Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD

Rodriguez‐Miguelez, Paula; Gregg, Justin R.; Seigler, Nichole; Bass, Leon; Thomas, Jeffrey; Pollock, Jennifer S.; Sullivan, Jennifer C.; Dillard, Thomas A.; Harris, Ryan A.

doi:10.1016/j.chest.2018.04.028

Cited by 15 publications

(10 citation statements)

References 53 publications

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“…The model is important in the light of the protective antioxidative and anti-inflammatory effects of BH4/sapropterin in models of cardiovascular diseases [5,6] or colitis [7], and inhibition of tumor growth upon GCH1 inhibition [8]. Sapropterin-hydrocholoride (Kuvan®) is a clinically available BH4 drug approved for treatment of genetic BH4 deficiency [9,10] and was also suggested as adjunctive treatment for cardiovascular disease [11,12], diabetes [13], depression and schizophrenia [14], and mycobacterial infection [15].…”

Section: Introductionmentioning

confidence: 99%

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

et al. 2021

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Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood–brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.

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Section: Introductionmentioning

confidence: 99%

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

et al. 2021

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“…The complexity of the BH 4 pathway in cancer cell growth remains to be fully elucidated. Nevertheless, it is evident from a number of preclinical and preliminary clinical studies that the BH 4 pathway may hold great therapeutic potential [ 32 , 33 , 34 ]. To date, however, while there appears to be great success in targeting the BH 4 pathway experimentally, translating such effects to a clinical setting and the development of novel therapeutics, has had only limited success.…”

Section: Discussionmentioning

confidence: 99%

In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing Approaches towards the Discovery of Effective BH4 Therapeutics

Hussein

2023

IJMS

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The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH4) biosynthetic pathway. Physiologically, BH4 plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH4 physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH4 production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH4 biosynthetic pathway using established therapeutic agents.

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“…Similar properties have been associated with vitamin A, which may play a role protecting lung epithelial cells from irritants [ 118 ]. Additionally, vitamin C may also have positive effects on vascular health [ 114 , 119 , 120 ], which is frequently impaired in patients with COPD. Thus, vitamin supplementation may be beneficial in patients with COPD by restoring antioxidant balance, reducing oxidative stress, and preventing further tissue damage [ 121 ].…”

Section: Vitamins a B C And Ementioning

confidence: 99%

The Role of Nutrition in the Development and Management of Chronic Obstructive Pulmonary Disease

Heefner,

Simovic,

Mize

et al. 2024

Nutrients

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Chronic obstructive pulmonary disease (COPD) is a prevalent lung condition associated with significant morbidity and mortality. The management of COPD classically involves pulmonary rehabilitation, bronchodilators, and corticosteroids. An aspect of COPD management that is currently lacking in the literature is nutritional management, despite the prevalence of inadequate nutritional status in patients with COPD. In addition, certain nutritional imbalances have been reported to increase the risk of COPD development. This review summarizes the current literature on the role diet and nutrients may play in the risk and management of COPD development.

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Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD

Abstract: ClinicalTrials.gov; No.: NCT01398943; URL: www.clinicaltrials.gov.

Cited by 15 publications

References 53 publications

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing Approaches towards the Discovery of Effective BH4 Therapeutics

The Role of Nutrition in the Development and Management of Chronic Obstructive Pulmonary Disease

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