Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Abstract Background Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer’s disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known. Methods Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/E4 compared to APOE3/E3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. Conclusions Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

10.21203/rs.3.rs-68804/v3 ◽

2021 ◽

Author(s):

Shaowei Wang ◽

Boyang Li ◽

Victoria Solomon ◽

Alfred Fonteh ◽

Stanley I. Rapoport ◽

...

Keyword(s):

Oxidative Stress ◽

Human Brain ◽

Phospholipase A2 ◽

Late Onset ◽

Ex Vivo ◽

Cytosolic Phospholipase A2 ◽

Calcium Dependent ◽

Cytosolic Phospholipase ◽

Primary Astrocytes ◽

And Oxidative Stress

Abstract Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/4 compared to APOE3/3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

10.21203/rs.3.rs-68804/v2 ◽

2021 ◽

Author(s):

Shaowei Wang ◽

Boyang Li ◽

Victoria Solomon ◽

Alfred Fonteh ◽

Stanley I. Rapoport ◽

...

Keyword(s):

Oxidative Stress ◽

Phospholipase A2 ◽

Late Onset ◽

Leukotriene B4 ◽

Cytosolic Phospholipase A2 ◽

Calcium Dependent ◽

Cytosolic Phospholipase ◽

Primary Astrocytes ◽

Oxide Synthase ◽

And Oxidative Stress

Abstract Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation and activity was identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway in human postmortem frontal cortical synaptosomes and astrocytes, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) in astrocytes. Inhibition of cPLA2 reduced LTB4, ROS, and iNOS levels in ApoE4 primary astrocytes to those in ApoE3 astrocytes. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

10.21203/rs.3.rs-68804/v1 ◽

2020 ◽

Author(s):

Shaowei Wang ◽

Boyang Li ◽

Victoria Solomon ◽

Alfred Fonteh ◽

Stanley I. Rapoport ◽

...

Keyword(s):

Oxidative Stress ◽

Phospholipase A2 ◽

Late Onset ◽

Leukotriene B4 ◽

Cytosolic Phospholipase A2 ◽

Calcium Dependent ◽

Cytosolic Phospholipase ◽

Primary Astrocytes ◽

Inos Inhibition ◽

And Oxidative Stress

Abstract Background Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and risk of developing late-onset Alzheimer disease (AD), but the mechanisms for this association are not clear. Activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within plaques of the AD brain. The relation between APOE4 genotype and cPLA2 activity is not known. Methods Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation and activity in relation to measures of inflammation and oxidative stress. Results Greater cPLA2 phosphorylation and activity were identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). Inhibition of cPLA2 reduced LTB4, ROS and iNOS levels in ApoE4 primary astrocytes to those of ApoE3 astrocytes. Conclusions Our findings implicate greater activation of cPLA2 signaling system with APOE4, that could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2017.08.009 ◽

2017 ◽

Vol 55 ◽

pp. 74-80 ◽

Cited By ~ 13

Author(s):

Mohammed S. El-Awady ◽

Manar A. Nader ◽

Maha H. Sharawy

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

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The Genetic Inactivation of Inducible Nitric Oxide Synthase (iNOS) Intensifies Fibrosis and Oxidative Stress in the Penile Corpora Cavernosa in Type 1 Diabetes

Journal of Sexual Medicine ◽

10.1111/j.1743-6109.2010.01884.x ◽

2010 ◽

Vol 7 (9) ◽

pp. 3033-3044 ◽

Cited By ~ 30

Author(s):

Monica G. Ferrini ◽

Steve Rivera ◽

Joanne Moon ◽

Dolores Vernet ◽

Jacob Rajfer ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Type 1 Diabetes ◽

Inducible Nitric Oxide Synthase ◽

Corpora Cavernosa ◽

Genetic Inactivation ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

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Cyclooxygenase-2 Inhibition Improves Vascular Endothelial Dysfunction in a Rat Model of Endotoxic Shock: Role of Inducible Nitric-Oxide Synthase and Oxidative Stress

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.104.077644 ◽

2004 ◽

Vol 312 (3) ◽

pp. 945-953 ◽

Cited By ~ 69

Author(s):

Agostino Virdis ◽

Rocchina Colucci ◽

Matteo Fornai ◽

Corrado Blandizzi ◽

Emiliano Duranti ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endotoxic Shock ◽

Vascular Endothelial ◽

Vascular Endothelial Dysfunction ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

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Inducible nitric oxide synthase plays a role in depression- and anxiety-like behaviors chronically induced by lipopolysaccharide in rats: Evidence from inflammation and oxidative stress

Behavioural Brain Research ◽

10.1016/j.bbr.2020.112720 ◽

2020 ◽

Vol 392 ◽

pp. 112720 ◽

Cited By ~ 1

Author(s):

Farimah Beheshti ◽

Milad Hashemzehi ◽

Mahmoud Hosseini ◽

Narges Marefati ◽

Sara Memarpour

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Depression And Anxiety ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

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Role of heme oxygenases in sepsis-induced diaphragmatic contractile dysfunction and oxidative stress

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00495.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. L476-L484 ◽

Cited By ~ 40

Author(s):

Esther Barreiro ◽

Alain S. Comtois ◽

Shawn Mohammed ◽

Larry C. Lands ◽

Sabah N. A. Hussain

Keyword(s):

Oxidative Stress ◽

Muscle Protein ◽

Contractile Dysfunction ◽

Heme Oxygenases ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Ventilatory Muscles ◽

Inducible Nitric Oxide

Heme oxygenases (HOs), essential enzymes for heme metabolism, play an important role in the defense against oxidative stress. In this study, we evaluated the expression and functional significance of HO-1 and HO-2 in the ventilatory muscles of normal rats and rats injected with bacterial lipopolysaccharide (LPS). Both HO-1 and HO-2 proteins were detected inside ventilatory and limb muscle fibers of normal rats. Diaphragmatic HO-1 and HO-2 expressions rose significantly within 1 and 12 h of LPS injection, respectively. Inhibition of the activity of inducible nitric oxide synthase (iNOS) in rats and absence of this isoform in iNOS−/− mice did alter sepsis-induced regulation of muscle HOs. Systemic inhibition of HO activity with chromium mesoporphyrin IX enhanced muscle protein oxidation and hydroxynonenal formation in both normal and septic rats. Moreover, in vitro diaphragmatic force generation declined substantially in response to HO inhibition both in normal and septic rats. We conclude that both HO-1 and HO-2 proteins play an important role in the regulation of muscle contractility and in the defense against sepsis-induced oxidative stress.

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Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032008000200013 ◽

2008 ◽

Vol 45 (2) ◽

pp. 156-162 ◽

Cited By ~ 34

Author(s):

Gustavo Pereira-Filho ◽

Clarissa Ferreira ◽

Alex Schwengber ◽

Cláudio Marroni ◽

Cláudio Zettler ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Glutathione Peroxidase ◽

Inducible Nitric Oxide Synthase ◽

Peroxidase Enzyme ◽

Oxide Synthase ◽

Cirrhotic Group ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. AIM: To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. METHODS: The animals were randomly in three experimentals groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.

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