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Redox Biology May 2021Human xanthine oxidoreductase (XOR) is a multiple-level regulated enzyme, resulting from a complicated evolutionary process that assigned it many physiological roles.... (Review)
Review
Human xanthine oxidoreductase (XOR) is a multiple-level regulated enzyme, resulting from a complicated evolutionary process that assigned it many physiological roles. The main XOR activities are: (i) xanthine dehydrogenase (XDH) activity that performs the last two steps of purine catabolism, from hypoxanthine to uric acid; (ii) xanthine oxidase (XO) activity that, besides purine catabolism, produces reactive oxygen species (ROS); (iii) nitrite reductase activity that generates nitric oxide, contributing to vasodilation and regulation of blood pressure; (iv) NADH oxidase activity that produces ROS. All these XOR activities contribute also to metabolize various endogenous and exogenous compounds, including some drugs. About XOR products, it should be considered that (i) uric acid is not only a proinflammatory agent, but also a fundamental antioxidant molecule in serum and (ii) XOR-derived ROS are essential to the inflammatory defensive response. Although XOR has been the object of a large number of studies, most of them were focused on the pathological consequences of its activity and there is not a clear and schematic picture of XOR physiological roles. In this review, we try to fill this gap, reporting and graphically schematizing the main roles of XOR and its products.
Topics: Humans; Nitric Oxide; Oxidation-Reduction; Reactive Oxygen Species; Uric Acid; Xanthine Dehydrogenase; Xanthine Oxidase
PubMed: 33578127
DOI: 10.1016/j.redox.2021.101882 -
Molecules (Basel, Switzerland) Feb 2023A personal perspective is provided regarding the work in several laboratories, including the author's, that has established the reaction mechanism of xanthine oxidase... (Review)
Review
A personal perspective is provided regarding the work in several laboratories, including the author's, that has established the reaction mechanism of xanthine oxidase and related enzymes.
Topics: Xanthine Oxidase; Electron Spin Resonance Spectroscopy; Molybdenum; Xanthine Dehydrogenase
PubMed: 36838909
DOI: 10.3390/molecules28041921 -
Theranostics 2022Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial...
SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways.
Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI. DAPA effects were evaluated both , in mice subjected to IRI, and , in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R). DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice. In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation. Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs. DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R. Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice. These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.
Topics: Actin Depolymerizing Factors; Animals; Benzhydryl Compounds; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Endothelial Cells; Glucosides; Humans; Ischemia; Mice; Myocardial Reperfusion Injury; Sodium-Glucose Transporter 2 Inhibitors; Xanthine Oxidase
PubMed: 35836807
DOI: 10.7150/thno.75121 -
Journal of Cerebral Blood Flow and... Jun 2023Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study...
Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.
Topics: Animals; Mice; Cognitive Dysfunction; Febuxostat; Hydrogen Peroxide; Mice, Inbred C57BL; Xanthine Oxidase; Stress, Psychological; Cerebrovascular Circulation; Cardiovascular Physiological Phenomena; Enzyme Inhibitors; Cerebrovascular Disorders; Free Radicals; Memory, Short-Term
PubMed: 36655326
DOI: 10.1177/0271678X231152551 -
Arteriosclerosis, Thrombosis, and... Feb 2021Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely...
OBJECTIVE
Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD.
CONCLUSIONS
Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.
Topics: Anemia, Sickle Cell; Animals; Disease Models, Animal; Enzyme Inhibitors; Erythrocytes; Febuxostat; Hemodynamics; Hemolysis; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Pulmonary Artery; Ventricular Function; Xanthine Oxidase; Mice
PubMed: 33267657
DOI: 10.1161/ATVBAHA.120.315081 -
The Journal of Nutritional Biochemistry Dec 2022Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the... (Review)
Review
Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition of xanthine oxidase, feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NF-ĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action, e.g., colchicine and colchicine analogues. Dietary flavonoids, i.e., chrysin, kaempferol, quercetin, fisetin, pelargonidin, apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidates for screening of newer anticancer leads.
Topics: Humans; Xanthine Oxidase; Flavonoids; Apigenin; Luteolin; Colchicine; Enzyme Inhibitors; Neoplasms
PubMed: 36049673
DOI: 10.1016/j.jnutbio.2022.109147 -
Redox Biology Feb 2019Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules... (Review)
Review
Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules or indirectly by upregulating enzymatic sources of reactive species. A key enzymatic source of these reactive species is the purine catabolizing enzyme, xanthine oxidase (XO) as the oxidation of hypoxanthine to xanthine and subsequent oxidation of xanthine to uric acid generates superoxide (O) and hydrogen peroxide (HO). While XO has been studied for over 120 years, much remains unknown regarding specific mechanistic roles for this enzyme in pathologic processes. This gap in knowledge stems from several interrelated issues including: 1) lethality of global XO deletion and the absence of tissue-specific XO knockout models have coalesced to relegate proof-of-principle experimentation to pharmacology; 2) XO is mobile and thus when upregulated locally can be secreted into the circulation and impact distal vascular beds by high-affinity association to the glycocalyx on the endothelium; and 3) endothelial-bound XO is significantly resistant (> 50%) to inhibition by allopurinol, the principle compound used for XO inhibition in the clinic as well as the laboratory. While it is known that circulating XO is elevated in hemolytic diseases including sickle cell, malaria and sepsis, little is understood regarding its role in these pathologies. As such, the aim of this review is to define our current understanding regarding the effect of hemolysis (free heme) on circulating XO levels as well as the subsequent impact of XO-derived oxidants in hemolytic disease processes.
