scholarly journals Nicotinamide Riboside Inhibits Alcohol-Induced Inflammation and Oxidative Stress in Macrophages

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 410-410
Author(s):  
Hyunju Kang ◽  
Young-Ki Park ◽  
Ji-Young Lee
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Mitochondrial Respiration ◽  
Nuclear Translocation ◽  
Antioxidant Properties ◽  
Sirtuin 1 ◽  
Mouse Bone Marrow ◽  
Nicotinamide Riboside ◽  
Mitochondrial Dna Copy Number ◽  
And Oxidative Stress

Abstract Objectives Macrophages play an essential role in the development of alcohol-induced inflammation. The objective of this study was to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor naturally found in milk, can attenuate alcohol-induced inflammation and oxidative stress in macrophages with the elucidation of mechanisms of action. Methods RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs) were stimulated with 80 mM ethanol with or without 1 mM of NR for 72 h. Expression of genes associated with inflammation and oxidative stress and cellular reactive oxygen species (ROS) accumulation were measured. Also, to evaluate the contribution of sirtuin 1 (SIRT1) to the NR's effect, cellular NAD + level (a cofactor of SIRT1), SIRT1 activity, and mitochondrial DNA copy number were measured. SIRT1 activity was inhibited or activated by sirtinol and resveratrol, respectively, to confirm SIRT1 functions further. Parameters related to mitochondrial respiration were determined using a Seahorse XFe24 Extracellular Flux analyzer. Results NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor kB p65 in macrophages. Increased cellular ROS levels by ethanol were also attenuated concomitantly with decreased expression of NADPH oxidase 2, a ROS-producing enzyme, by NR in both macrophage cell types. Ethanol decreased SIRT1 mRNA, protein and activity, cellular NAD + level, and mitochondrial DNA, all of which were markedly attenuated by NR. SIRT1 inhibition by sirtinol augmented the inflammatory effects of ethanol, while SIRT1 activation by resveratrol elicited the opposing results. Ethanol increased mitochondrial respiration, ATP production, and proton leak, but decreased maximal respiration and spare respiratory capacity. The ethanol-induced changes in mitochondrial respiration were abolished by NR. Conclusions NR showed anti-inflammatory and antioxidant properties in ethanol-treated macrophages by counteracting the effect of ethanol on lowering SIRT1 expression and cellular NAD+ levels. Therefore, NR may be a potential therapeutic agent for alcohol-induced inflammation and oxidative stress. Funding Sources This work is supported by the NIH 3R01DK108254-04S1.

scholarly journals Astaxanthin Inhibits Alcohol-Induced Inflammation and Oxidative Stress by Mediating the Sirtuin 1 and Histone Deacetylase 4 Axis in Macrophages

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 113-113
Author(s):  
Hyunju Kang ◽  
Young-Ki Park ◽  
Ji-Young Lee
Keyword(s):  
Oxidative Stress ◽  
Histone Deacetylase ◽  
Mitochondrial Respiration ◽  
Antioxidant Properties ◽  
Sirtuin 1 ◽  
Raw 264.7 ◽  
Raw 264.7 Macrophages ◽  
Sirt1 Expression ◽  
Histone Deacetylase 4 ◽  
And Oxidative Stress

Abstract Objectives We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, exerts anti-inflammatory and antioxidant properties in macrophages exposed to ethanol. In this study, to gain mechanistic insight, we explored the role of sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4) in the prevention of ethanol-induced inflammation and oxidative stress by ASTX in macrophages. Methods RAW 264.7 macrophages and bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and mice with macrophage specific-deletion of HDAC4 (Hdac4MKO) were used. Cells were stimulated with 80 mM ethanol in the absence or presence of 25 mM of ASTX for 72 h. The expression of genes associated with inflammation, SIRT1 and HDAC4 was measured. RAW 264.7 macrophages were treated with sirtinol or resveratrol, which are known inhibitor or activator of SIRT1 activity, respectively, to determine the effect of SIRT1 activity on HDAC4 expression. Parameters related to mitochondrial respiration were determined using a Seahorse XFe24 Extracellular Flux analyzer in both macrophage cell types. Results Ethanol decreased mRNA and protein levels of SIRT1 but increased those of HDAC4, which was attenuated by ASTX in RAW 264.7 macrophages. ASTX abolished an increase in acetylated histone H3 by ethanol in RAW 264.7 macrophages. Knockdown of HDAC4 increased SIRT1 expression, concomitantly decreasing ethanol-induced inflammatory gene expression. Furthermore, BMDMs from Hdac4MKO mice showed significant decreases in ethanol-induced inflammatory genes but an increase in SIRT1 expression compared with WT BMDMs. Ethanol increased mitochondrial respiration, ATP production, and proton leak, but decreased maximal respiration and spare respiratory capacity. The changes by ethanol were abolished by ASTX in RAW 264.7 macrophages. Compared with WT BMDMs, the ethanol-induced alterations in mitochondrial respiration were abrogated in Hdac4MKO BMDMs. Conclusions The anti-inflammatory and antioxidant properties of ASTX in ethanol-treated macrophages may be mediated, at least in part, by the crosstalk between SIRT1 and/HDAC4. This study, therefore, provides new mechanisms in preventing the alcohol-induced inflammation and oxidative stress through the crosstalk between SIRT1 and HDAC4. Funding Sources This study was supported by NIH 1R01DK108254–01.

