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Quantification of allantoin by isotope dilution. Peaks of endogenous allantoin from extraction of 25 ml of human serum (A) and nasal lavage fluids (B) without alkaline solid phase extraction. Quantifier ion at 398 m=z (solid line) and internal standard ion at 400 m=z (dotted line) are shown.
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Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced me...
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... in human serum by using allantoin-U-15 N 4 (yielding a triply labeled ion with an m=z of 401) to be <2 pmol (data not shown). When applied to pooled serum, plasma, or nasal-lavage samples from healthy subjects, our method yields clearly detectable concentrations of allantoin, and the selective ion chromatogram is free of confounding peaks (Fig. 1). Total variability and within-run variability were determined in pooled serum samples at low (1.2 mM), medium (2.4 mM), and high (14.6 mM) concentra- tions. This concentration range spans the majority of the clinical serum data observed (see later). Repeated data were collected in accordance with National Committee on Clinical ...
Citations
... Ozone readily reacts with uric acid to form allantoin [95], whose activation of imidazoline receptors causes multiple benefits (Section 6). For example, allantoin's engagement of imidazoline I3 receptors ameliorates pancreatic beta cell damage [8]. ...
... Hepatocytes are among the major uric acid producers in the body [241]. Allantoin is a major product of the reaction of uric acid with ozone but not with hydrogen peroxide (uncatalyzed reaction) or singlet oxygen [95,119,218]. During exercise, uric acid may protect hepatocytes by eliminating ozone. ...
Inhalation of tropospheric ozone increases the risk of respiratory diseases and the metabolic syndrome (MS). On the other hand, medical ozone therapy is used in the management of many chronic diseases including components of MS. However, medical ozone has not gained universal acceptance because the mechanisms involved therein are not fully understood. Ozone has also been reported to be endogenously formed in cells and organisms. Like medical ozone, endogenous ozone has not been fully embraced, due to limited understanding of the mechanisms of its formation. This review seeks to improve our understanding of the mechanisms of endogenous ozone formation by outlining previously proposed mechanisms, and suggesting new pathways based on reactions that have been reported to be involved in tropospheric ozone formation and electrochemical ozone production from water. New perspectives on the mechanisms of the harms of ozone inhalation and the benefits of medical ozone are discussed. It is hypothesized that endogenous ozone is involved in the harmful effects of particulate matter and ozone inhalation, as well as the benefits of medical ozone, nutraceuticals and physical activity. Thus, endogenous ozone should be regarded as a mainstream reactive oxygen species in redox biology.
... UVC inactivation significantly altered the metabolic profile of samples (Fig. 3A). We show that the differentially expressed metabolites between untreated and UVC-treated plasma samples are redox-active metabolites (Fig. 3B), suggesting that reactive oxygen species known to be produced during UVC irradiation (48) lead to sample oxidation during this procedure, similar to reactive oxygen species oxidation in vivo (49)(50)(51). Therefore, UVC inactivation is not suitable for metabolomic studies, especially when interrogating redox-active metabolites. ...
... Despite having negligible effects in the proteomic assays, we did observe that UVC inactivation significantly altered metabolomic profiles is human plasma samples. Specifically, we show that redox-active metabolites such as methionine and urate are oxidized following UVC inactivation, significantly increasing signals for methionine sulfoxide and allantoin, respectively (49,50). Similarly, bilirubin, which is oxidized to biliverdin (51), is significantly decreased with UVC treatment. ...
... Similarly, bilirubin, which is oxidized to biliverdin (51), is significantly decreased with UVC treatment. Therefore, UVC inactivation of clinical samples could lead to misleading biological interpretations, artificially skewing sample metabolites to a more oxidized profile (49)(50)(51). However, high-concentration methanol (≥80%) (59,60) and methanol/acetone mixtures (12,21) have previously been shown to successfully inactivate many viral-infected samples, including SARS-CoV-2 (16)(17)(18). ...
Due to the severity of COVID-19 disease, the U.S. Centers for Disease Control and Prevention and World Health Organization recommend that manipulation of active viral cultures of SARS-CoV-2 and respiratory secretions from COVID-19 patients be performed in biosafety level (BSL)3 laboratories. Therefore, it is imperative to develop viral inactivation procedures that permit samples to be transferred to lower containment levels (BSL2), while maintaining the fidelity of complex downstream assays to expedite the development of medical countermeasures. In this study, we demonstrate optimal conditions for complete viral inactivation following fixation of infected cells with commonly used reagents for flow cytometry, UVC inactivation in sera and respiratory secretions for protein and Ab detection, heat inactivation following cDNA amplification for droplet-based single-cell mRNA sequencing, and extraction with an organic solvent for metabolomic studies. Thus, we provide a suite of viral inactivation protocols for downstream contemporary assays that facilitate sample transfer to BSL2, providing a conceptual framework for rapid initiation of high-fidelity research as the COVID-19 pandemic continues.
