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Xiaoling Jiang, Huazhen Liu, Yongxian Shao, Mingzhi Peng, Wen Zhang, Duan Li, Xiuzhen Li, Yanna Cai, Ting Tan, Xinshuo Lu, Jianan Xu, Xueying Su, Yunting Lin, Zongcai Liu, Yonglan Huang, Chunhua Zeng, Ya-Ping Tang, Li Liu
BACKGROUND: GTP cyclohydrolase I (GTPCH) deficiency could impair the synthesis of tetrahydrobiopterin and causes metabolic diseases involving phenylalanine catabolism, neurotransmitter synthesis, nitric oxide production and so on. Though improvements could be achieved by tetrahydrobiopterin and neurotransmitter precursor levodopa supplementation, residual motor and mental deficits remain in some patients. An appropriate GTPCH deficiency animal model with clinical symptoms, especially the motor impairments, is still not available for mechanism and therapy studies yet...
February 8, 2019: Metabolism: Clinical and Experimental
Hiroki Kurosaki, Kentaro Yamaguchi, Kohei Man-Yoshi, Shin-Ichi Muramatsu, Satoshi Hara, Hiroshi Ichinose
Parkinson's disease (PD) is the second common neurodegenerative disorder. Deficit of the nigro-striatal dopaminergic neurons causes the motor symptoms of PD. While the oxidative stress is thought to be deeply involved in the etiology of PD, molecular targets for the oxidative insults has not been fully elucidated. 6R-5,6,7,8-Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase (TH), the rate-limiting enzyme for production of dopamine, and easily oxidized to its dihydro-form. In this study, we examined the alteration in the metabolism of BH4 caused by a parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
February 7, 2019: Neurochemistry International
Soniya Charles, Vijay Raj, Mohankumar Ramasamy, Kaliappan Ilango, Jesu Arockiaraj, Sakthivadivel Murugesan, Kanchana Mala
The role of 2,4-diamino-6-hydroxypyrimidine (DAHP), on cellular-senescence remains unclear as differential effects of DAHP have been reported in cardiovascular and cerebrovascular systems. We investigated the effect of pharmacologically-induced guanosine-triphosphate-cyclohydrolase1 (GTPCH1)-inhibition, through DAHP, on cellular-senescence in experimentally-induced diabetic and non-diabetic Wistar rats. Cellular-senescence was evaluated through senescence-associated events, namely, cell-cycle-arrest of peripheral blood mononuclear cells (PBMNCs); myocardial DNA fragmentation, total antioxidant capacity (TAC), telomerase-activity, nicotinamide adenine dinucleotide (NAD+)-content and tyrosine14-phosphorylation of caveolin1 (pY14) in similarly-aged, pubertal Wistar rats with streptozotocin (STZ) and/or DAHP...
January 25, 2019: European Journal of Pharmacology
Lin Xie, Dan Hu, Huan Qin, Wenliang Zhang, Shiyao Zhang, Yuan Feng, Haozhe Yao, Ying Xiao, Kai Yao, Xia Huang
AIMS: Exogenous tetrahydrobiopterin (BH4 ), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R)...
January 19, 2019: Life Sciences
Christian Ott, Agnes Bosch, Nicole Winzer, Stephanie Friedrich, Reinhard Schinzel, Frank Tegtmeier, Roland E Schmieder
AIMS: Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. METHODS: This double-blind, randomized, placebo-controlled, cross-over phase-I-study comprised 18 healthy men. Renal haemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively...
January 21, 2019: British Journal of Clinical Pharmacology
Rasmus Scheller, Amelie Stein, Sofie V Nielsen, Frederikke I Marin, Anne-Marie Gerdes, Miriam Di Marco, Elena Papaleo, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Phenylketonuria (PKU) is a genetic disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine to neurotoxic levels. Here, we analyzed the cellular stability, localization and interaction with wild-type PAH of twenty selected PKU-linked PAH protein missense variants. Several were present at reduced levels in human cells, and the levels increased in the presence of proteasome inhibitor, indicating that the proteins are proteasome targets. We found that all the tested PAH variants retained their ability to associate with wild-type PAH, and none formed aggregates, suggesting that they are only mildly destabilized in structure...
