Enzymes Of Purine Metabolism Research Articles

Integrative computational approach for hyperuricemia treatment: 3D QSAR, molecular docking and dynamics of flavonoid analogues as xanthine oxidase inhibitors

Hyperuricemia is characterized by an excessive accumulation of uric acid in the joints, and this condition remains a therapeutic challenge with limited options and significant side effects associated with conventional pharmacological treatments. This research aims to identify new molecular structures capable of inhibiting uric acid production by targeting key enzymes in purine metabolism. In this study, a comprehensive in silico analysis was conducted to explore the relationship between the chemical structure of flavonoid analogs and their inhibitory capacity on xanthine oxidase (XO). The results revealed that the analogs meet the structural requirements for xanthine oxidase inhibition. A 3D-QSAR model was generated, accurately predicting the biological activity of flavonoids targeting XO and identifying a potential lead compound with a q2 of 0.77 and R2 of 0.98. The CoMFA analysis disclosed how substituents affect XO affinity, with bulky groups enhancing it at positions R2 and R7. These strategies were applied and a new molecule was generated with better binding energy with the XO receptor. Electron-donating or accepting groups, such as phenyl and carbonyl, interact with amino acid residues (T1010 and R880) in XO's active site. Molecular docking analysis highlights different common interaction types in flavonoid-XO binding, emphasizing the importance of hydrogen and CH bonds. Previous studies underscore the significance of these specific residues in flavonoid-XO binding. Molecular dynamics showed that 3(R,S)-3′-Hydroxy-8-methoxyvestitol predominantly interacts through hydrophobic interactions, inducing a conformational change in the binding pocket and stabilizing the complex along with stable hydrogen bonds.

Interaction of Tri-Cyclic Nucleobase Analogs with Enzymes of Purine Metabolism: Xanthine Oxidase and Purine Nucleoside Phosphorylase.

Fluorescent markers play important roles in spectroscopic and microscopic research techniques and are broadly used in basic and applied sciences. We have obtained markers with fluorescent properties, two etheno derivatives of 2-aminopurine, as follows: 1,N2-etheno-2-aminopurine (1,N2-ε2APu, I) and N2,3-etheno-2-aminopurine (N2,3-ε2APu, II). In the present paper, we investigate their interaction with two key enzymes of purine metabolism, purine nucleoside phosphorylase (PNP), and xanthine oxidase (XO), using diffraction of X-rays on protein crystals, isothermal titration calorimetry, and fluorescence spectroscopy. Crystals were obtained and structures were solved for WT PNP and D204N-PNP mutant in a complex with N2,3-ε2APu (II). In the case of WT PNP-1,N2-ε2APu (I) complex, the electron density corresponding to the ligand could not be identified in the active site. Small electron density bobbles may indicate that the ligand binds to the active site of a small number of molecules. On the basis of spectroscopic studies in solution, we found that, in contrast to PNP, 1,N2-ε2APu (I) is the ligand with better affinity to XO. Enzymatic oxidation of (I) leads to a marked increase in fluorescence near 400 nm. Hence, we have developed a new method to determine XO activity in biological material, particularly suitable for milk analysis.

Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase

Allosteric regulation of inosine 5′-monophosphate dehydrogenase (IMPDH), an essential enzyme of purine metabolism, contributes to the homeostasis of adenine and guanine nucleotides. However, the precise molecular mechanism of IMPDH regulation in bacteria remains unclear. Using biochemical and cryo-EM approaches, we reveal the intricate molecular mechanism of the IMPDH allosteric regulation in mycobacteria. The enzyme is inhibited by both GTP and (p)ppGpp, which bind to the regulatory CBS domains and, via interactions with basic residues in hinge regions, lock the catalytic core domains in a compressed conformation. This results in occlusion of inosine monophosphate (IMP) substrate binding to the active site and, ultimately, inhibition of the enzyme. The GTP and (p)ppGpp allosteric effectors bind to their dedicated sites but stabilize the compressed octamer by a common mechanism. Inhibition is relieved by the competitive displacement of GTP or (p)ppGpp by ATP allowing IMP-induced enzyme expansion. The structural knowledge and mechanistic understanding presented here open up new possibilities for the development of allosteric inhibitors with antibacterial potential.