... Interestingly, a lower concentration of blood creatine was observed in metabolically healthy OB women after a lifestyle intervention for weight loss [63]. The last molecule identified was allantoin, an oxidation product of uric acid and purine metabolism used as a marker of oxidative stress [64]. Evidence for a link between allantoin and obesity is not available. ...
Although the composition of the human blood metabolome is influenced both by the health status of the organism and its dietary behavior, the interaction between these two factors has been poorly characterized. This study makes use of a previously published randomized controlled crossover acute intervention to investigate whether the blood metabolome of 15 healthy normal weight (NW) and 17 obese (OB) men having ingested three doses (500, 1000, 1500 kcal) of a high-fat (HF) meal can be used to identify metabolites differentiating these two groups. Among the 1024 features showing a postprandial response, measured between 0 h and 6 h, in the NW group, 135 were dose-dependent. Among these 135 features, 52 had fasting values that were significantly different between NW and OB men, and, strikingly, they were all significantly higher in OB men. A subset of the 52 features was identified as amino acids (e.g., branched-chain amino acids) and amino acid derivatives. As the fasting concentration of most of these metabolites has already been associated with metabolic dysfunction, we propose that challenging normal weight healthy subjects with increasing caloric doses of test meals might allow for the identification of new fasting markers associated with obesity.
... The low recoveries of allantoin indicated that this was not retained on SPE because of its high water solubility (logP = −3.14). Allantoin is not well retained on most SPE due to polar character, but by using strongly alkaline conditions can be facilitate retention of allantoin on anion-exchange matrices (Gruber et al. 2009). In our case, using buffer solution (slightly alkaline) for the allantoin elution on Strata NH 2 anion-exchange cartridge, causes a higher recovery than on the other cartridges. ...
... In some studies, the allantoin and uric acid was examined as indicator of bacterial nitrogen flow through the digestive system of ruminants, the main focus has been on for quantitative and analytical reasons. The similar quantities of allantoin and uric acid in milk were found by some authors (Sikka et al. 2001;Indyk and Woollard 2004;Gruber et al. 2009; T11 T2 T7 T12 T3 T8 T13 T4 T9 T14 T5 T10 T15 T16 T21 T26 T17 T22 T27 T18 T23 T28 T19 T24 T29 T20 T25 T11 T2 T7 T12 T3 T8 T13 T4 T9 T14 T5 T10 T15 T16 T21 T26 T17 T22 T27 T18 T23 T28 T19 T24 T29 T20 T25 . Allantoin output (mmol day -1 ) increased with increased percentage of concentrate in the diet (Schager et al. 2003) and comparable results for uric acid were obtained by Larsen and Moyes (2010). ...
In this study, simultaneous quantification of allantoin, uric acid, xanthine, and hypoxanthine in cow milk by solid phase extraction (SPE) and high performance liquid chromatography-diode array detection (HPLC-DAD) method was perform. Five different SPE cartridges were tested in order to evaluate the isolation of purine derivatives (PD) from cow milk. Chromatography was carried out on ODS-2 Hypersil column and 0.05 M (NH<sub>4</sub>)<sub>2</sub>HPO<sub>4</sub> buffer solution (pH = 7.76) as mobile phase. The HPLC-DAD validated method showed a linearity with regression coefficients higher than 0.999 and the limits of detection and quantification with values in the range 0.09–0.74 µg mL<sup>–1</sup> and 0.27–2.24 µg mL<sup>–1</sup>, respectively. The method showed good precision with a relative standard deviation (RSD) below 4.48%, while the accuracy ranged from 95.34 to 104.47% for all analytes. The best recovery degree of PD by SPE were obtained on Strata SCX cartridge for xanthine (87.79%) and hypoxanthine (89.02%); on Strata NH<sub>2</sub> for allantoin (35.09%) and on Strata C8 for uric acid (101.08%). Finally, the HPLC-DAD method with SPE on SCX cartridges was applied to quantify the PD in a batch of thirty cow milk samples.
