Attenuation by Reactive Oxygen Species of Glucocorticoid Suppression on Proopiomelanocortin Gene Expression in Pituitary Corticotroph Cells

Abstract Up-regulation of hypothalamo-pituitary-adrenal axis is maintained during acute inflammation and/or infection, in the face of sustained elevation of plasma glucocorticoid hormone. Inflammatory stress is usually associated with high plasma cytokine levels and increased generation of reactive oxygen species (ROS) as well. In this study, we examined the effect of ROS on the negative feedback regulation of glucocorticoid in hypothalamo-pituitary-adrenal axis using AtT20 corticotroph cells in vitro. When the cells were treated with H2O2, glucocorticoid suppression on the proopiomelanocortin gene promoter activity was attenuated in a dose-dependent manner. H2O2 also inhibited the ligand-stimulated nuclear translocation of glucocorticoid receptor. The released glucocorticoid suppression by H2O2 was not observed when the cells were cotreated with antioxidants. Together, these results suggest that increased ROS generation in the oxidative redox state attenuates the glucocorticoid negative feedback system, at least in part, by interfering with the nuclear translocation of glucocorticoid receptor and eliminating the repression on proopiomelanocortin gene expression.

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15-Deoxy-Δ12,14-prostaglandin J2Induces Heme Oxygenase-1 Gene Expression in a Reactive Oxygen Species-dependent Manner in Human Lymphocytes

Journal of Biological Chemistry ◽

10.1074/jbc.m400492200 ◽

2004 ◽

Vol 279 (21) ◽

pp. 21929-21937 ◽

Cited By ~ 80

Author(s):

Moisés Álvarez-Maqueda ◽

Rajaa El Bekay ◽

Gonzalo Alba ◽

Javier Monteseirín ◽

Pedro Chacón ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Heme Oxygenase ◽

Human Lymphocytes ◽

Reactive Oxygen ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Oxygen Species

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Respiratory Syncytial Virus Infection Induces a Reactive Oxygen Species-MSK1-Phospho-Ser-276 RelA Pathway Required for Cytokine Expression

Journal of Virology ◽

10.1128/jvi.01090-09 ◽

2009 ◽

Vol 83 (20) ◽

pp. 10605-10615 ◽

Cited By ~ 67

Author(s):

Mohammad Jamaluddin ◽

Bing Tian ◽

Istvan Boldogh ◽

Roberto P. Garofalo ◽

Allan R. Brasier

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Respiratory Syncytial Virus ◽

Inflammatory Response ◽

Target Gene ◽

Nuclear Translocation ◽

Reactive Oxygen ◽

Oxygen Species ◽

Target Gene Expression ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a human pathogen that induces airway inflammation, at least in part, by modulating gene expression programs in airway epithelial cells. The presence of RSV replication is detected by the intracellular retinoic acid-inducible gene I (RIG-I) RNA helicase that forms a productive signaling complex with the mitochondrion-anchored MAVS protein, resulting in nuclear translocation of the NF-κB transcription factor. Although nuclear translocation is a prerequisite for activation of the innate inflammatory response, recent studies show that separate pathways governing RelA activation are also required for target gene expression. In this study, we examine the mechanism of RelA phosphorylation and its requirement for RSV-induced gene expression. RSV infection produced a time-dependent RelA phosphorylation on serine (Ser) residues Ser-276 and Ser-536 in parallel with enhanced reactive oxygen species (ROS) stress. Inhibition of RSV-induced ROS inhibited formation of phospho-Ser-276 RelA without affecting phospho-Ser-536 RelA formation. RSV potently induced activation of cytoplasmic mitogen- and stress-related kinase 1 (MSK1) in an ROS-dependent manner. Inhibition of MSK1 using H89 and small interfering RNA knockdown both reduced RSV-induced phospho-Ser-276 RelA formation and expression of a subset of NF-κB-dependent genes. Direct examination of the role of phospho-Ser-276 in target gene expression by expression of a RelA Ser-276-to-Ala site mutation in RelA−/− mouse embryonic fibroblasts showed that the mutation was unable to mediate RSV-induced NF-κB-dependent gene expression. We conclude that RSV induces RelA activation in the innate inflammatory response via a pathway separate from that controlling RelA cytoplasmic release, mediated by ROS signaling to cytoplasmic MSK1 activation and RelA Ser-276 phosphorylation.

