Metabolic Profiling in Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4837-4837
Author(s):  
Borys Hrinczenko
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
De Novo ◽  
Purine Nucleotide ◽  
Salvage Pathway ◽  
Cell Disease ◽  
Synthetic Pathway ◽  
Purine Bases ◽  
Chronic Hemolysis ◽  
Hydroxyurea Therapy

Abstract Abstract 4837 Sickle cell disease (SCD) is a genetic blood disorder of hemoglobin with patients (pts) suffering from multiple complications. Patients are exposed to the clinical consequences of a hemolytic anemia associated with episodes of vascular vaso-occlusion. Lifelong episodes of painful crises lead to end-organ damage with shortened lifespan. The mutated hemoglobin S in the red cell polymerizes during hypoxia (venous circulation) leading to tissue inflammation and ischemia. The FDA approved drug hydroxyurea used to treat SCD increases fetal hemoglobin production thereby inhibiting hemoglobin S polymerization. Hydroxyurea therapy has been shown to improve morbidity and mortality in SCD patients. The metabolic demands of SCD patients are increased due to chronic hemolysis. The dietary supplement folic acid is recommended to meet some of the excess metabolic requirements. However, metabolic pathways associated with SCD are poorly understood or even explored. The components of the purine nucleotide synthetic pathway were analyzed in the serum of adult SCD patients in steady state. Purine nucleotides are made available for cells via two routes, either by de novo synthesis or by reusing of catabolized purine bases, mainly hypoxanthine. Salvaging the purine ring is more efficient in terms of ATP equivalents than de novo purine synthesis. Xanthine oxidase catalyzes the final reactions of the purine catabolism by consecutive oxidation of hypoxanthine to xanthine to uric acid. Levels of hypoxanthine, xanthine, uric acid as well as xanthine oxidase enzymatic activity (μU/mL) were evaluated in (1) SCD patients (n=5-9), (2) in SCD patients treated with hydroxyurea (n=5-9), and (3) normal adult controls (n=12). Hypoxanthine (μM), xanthine (μM) and uric acid (μM) levels all showed statistically significant (p<0.05) elevations in SCD patients when compared to controls; 14 ± 1 vs. 5 ± 1, 66 ± 8 vs. 22 ± 5, 1142 ± 60 vs. 735 ± 33, respectively. Xanthine oxidase enzymatic activity (μU/mL) also showed statistically significant (p<0.05) increases in SCD pts of 4.3 ± 1.1 vs. 0.9 ± 0.3 when compared to controls. However, SCD pts treated with hydroxyurea showed a statistically significant (p<0.05) drop of hypoxanthine, xanthine, and uric acid levels and also xanthine oxidase activity when compared to SCD pts; 8 ± 1 vs. 14 ± 1, 38 ± 5 vs. 66 ± 8, 780 ± 88 vs. 1142 ± 60, respectively. Furthermore, the hypoxanthine, xanthine, and uric acid levels and xanthine oxidase activity of SCD pts who were taking hydroxyurea were not statistically different from controls. Since levels of hypoxanthine, xanthine, and uric acid were all elevated in SCD pts this suggests that the nucleotide synthetic pathway may not have switched to the more efficient salvage pathway, as would be expected if the uric acid level were low or normal. Furthermore, an unexpected added benefit of hydroxyurea therapy may include down regulation of the overactive purine nucleotide synthetic pathway in SCD pts. The significant increase of purine related compounds such as hypoxanthine and xanthine without a decrease in uric acid suggest that metabolically active cells are not shunting purine bases to the more efficient salvage pathway for synthesis of nucleic acids and higher energy needs. The high proliferate erythropoietic turnover rate of chronic hemolysis requires large quantities of purine bases for transmission of ATP and synthesis of nucleic acids. The metabolic changes in SCD suggest that there is an ineffectual shunting of purine bases to the more efficient salvage pathway. Hydroxyurea therapy may allow for shunting to the more energy efficient salvage pathway resulting in less total body metabolic expenditure. Alternatively, hydroxyurea as a ribonucleotide reductase inhibitor decreases hematopoietic cell turnover which may lead to less purine metabolic requirements. Future metabolic studies will explore this and identify other important pathways for potential therapeutic intervention in SCD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gambaran Asam Urat Serum pada vegetarian Lacto - ovo