... Allantoin is a physiologic antioxidant that can be detected in human plasma and serum samples by GC-MS [71]. It was also demonstrated that determination of urinary allantoin concentrations by GC-MS was useful for evaluating the efficacy of clinical interventions in preterm neonates diagnosed with germinal matrix IVH [64]. ...
... Drugs targeting the Nrf2/ARE signaling pathway have therapeutic potential for reducing brain damage caused by OS and inflammation following ICH ( Figure 3). The drugs used to treat ICH animal models by regulating the Nrf2-ARE signaling pathway include glycyrrhizin [6], simvastatin [76], methyl hydrogen fumarate [77], nicotinamide mononucleotide [56], astaxanthin [55], mangiferin [71], RS9 [78], silymarin [79], sulforaphane [80], Hb pretreatment [81], melatonin [82], and recombinant human erythropoietin [83], calycosin [84], (-)-epicatechin [67], luteolin [85], and ghrelin [86]. ...
Oxidative stress (OS) is induced by the accumulation of reactive oxygen species (ROS) following intracerebral hemorrhage (ICH) and plays an important role in secondary brain injury caused by the inflammatory response, apoptosis, autophagy, and blood-brain barrier (BBB) disruption. This review summarizes the current state of knowledge regarding the pathogenic mechanisms of brain injury after ICH, markers for detecting OS, and therapeutic strategies that target OS to mitigate brain injury.
1. Introduction
ICH is a type of stroke characterized by spontaneous and nontraumatic bleeding in the brain that is associated with high morbidity and mortality rates [1]. ICH can be classified as primary and secondary. While treatment options for the former are limited, various strategies have been proposed for managing the latter [1].
Hematomal and perihematomal regions are biochemically active environments that sustain oxidative damage following ICH [2]. OS is defined as an imbalance between the formation of strong oxidants and physiologic antioxidant capacity [3]. ROS such as oxygen free radicals (e.g., superoxide (O2⁻) and hydroxyl radicals (OH⁻)) and nonradical compounds (e.g., hydrogen peroxide (H2O2) and hypochlorous acid), as well as reactive nitrogen species (RNS; e.g., nitric oxide (NO)) and a variety of nitrogenous compounds produced as metabolic byproducts, are the major drivers of oxidative damage [4] to proteins, lipids, and nucleic acids, which can induce inflammation, autophagy, apoptosis, and destruction of the BBB. OS is associated with dysregulation of cellular oxidation and reduction (redox) mechanisms; redox-sensitive thiols that are easily oxidized by nonradical oxidants such as H2O2 after ICH are essential for transcription factor regulation (e.g., nuclear factor erythroid 2-related factor (Nrf) 2 and nuclear factor- (NF-) κB) [5].
The Kelch-like ECH-associated protein (Keap) 1/Nrf2/antioxidant response element (ARE) signaling pathway is the main regulatory system protecting cells against oxidative damage. Nrf2 is a master regulator of the cellular response to oxidative stress, which is associated with the expression of antioxidant and detoxification enzymes and factors such as NAD(P)H: quinone oxidoreductase (NQO) 1, catalase (CAT), superoxide dismutase (SOD), heme oxygenase- (HO-) 1, glutathione peroxidase (GPX), and glutathione-S-transferase (GST) [6]. Nrf2 was shown to mitigate early brain injury after ICH by translocating to the nucleus following activation and binding to AREs to activate the transcription of genes encoding antioxidant enzymes [7].
2. ROS Production after ICH
2.1. Production of ROS by Activated Phagocytes and Nonphagocytic Cells following ICH
Activated neutrophils, microglia, and macrophages are the main sources of ROS following ICH. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is expressed on the surface of neutrophils and macrophages and stimulates the production of ROS in response to extracellular signals such as hormones and cytokines [8]. Nonphagocytic cells such as neurons, microglia, astrocytes, and cerebrovascular endothelial cells also express NOX [8–10]. To date, 7 NOX isozymes have been identified in nonphagocytic cells that use NADH or NADPH as an electron donor for ROS production [11]. While NOX activity is generally low in these cells, they continuously produce O2⁻ even in the absence of external stimulation [11]. Hypoxia after ICH induces conformational changes in gp91phox, the heme-binding subunit of NOX, which activates the protein and leads to the formation of NOX complexes and increased ROS production [12] The activation of NOX was also reported to be the main mechanism underlying ROS generation in a rabbit model of intraventricular hemorrhage (IVH) [13], and OS resulting from NOX activation was shown to contribute to collagenase-induced ICH and brain injury [14]. NOX2 protein level was upregulated in the striatum of mice 12 h after ICH, which peaked at 24 h [15], and another study found that gp91phox was primarily expressed in activated microglia and colocalized with peroxynitrite (ONOO−) 24 h after ICH in the injured hemisphere [16]. However, following ICH, activated leukocytes release myeloperoxidase (MPO), which catalyzes lipid peroxidation and causes OS at the site of injury [17]. Additionally, increased expression of inducible NO synthase (iNOS) in M1 microglia in conjunction with the release of proinflammatory mediators and cytotoxic substances caused significant tissue damage after ICH [18].