Mitochondrial DNA Copy Number in Peripheral Blood in the First Trimester of Pregnancy and Different Preeclampsia Clinical Phenotypes Development: A Pilot Study

2018 ◽  
Vol 26 (8) ◽  
pp. 1054-1061 ◽  
Author(s):  
Andrea Busnelli ◽  
Debora Lattuada ◽  
Stefania Ferrari ◽  
Marco Reschini ◽  
Barbara Colciaghi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Peripheral Blood ◽  
Copy Number ◽  
First Trimester ◽  
Control Group ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
First Trimester Of Pregnancy ◽  
And Oxidative Stress

Inflammation and oxidative stress are intrinsically linked to early poor placentation, typical of pregnancies complicated by preeclampsia associated with intrauterine growth restriction (PE-IUGR). Low mitochondrial DNA copy number (mtDNAcn) in peripheral blood constitutes a good peripheral surrogate marker of inflammation and oxidative stress. On these basis, we explored a possible correlation between mtDNAcn in peripheral blood in the first trimester of pregnancy and the PE-IUGR onset. To shed light on this issue, we setup a nested case–control study from a prospective cohort of pregnant women undergoing first-trimester aneuploidies screening. Two groups of patients affected by PE classified according to the clinical phenotype were identified: (1) patients who developed PE-IUGR and (2) patients who developed PE associated with appropriate for gestational age intrauterine fetal growth (PE-AGAf). Controls were women with a physiologic pregnancy matched to cases on the basis of age (±6 months, ratio 2:1). Mitochondrial DNA copy number was quantified using real-time polymerase chain reaction and normalized to nuclear DNA. The median (interquartile range) mtDNAcn in peripheral blood in patients with PE-IUGR (n = 12) and in patients with PE-AGAf (n = 16) was 70 (44-97) and 108 (95-145), respectively ( P = .004). Both these values were significantly lower than that detected in the control group (161[133-183], P < .001). The area under the receiver–operator curve for PE-IUGR and PE-AGAf were 0.94 (95% confidence interval [CI]: 0.88-1.00, P < .001) and 0.81 (95%CI: 0.70-0.91, P < .001), respectively. In conclusion, MtDNAcn in peripheral blood resulted significantly lower both in patients affected by PE-IUGR and in those affected by PE-AGAf when compared to controls. The accuracy of this biomarker resulted particularly good in predicting PE-IUGR.

scholarly journals One Week of CDAHFD Induces Steatohepatitis and Mitochondrial Dysfunction with Oxidative Stress in Liver

2021 ◽  
Vol 22 (11) ◽  
pp. 5851
Author(s):  
Takehito Sugasawa ◽  
Seiko Ono ◽  
Masato Yonamine ◽  
Shin-ichiro Fujita ◽  
Yuki Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Early Stage ◽  
Droplet Deposition ◽  
Nonalcoholic Fatty Liver ◽  
Stress Markers ◽  
Mitochondrial Dna Copy Number ◽  
Short Period ◽  
And Oxidative Stress

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports on the effects on mice of being fed a CDAHFD for long periods of 1 to 3 months. However, the effect of this diet over a short period is unknown. Therefore, we examined the effect of 1-week CDAHFD feeding on the mouse liver. Feeding a CDAHFD diet for only 1-week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis or cirrhosis. Additionally, it was demonstrated that CDAHFD significantly impaired mitochondrial respiration with severe oxidative stress to the liver, which is associated with a decreasing mitochondrial DNA copy number and complex proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that 1 week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of NASH in humans.

scholarly journals Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress

2001 ◽  
Vol 114 (9) ◽  
pp. 1643-1653 ◽  
Author(s):  
Z. Dastoor ◽  
J.L. Dreyer
Keyword(s):  
Oxidative Stress ◽  
Laser Scanning ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Apoptotic Cells ◽  
Transfected Cells ◽  
And Oxidative Stress

Recent studies indicating a role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in apoptosis or oxidative stress has been reported. Using confocal laser-scanning microscopy, we have investigated the cellular distribution of GAPDH in central nervous system (CNS)-derived cells (neuroblastoma mNB41A3), in non-CNS derived cells (R6 fibroblast) and in an apoptosis-resistant Bcl2 overexpressing cell line (R6-Bcl2). Induction of apoptosis by staurosporine or MG132 and oxidative stress by H(2)O(2) or FeCN enhanced the nuclear translocation of endogenous GAPDH in all cell types, as detected by immunocytochemistry. In apoptotic cells, GAPDH expression is three times higher than in non-apoptotic cells. Consistent with a role for GAPDH in apoptosis, overexpression of a GAPDH-green fluorescent protein (GAPDH-GFP) hybrid increased nuclear import of GAPDH-GFP into transfected cells and the number of apoptotic cells, and made them more sensitive to agents that induce apoptosis. Bcl2 overexpression prevents nuclear translocation of GAPDH and apoptosis in untransfected cells, but not in transfected cells that overexpress GAPDH-GFP. Our observations indicate that nuclear translocation of GAPDH may play a role in apoptosis and oxidative stress, probably related to the activity of GAPDH as a DNA repair enzyme or as a nuclear carrier for pro-apoptotic molecules.

Mitochondrial DNA in liver inflammation and oxidative stress

Life Sciences ◽  
2019 ◽  
Vol 236 ◽  
pp. 116464 ◽  
Author(s):  
Xufei Zhang ◽  
Xiuwen Wu ◽  
Qiongyuan Hu ◽  
Jie Wu ◽  
Gefei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Liver Inflammation ◽  
And Oxidative Stress

scholarly journals Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity

2019 ◽  
Vol 133 (13) ◽  
pp. 1505-1521 ◽  
Author(s):  
Dong Zheng ◽  
Yi Zhang ◽  
Ming Zheng ◽  
Ting Cao ◽  
Grace Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanism ◽  
Myocardial Dysfunction ◽  
Cardiac Injury ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Nicotinamide Riboside ◽  
And Oxidative Stress ◽  
Cultured Cardiomyocytes ◽  
Lysosomal Acidification

Abstract Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

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