Increased 8-hydroxy-2′-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus

Lee, H.-T.; Lin, Ching-Heng; Lee, C.-S.; Tsai, Chang‐Youh; Wei, Yau Huei

doi:10.1111/cei.12256

Cited by 63 publications

(66 citation statements)

References 32 publications

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“…The majority of the SLE patients included in this metabolomics study were of AA and Hispanic-American ancestry. In another study, lower mRNA expression of the genes encoding glycolytic enzymes has been shown in the leukocytes of Asian SLE patients as compared to controls [42]. It is currently unclear why this reduction in metabolic pathway activation in SLE blood is observed, but it has been independently shown in a number of studies, including the present one.…”

Section: Discussionsupporting

confidence: 53%

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations

Sharma

Jin

Rosenzweig

et al. 2015

Journal of Autoimmunity

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. We examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Peripheral blood was collected from African-American (AA) and European-American (EA) SLE patients and controls. CD4 T-cells, CD8 T-cells, monocytes, and B cells were purified by flow sorting, and each cell subset from each subject was run on a genome-wide expression array. Cases were compared to controls of the same ancestral background. The overlap in differentially expressed gene (DEG) lists between different cell types from the same ancestral background was modest (<10%), and only 5-8% overlap in DEG lists was observed when comparing the same cell type between different ancestral backgrounds. IFN-stimulated gene (ISG) expression was not up-regulated synchronously in all cell types from a given patient, for example a given subject could have high ISG expression in T and B cells, but not in monocytes. AA subjects demonstrated more concordance in ISG expression between cell types from the same individual, and AA patients demonstrated significant down-regulation of metabolic gene expression which was not observed in EA patients. ISG expression was significantly decreased in B cells in patients taking immunosuppressants, while ISGs in other cell types did not differ with medication use. In conclusion, gene expression was strikingly different between immune cell subsets and between ancestral backgrounds in SLE patients. These findings emphasize the critical importance of studying multiple ancestral backgrounds and multiple cell types in gene expression studies. Ancestral backgrounds which are not studied will not benefit from personalized medicine strategies in SLE.

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Section: Discussionsupporting

confidence: 53%

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations

Sharma

Jin

Rosenzweig

et al. 2015

Journal of Autoimmunity

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“…However, this increase was abrogated in Ogg1 −/− Nlrp3 −/− BM chimeric mice, suggesting that the mechanism by which Ogg1 deficiency leads to accelerated atherogenesis is at least in part through the NLRP3 inflammasome. While some human Ogg1 polymorphisms have been linked with various pathologies such as large artery atherosclerotic stroke in smokers 44 and SLE severity 45, 46 , no studies have yet demonstrated its role in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…It is reported that 8-OH-dG accumulation in mtDNA is increased 20-fold in livers of Ogg1 −/− mice compared to WT mice 59 . The human Ser326Cys (C8055G) OGG1 polymorphism is associated with decreased repair activity 60 and is linked to large artery atherosclerotic stroke in smokers 44 ; the C1245G polymorphism correlates with increased 8-OH-dG in leukocyte DNA and more severe manifestations of systemic lupus erythematosus (SLE) 45, 46 . Atherosclerosis is a well-recognized complication of SLE, but underlying mechanisms are complex and remain areas of active investigation.…”

Section: Discussionmentioning

confidence: 99%

Ogg1 -Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis

Tumurkhuu

Shimada

Dagvadorj

et al. 2016

Circulation Research

148

116

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Rationale Activation of NLRP3 inflammasome mediating IL-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis and mitochondria are central regulators of the NLRP3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase OGG1, is responsible for removing the most abundant form of oxidative DNA damage. Objective To test the role of OGG1 in development of atherosclerosis in mouse. Methods and Results We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of Ldlr KO mice fed a western diet. Ogg1−/−Ldlr−/− mice fed a western diet resulted in an increase in plaque size and lipid content. We found increased oxidized mtDNA, inflammasome activation, and apoptosis in atherosclerotic lesions and also higher serum IL-1β and IL-18 in Ogg1−/−Ldlr−/− mice compared with Ldlr−/−. Transplantation with Ogg1−/− bone marrow (BM) into Ldlr−/− mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1−/−Nlrp3−/− BM reversed the Ogg1−/− phenotype of increased plaque size. Ogg1−/− macrophages showed increased oxidized mtDNA and had greater amounts of cytosolic mtDNA and cytochrome c, increased apoptosis, and more IL-1β secretion. Finally, we found that proatherogenic miR-33 can directly inhibit human OGG1 expression and indirectly suppress both mouse and human OGG1 via AMPK. Conclusions OGG1 plays a protective role in atherogenesis by preventing excessive inflammasome activation. Our study provides insight into a new target for therapeutic intervention based on a link between oxidative mtDNA damage, OGG1, and atherosclerosis via NLRP3 inflammasome.

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“…Commonly assessed markers for oxidative stress are lipid oxidation products such as 8-isoprostane and malondialdehyde, and DNA oxidation products such as 8-hydroxy-2-deoxyguanosine (8-oxo-dG) which can be measured in blood and/or urine [33]. The activity of antioxidant enzymes, e.g., glutathione peroxidase or catalase, can also provide information regarding oxidative stress [34]. While multiple biomarkers have been developed that measure various types of oxidative stress, there are unresolved challenges in devising accurate and reproducible assays that can be applied to human studies [24,25].…”

Section: Resultsmentioning

confidence: 99%

Effects of Intentional Weight Loss on Markers of Oxidative Stress, DNA Repair and Telomere Length - a Systematic Review

2017

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Background: Altered levels of markers of oxidative stress, DNA repair, and telomere integrity have been detected in obese individuals and may underlie the pathogenesis of obesity-related diseases. However, whether or not such effects are reversed by intentional weight loss has not been systematically reviewed. Methods: A literature search in PubMed/Medline identified 2,388 articles of which 21 studies (randomized controlled trial (RCT) (n = 10) and non-randomized intervention studies (n = 11)) were classified as testing the effects of intentional weight loss on i) oxidative stress (n = 15), ii) DNA repair (n = 2), and iii) telomere length (n = 4). Results: Across a broad range of intervention designs, diet-, exercise-, surgery-, balloon-induced weight loss regimens decreased oxidative stress measures. Studies investigating DNA repair capacity or telomere length as endpoints after weight loss were less common in number and yielded null or inconsistent results, respectively. Conclusion: While this systematic review supports a role for intentional weight loss in reducing obesity-associated oxidative stress, it is not clear whether the effects are primary outcomes or secondary to improvement in obesity-associated insulin resistance and/or chronic inflammation. Although the lack of effect of intentional weight loss on DNA repair capacity might be anticipated given that oxidative stress is reduced, additional studies are needed. The inconsistent effects of weight loss on telomere length or DNA repair suggest the need for a re-assessment of intervention designs and assay methodology to definitively address this topic.

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Increased 8-hydroxy-2′-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus

Cited by 63 publications

References 32 publications

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations

Ogg1 -Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis

Effects of Intentional Weight Loss on Markers of Oxidative Stress, DNA Repair and Telomere Length - a Systematic Review

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