Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. Amino acid sequence of rat liver xanthine dehydrogenase and identification of the cleavage sites of the enzyme protein during irreversible conversion by trypsin.

Amaya, Yoshihiro; Yamazaki, Kaoru; Sato, Masayuki; Noda, Kôichi; Nishino, Tomoko

doi:10.1016/s0021-9258(18)77283-9

Cited by 256 publications

(33 citation statements)

References 35 publications

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“…1B). It has been reported previously that these fragments are generated from XDH by proteolysis in vivo and possess high XO activity [22]. A Western-type diet also increase hepatic CD40 mRNA expression, which was used as a marker of hepatic activation [23].…”

Section: Western-type Diet Increases Liver Xanthine Oxidase Contentmentioning

confidence: 94%

Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet

Schröder

Vecchione

Jung

et al. 2006

Free Radical Biology and Medicine

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Hyperlipidemia enhances xanthine oxidase (XO) activity. XO is an important source of reactive oxygen species (ROS). Since ROS are thought to promote atherosclerosis, we hypothesized that XO is involved in the development of atherosclerosis. ApoE(-/-) mice were fed a Western-type (WD) or control diet. In subgroups, tungsten (700 mg/L) was administered to inhibit XO. XO is a secreted enzyme which is formed in the liver as xanthine dehydrogenase (XDH) and binds to the vascular endothelium. High expression of XDH was found in the liver and WD increased liver XDH mRNA and XDH protein expression. WD induced the conversion of XDH to the radical-forming XO. Moreover, WD increased the hepatic expression of CD40, demonstrating activation of hepatic cells. Aortic tissue of ApoE(-/-) mice fed a WD for 6 months exhibited marked atherosclerosis, attenuated endothelium-dependent relaxation to acetylcholine, increased vascular oxidative stress, and mRNA expression of the chemokine KC. Tungsten treatment had no effect on plasma lipids but lowered the plasma XO activity. In animals fed a control diet, tungsten had no effect on radical formation, endothelial function, or atherosclerosis development. In mice fed a WD, however tungsten attenuated the vascular superoxide anion formation, prevented endothelial dysfunction, and attenuated KC mRNA expression. Most importantly, tungsten treatment largely prevented the development of atherosclerosis in the aorta of ApoE(-/-) mice on WD. Therefore, tungsten, potentially via the inhibition of XO, prevents the development of endothelial dysfunction and atherosclerosis in ApoE(-/-) mice on WD.

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Section: Western-type Diet Increases Liver Xanthine Oxidase Contentmentioning

confidence: 94%

Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet

Schröder

Vecchione

Jung

et al. 2006

Free Radical Biology and Medicine

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“…Oxidation of cysteine residues 535 and 992 in rat or bovine XDH or limited proteolysis turns XDH into XO (23,72,693,773,803,994). XO shows a decreased affinity for NAD ϩ and increased O 2 affinity.…”

Section: Ros Generation By Xormentioning

confidence: 99%

Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation

Tejero

Shiva

Gladwin

2019

Physiological Reviews

380

276

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Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease.

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“…The increased O 2 availability that follows blood flow restoration in the oxygen-depleted tissue fuels the production of free radicals by complex I and III of the mitochondrial ETC and other pro-oxidant enzymes [ 13 ]. An example is provided by the proteolytic conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO) [ 14 ], boosted by the intracellular influx of calcium in energy-depleted cells: this enzyme, using xanthine or hypoxanthine as reaction substrates and O 2 as a cofactor, generates uric acid and O 2 •− , thus further enhancing intracellular ROS production [ 15 ]. The free radical burst that follows reperfusion further contributes to impair mitochondrial phosphorylation, feeding a vicious circle that finally results in secondary energy failure and programmed neuronal death [ 16 ].…”

Section: Pathophysiological Mechanisms Of Oxidative Brain Damagementioning

confidence: 99%

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

et al. 2021

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Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

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Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. Amino acid sequence of rat liver xanthine dehydrogenase and identification of the cleavage sites of the enzyme protein during irreversible conversion by trypsin.

Cited by 256 publications

References 35 publications

Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet

Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet

Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

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