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Negative feedback regulation of reactive oxygen species on AT1 receptor gene expression

British Journal of Pharmacology ◽

10.1038/sj.bjp.0703623 ◽

2000 ◽

Vol 131 (4) ◽

pp. 795-803 ◽

Cited By ~ 41

Author(s):

Georg Nickenig ◽

Kerstin Strehlow ◽

Anselm T Bäumer ◽

Stefanie Baudler ◽

Sven Waßmann ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Negative Feedback ◽

Receptor Gene ◽

Reactive Oxygen ◽

Feedback Regulation ◽

At1 Receptor ◽

Oxygen Species ◽

Negative Feedback Regulation ◽

Receptor Gene Expression

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BMAL1 Modulates Epidermal Healing in a Process Involving the Antioxidative Defense Mechanism

International Journal of Molecular Sciences ◽

10.3390/ijms21030901 ◽

2020 ◽

Vol 21 (3) ◽

pp. 901

Author(s):

Ericka J. D. Silveira ◽

Carlos H. V. Nascimento Filho ◽

Veronica Q. Yujra ◽

Liana P. Webber ◽

Rogerio M. Castilho ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Reactive Oxygen Species ◽

Epithelial Cells ◽

Clock Genes ◽

Reactive Oxygen ◽

Dependent Manner ◽

Oxygen Species ◽

Skin Healing

The circadian rhythm regulates the physiology and behavior of living organisms in a time-dependent manner. Clock genes have distinct roles including the control over gene expression mediated by the transcriptional activators CLOCK and BMAL1, and the suppression of gene expression mediated by the transcriptional repressors PER1/2 and CRY1/2. The balance between gene expression and repression is key to the maintenance of tissue homeostasis that is disrupted in the event of an injury. In the skin, a compromised epithelial barrier triggers a cascade of events that culminate in the mobilization of epithelial cells and stem cells. Recruited epithelial cells migrate towards the wound and reestablish the protective epithelial layer of the skin. Although we have recently demonstrated the involvement of BMAL and the PI3K signaling in wound healing, the role of the circadian clock genes in tissue repair remains poorly understood. Here, we sought to understand the role of BMAL1 on skin healing in response to injury. We found that genetic depletion of BMAL1 resulted in delayed healing of the skin as compared to wild-type control mice. Furthermore, we found that loss of Bmal1 was associated with the accumulation of Reactive Oxygen Species Modulator 1 (ROMO1), a protein responsible for inducing the production of intracellular reactive oxygen species (ROS). The slow healing was associated with ROS and superoxide dismutase (SOD) production, and pharmacological inhibition of the oxidative stress signaling (ROS/SOD) led to cellular proliferation, upregulation of Sirtuin 1 (SIRT1), and rescued the skin healing phenotype of Bmal1−/− mice. Overall, our study points to BMAL1 as a key player in tissue regeneration and as a critical regulator of ROMO1 and oxidative stress in the skin.

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Homocysteine induces VCAM-1 gene expression through NF-κB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00432.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. H2344-H2354 ◽

Cited By ~ 77

Author(s):

Maria Annunziata Carluccio ◽

Maria Assunta Ancora ◽

Marika Massaro ◽

Marisa Carluccio ◽

Egeria Scoditti ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Mediterranean Diet ◽

Nuclear Translocation ◽

Reactive Oxygen ◽

Intracellular Reactive Oxygen Species ◽

Northern Analysis ◽

Mrna Levels ◽

Oxygen Species ◽

Polyphenolic Antioxidants

Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-κB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans-resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-κB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 μmol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-κB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-κB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IκB-α and IκB-β by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47phox subunit. NF-κB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by >60% at 10−6 mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-κB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage.

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PAC1 regulates receptor tyrosine kinase transactivation in a reactive oxygen species-dependent manner

Peptides ◽

10.1016/j.peptides.2018.09.005 ◽

2019 ◽

Vol 120 ◽

pp. 170017

Author(s):

Terry W. Moody ◽

Lingaku Lee ◽

Tatiana Iordanskaia ◽

Irene Ramos-Alvarez ◽

Paola Moreno ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Reactive Oxygen ◽

Dependent Manner ◽

Oxygen Species

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Blockage of Potassium Channel Inhibits Proliferation of Glioma Cells Via Increasing Reactive Oxygen Species

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504014x14098532393518 ◽

2014 ◽

Vol 22 (1) ◽

pp. 57-65 ◽

Cited By ~ 1

Author(s):

Li Hu ◽

Li-Li Li ◽

Zhi-Guo Lin ◽

Zhi-Chao Jiang ◽

Hong-Xing Li ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Cycle ◽

Glioma Cell ◽

Glioma Cells ◽

Reactive Oxygen ◽

Dependent Manner ◽

Oxygen Species ◽

Brain Glioma ◽

Protein Levels ◽

Glioma Cell Proliferation

The potassium (K+) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K+ channels, to block K+ channels in glioma cells, and antioxidant N-acetyl-l-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumor-suppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K+ channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21Cip1-dependent signaling pathway, consequently leading to glioma cell cycle arrest.

