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Cell Reports. Medicine Aug 2023Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role...
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
Topics: Animals; Mice; Mercaptopurine; Azathioprine; Immunosuppressive Agents; Biological Availability; Inflammatory Bowel Diseases; Colitis; Bacteria
PubMed: 37586320
DOI: 10.1016/j.xcrm.2023.101153 -
Insects May 2024Pteridines are important cofactors for many biological functions of all living organisms, and they were first discovered as pigments of insects, mainly in butterfly... (Review)
Review
Pteridines are important cofactors for many biological functions of all living organisms, and they were first discovered as pigments of insects, mainly in butterfly wings and the eye and body colors of insects. Most of the information on their structures and biosynthesis has been obtained from studies with the model insects and the silkworm . This review discusses, and integrates into one metabolic pathway, the different branches which lead to the synthesis of the red pigments "drosopterins", the yellow pigments sepiapterin and sepialumazine, the orange pigment erythropterin and its related yellow metabolites (xanthopterin and 7-methyl-xanthopterin), the colorless compounds with violet fluorescence (isoxanthopterin and isoxantholumazine), and the branch leading to tetrahydrobiopterin, the essential cofactor for the synthesis of aromatic amino acids and biogenic amines.
PubMed: 38786926
DOI: 10.3390/insects15050370 -
Revista Espanola de Enfermedades... Nov 2023Febuxostat is a drug from the group of xanthine dehydrogenase inhibitors and is used in the treatment of hyperuricemia and gouty arthritis. However, it is not free of...
Febuxostat is a drug from the group of xanthine dehydrogenase inhibitors and is used in the treatment of hyperuricemia and gouty arthritis. However, it is not free of adverse effects, including alteration of liver profile tests. This is why we must pay attention to this type of adverse events in case it is necessary to suspend treatment. We present a clinical case of acute hepatitis secondary to Febuxostat.
PubMed: 37982551
DOI: 10.17235/reed.2023.10047/2023 -
Redox Biology Nov 2023We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the...
We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the cellular signaling and export mechanisms underpinning this process were not identified. Here, we present novel data showing hepatocytes upregulate XOR expression/protein abundance and actively release it to the extracellular compartment following exposure to hemopexin-bound hemin, hemin or free iron. For example, murine (AML-12 cells) hepatocytes treated with hemin (10 μM) exported XOR to the medium in the absence of cell death or loss of membrane integrity (2.0 ± 1.0 vs 16 ± 9 μU/mL p < 0.0001). The path of exocytosis was found to be noncanonical as pretreatment of the hepatocytes with Vaculin-1, a lysosomal trafficking inhibitor, and not Brefeldin A inhibited XOR release and promoted intracellular XOR accumulation (84 ± 17 vs 24 ± 8 hemin vs 5 ± 3 control μU/mg). Interestingly, free iron (Fe and Fe) induced similar upregulation and release of XOR compared to hemin. Conversely, concomitant treatment with hemin and the classic transition metal chelator DTPA (20 μM) or uric acid completely blocked XOR release (p < 0.01). Our previously published time course showed XOR release from hepatocytes likely required transcriptional upregulation. As such, we determined that both Sp1 and NF-kB were acutely activated by hemin treatment (∼2-fold > controls for both, p < 0.05) and that silencing either or TLR4 with siRNA prevented hemin-induced XOR upregulation (p < 0.01). Finally, to confirm direct action of these transcription factors on the Xdh gene, chromatin immunoprecipitation was performed indicating that hemin significantly enriched (∼5-fold) both Sp1 and NF-kB near the transcription start site. In summary, our study identified a previously unknown pathway by which XOR is upregulated via SP1/NF-kB and subsequently exported to the extracellular environment. This is, to our knowledge, the very first study to demonstrate mechanistically that XOR can be specifically targeted for export as the seminal step in a compensatory response to heme/Fe overload.