Exploring the mechanism and inhibitory effect of robinin on xanthine oxidase using multi-spectroscopy and molecular dynamics simulation methods

Xanthine oxidase (XOD) is a key enzyme in purine metabolism that is tightly associated with hyperuricemia (HUA). Natural flavonoids can inhibit XOD activity. In this study, the inhibitory activity and mechanism of the novel flavonoid robinin on XOD were analyzed using enzyme inhibition kinetics, multispectral techniques, molecular docking, and molecular dynamics (MD) simulations. Robinin reversibly inhibited the activity of XOD in a mixed competitive manner, with an IC50 value of 31.79 ± 0.15 μg/mL. Moreover, robinin spontaneously binds to a specific site on XOD and effectively quenches its intrinsic fluorescence via a single static quenching mechanism. The combination of XOD and robinin induced secondary structure rearrangement and conformational changes in XOD and prevented the entry of substrates, thus producing a strong inhibitory effect. Molecular docking and MD simulation revealed that robinin mainly binds to XOD through hydrogen bonding and hydrophobic interactions to form more stable complexes with a binding energy of −7.4 kcal/mol. Overall, this study established a theoretical reference for robinin as a promising natural XOD inhibitor for relieving HUA.

Interplay between mTOR and Purine Metabolism Enzymes and Its Relevant Role in Cancer.

Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are characterized by an increased "de novo" synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes of purine metabolism are the targets of drugs as antineoplastic agents, and a better knowledge of the mechanisms underlying their regulation would be of great help in finding new therapeutic approaches. The mammalian target of the rapamycin (mTOR) signaling pathway, which is often activated in cancer cells, promotes anabolic processes and is a major regulator of cell growth and division. Among the numerous effects exerted by mTOR, noteworthy is its empowerment of the "de novo" synthesis of nucleotides, accomplished by supporting the formation of purinosomes, and by increasing the availability of necessary precursors, such as one-carbon formyl group, bicarbonate and 5-phosphoribosyl-1-pyrophosphate. In this review, we highlight the connection between purine and mitochondrial metabolism, and the bidirectional relation between mTOR signaling and purine synthesis pathways.

Relationship between the outcomes of intensive phase therapy in patients with newly diagnosed infiltrative pulmonary tuberculosis and activity of purine metabolism enzymes as well as CD3+CD8+ lymphocyte level

Monitoring activity of inflammatory process and lymphocyte subsets can help assess the effectiveness of intensive phase therapy (IPT) already in the early stages of treatment. The goal is to evaluate changes in the concentration and activity of enzymes associated with purine metabolism and peripheral blood lymphocyte subset composition, and to determine their relationship with IPT effectiveness in patients with newly diagnosed infiltrative pulmonary tuberculosis (IPTb). Materials and methods. In 141 IPTb patients, the IPT data were presented as follows: “significant improvement” (SI) — disappearance of intoxication symptoms, abacillation, closure of decay cavities; “less pronounced improvement” (LMI) — eliminated symptoms of intoxication, abacillation, pronounced resorption of focal and infiltrative changes, reduction of decay cavities. We assessed the activity of adenosine deaminase in blood serum (eADA-1, 2), mononuclear cells and neutrophils, the concentration of blood serum ecto-5'-nucleotidase (eHT5E), CD26 (DPPV) in blood serum (s, soluble form) and mononuclear cells (m, membrane form), subpopulation composition. Results. Patients exhibit increased concentrations of eNT5E, mCD26 (DPPIV) and eADA-2 activity, and decreased intracellular ADA-1 activity. In the “LMI” group, after IPT, an increased sCD26 (DPPV) level was noted. The groups differed in lymphocyte counts and percentage of CD3+CD8+ cells. eADA-2 activity was higher in the LMI group and increased after IPT, in contrast to comparison group. mCD26 (DPPIV) concentrations are higher in PD patients before therapy and after IPT. Conclusion. Thus, the outcome of IPT in IPTb patients is associated with altered T-lymphocyte populations and severity of the inflammatory process. Studying the activity of membrane and soluble eADA-2, CD26 (DPPIV) and percentage of CD3+CD8+ T-lymphocytes in the early stages of therapy can provide the necessary information for correcting personalized pathogenetic therapy of patients with newly diagnosed IPTb.

