ROS) generation, and NADPH oxidases are important sources of ROS. We hypothesized that NADPH oxidases mediate blood-brain barrier (BBB) disruption and contribute to tissue damage in ischemia/reperfusion. Ischemia was induced by filament occlusion of the middle cerebral artery in mice for 2 hours followed by reperfusion. BBB permeability was measured by Evans blue extravasation. Monolayer permeability was determined from transendothelial electrical resistance of cultured porcine brain capillary endothelial cells. BBB permeability was increased in the ischemic hemisphere 1 hour after reperfusion. In NADPH oxidase-knockout (gp91phox(-/-)) mice, middle cerebral artery occlusion-induced BBB disruption and lesion volume were largely attenuated compared with those in wild-type mice. Inhibition of NADPH oxidase by apocynin prevented BBB damage. In porcine brain capillary endothelial cells, hypoxia/reoxygenation induced translocation of the NADPH oxidase activator Rac-1 to the membrane. In vivo inhibition of Rac-1 by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin or Clostridium difficile lethal toxin B also prevented the ischemia/reperfusion-induced BBB disruption. Stimulation of porcine brain capillary endothelial cells with H(2)O(2) increased permeability, an effect attenuated by inhibition of phosphatidyl inositol 3-kinase or c-Jun N-terminal kinase but not blockade of extracellular signal-regulated kinase-1/2 or p38 mitogen-activated protein kinase. Inhibition of Rho kinase completely prevented the ROS-induced increase in permeability and the ROS-induced polymerization of the actin cytoskeleton. Activation of Rac and subsequently of the gp91phox containing NADPH oxidase promotes cerebral ROS formation, which then leads to Rho kinase-mediated endothelial cell contraction and disruption of the BBB. Inhibition of NADPH oxidase is a promising approach to reduce brain injury after stroke.

                Author and article information

                Aging Cell
                Aging Cell
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                03 February 2017
                April 2017
                : 16
                : 2 ( doiID: 10.1111/acel.2017.16.issue-2 )
                : 414-421
                [ 1 ] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro‐Psycho‐Diseases and Institute of Neuroscience The Second Affiliated Hospital of Soochow University Suzhou 215004China
                [ 2 ]Suzhou Municipal Hospital Suzhou 215002China
                [ 3 ] Department of EmergencyShanxi Provincial People's Hospital Taiyuan 030001China
                [ 4 ] Translational Center for Stem Cell Research Tongji Hospital Stem Cell Research CenterTongji University School of Medicine Shanghai 200065China
                [ 5 ] Department of Psychiatry and Biobehavioral Sciences David Geffen School of MedicineUniversity of California, Los Angeles Los Angeles CA 90095USA
                [ 6 ] Department of Neurology Jiangsu Key Laboratory of Translational Research and Therapy for Neuro‐Psycho‐Diseases The Second Affiliated Hospital of Soochow UniversitySoochow University Suzhou 215004China
                [ 7 ] The Central Laboratory Shenzhen Second People's Hospitalthe First Affiliated Hospital of Shenzhen University Shenzhen 518035China
                Author notes
                [* ] Correspondence

                Dr. Xinchun Jin, Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004 China. Tel.: 86 51265883557; fax: 8651265883602; e‐mail xinchunjin@ 123456gmail.com   or Dr. Jie Liu, Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200065 China, Tel.: 021 66111590; fax: 021 66111590; e‐mail liujie3131@ 123456hotmail.com  or  Dr. Wenlan Liu, the Central Laboratory, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China 518035. Tel.: 86 755 83770445; fax: 86 755 83770445; e‐mail williu@ 123456szu.edu.cn


                The authors contributed equally to this work.

                © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 0, Pages: 8, Words: 6063
                Funded by: Soochow University Research startup fund
                Award ID: Q421500113
                Funded by: National Natural Science Foundation of China
                Award ID: 31271371
                Award ID: 81371328
                Award ID: 81571149
                Award ID: 81671145
                Funded by: Natural Science Foundation of Jiangsu Province of China
                Award ID: L221506415
                Funded by: Shenzhen Science and Technology Innovation Commission
                Award ID: KQCX20140521101427034
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions of China
                Original Article
                Original Articles
                Custom metadata
                April 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:23.03.2017

                Cell biology

                ampk, blood–brain barrier, lipopolysaccharide, melatonin, old mice, tight junction protein


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