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Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-?B pathways in macrophages.

ABSTRACT: Hyperglycemia is a risk factor for cardiovascular mortality and morbidity, and directly responsible for exacerbating macrophage activation and atherosclerosis. We showed that gold nanoparticles (AuNPs) reduce the high glucose (HG)-induced atherosclerosis-related complications in macrophages via oxidative-nitrosative stress-regulated inflammation and apoptosis. The effects of AuNPs on oxidative-nitrosative stress markers such as cellular antioxidants were attenuated by HG exposure, leading to reduction in the accumulation of reactive oxygen/nitrogen species in cellular compartments. Further, these abnormalities of antioxidants level and reactive oxygen/nitrogen species accumulations initiate cellular stress, resulting in the activation of nuclear factor ?B (NF-?B) via ERK1/2mitogen-activated protein kinase (MAPK)/Akt/tuberin-mammalian target of rapamycin (mTOR) pathways. The activated NF-?B stimulates inflammatory mediators, which subsequently subdue biomolecules damage, leading to aggravation of the inflammatory infiltration and immune responses. Treatment of AuNPs inhibits the intracellular redox-sensitive signaling pathways, inflammation, and apoptosis in macrophages. Together, our results indicate that AuNPs may modulate HG-induced oxidative-nitrosative stress. These effects may be sealed tight due to the fact that AuNPs treatment reduces the activation of NF-?B by ERK1/2MAPK/Akt/tuberin-mTOR pathways-mediated inflammatory genes expression and cellular stress responses, which may be beneficial for minimizing the atherosclerosis.

SUBMITTER: Rizwan H

PROVIDER: S-EPMC5566318 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-κB pathways in macrophages.

Rizwan Huma H Mohanta Jagdeep J Si Satyabrata S Pal Arttatrana A

International journal of nanomedicine 20170817

Hyperglycemia is a risk factor for cardiovascular mortality and morbidity, and directly responsible for exacerbating macrophage activation and atherosclerosis. We showed that gold nanoparticles (AuNPs) reduce the high glucose (HG)-induced atherosclerosis-related complications in macrophages via oxidative-nitrosative stress-regulated inflammation and apoptosis. The effects of AuNPs on oxidative-nitrosative stress markers such as cellular antioxidants were attenuated by HG exposure, leading to red ...[more]

PMID: 28860752

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Project description:Diabetic retinopathy is a leading cause of visual loss and blindness, characterized by microvascular dysfunction. Hyperglycemia is considered the major pathogenic factor for the development of diabetic retinopathy and is associated with increased oxidative/nitrosative stress in the retina. Since heme oxygenase-1 (HO-1) is an enzyme with antioxidant and protective properties, we investigated the potential protective role of HO-1 in retinal endothelial cells exposed to high glucose and oxidative/nitrosative stress conditions. Retinal endothelial cells were exposed to elevated glucose, nitric oxide (NO) and hydrogen peroxide (H(2)O(2)). Cell viability and apoptosis were assessed by MTT assay, Hoechst staining, TUNEL assay and Annexin V labeling. The production of reactive oxygen species (ROS) was detected by the oxidation of 2',7'-dichlorodihydrofluorescein diacetate. The content of HO-1 was assessed by immunobloting and immunofluorescence. HO activity was determined by bilirubin production. Long-term exposure (7 days) of retinal endothelial cells to elevated glucose decreased cell viability and had no effect on HO-1 content. However, a short-time exposure (24 h) to elevated glucose did not alter cell viability, but increased both the levels of intracellular ROS and HO-1 content. Moreover, the inhibition of HO with SnPPIX unmasked the toxic effect of high glucose and revealed the protection conferred by HO-1. Oxidative/nitrosative stress conditions increased cell death and HO-1 protein levels. These effects of elevated glucose and HO inhibition on cell death were confirmed in primary endothelial cells (HUVECs). When cells were exposed to oxidative/nitrosative stress conditions there was also an increase in retinal endothelial cell death and HO-1 content. The inhibition of HO enhanced ROS production and the toxic effect induced by exposure to H(2)O(2) and NOC-18 (NO donor). Overexpression of HO-1 prevented the toxic effect induced by H(2)O(2) and NOC-18. In conclusion, HO-1 exerts a protective effect in retinal endothelial cells exposed to hyperglycemic and oxidative/nitrosative stress conditions.

Project description:BackgroundIt is well established that both cerebral hypoperfusion/stroke and type 2 diabetes are risk factors for Alzheimer's disease (AD). Recently, the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has begun to be established. However, the role of the key common denominator, namely nitric oxide (NO), in AD is largely unknown. In this study, we investigated redox regulation of BACE1, the rate-limiting enzyme responsible for the ?-cleavage of APP to A? peptides.ResultsHerein, we studied events such as S-nitrosylation, a covalent modification of cysteine residues by NO, and H2O2-mediated oxidation. We found that NO and H2O2 differentially modulate BACE1 expression and enzymatic activity: NO at low concentrations (<100 nM) suppresses BACE1 transcription as well as its enzymatic activity while at higher levels (0.1-100 ?M) NO induces S-nitrosylation of BACE1 which inactivates the enzyme without altering its expression. Moreover, the suppressive effect on BACE1 transcription is mediated by the NO/cGMP-PKG signaling, likely through activated PGC-1?. H2O2 (1-10 ?M) induces BACE1 expression via transcriptional activation, resulting in increased enzymatic activity. The differential effects of NO and H2O2 on BACE1 expression and activity are also reflected in their opposing effects on A? generation in cultured neurons in a dose-dependent manner. Furthermore, we found that BACE1 is highly S-nitrosylated in normal aging brains while S-nitrosylation is markedly reduced in AD brains.ConclusionThis study demonstrates for the first time that BACE1 is highly modified by NO via multiple mechanisms: low and high levels of NO suppress BACE1 via transcriptional and post translational regulation, in contrast with the upregulation of BACE1 by H2O2-mediated oxidation. These novel NO-mediated regulatory mechanisms likely protect BACE1 from being further oxidized by excessive oxidative stress, as from H2O2 and peroxynitrite which are known to upregulate BACE1 and activate the enzyme, resulting in excessive cleavage of APP and A? generation; they likely represent the crucial house-keeping mechanism for BACE1 expression/activation under physiological conditions.

Dataset Information

Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-?B pathways in macrophages.

Publications

Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-κB pathways in macrophages.

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