Topics: Animals; Disease Susceptibility; Drug Discovery; Endothelium, Vascular; Gene Expression Regulation; Hemolysis; Humans; Oxidants; Oxidation-Reduction; Reactive Oxygen Species; Xanthine Oxidase
PubMed: 30580157
DOI: 10.1016/j.redox.2018.101072 -
Frontiers in Immunology 2022Stroke is one of the most common cerebrovascular diseases. Despite significant progress in understanding stroke pathogenesis, cases are still increasing. Thus,...
Stroke is one of the most common cerebrovascular diseases. Despite significant progress in understanding stroke pathogenesis, cases are still increasing. Thus, laboratory biomarkers of stroke are sought to allow rapid and non-invasive diagnostics. Ischemia-reperfusion injury is an inflammatory process with characteristic cellular changes leading to microvascular disruption. Several studies have shown that hyperactivation of xanthine oxidase (XO) is a major pathogenic factor contributing to brain dysfunction. Given the critical role of XO in stroke complications, this study aimed to evaluate the activity of the enzyme and its metabolic products in the saliva of stroke subjects. Thirty patients in the subacute phase of stroke were included in the study: 15 with hemorrhagic stroke and 15 with ischemic stroke. The control group consisted of 30 healthy subjects similar to the cerebral stroke patients regarding age, gender, and status of the periodontium, dentition, and oral hygiene. The number of individuals was determined based on our previous experiment (power of the test = 0.8; α = 0.05). The study material was mixed non-stimulated whole saliva (NWS) and stimulated saliva (SWS). We showed that activity, specific activity, and XO output were significantly higher in NWS of ischemic stroke patients than in hemorrhagic stroke and healthy controls. Hydrogen peroxide and uric acid levels were also considerably higher in NWS of ischemic stroke patients. Using receiver operating curve (ROC) analysis, we demonstrated that XO-specific activity in NWS distinguishes ischemic stroke from hemorrhagic stroke (AUC: 0.764) and controls (AUC: 0.973) with very high sensitivity and specificity. Saliva collection is stress-free, requires no specialized medical personnel, and allows continuous monitoring of the patient's condition through non-invasive sampling multiple times per day. Salivary XO also differentiates with high accuracy (100%) and specificity (93.75%) between stroke patients with mild to moderate cognitive decline (AUC = 0.988). Thus, salivary XO assessment may be a potential screening tool for a comprehensive neuropsychological evaluation. To summarize, our study demonstrates the potential utility of salivary XO in the differential diagnosis of stroke.
Topics: Biomarkers; Hemorrhagic Stroke; Humans; Ischemic Stroke; Stroke; Xanthine Oxidase
PubMed: 35603179
DOI: 10.3389/fimmu.2022.897413 -
Seminars in Nephrology Sep 2011The association between increased uric acid (UA) levels and cardiovascular disease (CVD) has been observed and studied for many decades. The value of UA as an... (Review)
Review
The association between increased uric acid (UA) levels and cardiovascular disease (CVD) has been observed and studied for many decades. The value of UA as an independent factor within the metabolic risk profile for prediction of CVD in the normal population remains an issue of ongoing discussion. In turn, increasing evidence suggests that among patients with established CVD such as heart failure UA is an independent marker of disease state and prognosis. Increased UA levels may be an indicator of up-regulated activity of xanthine oxidase, a powerful oxygen radical-generating system in human physiology. Increased reactive oxygen species (ROS) accumulation contributes to endothelial dysfunction, metabolic and functional impairment, inflammatory activation, and other features of cardiovascular pathophysiology. Accordingly, inhibition of xanthine oxidase activity has been shown to improve a range of surrogate markers in patients with CVD, but this effect seems to be confined to hyperuricemic patients because disappointing results were reported in studies with normouricemic patients. In this review we summarize current evidence on hyperuricemia in CVD. The value of UA as a biomarker and as a potential therapeutic target for tailored metabolic treatment in CVD is discussed.
Topics: Biomarkers; Cardiovascular Diseases; Heart Failure; Humans; Hyperuricemia; Reactive Oxygen Species; Severity of Illness Index; Uric Acid; Xanthine Oxidase
PubMed: 22000650
DOI: 10.1016/j.semnephrol.2011.08.007 -
International Journal of Molecular... May 2020Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent...
Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation . However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation . Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Topics: Allopurinol; Catalysis; Dose-Response Relationship, Drug; Flavonoids; Mercaptopurine; Oxidation-Reduction; Xanthine; Xanthine Oxidase
PubMed: 32380641
DOI: 10.3390/ijms21093256