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Christy P. Hapendatu ◽  
Youla A. Assa ◽  
Michaela E. Paruntu
Keyword(s):  
Uric Acid ◽  
Nucleic Acid ◽  
Serum Uric Acid ◽  
Food Consumption ◽  
Sampling Method ◽  
De Novo ◽  
Salvage Pathway ◽  
De Novo Synthesis ◽  
Cross Sectional ◽  
High Uric Acid

Abstract: Purine is generated through three mechanisms: de novo synthesis, salvage pathway, and food consumption. Most purine derived from food is converted to uric acid directly, without the occurrence of nucleic acid network. Lacto-ovo vegetarian is a lifestyle that consist of consuming food like vegetables, fruits, nuts, tofu, tempe plus milk and eggs. The intake of food in vegetarian lacto-ovo, some of them are high in purines. The purpose of this research is to describe serum uric acid levels in lacto-ovo vegetarians. This study used a cross sectional with a total sampling as the sampling method. There were 25 respondents that participated in this study. From 25 respondents found as many as seven respondents (28%) who had high uric acid levels and 18 respondent (72%) had serum uric acid levels in the normal range.Keywords: Purin, Uric Acid, Vegetarian Lacto-ovoAbstrak : Purin dihasilkan melalui tiga mekanisme yaitu sintesis de novo, jalur penyelamatan, dan konsumsi makanan. Sebagian besar purin yang bersal dari makanan akan diubah menjadi asam urat secara langsung tanpa terjadinya asam nukleat jaringan. Vegetarian Lacto-ovo merupakan gaya hidup yang mengonsumsi golongan makanan seperti sayuran, buah-buahan, kacang-kacangan, tahu, tempe ditambah susu dan telur. Asupan makanan yang di konsumsi vegetarian lacto-ovo beberapa di antaranya merupakan bahan makanan yang tinggi purin. Tujuan dari penelitian ini untuk mengetahui gambaran kadar asam urat serum pada vegetarian lacto-ovo. Penelitian ini menggunakan desain penelitian deskriptif cross sectional dengan pengambilan sampel menggunakan metode total sampling. Penelitian ini diikuti oleh 25 responden. Dari 25 responden ditemukan sebanyak 7 responden (28%) yang memiliki kadar asam urat yang tinggi dan sebagian besar (72%) mempunyai kadar asam urat serum dalam batas normal.Kata kunci : Purin, Asam Urat, Vegetarian Lacto-ovo

scholarly journals Allopurinol Prevents the Lipogenic Response Induced by an Acute Oral Fructose Challenge in Short-Term Fructose Fed Rats

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 601 ◽  
Author(s):  
García-Arroyo ◽  
Monroy-Sánchez ◽  
Muñoz-Jiménez ◽  
Gonzaga ◽  
Andrés-Hernando ◽  
...  
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Tap Water ◽  
De Novo Lipogenesis ◽  
Sprague Dawley ◽  
Short Term ◽  
Alcoholic Fatty Liver ◽  
High Fructose

We investigated whether short term high fructose intake may induce early hepatic dysfunction in rats and to test whether allopurinol treatment may have beneficial effects. Twenty male Sprague-Dawley rats received 20% fructose in drinking water (10 treated with allopurinol and 10 received vehicle) and 10 control rats received tap water. After 14 days, the hepatic response to an acute fructose load was evaluated, and in fasted animals, respirometry studies in freshly isolated mitochondria were performed. In fasting rats, we did not find differences in systemic or hepatic uric acid and triglyceride concentrations among the groups, but mitochondrial respiratory control rate was significantly decreased by high fructose feeding and correlated with a reduced expression of Complex I, as well as decreased aconitase-2 activity. On the other hand, in fructose fed rats, an acute fructose load increased systemic and hepatic uric acid, triglycerides and oxidative stress. Fructose feeding was also associated with fructokinase and xanthine oxidase overexpression and increased liver de novo lipogenesis program (fatty acid synthase (FAS) and cell death-inducing DFFA-like effector C (CIDEC) overexpression, ATP citrate lyase (ACL) and acetyl coA carboxylase (ACC) overactivity and decreased AMP-activated protein kinase (AMPk) and endothelial nitric oxide synthase (eNOS) activation). Allopurinol treatment prevented hepatic and systemic alterations. These data suggest that early treatment with xanthine oxidase inhibitors might provide a therapeutic advantage by delaying or even halting the progression of non-alcoholic fatty liver disease (NAFLD).