Insights into the ATP / GTP selectivity of a GTPase, adenylosuccinate synthetase from Leishmania donovani

Many GTPases have been shown to utilize ATP too as the phosphoryl donor. Both GTP and ATP are important molecules in the cellular environments and play multiple and discrete functional role within the cells. In our present study, we showed that one of the purine metabolic enzymes Adenylosuccinate synthetase from Leishmania donovani (LdAdSS) which belongs to the BioD-superfamily of GTPases can also carry out the catalysis by hydrolysing ATP instead of its cognate substrate GTP albeit with less efficiency. Biochemical and biophysical studies indicated its ability to bind to ATP too but at a higher concentration of ATP compared to that of GTP. Sequence analysis and molecular dynamic simulations suggested that residues of the switch loop and the G4-G5 (593SAXD596) connected motif of LdAdSS plays a role in determining the nucleotide specificity. Though the crucial interaction between Asp596 and the nucleotide is broken when ATP is bound, interactions between the Ala594 and the adenine ring of ATP could still hold ATP in the GTP binding site. The results of the present study suggested that though LdAdSS is GTP specific, it still shows ATP hydrolysing activity.

Recent developments in synthetic strategies and pharmacological outcomes of synthetic xanthine oxidase inhibitors: A comprehensive review

AbstractXanthine oxidase is an important enzyme in purine metabolism that converts hypoxanthine to xanthine and subsequently xanthine to uric acid. Its elevated levels result in an abnormal accumulation of uric acid that results in gout and other pathological conditions, which makes it a prime target for the management of gout. Considering this, numerous reports have been published by the various research groups across the globe focusing on the development of effective xanthine oxidase inhibitors. On that ground, numerous review articles are also available describing the pharmacological outputs of these reports, but a composition highlighting the synthetic strategies used in these research works is still missing. This review will focus on various synthetic strategies adopted by different research groups in developing xanthine oxidase inhibitors with their pharmacological outcomes, along with structure activity relationships. This review will help researchers and pharmaceutical chemists in the design and development of new xanthine oxidase inhibitor leads that are highly efficient and have fewer side effects than existing ones.

Understanding Hyperuricemia: Pathogenesis, Potential Therapeutic Role of Bioactive Peptides, and Assessing Bioactive Peptide Advantages and Challenges.

Hyperuricemia is a medical condition characterized by an elevated level of serum uric acid, closely associated with other metabolic disorders, and its global incidence rate is increasing. Increased synthesis or decreased excretion of uric acid can lead to hyperuricemia. Protein peptides from various food sources have demonstrated potential in treating hyperuricemia, including marine organisms, ovalbumin, milk, nuts, rice, legumes, mushrooms, and protein-rich processing by-products. Through in vitro experiments and the establishment of cell or animal models, it has been proven that these peptides exhibit anti-hyperuricemia biological activities by inhibiting xanthine oxidase activity, downregulating key enzymes in purine metabolism, regulating the expression level of uric acid transporters, and restoring the composition of the intestinal flora. Protein peptides derived from food offer advantages such as a wide range of sources, significant therapeutic benefits, and minimal adverse effects. However, they also face challenges in terms of commercialization. The findings of this review contribute to a better understanding of hyperuricemia and peptides with hyperuricemia-alleviating activity. Furthermore, they provide a theoretical reference for developing new functional foods suitable for individuals with hyperuricemia.

