Experimental evidence of oxidative stress in patients with l-2-hydroxyglutaric aciduria and that l-carnitine attenuates in vitro DNA damage caused by d-2-hydroxyglutaric and l-2-hydroxyglutaric acids

Rodrigues, Daiane; Coelho, Daniella de Moura; Sitta, Ângela; Jacques, Carlos Eduardo Diaz; Hauschild, Tatiane Cristina; Manfredini, Vanusa; Bakkali, Abdellatif; Struys, Eduard A.; Jakobs, Cornelis; Wajner, Moaçir; Vargas, Carmen Regla

doi:10.1016/j.tiv.2017.04.006

Cited by 28 publications

(32 citation statements)

References 57 publications

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“…L-car treatment was also able to significantly reduce these levels, implying prevention of protein oxidation by this compound. 36 We also showed here a significant increase of urinary oxidized guanine species that represent a good marker of DNA damage in patients 15 at diagnosis compared to controls and that L-car was able to reduce these levels in treated compared with nontreated patients. 19,20 Glutaric and 3HGs have been shown to be capable of stimulating the production of ROS, 19 as well as reducing antioxidant defenses, like GSH levels and antioxidant enzymes activity, in mice brain.…”

Section: Discussionsupporting

confidence: 62%

“…16,17,19,20,22 As a matter of fact, it was also demonstrated that GA, the major organic acid accumulating in GA-I, is capable of causing protein damage and lipoperoxidation. [13][14][15]32,33 However, to the best of our knowledge, there are yet no studies in the literature focusing the involvement of oxidative stress in patients affected by this disease, neither whether L-car could potentially counteract this deleterious process due to its antioxidant and antiinflammatory properties. Data represent the median (min: max).…”

Section: Discussionmentioning

confidence: 99%

“…5,6 GA-I is considered a cerebral organic aciduria once the symptoms are mainly neurologic without systemic manifestations. [12][13][14][15] The mechanisms involved in GA-I pathogenesis are still poorly understood, although some studies carried out in animal models have demonstrated neurotoxic effects caused by GA and 3HG such as alterations on the GABAergic and glutamatergic systems, mitochondrial dysfunction, and oxidative stress. 8 The prognosis of GA-I depends on early diagnosis and treatment based on the restriction of the intake of lysine, with supplementation of L-car.…”

Section: Introductionmentioning

confidence: 99%

“…7 Diagnosis is performed by elevated levels of the metabolites in urine and C5DC in blood of patients by chromatographic methods. [15][16][17][18][19][20] In the last years, many studies have focused on the role of free radicals as tissue damage mediators in human diseases. L-car increases the excretion of the accumulated metabolites and replenishes its depleted tissues stores.…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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 level of damaged bases was quantified using the DNA/RNA Oxidative Damage ELISA Kit (Cayman Chemical, USA) according to the manufacturer's instruction and previous papers (43,44). Briefly, this technique is a competitive ELISA assay between oxidatively damaged guanosine bases (8-hydroxy-2′-deoxaguanosine from DNA, and 8-hydroxyguanine from either DNA or RNA) and 8-hydroxy deoxaguanosine acetylcholinesterase conjugate (DNA/RNA oxidative Damage Tracer) for a limited amount of Oxidative Damage Monoclonal antibody (mAb).…”

Section: Measurement Of Oxidative Dna Damagementioning

confidence: 99%

DNA glycosylase NEIL2 preventsFusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Sayed

Chakraborty

Ali

et al. 2020

Preprint

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Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80-85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stemcell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cytokines..Murine CRC model also showed downregulation of the NEIL2 transcript and accumulation of DNA damage. Importantly, analysis of publicly available transcriptomic data showed that the downregulation of NEIL2 is specific for MSS compared to MSI CRCs. We thus conclude that the pathogenic bacterial infection-induced downregulation of NEIL2, and consequent accumulation of DNA damage, play critical roles in the progression of CRC.

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Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti‐inflammatory effect of L‐carnitine

Faverzani

Hammerschmidt

Mescka

et al. 2023

Cell Biochemistry & Function

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Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L‐carnitine (L‐car) deficiency, compound that has demonstrated an antioxidant and anti‐inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro‐ and anti‐inflammatory cytokines, as well as the L‐car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L‐car levels in the patients under treatment. Inverse correlation between Phe versus L‐car and nitrate plus nitrite versus L‐car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)‐1β, interferons (IFN)‐gamma, IL‐2, tumor necrosis factor (TNF)‐alpha, IL‐8 and IL‐6 in the patients at late diagnosis compared to controls, and IL‐8 in the patients at early diagnosis and treatment compared to controls. Increased IL‐2, TNF‐alpha, IL‐6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL‐6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN‐gamma and L‐car in treated patients. Otherwise, it was observed that there were increased IL‐4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8‐isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro‐oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L‐car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.

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Experimental evidence of oxidative stress in patients with l-2-hydroxyglutaric aciduria and that l-carnitine attenuates in vitro DNA damage caused by d-2-hydroxyglutaric and l-2-hydroxyglutaric acids

Cited by 28 publications

References 57 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

DNA glycosylase NEIL2 preventsFusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti‐inflammatory effect of L‐carnitine

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