scholarly journals Purine-Metabolising Enzymes and Apoptosis in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1354 ◽  
Author(s):  
Camici ◽  
Garcia-Gil ◽  
Pesi ◽  
Allegrini ◽  
Tozzi
Keyword(s):  
Molecular Mechanisms ◽  
Purine Nucleoside Phosphorylase ◽  
De Novo ◽  
Tumour Cells ◽  
Purine Nucleotide ◽  
Salvage Pathway ◽  
Nucleotide Synthesis ◽  
Deoxynucleoside Triphosphate ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
Salvage Pathways

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

scholarly journals Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease

2020 ◽  
Author(s):  
Heidi M. Schmidt ◽  
Katherine C. Wood ◽  
Sara E. Lewis ◽  
Scott A. Hahn ◽  
Xena M. Williams ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Xanthine Oxidase ◽  
Sickle Cell ◽  
Vascular Function ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Chronic Hemolysis ◽  
Oxidant Production

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.

Chain-breaking/Preventive Antioxidant, Urate-lowering, and Anti-inflammatory Effects of Pure Curcumin

2020 ◽  
Vol 17 (1) ◽  
pp. 66-74
Author(s):  
Seghira Bisset ◽  
Widad Sobhi ◽  
Chawki Bensouici ◽  
Abdelhalim Khenchouche
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Acid Production ◽  
Biological Activities ◽  
Antioxidant Effect ◽  
Metal Chelating ◽  
Wide Range ◽  
Chain Breaking ◽  
Pharmaceutical Industries ◽  
Anti Inflammatory

Background: Several researches have shown that therapeutic compounds or phytochemicals from natural sources are important in the food as it is valuable in pharmaceutical industries due to their fewer side effects and potent against various diseases. Curcumin, a major polyphenol derived from turmeric spice, which used in many foods, has a wide range of biological activities, with quite a safety. Objective: The goal of this study was to investigate the antioxidant, urate-lowering, and antiinflammatory effects of pure curcumin. Methods: The antioxidant activity was evaluated for chain-breaking antioxidant effect (radicalscavenging and reducing abilities assays) and for preventive antioxidant effect with metal chelating assay, the urate-lowering was assayed on aspectrophotometer by measuring the inhibition of uric acid production by xanthine oxidase (XO) enzyme, and the anti-inflammatory effect was estimated using in vitro albumin denaturation inhibition. Results: Curcumin showed a significant and good chain-breaking antioxidant effect, both in free radical- scavenging assays (Galvinoxyl radical, ABTS, and hydroxyl radical), and in reducing abilities methods (reducing power, Cupric ion reducing antioxidant capacity and O-phenanthroline assays). In preventive antioxidant effect, assessed with the metal chelating assay, curcumin showed significant effect but with high concentration compared with standard. In the xanthine/xanthine oxidase system, curcumin significantly inhibited uric acid production (IC50=0.71 ± 0.06 mg/mL). Regarding antiinflammatory activity, curcumin showed significant inhibition of albumin denaturation with an IC50 value of 1181.69 ± 1.11μg/mL. Conclusion: These results indicated that curcumin showed promising antioxidant, anti-gout and antiinflammatory properties and might be used as potential, natural drugs against oxidative and inflammation- related diseases.