2.2. Increased ROS Production in Mitochondria following ICH
Another important ROS is O2⁻ produced by mitochondria, which is generated as a byproduct of biological oxidation during mitochondrial respiration under physiologic conditions [19]. In most cells, the electron transport chain consumes 90% of cellular oxygen; 2% of this is transformed into oxygen free radicals in the mitochondrial inner membrane and matrix [20, 21]. Electrons that leak from the respiratory chain react with oxygen to form O2⁻. Mitochondrial O2⁻ is detoxified to H2O2 by SOD, then to O2 and H2O by antioxidant enzymes such as CAT and GPX. However, O2⁻ that elude antioxidant mechanisms can damage proteins, lipids, and DNA [21]. There are 7 known sources of O2⁻ in mammalian mitochondria: the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, complex I flavin (site IF), electron-transferring flavoprotein: Q oxidoreductase in fatty acid beta oxidation, pyruvate, and 2-oxoglutarate dehydrogenase, with site IQ and site IIIQo having the highest production capacities [21].
Mitochondria are storage sites for calcium ions (Ca²⁺). Under ischemia/reperfusion (I/R), excessive glutamate levels can cause an influx of Ca²⁺ into neurons via N-methyl-d-aspartic acid receptor (NMDAR), a ligand-gated ion channel [22]. Activation of the NMDAR leads to further Ca²⁺ influx, with increased levels in the cytosol and mitochondrial Ca²⁺ loading. Thrombin produced after ICH leads to Src kinase activation by activating protease-activated receptor 1 (PAR1), which phosphorylates and activates NMDAR. PARs are a subfamily of G protein-coupled receptors (GPCRs) with four members, namely, PAR1, PAR2, PAR3, and PAR4. PAR1 is highly expressed in many different cell types. PAR1 plays an important role in astrocyte proliferation, stimulus-induced long-term potentiation (LTP), and nerve growth factor (NGF) secretion. PAR1 enhances Src-mediated tyrosine phosphorylation of NMDA receptor in ICH [23]. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor by glutamate after ICH in motor neurons also increased Ca²⁺ and Na+ influx and mitochondrial Ca²⁺ loading [22]. Following ICH, Ca²⁺ stored in the endoplasmic reticulum (ER) is thought to be sequestered by mitochondria. Mitochondrial Ca²⁺ loading reduces mitochondrial membrane potential (MMP) and opens the mitochondrial permeability transition pore (MPTP), resulting in mitochondrial damage and disruption of the mitochondrial respiratory chain; together, these processes result in the release of excess ROS [22].
2.3. Increased ROS Production by the ER following ICH
The ER is the site of protein synthesis, posttranslational modification, folding, and trafficking. ICH can cause ER stress (ERS), which is characterized by protein misfolding, accumulation of abnormal proteins, and Ca²⁺ imbalance, all of which trigger the unfolded protein response (UPR) [24]. Glutamate excitotoxicity and the inflammatory response can result in ERS. When ICH causes ERS, ROS are generated by NOX4 in the internal membrane. ROS then acts as a signaling intermediate that subsequently mitigates ERS via the UPR. If ERS is not alleviated, the delayed expression of proteins such as C/EBP homologous protein (CHOP) causes a secondary increase in ROS levels [25]. Additionally, disulfide bonds in proteins translated in the ER are highly sensitive to changes in redox balance; thus, both reducing and oxidizing conditions can disrupt protein folding and cause ERS. On the other hand, oxidative protein folding is a major source of intracellular ROS production [26]; during this process, thiol groups on the cysteines of peptides are oxidized and form disulfide bonds [26]. After accepting electrons from protein disulfide isomerase (PDI), ER oxidoreductin (ERO) 1 transfers electrons to molecular oxygen to generate H2O2, the major type of ROS formed in the ER lumen [26]. In the ERS following ICH, disruption of disulfide bond formation leads to ROS accumulation and OS [26]. Inositol 1,4,5-trisphosphate receptor and voltage-dependent anion channel—which are located in the ER and mitochondria, respectively—form a complex with the chaperone protein glucose-regulated protein (GRP) 75, thus physically connecting the 2 organelles [22]. Upon ERS, Ca²⁺ transfer at the contact points between the ER and mitochondria leads to mitochondrial dysfunction, thereby increasing mitochondrial ROS production, resulting in cellular stress or neuronal death. Although there have been few studies investigating the relationship between ERS and ICH, given the interaction between ERS and microglial activation [27], neuroinflammation, and autophagy after ICH, clarification of this point can inspire new avenues for ICH treatment.