Topics: Animals; Mice; Xanthine Dehydrogenase; Hemin; Iron; NF-kappa B; Heme; Hepatocytes
PubMed: 37703667
DOI: 10.1016/j.redox.2023.102866 -
Endocrine Journal Jul 2023Visceral fat-based metabolic syndrome has a strong impact on atherosclerotic cardiovascular disease (CVD), clustering diabetes, dyslipidemia, hypertension,... (Review)
Review
Visceral fat-based metabolic syndrome has a strong impact on atherosclerotic cardiovascular disease (CVD), clustering diabetes, dyslipidemia, hypertension, hyperuricemia, and non-alcoholic fatty liver disease (NAFLD). Adiponectin, a protein specifically secreted by adipocytes, circulates abundantly in the human bloodstream, but its concentration decreases under pathological conditions such as visceral fat accumulation. Extensive clinical evidence has demonstrated that hypoadiponectinemia is associated with the development of CVD and chronic organ diseases. Although several binding partners of adiponectin, such as AdipoR1/2, have been identified, how adiponectin exerts its multiple beneficial effects on various organs remains to be fully elucidated. Recent progress in adiponectin research has revealed that adiponectin accumulates on cardiovascular tissues by binding to a unique glycosylphosphatidylinositol-anchored T-cadherin. The adiponectin/T-cadherin complex enhances exosome biogenesis and secretion, which may contribute to the maintenance of cellular homeostasis and tissue regeneration, particularly in the vasculature. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catabolizes hypoxanthine and xanthine to uric acid. XOR produces reactive oxygen species in the reaction process, suggesting that XOR is involved in the pathological mechanism underlying CVD progression. Recent findings from clinical and laboratory studies have shown strong positive correlations between plasma XOR activity and liver enzymes. Furthermore, especially in NAFLD conditions, excessive hepatic XOR leaked into the bloodstream accelerates purine catabolism in the circulation, using hypoxanthine secreted from vascular endothelial cells and adipocytes, which can promote vascular remodeling. In this review, we focused on the cardiovascular significance of adipose-derived adiponectin and liver-derived XOR in the development of CVD associated with metabolic syndrome.
Topics: Humans; Metabolic Syndrome; Adiponectin; Xanthine Dehydrogenase; Non-alcoholic Fatty Liver Disease; Endothelial Cells; Obesity; Hypertension; Hypoxanthines
PubMed: 37316258
DOI: 10.1507/endocrj.EJ23-0160 -
International Journal of Molecular... Sep 2023Patient outcomes for severe sepsis and septic shock remain poor. Excessive oxidative stress accelerates organ dysfunction in severe acute illnesses. Uric acid (UA) is...
Patient outcomes for severe sepsis and septic shock remain poor. Excessive oxidative stress accelerates organ dysfunction in severe acute illnesses. Uric acid (UA) is the most abundant antioxidant. We hypothesized that UA and related molecules, which play a critical role in antioxidant activity, might be markers of oxidative stress in sepsis. The study aimed to clarify the clinical significance of UA and the relationship between UA, molecules related to UA, and outcomes by measuring blood UA, xanthine dehydrogenase (XDH), and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels over time. Blood UA levels in septic patients were correlated with the SOFA score (ρ = 0.36, < 0.0001) and blood XDH levels (ρ = 0.27, < 0.0001). Blood XDH levels were correlated with the SOFA score (ρ = 0.59, < 0.0001) and blood 8-OHdG levels (ρ = -0.32, < 0.0001). Blood XDH levels were persistently high in fatal cases. Blood XDH level (OR 8.84, 95% CI: 1.42-91.2, = 0.018) was an independent factor of poor outcomes. The cutoff of blood XDH level was 1.38 ng/mL (sensitivity 92.8%, specificity 61.9%), and those 1.38 ng/mL or higher were associated with a significantly reduced survival rate (blood XDH level > 1.38 ng/mL: 23.7%, blood XDH level < 1.38 ng/mL: 96.3%, respectively, = 0.0007). Elevated UA levels due to elevated blood XDH levels in sepsis cases may reduce oxidative stress. Countermeasures against increased oxidative stress in sepsis may provide new therapeutic strategies.
