Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents

Azzarà, Alessia; Pirillo, Chiara; Giovannini, C; Federico, Giovanni; Scarpato, Roberto

doi:10.1016/j.mrfmmm.2016.05.001

Cited by 26 publications

(18 citation statements)

References 32 publications

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“…Lymphocytes from people with obesity had more mitomycin C-induced DNA damage compared to cells from normal weight subjects [33]. However, available data regarding the relationship between obesity and levels of oxidized bases in DNA such as 8-oxodG and 8-OHdG are inconsistent [34,35,36,37].…”

Section: Obesity and Dna Damagementioning

confidence: 99%

“…An inverse association between BMI and nucleotide excision repair (NER) capacity was found in young females [53]. Presence of obesity was also recognized to alter the repair of DSBs induced by genotoxic agents [34]. Obesity-associated enhanced ROS production can modulate the DNA damage response through the impact on the expressions of genes involved in DNA repair (Figure 2) [54,55].…”

Section: Obesity and Dna Damagementioning

confidence: 99%

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Obesity, DNA Damage, and Development of Obesity-Related Diseases

Włodarczyk

2019

IJMS

169

116

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Obesity has been recognized to increase the risk of such diseases as cardiovascular diseases, diabetes, and cancer. It indicates that obesity can impact genome stability. Oxidative stress and inflammation, commonly occurring in obesity, can induce DNA damage and inhibit DNA repair mechanisms. Accumulation of DNA damage can lead to an enhanced mutation rate and can alter gene expression resulting in disturbances in cell metabolism. Obesity-associated DNA damage can promote cancer growth by favoring cancer cell proliferation and migration, and resistance to apoptosis. Estimation of the DNA damage and/or disturbances in DNA repair could be potentially useful in the risk assessment and prevention of obesity-associated metabolic disorders as well as cancers. DNA damage in people with obesity appears to be reversible and both weight loss and improvement of dietary habits and diet composition can affect genome stability.

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Section: Obesity and Dna Damagementioning

confidence: 99%

Section: Obesity and Dna Damagementioning

confidence: 99%

Obesity, DNA Damage, and Development of Obesity-Related Diseases

Włodarczyk

2019

IJMS

169

116

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“…A broad range of DNA lesions has been recognized in people with obesity [100][101][102]. Enhanced DNA damage was also reported in patients with obesity-related diseases such as type 2 diabetes and metabolic syndrome [103].…”

Section: Discussionmentioning

confidence: 99%

TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women

Włodarczyk

Ciebiera²

2019

Mol Biol Rep

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Obesity is associated with inflammation, which can disturb genome stability. Tumor necrosis factor (TNF-α) polymorphism was found to affect TNF-α protein production and inflammation. Therefore, the present study illustrates the relationship between TNF-α polymorphism, the degree of inflammation assessed by serum high sensitivity C-reactive protein concentration (CRP-hs) and basal DNA damage in patients with obesity (BMI 30-34.9 kg/m 2) and control subjects with proper body mass (BMI < 25 kg/m 2). A total of 115 participants (75 obese premenopausal women; and 40 age-, and gender-matched controls) were included. Biochemical parameters (serum concentrations of total-cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, glucose, apolipoprotein AI, CRP-hs) and endogenous DNA damage (determined by comet assay) were measured. TNF-α G-308A polymorphism (rs1800629) was analyzed by PCR-RFLP (PCR-restriction fragments length polymorphism). An effect of TNF-α genotype on serum CRP-hs concentration was noted (p = 0.031). In general, carriers of the rare A allele of the TNF-α G-308A polymorphism had significantly lower endogenous DNA damage and serum CRPhs concentrations than GG homozygotes, however, the protective effect of the A allele was especially visible in non-obese women. Serum CRP-hs concentrations and levels of DNA damage (% DNA in tail) were significantly higher in obese than in controls (p = 0.001 and p < 0.0001, respectively). The adjusted multiple linear regression analyses revealed a significant, independent impact of obesity on DNA damage (p = 0.00000) and no effect of other covariates i.e. age, TNF-α genotype and serum CRP-hs concentration. Our study showed that obesity has a significant impact on the levels of endogenous DNA damage. Obesity abolished the protective effect of A allele of the TNF-α G-308A polymorphism on DNA damage and on inflammation development observed in non-obese A allele carriers.