Study of changes in the activity levels of purine nucleoside phosphorylase and the role of nitric oxide in the development of pathology in alloxan-diabetic rats

The problem of treating diabetes mellitus has not been resolved to this day; it requires a detailed study of various links of pathogenesis at the molecular level. In diabetes, conditions arise for the formation of oxidative stress. Diabetes mellitus is associated with the early development of cardiovascular complications, the immune e system is destroyed. Endothelial cells produce nitric oxide (NO), a substance that is able to maintain a balance of vascular tone, coagulation and inflammation. Purine nucleoside phosphorylase (PNP) is one of the most important enzymes of purine metabolism, which characterizes the immune status of the organism. The aim of this study was to study the enzymatic activity of PNP, as well as to determine the levels of nitric oxide in the blood serum, liver and pancreas in albino rats with simulated alloxan diabetes. The results of our studies on the detection of changes in the activity of PNP in the pancreas on the model of alloxandiabetic rats showed that at the late stage, the activity of PNP in the pancreas is completely suppressed, which indicates significant changes in the immune status of the body, the content of nitric oxide increases. Understanding the complex metabolic disorders that interact with the NO system may provide us with additional therapeutic options to reduce cardiovascular morbidity and mortality in diabetes mellitus. Indicators of NO and PNP can be used as additional paraclinical indicators for early diagnosis and to identify and clarify the degree of activity of the pathological process, the nature of the course, the stage of the disease, which contributes to the appointment of individualized adequate therapy.

Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals.

Although the type-I interferon (IFN-I) response is considered vertebrate-specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN-I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN-I response evolved in a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG-I-like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN-I response, as well as the similar consequences of these defense programs on organismal development.

Purine Metabolism and Pyrimidine Metabolism Alteration Is a Potential Mechanism of BDE-47-Induced Apoptosis in Marine Rotifer Brachionus plicatilis.

This present study was conducted to provide evidence and an explanation for the apoptosis that occurs in the marine rotifer Brachionus plicatilis when facing 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) stress. Metabolomics analysis showed that aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, and arginine biosynthesis were the top three sensitive pathways to BDE-47 exposure, which resulted in the reduction in the amino acid pool level. Pyrimidine metabolism and purine metabolism pathways were also significantly influenced, and the purine and pyrimidine content were obviously reduced in the low (0.02 mg/L) and middle (0.1 mg/L) concentration groups while increased in the high (0.5 mg/L) concentration group, evidencing the disorder of nucleotide synthesis and decomposition in B. plicatilis. The biochemical detection of the key enzymes in purine metabolism and pyrimidine metabolism showed the downregulation of Glutamine Synthetase (GS) protein expression and the elevation of Xanthine Oxidase (XOD) activity, which suggested the impaired DNA repair and ROS overproduction. The content of DNA damage biomarker (8-OHdG) increased in treatment groups, and the p53 signaling pathway was found to be activated, as indicated by the elevation of the p53 protein expression and Bax/Bcl-2 ratio. The ROS scavenger (N-acetyl-L-cysteine, NAC) addition effectively alleviated not only ROS overproduction but also DNA damage as well as the activation of apoptosis. The combined results backed up the speculation that purine metabolism and pyrimidine metabolism alteration play a pivotal role in BDE-47-induced ROS overproduction and DNA damage, and the consequent activation of the p53 signaling pathway led to the observed apoptosis in B. plicatilis.

