8-hydroxy-2-desoxyguanosine serum concentrations as a marker of DNA damage in patients with classical galactosaemia

Schulpis, Kleopatra H.; Papassotiriou, Ioannis; Tsakiris, Stylianos

doi:10.1080/08035250500297810

Cited by 14 publications

(10 citation statements)

References 33 publications

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“…That said, anecdotal studies have shown that galactosemic patients on poor dietary control display increased markers of oxidative stress yet lower total antioxidant status (Schulpis et al, 2005; Schulpis et al, 2006). Considering that antioxidant supplements (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Paradoxically, despite heightened oxidative stress biomarkers, galactose-treated rodents, flies and tissue culture cells also demonstrated evidence of lower than expected antioxidant enzyme activities (Cui et al, 2004; Cui et al, 2006), suggesting that the normal defences might be compromised; no mechanism has yet been established. Of note, anecdotal studies have shown that galactosemic patients on poor dietary control also displayed lower total antioxidant status along with remarkably increased markers of oxidative stress (Schulpis et al, 2005; Schulpis et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia

Jumbo-Lucioni

Hopson

Hang

et al. 2012

Disease Models &Amp; Mechanisms

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SUMMARYClassic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia

Jumbo-Lucioni

Hopson

Hang

et al. 2012

Disease Models &Amp; Mechanisms

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“…Moreover, the etiology of the disease is still poorly understood [9,10]. Patients with classical galactosemia present alteration in markers of oxidative stress and in activities of Na + , K + -ATPase, and Mg 2+ -ATPase in blood [11,12]. The treatment of patients' fibroblasts with GAL alters calcium homeostasis and causes reticular stress [13].…”

Section: Introductionmentioning

confidence: 99%

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

et al. 2016

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Classical galactosemia is an inborn error of carbohydrate metabolism in which patients accumulate high concentration of galactose in the brain. The most common treatment is a galactose-restricted diet. However, even treated patients develop several complications. One of the most common symptoms is motor coordination impairment, including affected gait, balance, and speech, as well as tremor and ataxia. In the present study, we investigated the effects of intracerebroventricular galactose administration on motor coordination, as well as on histological and biochemical parameters in cerebellum of adult rats. Wistar rats received 5 μL of galactose (4 mM) or saline by intracerebroventricular injection. The animals performed the beam walking test at 1 and 24 h after galactose administration. Histological and biochemical parameters were performed 24 h after the injections. The results showed motor coordination impairment at 24 h after galactose injection. Galactose also decreased the number of cells in the molecular and granular layers of the cerebellum. The immunohistochemistry results suggest that the cell types lost by galactose are neurons and astrocytes in the spinocerebellum and neurons in the cerebrocerebellum. Galactose increased active caspase-3 immunocontent and acetylcholinesterase activity, decreased acetylcholinesterase immunocontent, glutathione, and BDNF levels, as well as caused protein and DNA damage. Our results suggest that galactose induces histological and biochemical changes in cerebellum, which can be associated with motor coordination impairment.

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“…41 with moderate or very restricted diet. 64 In addition, experiments in rats fed with high dose of galactose showed the increase of lipid peroxidation and a decrease of antioxidant enzymes such as superoxide dismutase (SOD) and catalase in their brain. 41,65 Experiments in Drosophila showed an increase in oxidative stress and decrease in antioxidant defences after galactose treatment compared to control.…”

Section: Pseudotumor Cerebri and Cataractsmentioning

confidence: 99%

Galactose‐1‐phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long‐term complications and allelic variants

2017

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Galactosemia type 1 is an autosomal recessive disorder of galactose metabolism, determined by a deficiency in the enzyme galactose-1-phosphate uridyltransferase (GALT). GALT deficiency is classified as severe or variant depending on biochemical phenotype, genotype and potential to develop acute and long-term complications. Neonatal symptoms usually resolve after galactose-restricted diet; however, some patients, despite the diet, can develop long-term complications, in particular when the GALT enzyme activity results absent or severely decreased. The mechanisms of acute and long-term complications are still discussed and several hypotheses are presented in the literature like enzymatic inhibition, osmotic stress, endoplasmic reticulum stress, oxidative stress, defects of glycosylation or epigenetic modification. This review summarizes the current knowledge of galactosemia, in particular the putative mechanisms of neonatal and long-term complications and the molecular genetics of GALT deficiency.

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8-hydroxy-2-desoxyguanosine serum concentrations as a marker of DNA damage in patients with classical galactosaemia

Abstract: a) Low TAS and high Gal-1-P levels are implicated with high 8-OHdG blood levels in galactosaemic patients; b) 8-OHdG may be a sensitive biomarker of DNA damage in patients with classical galactosaemia.

Cited by 14 publications

References 33 publications

Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia

Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

Galactose‐1‐phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long‐term complications and allelic variants

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