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“…Whole body HMGB1-knockout mice dye shortly after birth, while knockdown experiments in various cells including 3T3L1 leads to an accumulation of yH2AX suggesting that DNA damage occurs during loss of HMGB1 13–15. Obese individuals are more prone to DNA damage as compared with normal weight adolescents,16 but do also have an improved potential to repair occurred lesions 17. Azzarà et al showed different repair kinetics of DSBs in obese versus lean derived lymphocytes along with differences in HMGB1 expression level 17.…”

Section: Introductionmentioning

confidence: 99%

“…Obese individuals are more prone to DNA damage as compared with normal weight adolescents,16 but do also have an improved potential to repair occurred lesions 17. Azzarà et al showed different repair kinetics of DSBs in obese versus lean derived lymphocytes along with differences in HMGB1 expression level 17. There is no doubt that HMGB1 is an important regulator of DNA repair while the precise mechanism is still under debate 14.…”

Section: Introductionmentioning

confidence: 99%

Role of the DNA repair genesH2AXandHMGB1in human fat distribution and lipid profiles

Rohde

Rønningen

Poulsen

et al. 2020

BMJ Open Diab Res Care

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Significance of this studyWhat is already known about this subject? ► DNA damage in adipocytes occurs early in obesity and is related to increased inflammation ► HMGB1 level are elevated during adipogenesis which acts as alarm signal of inflammation. In contrast, nuclear HMGB1 is thought to be involved in DNA repair mechanisms like H2AX, which is a key driver for DNA repair. The formation of yH2AX foci serves as earliest signal of occured DNA damage and initiates downstream signalling. ► While both, HGMB1 and H2AX protein level are well established markers of inflammtion and DNA repair, regulatory mechanisms of their gene expression level have scarcely been analysed so far, especially in the context of adipose tissue distribution.What are the new findings?► DNA damage contributes to adipose tissue inflammation and is related to metabolic diseases. We here sought to understand the fat depot-specific regulation of the DNA repair genes H2AX and HMGB1. ► We show differential gene expression pattern of H2AX and HMGB1 in subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) which is linked to DNA methylation and/or H2AX 3'untranslated region (3'UTR) variant rs7350. Further, we observed associations with lipid metabolites and with the OVAT/SAT ratio.How might these results change the focus of research or clinical practice?► Our data shed light on the impact of adipose tissue depot-specific regulation of DNA repair genes linking DNA methylation to lipid metabolism and fat distribution. Our data might help to understand the individual risk for developing comorbidities of obesity. AbStrActIntroduction Regional fat distribution strongly relates to metabolic comorbidities. We identified the DNA repair genes H2AX and HMGB1 to be differentially expressed between human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) depots. As increased DNA damage is linked to metabolic disease, we here sought to analyze whether depot-specific H2AX and HMGB1 expression is related to anthropometric and metabolic profiles of obesity. We further tested for different H2AX mRNA regulatory mechanisms by analyzing promoter DNA methylation and genotyped rs7350 in the H2AX locus.Research design and methods Gene expression (OVAT n=48; SAT n=55) and DNA promoter methylation data (OVAT and SAT n=77) were extracted from an existing dataset as described elsewhere. Genotype data for the 3'untranslated region (3'UTR) H2AX variant rs7350 were generated by using the TaqMan genotyping system in 243 subjects of the same cohort. Statistical analyses were done using SPSS statistics software 24 and GraphPad Prism 6.Results We identified H2AX being higher (p=0.002) and HMGB1 being less expressed (p=0.0001) in OVAT compared with SAT. Further, we observed positive interdepot correlations of OVAT and SAT for both HMGB1 (p=1×10 -6 ) and H2AX mRNA levels (p=0.024). Depotspecific associations were observed for both genes' methylation levels with either high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerid...

show abstract

Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents

Cited by 26 publications

References 32 publications

Obesity, DNA Damage, and Development of Obesity-Related Diseases

Obesity, DNA Damage, and Development of Obesity-Related Diseases

TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women

Role of the DNA repair genesH2AXandHMGB1in human fat distribution and lipid profiles

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