Redox-active Cu(II)–Aβ causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner

2012 ◽  
Vol 237 (2) ◽  
pp. 499-506 ◽  
Author(s):  
Claire Howells ◽  
Katrina Saar ◽  
Emma Eaton ◽  
Shannon Ray ◽  
Peep Palumaa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cortical Neurons ◽  
Dependent Manner ◽  
Redox Active ◽  
Cultured Cortical Neurons ◽  
Stress Dependent

scholarly journals Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus

2018 ◽  
Vol 314 (3) ◽  
pp. F462-F470 ◽  
Author(s):  
Yoshifumi Kurosaki ◽  
Akemi Imoto ◽  
Fumitaka Kawakami ◽  
Masanori Yokoba ◽  
Tsuneo Takenaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Hydrogen Peroxide ◽  
High Glucose ◽  
Renal Cortex ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphorylated Akt ◽  
Stress Dependent ◽  
Phosphatidylinositol 3

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

scholarly journals Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation

2020 ◽  
Author(s):  
Detmar Kolijn ◽  
Steffen Pabel ◽  
Yanna Tian ◽  
Mária Lódi ◽  
Melissa Herwig ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Linear Regression Analysis ◽  
Lipid Peroxide ◽  
Dependent Manner ◽  
Preserved Ejection Fraction ◽  
Human Heart Failure ◽  
Stress Dependent

Abstract Aims Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). Methods and results The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1α in HFpEF appeared as dimers/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress/eNOS-dependent PKGIα oxidation and polymerization resulting in a higher fraction of PKGIα monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGIα activity in HFpEF increased upon empagliflozin leading to improved phosphorylation of myofilament proteins. In skinned HFpEF cardiomyocytes, empagliflozin improved cardiomyocyte stiffness in an anti-oxidative/PKGIα-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGIα polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients. Conclusion Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO–sGC–cGMP–cascade and PKGIα activity via reduced PKGIα oxidation and polymerization leading to less pathological cardiomyocyte stiffness.

scholarly journals Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system

2018 ◽  
Vol 293 (47) ◽  
pp. 18242-18269 ◽  
Author(s):  
Kelsey Murphy ◽  
Killian Llewellyn ◽  
Samuel Wakser ◽  
Josef Pontasch ◽  
Natasha Samanich ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant System ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Antioxidant Defense System ◽  
Related Factor ◽  
Dependent Manner ◽  
Amyloid Aβ

Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood–brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide–stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.

scholarly journals Stearic acid protects primary cultured cortical neurons against oxidative stress

2007 ◽  
Vol 28 (3) ◽  
pp. 315-326 ◽  
Author(s):  
Ze-jian WANG ◽  
Cui-ling LIANG ◽  
Guang-mei LI ◽  
Cai-yi YU ◽  
Ming YIN
Keyword(s):  
Oxidative Stress ◽  
Stearic Acid ◽  
Cortical Neurons ◽  
Cultured Cortical Neurons

scholarly journals Tumor-associated macrophages favor C26 murine colon carcinoma cell proliferation in an oxidative stress-dependent manner

2017 ◽  
Vol 37 (4) ◽  
pp. 2472-2480 ◽  
Author(s):  
Lavinia Luput ◽  
Emilia Licarete ◽  
Alina Sesarman ◽  
Laura Patras ◽  
Marius Costel Alupei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Colon Carcinoma ◽  
Carcinoma Cell ◽  
Dependent Manner ◽  
Tumor Associated Macrophages ◽  
Murine Colon Carcinoma ◽  
Stress Dependent ◽  
Murine Colon

scholarly journals C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk receptor-dependent manner in cultured cortical neurons

2003 ◽  
Vol 373 (2) ◽  
pp. 613-620 ◽  
Author(s):  
Carles GIL ◽  
Imane CHAIB-OUKADOUR ◽  
José AGUILERA
Keyword(s):  
Protein Kinase ◽  
Rat Brain ◽  
Heavy Chain ◽  
Tetanus Toxin ◽  
Cortical Neurons ◽  
Dependent Manner ◽  
Erk Pathway ◽  
Trk Receptor ◽  
Pkc Isoforms ◽  
Cultured Cortical Neurons

Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177–182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97–103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A receptor, phospholipase Cγ-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (HC-TeTx). TeTx and HC-TeTx induce fast and transient phosphorylation of Trk receptor at Tyr674 and Tyr675, but not at Tyr490, although the potency of TeTx in this action was higher when compared with HC-TeTx action. Moreover, HC-TeTx and TeTx also induced phosphorylation of Akt (at Ser473 and Thr308) and of ERK-1/2 (Thr202/Tyr204), in a time- and concentration-dependent manner. The detection of TeTx- and HC-TeTx-induced phosphorylation at Ser9 of glycogen synthase kinase 3β confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk receptors, demonstrates their necessary participation in the HC-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cγ-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear HC-TeTx-induced translocation of PKC-α and -β, but not of PKC-ε.

Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons

2000 ◽  
Vol 288 (2) ◽  
pp. 163-166 ◽  
Author(s):  
Takumi Satoh ◽  
Daisaku Nakatsuka ◽  
Yasuyoshi Watanabe ◽  
Izumi Nagata ◽  
Haruhiko Kikuchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Cortical Neurons ◽  
Neuronal Cell ◽  
Kinase Inhibition ◽  
Neuronal Cell Line ◽  
Cultured Cortical Neurons ◽  
Erk Kinase

scholarly journals Sporadic activation of an oxidative stress–dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies

2020 ◽  
Vol 13 (627) ◽  
pp. eaba4200 ◽  
Author(s):  
Elizabeth J. Pereira ◽  
Joseph S. Burns ◽  
Christina Y. Lee ◽  
Taylor Marohl ◽  
Delia Calderon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Epithelial Cells ◽  
Stress Tolerance ◽  
Cell Lines ◽  
Epithelial Tissue ◽  
Dependent Manner ◽  
P53 Signaling ◽  
Breast Epithelial ◽  
Stress Dependent

Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative stress within 3D cultures. Inhibition of NRF2 or p53 individually disrupted some of the transcripts defining the regulatory state but did not yield a notable phenotype in nontransformed breast epithelial cells. In contrast, combined perturbation prevented 3D growth in an oxidative stress–dependent manner. By integrating systems models of NRF2 and p53 signaling in a single oxidative stress network, we recapitulated these observations and made predictions about oxidative stress profiles during 3D growth. NRF2 and p53 signaling were similarly coordinated in normal breast epithelial tissue and hormone-negative ductal carcinoma in situ lesions but were uncoupled in triple-negative breast cancer (TNBC), a subtype in which p53 is usually mutated. Using the integrated model, we correlated the extent of this uncoupling in TNBC cell lines with the importance of NRF2 in the 3D growth of these cell lines and their predicted handling of oxidative stress. Our results point to an oxidative stress tolerance network that is important for single cells during glandular development and the early stages of breast cancer.

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