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Ethyl Rosmarinate Protects High Glucose-Induced Injury in Human Endothelial Cells

Molecules ◽

10.3390/molecules23123372 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3372 ◽

Cited By ~ 3

Author(s):

Yan-Hui Shen ◽

Li-Ying Wang ◽

Bao-Bao Zhang ◽

Qi-Ming Hu ◽

Pu Wang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Cells ◽

Protective Effect ◽

High Glucose ◽

Reactive Oxygen ◽

Annexin V ◽

Ros Generation ◽

Dependent Manner ◽

Oxygen Species ◽

Jnk Pathway

Ethyl rosmarinate (RAE) is one of the active constituents from Clinopodium chinense (Benth.) O. Kuntze, which is used for diabetic treatment in Chinese folk medicine. In this study, we investigated the protective effect of RAE on high glucose-induced injury in endothelial cells and explored its underlying mechanisms. Our results showed that both RAE and rosmarinic acid (RA) increased cell viability, decreased the production of reactive oxygen species (ROS), and attenuated high glucose-induced endothelial cells apoptosis in a dose-dependent manner, as evidenced by Hochest staining, Annexin V–FITC/PI double staining, and caspase-3 activity. RAE and RA both elevated Bcl-2 expression and reduced Bax expression, according to Western blot. We also found that LY294002 (phosphatidylinositol 3-kinase, or PI3K inhibitor) weakened the protective effect of RAE. In addition, PDTC (nuclear factor-κB, or NF-κB inhibitor) and SP600125 (c-Jun N-terminal kinase, or JNK inhibitor) could inhibit the apoptosis in endothelial cells caused by high glucose. Further, we demonstrated that RAE activated Akt, and the molecular docking analysis predicted that RAE showed more affinity with Akt than RA. Moreover, we found that RAE inhibited the activation of NF-κB and JNK. These results suggested that RAE protected endothelial cells from high glucose-induced apoptosis by alleviating reactive oxygen species (ROS) generation, and regulating the PI3K/Akt/Bcl-2 pathway, the NF-κB pathway, and the JNK pathway. In general, RAE showed greater potency than RA equivalent.

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Drosophila hemocytes recognize lymph gland tumors of mxc mutants and activate the Toll pathway in reactive oxygen species-dependent manner

10.1101/2021.12.17.473119 ◽

2021 ◽

Author(s):

Suzuko Kinoshita ◽

Kazuki Takarada ◽

Yoshihiro H. Inoue

Keyword(s):

Reactive Oxygen Species ◽

Fat Body ◽

Ectopic Expression ◽

Reactive Oxygen ◽

Underlying Mechanism ◽

Innate Immune ◽

Dependent Manner ◽

Oxygen Species ◽

Matrix Metalloproteinase 1 ◽

Membrane Components

Mechanisms of cancer cell recognition and elimination by the innate immune system remains unclear. Circulating hemocytes are associated with the hematopoietic tumors in Drosophila mxcmbn1 mutant larvae. The innate immune signalling pathways are activated in the fat body to suppress the tumor growth by inducing antimicrobial peptides (AMP). Here, we investigated the regulatory mechanism underlying the activation in the mutant. Reactive oxygen species accumulated in the hemocytes due to induction of dual oxidase and its activator. The hemocytes were also localized on the fat body. These were essential for transmitting the information on tumors toward the fat body to induce AMP expression. Regarding to the tumor recognition, we found that matrix metalloproteinase 1 (MMP1) and MMP2 were highly expressed in the tumors. Ectopic expression of MMP2 was associated with AMP induction in the mutants. Furthermore, the basement membrane components in the tumors were reduced and ultimately lost. The hemocytes may recognize the disassembly in the tumors. Our findings highlight the underlying mechanism via which macrophage-like hemocytes recognize tumor cells and relay the information toward the fat body to induce AMPs. and contribute to uncover the immune system's roles against cancer.

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Spatial Regulation of Reactive Oxygen Species via G6PD in Brown Adipocytes Supports Thermogenic Function

10.2337/figshare.16556181 ◽

2021 ◽

Author(s):

Jee Hyung Sohn ◽

Yul Ji ◽

Chang-Yun Cho ◽

Hahn Nahmgoong ◽

Sangsoo Lim ◽

...

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species ◽

Redox Potentials ◽

Brown Adipocytes ◽

Erk Activation ◽

Brown Adipose ◽

Erk Inhibition ◽

Glucose 6 Phosphate Dehydrogenase

Reactive oxygen species (ROS) are associated with various roles of brown adipocytes. Glucose-6-phosphate dehydrogenase (G6PD) controls cellular redox potentials by producing NADPH. Although G6PD upregulates cellular ROS levels in white adipocytes, the roles of G6PD in brown adipocytes remain elusive. Here, we found that G6PD defect in brown adipocytes impaired thermogenic function through excessive cytosolic ROS accumulation. Upon cold exposure, G6PD-deficient mutant (G6PDmut) mice exhibited cold intolerance and downregulated thermogenic gene expression in brown adipose tissue (BAT). In addition, G6PD-deficient brown adipocytes had increased cytosolic ROS levels, leading to ERK activation. In BAT of G6PDmut mice, administration of antioxidant restored the thermogenic activity by potentiating thermogenic gene expression and relieving ERK activation. Consistently, body temperature and thermogenic execution were rescued by ERK inhibition in cold-exposed G6PDmut mice. Taken together, these data suggest that G6PD in brown adipocytes would protect against cytosolic oxidative stress, leading to cold-induced thermogenesis.

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