CSF markers of inflammation help identify tau pathology but not amyloid in a heterogenous clinical population

AbstractBackgroundNeuroinflammation and activation of the immune system is an integral part of Alzheimer’s Dementia (AD) pathology. Inflammatory mediators exacerbate the production of amyloid‐β, the propagation of tau pathology and neuronal loss. This study evaluates whether CSF markers of inflammation can help evaluate changes in amyloid and tau pathology in a heterogenous clinical population.MethodsCSF samples from 105 patients referred to the Wessex Neurology Clinic due to cognitive complaints were analysed. Measurements of AD biomarkers were used to classify the samples based on previously published thresholds (Ab42<680pg/ml for an amyloid positive test, pTau>56pg/ml for a Tau positive test and Total Tau>355pg/ml for a test positive for neurodegeneration). Based on these biomarker results, the likelihood of AD was evaluated using the Paris Lille Montpellier (PLM) scale. 102 markers of inflammation were measured on CSF using the Mesoscale and OLINK platforms. Receiver Operator Characteristic (ROC) curves were used to evaluate if inflammation markers can accurately identify patients with amyloid and tau pathology.Results56 patients were amyloid positive, 43 were tau positive and 44 were positive for neurodegeneration. 52 different inflammation markers were detected in over 90% of samples. From these, 26 markers correlate significantly with pTau and Total Tau measurements, while no markers correlate with Ab42 measurements. Adenosine Deaminase (ADA), an enzyme of purine metabolism and marker of cellular immunity, most strongly correlates with pTau and Total Tau (Spearman’s Rho 0.62 and 0.60 respectively, p<0.001). Analysis of Variance indicates significantly higher levels of ADA in patients with higher PLM scores and thus higher likelihood of AD (p<0.001). Finally, ROC analysis indicates that ADA can identify Tau positive patients (pTau>56pg/ml) with an Area Under the Curve (AUC) of 0.76 and Neurodegeneration positive patients (Total Tau>355pg/ml) with an AUC of 0.82.ConclusionIn this clinical patient cohort, inflammation levels increase with tau pathology but do not change with amyloid. ADA, a marker of cellular immunity, provides a sensitive and specific marker of Tau and Neurodegeneration in AD. Further work is required to assess the prognostic capabilities of ADA in larger patient cohorts and when used in conjunction with established AD biomarkers.

Enzymes of purine metabolism — biomarkers for the diagnostics of tuberculous pleurisy in patients with HIV infection

The objective of the study was to evaluate the information content of determining the activity of adenosine deaminase and adenosine deaminase-2 in the diagnosis of tuberculous pleurisy in patients with HIV infection.Materials and methods. A total of 378 patients with pleural effusion were retrospectively examined. In 215 cases, tuberculous pleurisy was detected (TP); and 163 patients had non-tuberculous pleural effusion (non-TP). As much as 27 patients in the TP group were HIV co-infected (TP/HIV+), the remaining 188 patients were HIV — negative (TP/HIV–). In all the patients, the activity of total adenosine deaminase (ADA) and its isoenzymes (ADA-1 and ADA-2) in the pleural fluid was determined.Results and discussion. In the TP group, the activity of total ADA (95.5 [67.7; 115.4] versus 82.0 [59.6; 100.0] U/L, p=0.1), ADA-1 (14.2 [5.8; 20.5] versus 12.1 [6.1; 23.7] U/L, p=0.9) and ADA-2 (78,1 [38.1; 93.1] versus 62.4 [35.4; 82.2] U/L, p=0,1) did not depend on HIV status. The activity of these indicators was determined above the threshold level — total ADA in 96.3% and 95.2%, ADA-1 in 25.9% and 30.8% and ADA-2 in 92.6% and 83.3% of cases in the «TP/HIV+» and «TP/HIV–» groups, respectively. A negative correlation between ADA-1 activity and HIV viral load in the group of patients with tuberculous pleurisy and HIV infection (r=–0.45; p=0.008), as well as in the subgroup of TP/HIV+ patients who received (r=–0.9; p=0.008) and in those who didn’t receive ART (r=–0.47; p=0.04) was obtained. Our results show that a total ADA activity increase in the patients with tuberculous pleurisy, regardless of patients’ HIV status, occur due to ADA-2. Thus, the increase in activity of total ADA and ADA-2 in our study was caused by active tuberculosis, not by the presence or absence of HIV co-infection. Also, the ADA-2 activity in HIV-infected patients is likely consistent with ADA-2 important role in cellular immune responses.Conclusion. Our data indicate the participation of purine metabolism enzymes in the pathogenesis of HIV infection. At the same time, adenosine deaminase activity is not a specific biomarker of individual changes characteristic of HIV infection. The study results suggest that the total adenosine deaminase and adenosine deaminase-2 activity increase is a valuable and diagnostically significant marker of tuberculous pleurisy in HIV-infected patients. The value of adenosine deaminase and adenosine deaminase-2 activity remains high even in the patients having severe immunosuppression, which allows them to be actively used for rapid diagnostics and hence, early TB therapy initiation.