January 16, 2019: Human Mutation
Marie R Mooney, Dirk Geerts, Eric J Kort, André S Bachmann
Neuroblastoma (NB) is a tumor arising from the sympathetic nervous system during infancy and early childhood. High-risk patients who relapse often fail to respond to further therapy, which results in 5-year survival rate for this patient group below 5%. Therefore, there continues to be an urgent need for innovative treatments. Recently, we found that sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid arthritis and ulcerative colitis induces anti-proliferative effects in NB tumor cells...
January 9, 2019: Biochemical Pharmacology
Gerdien A H Korte-Bouws, Eline Albers, Marije Voskamp, Hendrikus Hendriksen, Lidewij R de Leeuw, Onur Güntürkün, Sytze de Roock, Sebastiaan J Vastert, S Mechiel Korte
Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate⁻cyclohydrolase-1 (GTP⁻CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4)...
January 8, 2019: Pharmaceuticals
Sheela Nagarkoti, Samreen Sadaf, Deepika Awasthi, Tulika Chandra, Kumaravelu Jagavelu, Sachin Kumar, Madhu Dikshit
Recent report from this lab has shown role of Rac2 in the translocation of iNOS to the phagosomal compartment of PMNs following phagocytosis of beads. Present study was undertaken to further assess the status and role of tetrahydrobiopterin (BH4 ), a redox sensitive cofactor, and L-arginine, the substrate of NOS, in sustained nitric oxide (.NO) production in killing of phagocytosed microbes ( E.coli ) by human PMNs. Time dependent study revealed consistent. NO and reactive oxygen species (ROS) production in the PMNs following phagocytosis of beads...
January 8, 2019: Free Radical Research
Andreas Daiber, Ning Xia, Sebastian Steven, Matthias Oelze, Alina Hanf, Swenja Kröller-Schön, Thomas Münzel, Huige Li
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity...
January 7, 2019: International Journal of Molecular Sciences
Anish Engineer, Tana Saiyin, Xiangru Lu, Andrew S Kucey, Brad L Urquhart, Thomas A Drysdale, Kambiz Norozi, Qingping Feng
Background Tetrahydrobiopterin is a cofactor of endothelial NO synthase ( eNOS ), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of tetrahydrobiopterin on eNOS uncoupling and congenital heart defects ( CHD s) induced by pregestational diabetes mellitus in mice. Methods and Results Adult female mice were induced to pregestational diabetes mellitus by streptozotocin and bred with normal male mice to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation...
November 6, 2018: Journal of the American Heart Association
Dalia G Mostafa, Salwa Fares Ahmed, Ola A Hussein
Cadmium (Cd) has been recognized as one of the most important environmental and industrial pollutants. This study investigated the impact of acute exposure to Cd on oxidative stress and the inflammatory marker interleukin-6 (IL-6) in the plasma of rats and the histological picture of liver and kidney, as well as to examine the potential protective effect of tetrahydrobiopterin (BH4). METHODS: Rats were divided into control group, Cd group that received a single intraperitoneal (i.p.) dose of 4 mg/kg b...
December 29, 2018: Ultrastructural Pathology
Eileen McNeill, Elena Stylianou, Mark J Crabtree, Rachel Harrington-Kandt, Anna-Lena Kolb, Marina Diotallevi, Ashley B Hale, Paulo Bettencourt, Rachel Tanner, Matthew K O'Shea, Magali Matsumiya, Helen Lockstone, Julius Müller, Helen A Fletcher, David R Greaves, Helen McShane, Keith M Channon
Inducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth of Mycobacterium tuberculosis (M.tb), presumably via nitric oxide (NO) mediated killing. Here we show that leukocyte-specific deficiency of NO production, through targeted loss of the iNOS cofactor tetrahydrobiopterin (BH4), results in enhanced control of M.tb infection; by contrast, loss of iNOS renders mice susceptible to M.tb. By comparing two complementary NO-deficient models, Nos2-/- mice and BH4 deficient Gch1fl/fl Tie2cre mice, we uncover NO-independent mechanisms of anti-mycobacterial immunity...