2.4. Hemoglobin (Hb) Toxicity after ICH
Hb toxicity is induced by free radicals generated via Fenton-type reactions and by oxidative damage to proteins, nucleic acids, and lipids [28]. During its conversion to methemoglobin, oxyhemoglobin releases O2⁻, which in turn forms OH− and contributes to ROS production [29]. Hb, a major component of erythrocytes, is a heterotetramer composed of α and β globin subunits that each bind a heme molecule. Hb induces the expression of iNOS by M1 microglia and neutrophils after ICH. NOS is expressed by endothelial cells, macrophages, neurophagocytes, and nerve cells; there are 2 isoenzymes besides iNOS—namely, neural and endothelial NOS [30]. Overexpression of iNOS or endothelial NOS and the consequent overproduction of NO lead to changes in tight junction proteins and can potentially disrupt the BBB [31]. Following ICH, heme is released by Hb and decomposed into bilirubin, free iron, and carbon monoxide.
2.5. Increased ROS Production by Heme following ICH
Heme (ferrous protoporphyrin IX) is a reactive, low molecular weight form of iron that participates in Fenton-type oxygen radical reactions in neurons, microglia, and neutrophils [32]. Hemin, the oxidized form of heme, accumulates in intracranial hematomas and is a potent oxidant [33]. Hemin is bound by hemopexin in serum, and the complex is translocated into the cell via lipoprotein receptor-related protein (LRP) 1. Intracellular hemin is degraded into bilirubin, Fe²⁺, and carbon monoxide. Fe²⁺ derived from hemin can generate OH−—the most reactive oxygen radical—via the Fenton reaction, leading to an increase in ROS levels [22].
2.6. Increased ROS Production from Ferrous Iron and Ferritin following ICH
Ferrous iron is one of the main contributors to OS following ICH. Free iron catalyzes the conversion of O2⁻ and H2O2 into OH− via the Fenton reaction while oxidizing iron from a divalent to a trivalent form [34]. Ferrous iron is transported into the cell through divalent metal transporter (DMT) 1 and into mitochondria by ATP-binding cassette- (ABC-) 7 [22], resulting in OS. Ferritin functions as a source of iron in lipid peroxidation; the release of iron from ferritin is mediated by O2⁻ [34] (Figure 1). Knowledge of the mechanisms and dynamics of ROS generation following ICH can guide the development of drugs for the treatment of ICH that act by mitigating OS.
... Control refers to age-matched healthy subjects. F 2 -and F 4 -isoprostanes are well established biomarkers of oxidative lipid damage and allantoin is a biomarker of oxidative degradation of urate [8,[92][93][94][95]. ...
In this mini-reflection, I explain how during my doctoral work in a Botany Department I first became interested in H2O2 and later in my career in other reactive oxygen species, especially the role of “catalytic” iron and haem compounds (including leghaemoglobin) in promoting oxidative damage. The important roles that H2O2, other ROS and dietary plants play in respect to humans are discussed.
I also review the roles of diet-derived antioxidants in relation to human disease, presenting reasons why clinical trials using high doses of natural antioxidants have generally given disappointing results. Iron chelators and ergothioneine are reviewed as potential cytoprotective agents with antioxidant properties that may be useful therapeutically. The discovery of ferroptosis may also lead to novel agents that can be used to treat certain diseases.
... Allantoin was measured in plasma as previously published by our laboratory [2,5,6] using an adaptation of the methods developed by Gruber et al. [19] and Pavitt et al. [20]. Plasma (50 μL) was transferred to an Eppendorf tube containing 5 × 10 −10 mol internal standard (50 μL 10 μM [ 15 N]-labeled allantoin). ...
To examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance.
Utilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R).
Oral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress.
A single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.