Purine nucleoside phosphorylase: A new pharmacological target in sickle cell disease and hemolytic vasculopathy

Under hemolytic conditions, there is a significant interaction among red blood cells (RBCs), endothelial cells (ECs), and platelets in the injured vasculature. In sickle cell disease (SCD), this interaction leads to painful vaso-occlusive crisis and end organ damage, results in poor quality of life, and unacceptably short life expectancy. We propose that these cells share two biochemical properties that are highly relevant to SCD. First, per cell volume, RBCs have the highest level of purine nucleoside phosphorylase (PNP, a key enzyme in purine metabolism), and ECs and platelets are very rich in PNP. Second, RBCs have to, ECs choose to, and platelets, when activated, switch to using glycolysis as a major pathway for intermediate phosphates and ATP production. We propose that these similarities are highly relevant to sickle cell disease (SCD) and hemolytic vascular injury. Human PNP catalyzes the phosphorolysis of guanosine/ deoxyguanosine and inosine /deoxyinosine into guanine and hypoxanthine, respectively, and generates ribose-1-phosphate and deoxyribose-1-phosphate. This results in forming a large amount of downstream pro-oxidant and vasculotoxic xanthines.Recently, we have detected that in SCD, hemolysis is associated with increased activity of extracellular PNP, accelerated guanosine and inosine metabolism, and augmented extracellular production of vasculotoxic hypoxanthine and xanthine. We identify PNP as a critical pathogenic mechanism in SCD and have proposed a link between PNP activity and the glycolytic production of intermediate phosphates and ATP. This link promotes (i) RBC sickling/hemolysis, (ii.) hemolytic angioproliferation, (iii.) oxidative vascular injury, and (iv.) platelets activation/aggregation.Furthermore, PNP accelerates guanosine/inosine metabolism and may diminish their well-documented anti-inflammatory, anti-ischemic, anti-thrombotic, and anti-nociceptive effects. We hypothesize that inhibition of PNP may lessen those four (i.to iv.) deleterious events and may potentiate the beneficial effects of guanosine/inosine, reducing the risk of vaso-occlusion and organ damage in SCD patients. Thereby, the PNP inhibitors may serve as a multipronged treatment approach for SCD.

Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing.

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

Microbiota as a new pathogenetic factor in the development of chronic hyperuricemia and gout. Part I: the current state of the problem

The gut microbiota plays a key role in metabolism and immune regulation, and imbalance in microbial composition can contribute to various diseases. We present up-to-date data on the role of the gut microbiota in the occurrence of chronic hyperuricemia (HU) and gout, which is associated with the influence of the microbiota on the synthesis of purine-metabolizing enzymes and pro-inflammatory cytokines. It has been shown that the gut microbiota plays an important role in the pathophysiology of gout and can serve as a new target for therapy. Currently, the microbial index of gout is considered as a potential method for early diagnosis of the disease, possibly already at the preclinical stage. The gut microbiota can be a starting point in the study of the pathogenesis of HU and gout. This makes it necessary to assess the pathogenetic relationship between individual specific microorganisms, the microbiota as a whole, and the development of uric acid (UA) metabolism disorders that contribute to the onset of HU and its transformation into gout. It is assumed that this approach will provide a more complete understanding of the gut microbiota participation in the synthesis of UA and its extrarenal excretion, as well as of bacteria and bacterial enzymes that can be used as a probiotic coadjuvant for the treatment and prevention of gout.