PubMed: 37762160
DOI: 10.3390/ijms241813857 -
Microorganisms Jun 2023Molybdenum (Mo) is vital for the activity of a small but essential group of enzymes called molybdoenzymes. So far, specifically five molybdoenzymes have been discovered... (Review)
Review
Molybdenum (Mo) is vital for the activity of a small but essential group of enzymes called molybdoenzymes. So far, specifically five molybdoenzymes have been discovered in eukaryotes: nitrate reductase, sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and mARC. In order to become biologically active, Mo must be chelated to a pterin, forming the so-called Mo cofactor (Moco). Deficiency or mutation in any of the genes involved in Moco biosynthesis results in the simultaneous loss of activity of all molybdoenzymes, fully or partially preventing the normal development of the affected organism. To prevent this, the different mechanisms involved in Mo homeostasis must be finely regulated. is a unicellular, photosynthetic, eukaryotic microalga that has produced fundamental advances in key steps of Mo homeostasis over the last 30 years, which have been extrapolated to higher organisms, both plants and animals. These advances include the identification of the first two molybdate transporters in eukaryotes (MOT1 and MOT2), the characterization of key genes in Moco biosynthesis, the identification of the first enzyme that protects and transfers Moco (MCP1), the first characterization of mARC in plants, and the discovery of the crucial role of the nitrate reductase-mARC complex in plant nitric oxide production. This review aims to provide a comprehensive summary of the progress achieved in using as a model organism in Mo homeostasis and to propose how this microalga can continue improving with the advancements in this field in the future.
PubMed: 37512844
DOI: 10.3390/microorganisms11071671 -
Microbiology Spectrum Aug 2023The xanthine oxidoreductase (XOR) family are metal-containing enzymes that use the molybdenum cofactor (Moco), 2Fe-2S clusters, and flavin adenine dinucleotide (FAD) for...
The xanthine oxidoreductase (XOR) family are metal-containing enzymes that use the molybdenum cofactor (Moco), 2Fe-2S clusters, and flavin adenine dinucleotide (FAD) for their catalytic activity. This large molybdoenzyme family includes xanthine, aldehyde, and CO dehydrogenases. XORs are widely distributed from bacteria to humans due to their key roles in the catabolism of purines, aldehydes, drugs, and xenobiotics, as well as interconversions between CO and CO. Assessing the effect of excess metals on the Rubrivivax gelatinosus bacterium, we found that exposure to copper (Cu) or cadmium (Cd) caused a dramatic decrease in the activity of a high-molecular-weight soluble complex exhibiting nitroblue tetrazolium reductase activity. Mass spectrometry and genetic analyses showed that the complex corresponds to a putative CO dehydrogenase (pCOD). Using mutants that accumulate either Cu or Cd in the cytoplasm, we show that Cu or Cd is a potent inhibitor of XORs (pCOD and the xanthine dehydrogenase [XDH]) . This is the first demonstration that Cu affects Moco-containing enzymes. The specific inhibitory effect of these compounds on the XOR activity is further supported by direct addition of competing metals to protein extracts. Moreover, emphasis is given on the inhibitory effect of Cu on bovine XOR, showing that the XOR family could be a common target of Cu. Given the conservation of XOR structure and function across the tree of life, we anticipate that our findings could be transferable to other XORs and organisms. The high toxicity of Cu, Cd, Pb, As, and other metals arises from their ability to cross membranes and target metalloenzymes in the cytoplasm. Identifying these targets provides insights into the toxicity mechanisms. The vulnerability of metalloenzymes arises from the accessibility of their cofactors to ions. Accordingly, many enzymes whose cofactors are solvent exposed are likely to be targets of competing metals. Here, we describe for the first time, with and experiments, a direct effect of excess Cu on the xanthine oxidoreductase family (XOR/XDH/pCOD). We show that toxic metal affects these Moco enzymes, and we suggest that access to the Moco center by Cu ions could explain the Cu inhibition of XORs in living organisms. Human XOR activity is associated with hyperuricemia, xanthinuria, gout arthritis, and other diseases. Our findings highlight XOR as a Cu target and thus support the potential use of Cu in metal-based therapeutics against these diseases.