... The small size and the high polarity of allantoin, however, make its quantification challenging, thus limiting its exploitation as a biomarker. The general methods used for allantoin measurements require sensitive and specific instrumentations and exploit critical or time-consuming techniques like chemical derivatization, gas or liquid chromatography associated with mass spectrometry (GC/LC-MS), capillary electrophoresis and enzyme cycling assays [3,4,8,[15][16][17][18][19][20][21]. To overcome these limits, we proposed a novel assay based on the enzymatic production of allantoate from allantoin, and its subsequent chemical conversion into a fluorescent compound, detectable with a bench fluorescence plate reader [22]. ...
Allantoin, the natural end product of purine catabolism in mammals, is non-enzymatically produced from the scavenging of reactive oxygen species through the degradation of uric acid. Levels of allantoin in biological fluids are sensitively influenced by the presence of free radicals, making this molecule a candidate marker of acute oxidative stress in clinical analyses. With this aim, we exploited allantoinase—the enzyme responsible for allantoin hydrolization in plants and lower organisms—for the development of a biosensor exploiting a fast enzymatic-chemical assay for allantoin quantification. Recombinant allantoinase was entrapped in a wet nanoporous silica gel matrix and its structural properties, function, and stability were characterized through fluorescence spectroscopy and circular dichroism measurements, and compared to the soluble enzyme. Physical immobilization in silica gel minimally influences the structure and the catalytic efficiency of entrapped allantoinase, which can be reused several times and stored for several months with good activity retention. These results, together with the relative ease of the sol-gel preparation and handling, make the encapsulated allantoinase a good candidate for the development of an allantoin biosensor.
... Spices are naturally rich in polyphenolic antioxidants (Shan et al., 2005;Yashin et al., 2017), although very few well-controlled randomized trials have investigated the effects of spice consumption on in vivo redox status in humans (Srinivasan, 2014). Furthermore, previous studies have suggested the utility of allantoin as a biomarker of oxidative stress (Grootveld and Halliwell, 1987;Benzie et al., 1999;Gruber et al., 2009) although, controlled dose response studies with dietary antioxidants to test this in humans have been limited. We have therefore investigated whether consumption of polyphenol rich curry, in two separate doses can modulate postprandial plasma concentrations of allantoin and allantoin to uric acid ratio and compared them with a more established marker, i.e., 8-iso Prostaglandin F 2α (F2-isoprostanes). ...
While dietary or supplementary antioxidants are thought to inhibit or delay oxidation of biological molecules, their utility in vivo has been marred by equivocal evidence. Consumption of polyphenol rich foods has been thought to alleviate postprandial oxidative stress and/or improve endothelial function. Although, previous studies suggested the utility of allantoin as a biomarker of oxidative stress, controlled dose response studies with dietary antioxidants to test this in humans have been limited. We therefore investigated the effects of 2 doses of polyphenol rich curry consumption on postprandial plasma concentrations of allantoin, allantoin to uric acid ratio, F2-isoprostanes using liquid chromatography-tandem mass spectrometry (LCMS-MS) and measured endothelial function using peripheral arterial tonometry (endoPAT). In a randomized controlled crossover trial in 17 non-smoking, healthy, Chinese men, aged 23.7 ± 2.4 years and BMI 23.1 ± 2.3 kg/m2, the volunteers consumed 3 test meals in a random order, consisting of either non-curry Dose 0 Control (D0C, 0 g spices), or Dose 1 Curry (D1C, 6 g spices) or Dose 2 Curry (D2C, 12 g spices), after overnight fast. There were significant reductions in postprandial allantoin concentrations (p < 0.001) and allantoin to uric acid ratio (p < 0.001) at 2 h and 3 h following test meal consumption, indicating improvements in postprandial redox balance with increasing curry doses, although there were no differences between treatments on F2-isoprostane concentrations or on RHI (measured at 2 h only). Allantoin may have a utility as a biomarker of redox balance, in an acute setting. The study was registered at www.clinicaltrials.gov (Identifier No. NCT02599272).
... Allantoin, a non-enzymatic oxidative product of uric acid in humans, can be used as a biomarker for oxidative stress (Zitnanova et al., 2004;Gruber et al., 2009). The decrease in plasma allantoin levels suggests that ISO was able to ameliorate oxidative stress in vivo. ...
Background: Isorhapontigenin (trans–3,5,4′-trihydroxy–3′–methoxystilbene, ISO), a dietary resveratrol (trans–3,5,4′–trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats.
Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–tandem mass spectrometry (GC–MS/MS), respectively.
Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (Cmax/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its Cmax/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects.
Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.