Systemic Endothelial Function, Plasma Xanthine Oxidoreductase Activity, and Blood Pressure Variability in Patients with Stable Coronary Artery Disease.

Background and Objectives: Although previous studies showed that an activity of xanthine oxidoreductase (XOR), a rate-limiting enzyme in purine metabolism, beyond the serum uric acid level, was associated with the development of coronary artery disease (CAD), the underlying mechanisms are unclear. Because endothelial dysfunction and a greater blood pressure (BP) variability may play a role, we investigated the relations among the endothelial function, XOR, and BP variability. Materials and Methods: This was a post-hoc study using pooled data of patients with a stable CAD from two prospective investigations, in which the systemic endothelial function was assessed with the reactive hyperemia index (RHI) and the XOR activity was measured. The BP variability was evaluated using BP measurements during the three- and four-day hospitalization. Results: A total of 106 patients with a stable CAD undergoing a percutaneous coronary intervention were included. Of the 106 patients, 46 (43.4%) had a systemic endothelial dysfunction (RHI < 1.67). The multivariable analysis identified a higher body mass index (BMI), female gender, and diabetes as factors associated with an endothelial dysfunction. A higher BMI was also related to an elevated XOR activity, in addition to current smoking. No significant correlation was observed between the RHI and XOR activity. Similarly, the in-hospital BP variability was associated with neither the endothelial function nor XOR. Conclusions: Among patients with a stable CAD, several factors were identified as being associated with a systemic endothelial dysfunction or an elevated XOR activity. However, no direct relations between the endothelial function, XOR, and BP variability were found.

Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout.

The incidence of hyperuricemia (HUA) and gout continuously increases and has become a major public health problem. The gut microbiota, which colonizes the human intestine, has a mutually beneficial and symbiotic relationship with the host and plays a vital role in the host’s metabolism and immune regulation. Structural changes or imbalance in the gut microbiota could cause metabolic disorders and participate in the synthesis of purine-metabolizing enzymes and the release of inflammatory cytokines, which is closely related to the occurrence and development of the metabolic immune disease HUA and gout. The gut microbiota as an entry point to explore the pathogenesis of HUA and gout has become a new research hotspot. This review summarizes the characteristics of the gut microbiota in patients with HUA and gout. Meanwhile, the influence of different dietary structures on the gut microbiota, the effect of the gut microbiota on purine and uric acid metabolism, and the internal relationship between the gut microbiota and metabolic endotoxemia/inflammatory factors are explored. Moreover, the intervention effects of probiotics, prebiotics, and fecal microbial transplantation on HUA and gout are also systematically reviewed to provide a gut flora solution for the prevention and treatment of related diseases.

Effects of curcumin‐based photodynamic treatment combined with low‐temperature storage on shelf life and purine content of Litopenaeus vannamei

In this study, the effects of photodynamic treatment on the shelf life and purine content of Litopenaeus vannamei under low-temperature storage conditions were investigated. Indicators of shelf life were detected to evaluate the shelf life, and the change of purine content during storage detected by HPLC. The results showed that compared with cold storage, the shelf life of shrimp was extended from 3 days to 8 days with the treatment of microcrystalline storage. Moreover, the shelf life of shrimp was extended to 12 days when stored with the photodynamic treatment combined with microcrystalline storage (PDT + MT). The content of hypoxanthine decreased significantly after 24 h storage, which may be related to the inhibition of 5′-NT, PNP, ADA, and XOD activities. This study provided scientific support for the popularization and application of photodynamic technology in the storage of shrimp. Novelty impact statement Photodynamic technology is helpful to prolong the shelf life of shrimp during low-temperature. Photodynamic combined with low-temperature can affect purine content by affecting purine metabolism enzymes.