Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

Schmitz, Katja; Trautmann, Sandra; Hahnefeld, Lisa; Fischer, Caroline; Schreiber, Yannick; Wilken-Schmitz, Annett; Brunkhorst, R.; Werner, Ernst R.; Watschinger, Katrin; Wicker, Sabine; Thomas, Dominique; Geißlinger, Gerd; Tegeder, Irmgard

doi:10.1007/s13311-021-01043-4

Cited by 7 publications

(4 citation statements)

References 88 publications

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“…Additionally, the content of biopterin in LN patients' serum exhibited a marked decrease. Other studies reported similar findings in patients with SLE, rheumatoid arthritis (RA), and multiple sclerosis (MS), associating this abnormal change with excessive autoimmune responses 19 , 20 . However, the specific mechanism remains unclear.…”

Section: Discussionsupporting

confidence: 52%

GC/MS and LC/MS serum metabolomic analysis of Chinese LN patients

Wang,

Kou,

Long

et al. 2024

Sci Rep

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China, being a densely populated nation, faces a substantial economic burden due to a high incidence of lupus nephritis (LN) cases. The concealed onset of LN has resulted in many individuals have missed the optimal timing for treatment. The aim of the research is to study the serum metabolomics of Chinese LN patients using gas chromatography (GC)/mass spectrometry (MS) and liquid chromatography (LC)/MS to identify potential diagnostic markers. Fifty LN patients and fifty normal controls, matched for Body Mass Index (BMI) and age, were selected. Serum analysis was conducted using GC/MS and LC/MS, followed by multivariate statistical analysis. Various multidimensional analyses, including principal component analysis, partial least squares discrimination analysis, and orthogonal partial least squares discrimination analysis, along with one-dimensional analyses such as t-tests, were performed. Metabolites with variable importance in projection value > 1 and a p-value < 0.05 were considered critical biomarkers for LN. Furthermore, identified biomarkers delineated relevant metabolic pathways, and a metabolic pathway map was obtained from the database. Forty-one metabolites were identified as potential LN biomarkers, primarily associated with immune regulation, energy metabolism, intestinal microbial metabolism, renal damage, and oxidative stress. The potential for diagnosing LN and other diseases through metabolomics is demonstrated. Future research should explore larger sample sizes, metabolomic comparisons across different diseases and health states, and integration of metabolomics with clinical diagnostics. Such studies will enhance the understanding of metabolomics in medical diagnosis and provide robust support for its practical application.

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Section: Discussionsupporting

confidence: 52%

GC/MS and LC/MS serum metabolomic analysis of Chinese LN patients

Wang,

Kou,

Long

et al. 2024

Sci Rep

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“…Of interest, recent work demonstrated elevated mRNA levels of CerS3 and 6 in brain endothelial cells of evoked autoimmune encephalomyelitis mice, suggesting their implication in the rising levels of Cer related to endothelial dysfunction ( Schmitz et al, 2021 ).…”

Section: Stroke and Ceramide Metabolismmentioning

confidence: 99%

Involvement of Ceramide Metabolism in Cerebral Ischemia

Ouro

Correa-Paz²,

Maqueda³

et al. 2022

Front. Mol. Biosci.

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Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in worldwide. Although reperfusion therapies have shown efficacy in a limited number of patients with acute ischemic stroke, neuroprotective drugs and recovery strategies have been widely assessed, but none of them have been successful in clinical practice. Therefore, the search for new therapeutic approaches is still necessary. Sphingolipids consist of a family of lipidic molecules with both structural and cell signaling functions. Regulation of sphingolipid metabolism is crucial for cell fate and homeostasis in the body. Different works have emphasized the implication of its metabolism in different pathologies, such as diabetes, cancer, neurodegeneration, or atherosclerosis. Other studies have shown its implication in the risk of suffering a stroke and its progression. This review will highlight the implications of sphingolipid metabolism enzymes in acute ischemic stroke.

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“…BH4 availability has been shown to act as a rate-limiting factor for T cell proliferation and activity in diverse models of immunity, including within solid tumors ( 20 , 64 ). This acceleration in T cell proliferation may occur due to increased iron-redox recycling of T cell mitochondrial cytochrome c which otherwise results in defective oxidative phosphorylation and superoxide production upon TCR stimulation ( 20 , 35 ).…”

Section: Bh4 Metabolism In Tumorigenesismentioning

confidence: 99%

Biopterin metabolism and nitric oxide recoupling in cancer

Clark,

Lai,

Agarwal

et al. 2024

Front. Oncol.

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Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.

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Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

Cited by 7 publications

References 88 publications

GC/MS and LC/MS serum metabolomic analysis of Chinese LN patients

GC/MS and LC/MS serum metabolomic analysis of Chinese LN patients

Involvement of Ceramide Metabolism in Cerebral Ischemia

Biopterin metabolism and nitric oxide recoupling in cancer

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