Allopurinol and Loss of Consciousness in a 78-old Year Man Suffering from Gout

2020 ◽  
Vol 20 (2) ◽  
pp. 253-256 ◽  
Author(s):  
Mahnaz Arian ◽  
Mina AkbariRad ◽  
Ahmad Bagheri Moghaddam ◽  
Abdollah Firoozi ◽  
Mohammad Jami
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Kidney Stones ◽  
Oxidase Inhibitor ◽  
Loss Of Consciousness ◽  
Drug Induced ◽  
Xanthine Oxidase Inhibitor ◽  
Case Presentation ◽  
Maculopapular Rashes ◽  
Reduced State

: Allopurinol is an FDA -Approved xanthine oxidase inhibitor, which is effective in the treatment of gout, hyperuricemia and uremic kidney stones in patients with an increased level of uric acid excretion. Xanthine oxidase acts by converting hypoxanthine and xanthine into uric acid, and therefore its inhibition results in decreased production of uric acid. The most common side effects of this medication are as follows: maculopapular rashes, hives, itching, headache, dizziness, abnormal hair loss, fever and hypersensitivity reaction. Case Presentation: This report represents a case of drug-induced meningitis of a senile man who ended up in the ICU due to the remarkably reduced state of consciousness.

scholarly journals To Give or Not to Give: RhD Immunoglobulin for an RHD*39 Pregnant Woman with Sickle Cell Disease

2021 ◽  
pp. 1-5
Author(s):  
Justin E. Juskewitch ◽  
Craig D. Tauscher ◽  
Sheila K. Moldenhauer ◽  
Jennifer E. Schieber ◽  
Eapen K. Jacob ◽  
...  
Keyword(s):  
Pregnant Woman ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pregnancy Termination ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Childbearing Age ◽  
Procedural Complications ◽  
History Of ◽  
Chronic Hemolysis

Introduction: Patients with sickle cell disease (SCD) have repeated episodes of red blood cell (RBC) sickling and microvascular occlusion that manifest as pain crises, acute chest syndrome, and chronic hemolysis. These clinical sequelae usually increase during pregnancy. Given the racial distribution of SCD, patients with SCD are also more likely to have rarer RBC antigen genotypes than RBC donor populations. We present the management and clinical outcome of a 21-year-old pregnant woman with SCD and an RHD*39 (RhD[S103P], G-negative) variant. Case Presentation: Ms. S is B positive with a reported history of anti-D, anti-C, and anti-E alloantibodies (anti-G testing unknown). Genetic testing revealed both an RHD*39 and homozygous partial RHCE*ceVS.02 genotype. Absorption/elution testing confirmed the presence of anti-G, anti-C, and anti-E alloantibodies but could not definitively determine the presence/absence of an anti-D alloantibody. Ms. S desired to undergo elective pregnancy termination and the need for postprocedural RhD immunoglobulin (RhIG) was posed. Given that only the G antigen site is changed in an RHD*39 genotype and the potential risk of RhIG triggering a hyperhemolytic episode in an SCD patient, RhIG was not administered. There were no procedural complications. Follow-up testing at 10 weeks showed no increase in RBC alloantibody strength. Discussion/Conclusion: Ms. S represents a rare RHD*39 and partial RHCE*ceVS.02 genotype which did not further alloimmunize in the absence of RhIG administration. Her case also highlights the importance of routine anti-G alloantibody testing in women of childbearing age with apparent anti-D and anti-C alloantibodies.

scholarly journals Uric Acid, Oxidative Stress and Inflammation in Chronic Heart Failure with Reduced Ejection Fraction

2015 ◽  
Vol 23 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Adriana Iliesiu ◽  
Alexandru Campeanu ◽  
Daciana Marta ◽  
Irina Parvu ◽  
Gabriela Gheorghe
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Uric Acid ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Xanthine Oxidase ◽  
Left Ventricular ◽  
Paraoxonase 1 ◽  
Lv Function ◽  
The Relationship

