Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice

Guerreiro, Gilian; Faverzani, Jéssica Lamberty; Moura, Alana Pimentel; Volfart, Vitoria; Reis, Bianca Gome dos; Sitta, Ângela; Gonzalez, Esteban Alberto; Rosa, Gabriel de Lima; Coitinho, Adriana Simon; Baldo, Guilherme; Wajner, Moaçir; Vargas, Carmen Regla

doi:10.1016/j.abb.2021.108970

Cited by 7 publications

(4 citation statements)

References 39 publications

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“…Specifically, glutaroyl carnitine (C5DC) was the only metabolite that remained significant on elevated CRP levels after FDR correction in the IVW analysis. In line with us, C5DC levels were positively correlated with the inflammatory marker IL-1β (Guerreiro et al, 2021). Increased C5DC levels are linked to cardiovascular risks (Zhao et al, 2020) and aging (Carlsson et al, 2021), both of which are commonly accompanied by prolonged chronic inflammation (Shi et al, 2021).…”

Section: Discussionsupporting

confidence: 81%

Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis

Liu,

Zhu,

Guo

et al. 2024

Front. Microbiol.

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BackgroundInflammation serves as a key pathologic mediator in the progression of infections and various diseases, involving significant alterations in the gut microbiome and metabolism. This study aims to probe into the potential causal relationships between gut microbial taxa and human blood metabolites with various serum inflammatory markers (CRP, SAA1, IL-6, TNF-α, WBC, and GlycA) and the risks of seven common infections (gastrointestinal infections, dysentery, pneumonia, bacterial pneumonia, bronchopneumonia and lung abscess, pneumococcal pneumonia, and urinary tract infections).MethodsTwo-sample Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW), maximum likelihood, MR-Egger, weighted median, and MR-PRESSO.ResultsAfter adding other MR models and sensitivity analyses, genus Roseburia was simultaneously associated adversely with CRP (Beta IVW = −0.040) and SAA1 (Beta IVW = −0.280), and family Bifidobacteriaceae was negatively associated with both CRP (Beta IVW = −0.034) and pneumonia risk (Beta IVW = −0.391). After correction by FDR, only glutaroyl carnitine remained significantly associated with elevated CRP levels (Beta IVW = 0.112). Additionally, threonine (Beta IVW = 0.200) and 1-heptadecanoylglycerophosphocholine (Beta IVW = −0.246) were found to be significantly associated with WBC levels. Three metabolites showed similar causal effects on different inflammatory markers or infectious phenotypes, stearidonate (18:4n3) was negatively related to SAA1 and urinary tract infections, and 5-oxoproline contributed to elevated IL-6 and SAA1 levels. In addition, 7-methylguanine showed a positive correlation with dysentery and bacterial pneumonia.ConclusionThis study provides novel evidence confirming the causal effects of the gut microbiome and the plasma metabolite profile on inflammation and the risk of infection. These potential molecular alterations may aid in the development of new targets for the intervention and management of disorders associated with inflammation and infections.

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Section: Discussionsupporting

confidence: 81%

Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis

Liu,

Zhu,

Guo

et al. 2024

Front. Microbiol.

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“…To assessed this relationship between oxidative stress and inflammation, in this study, we evaluated the levels of proinflammatory process in patients with maple syrup urine disease (MSUD) 35 and of the administration of L-car in an animal model knockout of glutaric acidemia type 1 (GA1). 36 Besides, IL-8 levels were increased in the phenylketonuric patients at early and late diagnosis and under treatment compared to the controls, although it can be observed a tendency to a decrease during treatment. In this context, it is emphasized that increased proinflammatory cytokines can be related to an excessive production of reactive species, contributing to inflammation.…”

Section: Resultsmentioning

confidence: 77%

“…In addition, it can be seen that the treated group presented a significant decrease in the IL‐6 levels, indicating that the dietary treatment with L‐car was able to reduce the levels of this proinflammatory cytokine. Previous studies in other inborn error of metabolism reinforce beneficial role of L‐car against the proinflammatory process in patients with maple syrup urine disease (MSUD) 35 and of the administration of L‐car in an animal model knockout of glutaric acidemia type 1 (GA1) 36 . Besides, IL‐8 levels were increased in the phenylketonuric patients at early and late diagnosis and under treatment compared to the controls, although it can be observed a tendency to a decrease during treatment.…”

Section: Discussionmentioning

confidence: 99%

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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“…Oxidative stress and neuroinflammation have been postulated to be involved in the pathogenesis of GA I, as observed by many studies using GA I animal models and cells from patients ( Wajner, 2019 ; Wajner et al, 2019 ; Guerreiro et al, 2021 ), as well as of many other neurologic diseases ( Freeman and Ting, 2016 ). As for the role of oxidative stress and Nrf2 pathway disruption in the pathophysiology of GA I, a study showed that the administration of quinolinic acid (QA), a metabolite synthesized by the kynurenine pathway during inflammatory process, induced oxidative stress in young Gcdh –/– mice fed a high Lys chow ( Seminotti et al, 2016 ).…”

Section: Nrf2 Signaling Disruption In Inherited Metabolic Disordersmentioning

confidence: 99%

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Seminotti

Grings

Tucci

et al. 2021

Front. Cell. Neurosci.

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Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

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Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice

Cited by 7 publications

References 39 publications

Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis

Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis

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

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

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