Topics: Animals; Cattle; Humans; Xanthine Dehydrogenase; Cadmium; Metalloproteins; Metals
PubMed: 37458582
DOI: 10.1128/spectrum.04814-22 -
Nutrients Oct 2023Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism...
Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism is unclear. Similar to CVDs, gout attacks occur more frequently in the morning and at night. A possible reason for this is the diurnal variation in uric acid (UA), However, scientific data regarding this variation in patients with CVD are not available. Thus, we aimed to investigate diurnal variations in serum levels of UA and plasma levels of xanthine, hypoxanthine, and xanthine oxidoreductase (XOR) activity, which were measured at 18:00, 6:00, and 12:00 in male patients with coronary artery disease. Thirty eligible patients participated in the study. UA and xanthine levels significantly increased from 18:00 to 6:00 but significantly decreased from 6:00 to 12:00. By contrast, XOR activity significantly increased both from 18:00 to 6:00 and 6:00 to 12:00. Furthermore, the rates of increase in UA and xanthine levels from night to morning were significantly and positively correlated. In conclusion, UA and xanthine showed similar diurnal variations, whereas XOR activity showed different diurnal variations. The morning UA surge could be due to UA production. The mechanism involved XOR activity, but other factors were also considered.
Topics: Humans; Male; Xanthine; Uric Acid; Xanthine Dehydrogenase; Coronary Artery Disease; Gout
PubMed: 37892555
DOI: 10.3390/nu15204480 -
Allantoin: A Potential Compound for the Mitigation of Adverse Effects of Abiotic Stresses in Plants.Plants (Basel, Switzerland) Aug 2023Stress-induced alterations vary with the species of plants, the intensity and duration of the exposure, and stressors availability in nature or soil. Purine catabolism... (Review)
Review
Stress-induced alterations vary with the species of plants, the intensity and duration of the exposure, and stressors availability in nature or soil. Purine catabolism acts as an inherent defensive mechanism against various abiotic stresses and plays a pivotal role in the stress acclimatisation of plants. The intermediate metabolite of purine catabolism, allantoin, compensates for soil nitrogen deficiency due to the low carbon/nitrogen ratio, thereby maintaining nitrogen homeostasis and supporting plant growth and development. Allantoin accounts for 90% of the total nitrogenous compound in legumes, while it contributes only 15% in non-leguminous plants. Moreover, studies on a variety of plant species have reported the differential accumulation of allantoin in response to abiotic stresses, endowing allantoin as a stress modulator. Allantoin functions as signalling molecule to stimulate stress-responsive genes (; pyrroline-5-carboxylase synthase) and ROS (reactive oxygen species) scavenging enzymes (antioxidant). Moreover, it regulates cross-talk between the abscisic acid and jasmonic acid pathway, and maintains ion homeostasis by increasing the accumulation of putrescine and/or spermine, consequently enhancing the tolerance against stress conditions. Further, key enzymes of purine catabolism (xanthine dehydrogenase and allantoinase) have also been explored by constructing various knockdown/knockout mutant lines to decipher their impact on ROS-mediated oxidative injury in plants. Thus, it is established that allantoin serves as a regulatory signalling metabolite in stress protection, and therefore a lower accumulation of allantoin also reduces plant stress tolerance mechanisms. This review gives an account of metabolic regulation and the possible contribution of allantoin as a photo protectant, osmoprotectant, and nitrogen recycler to reduce abiotic-stress-induced impacts on plants.
PubMed: 37687306
DOI: 10.3390/plants12173059