Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells

Biancini, Giovana Brondani; Morás, Ana Moira; Reinhardt, Luiza Steffens; Busatto, Franciele Faccio; Sperotto, Nathalia Denise de Moura; Saffi, Jenifer; Moura, Dinara Jaqueline; Giugliani, Roberto; Vargas, Carmen Regla

doi:10.1111/nep.12977

Cited by 14 publications

(17 citation statements)

References 24 publications

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“…36,38 Moreover, oxidative damage to DNA and RNA is related to a several number of pathologies 39,40 involving defects in important processes such as transcription and replication, finally resulting in cell death and mutagenesis. In this regard, GA, the major organic acid accumulated in GA-I, increased the DNA DI in peripheral leukocytes in a dose-dependent fashion that was attenuated by L-car treatment.…”

Section: Discussionmentioning

confidence: 99%

“…It is emphasized that ROS can attack nuclear and mitochondrial DNA generating oxidized forms, mainly urinary 8-OH-dG, that are continuously repaired, and the injured nucleosides are excreted in the urine. 36,38 Moreover, oxidative damage to DNA and RNA is related to a several number of pathologies 39,40 involving defects in important processes such as transcription and replication, finally resulting in cell death and mutagenesis. 36 As for to the antioxidant defenses, our data demonstrate that GA-I patients have a reduction of urinary antioxidant capacity at diagnosis and that L-car treatment was able to improve the antioxidant status in these patients.…”

Section: Discussionmentioning

confidence: 99%

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Oxidative damage in glutaric aciduria type I patients and the protective effects of l‐carnitine treatment

Guerreiro

Faverzani

Jacques

et al. 2018

J of Cellular Biochemistry

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The deficiency of the enzyme glutaryl-CoA dehydrogenase, known as glutaric acidemia type I (GA-I), leads to the accumulation of glutaric acid (GA) and glutarilcarnitine (C5DC) in the tissues and body fluids, unleashing important neurotoxic effects. l-carnitine (l-car) is recommended for the treatment of GA-I, aiming to induce the excretion of toxic metabolites. l-car has also demonstrated an important role as antioxidant and anti-inflammatory in some neurometabolic diseases. This study evaluated GA-I patients at diagnosis moment and treated the oxidative damage to lipids, proteins, and the inflammatory profile, as well as in vivo and in vitro DNA damage, reactive nitrogen species (RNS), and antioxidant capacity, verifying if the actual treatment with l-car (100 mg kg day ) is able to protect the organism against these processes. Significant increases of GA and C5DC were observed in GA-I patients. A deficiency of carnitine in patients before the supplementation was found. GA-I patients presented significantly increased levels of isoprostanes, di-tyrosine, urinary oxidized guanine species, and the RNS, as well as a reduced antioxidant capacity. The l-car supplementation induced beneficial effects reducing these biomarkers levels and increasing the antioxidant capacity. GA, in three different concentrations, significantly induced DNA damage in vitro, and the l-car was able to prevent this damage. Significant increases of pro-inflammatory cytokines IL-6, IL-8, GM-CSF, and TNF-α were shown in patients. Thus, the beneficial effects of l-car presented in the treatment of GA-I are due not only by increasing the excretion of accumulated toxic metabolites, but also by preventing oxidative damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oxidative damage in glutaric aciduria type I patients and the protective effects of l‐carnitine treatment

Guerreiro

Faverzani

Jacques

et al. 2018

J of Cellular Biochemistry

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“…As a consequence of ischemia, these are irreversible situations that will lead to end-stage kidney disease [47][48][49][50][51][52][53]. In this regard, different studies have shown the participation of some mediators involved in such mechanisms in FD [42,43,46,[54][55][56][57]. It is also important to consider especially proteinuria, since it is considered an important variable for the diagnosis and monitoring of patients with Fabry disease.…”

Section: Pathogenesismentioning

confidence: 99%

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Carnicer-Cáceres

Arranz-Amo

Cea-Arestin

et al. 2021

JCM

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Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

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“…Recent data highlighted the role of oxidative stress in FD pathophysiology. FD patients present high lipid and protein oxidative damage, decreased antioxidant defences and increased inflammatory biomarkers and cytokines [3][4][5][6][7][8][9][10]. Excess intracellular Gb3 induces oxidative stress and up-regulates the expression of cellular adhesion molecules in vascular endothelial cells [5].…”

Section: Introductionmentioning

confidence: 99%

“…Excess intracellular Gb3 induces oxidative stress and up-regulates the expression of cellular adhesion molecules in vascular endothelial cells [5]. Moreover, it has been suggested that pro-oxidant state occurs, is correlated and seems to be induced by Gb3 in Fabry patients [9].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress biomarkers in Fabry disease: is there a room for them?

et al. 2020

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Background Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. Methods We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. Results AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. Conclusions Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

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Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells

Cited by 14 publications

References 24 publications

Oxidative damage in glutaric aciduria type I patients and the protective effects of l‐carnitine treatment

Oxidative damage in glutaric aciduria type I patients and the protective effects of l‐carnitine treatment

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Oxidative stress biomarkers in Fabry disease: is there a room for them?

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