Abstract Background. Oxidative stress (OS) and inflammation are major mechanisms involved in the progression of chronic heart failure (CHF). Serum uric acid (sUA) is related to CHF severity and could represent a marker of xanthine-oxidase activation. The relationship between sUA, oxidative stress (OS) and inflammation markers was assessed in patients with moderate-severe CHF and reduced left ventricular (LV) ejection fraction (EF). Methods. In 57 patients with stable CHF, functional NYHA class III, with EF<40%, the LV function was assessed by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels and echocardiographically through the EF and E/e’ ratio, a marker of LV filling pressures. The relationship between LV function, sUA, malondialdehyde (MDA), myeloperoxidase (MPO), paraoxonase 1 (PON-1) as OS markers and high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) as markers of systemic inflammation was evaluated. Results. The mean sUA level was 7.9 ± 2.2 mg/dl, and 61% of the CHF patients had hyperuricemia. CHF patients with elevated LV filling pressures (E/e’ ≥ 13) had higher sUA (8.6 ± 2.3 vs. 7.3 ± 1.4, p=0.08) and NT-proBNP levels (643±430 vs. 2531±709, p=0.003) and lower EF (29.8 ± 3.9 % vs. 36.3 ± 4.4 %, p=0.001). There was a significant correlation between sUA and IL-6 (r = 0.56, p<0.001), MDA (r= 0.49, p= 0.001), MPO (r=0.34, p=0.001) and PON-1 levels (r= −0.39, p= 0.003). Conclusion. In CHF, hyperuricemia is associated with disease severity. High sUA levels in CHF with normal renal function may reflect increased xanthine-oxidase activity linked with chronic inflammatory response.

scholarly journals Bactericidal activity of a superoxide anion-generating system. A model for the polymorphonuclear leukocyte.

1979 ◽  
Vol 149 (1) ◽  
pp. 27-39 ◽  
Author(s):  
H Rosen ◽  
S J Klebanoff
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Bactericidal Activity ◽  
Parent Strain ◽  
Carotenoid Pigments ◽  
Bacterial Killing ◽  
Oxidase System ◽  
System A ◽  
Presence And Absence ◽  
Generating System

The acetaldehyde-xanthine oxidase system in the presence and absence of myeloperoxidase (MPO) and chloride has been employed as a model of the oxygen-dependent antimicrobial systems of the PMN. The unsupplemented xanthine oxidase system was bactericidal at relatively high acetaldehyde concentrations. The bactericidal activity was inhibited by superoxide dismutase (SOD), catalase, the hydroxyl radical (OH.) scavengers, mannitol and benzoate, the singlet oxygen (1O2) quenchers, azide, histidine, and 1,4-diazabicyclo[2,2,2]octane (DABCO) and by the purines, xanthine, hypoxanthine, and uric acid. The latter effect may account for the relatively weak bactericidal activity of the xanthine oxidase system when purines are employed as substrate. A white, carotenoid-negative mutant strain of Sarcina lutea was more susceptible to the acetaldehyde-xanthine oxidase system than was the yellow, carotenoid-positive parent strain. Carotenoid pigments are potent 1O2 quenchers. The xanthine oxidase system catalyzes the conversion of 2,5-diphenylfuran to cis-dibenzoylethylene, a reaction which can occur by a 1O2 mechanism. This conversion is inhibited by SOD, catalase, azide, histidine, DABCO, xanthine, hypoxanthine, and uric acid but is only slightly inhibited by mannitol and benzoate. The addition of MPO and chloride to the acetaldehyde-xanthine oxidase system greatly increases bactericidal activity; the minimal effective acetaldehyde concentration is decreased 100-fold and the rate and extent of bacterial killing is increased. The bactericidal activity of the MPO-supplemented system is inhibited by catalase, benzoate, azide, DABCO, and histidine but not by SOD or mannitol. Thus, the acetaldehyde-xanthine oxidase system which like phagocytosing PMNs generates superoxide (O.2-) and hydrogen peroxide, is bactericidal both in the presence and absence of MPO and chloride. The MPO-supplemented system is considerably more potent; however, when MPO is absent, bactericidal activity is observed which may be mediated by the interaction of H2O2 and O.2- to form OH. and 1O2.

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