December 20, 2018: Nature Communications
Hong Li, Qiang Li, Yixuan Zhang, Wenting Liu, Bo Gu, Taro Narumi, Kin Lung Siu, Ji Youn Youn, Peiqing Liu, Xia Yang, Hua Cai
We have shown that hydrogen peroxide (H2 O2 ) downregulates tetrahydrobiopterin salvage enzyme DHFR (dihydrofolate reductase) to result in eNOS (endothelial NO synthase) uncoupling and elevated blood pressure. Here, we aimed to delineate molecular mechanisms underlying H2 O2 downregulation of endothelial DHFR by examining transcriptional pathways hypothesized to modulate DHFR expression and effects on blood pressure regulation of targeting these novel mechanisms. H2 O2 dose and time dependently attenuated DHFR mRNA and protein expression and enzymatic activity in endothelial cells...
January 2019: Hypertension
Sarah Ekeloef, Camilla Godthaab, Anne Marie V Schou-Pedersen, Jens Lykkesfeldt, Ismail Gögenur
BACKGROUND: Myocardial injury after noncardiac surgery is common and associated with major adverse cardiac events. Surgery induces acute endothelial dysfunction, which might be central in the pathophysiology of myocardial injury; however, the relationship between surgical stress and endothelial function remains incompletely understood. OBJECTIVES: This study aimed to assess the acute peri-operative changes in endothelial function after minor elective abdominal surgery...
December 12, 2018: European Journal of Anaesthesiology
Satoshi Hara, Soichiro Fukumura, Hiroshi Ichinose
6-Pyruvoyl tetrahydropterin synthase (PTS) converts 7, 8-dihydroneopterin triphosphate into 6-pyruvoyltetrahydropterin and is a critical enzyme for the de novo synthesis of tetrahydrobiopterin, an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. Neopterin derived from 7,8-dihydroneopterin triphosphate is secreted by monocytes/macrophages, and is a well-known biomarker for cellular immunity. Because PTS activity in the cell can be a determinant of neopterin production, here we used recombinant human PTS protein to investigate how its activity is regulated, especially depending on redox conditions...
December 4, 2018: Journal of Biological Chemistry
Yuxiang Zheng, Ting-Yu Lin, Gina Lee, Marcia N Paddock, Jessica Momb, Zhe Cheng, Qian Li, Dennis L Fei, Benjamin D Stein, Shivan Ramsamooj, Guoan Zhang, John Blenis, Lewis C Cantley
Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF)...
November 29, 2018: Cell
Katja Zschiebsch, Caroline Fischer, Annett Wilken-Schmitz, Gerd Geisslinger, Keith Channon, Katrin Watschinger, Irmgard Tegeder
GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron-specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain...
November 18, 2018: Journal of Cellular and Molecular Medicine
Gaurav Taneja, Akash Sud, Narayan Pendse, Bishnu Panigrahi, Ashish Kumar, Arun K Sharma
The endothelium is a thin innermost layer of flat cells which release various mediators including endothelin-1 (ET-1), prostanoids, von Willebrand factor (vWF) and endothelium-derived relaxing factor (EDRF; nitric oxide) to regulate vascular tone. Endothelial nitric oxide synthase (eNOS) is a key enzyme that generates nitric oxide (NO). NO maintains vascular homeostasis and cardiac functions by influencing major vascular protective properties such as anti-platelet, anti-proliferative, anti-migratory, antioxidant and anti-inflammatory action in vessels...
November 17, 2018: Cardiovascular Toxicology
Jin Hee Jeong, Nichole Lee, Matthew A Tucker, Paula Rodriguez-Miguelez, Jacob Looney, Jeffrey Thomas, Casandra C Derella, Ahmed A El-Marakby, Jacqueline B Musall, Jennifer C Sullivan, Kathleen T McKie, Caralee Forseen, Gareth W Davison, Ryan A Harris
Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus, the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. METHODS: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited...
November 15, 2018: Journal of Applied Physiology
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