Xanthine Oxidase Inhibitor Research Articles

Assessment of the In Vitro Effects of Six Selected Plant Extracts on Xanthine Oxidase

Background: Gouty arthritis is one of the most prevalent forms of arthritis caused by the deposition of uric acids mostly in joints, due to hyperuricemia. Xanthine oxidase (XO) is a key enzyme of the purine degradation pathway, catalysing the oxidation of hypoxanthine to xanthine and further to uric acid; increased activity leads to hyperuricemia hence a need to control XO activity. Commonly used therapeutic approach is the use of XO inhibitors. This study aimed to investigate if Vitis vinifera, Malus sylvestris fruit peels, Cymbopogon citratum leaves, Mucuna Pruriens leaves, Zanha africana roots and leaves, Mimosa pudica roots extracts have a Xanthine Oxidase inhibitory potential in vitro. Methodology: Air dried samples were crushed into powder using a mortar and pestle. Maceration and percolation extraction methods were used to obtain active secondary metabolites from plant materials at 10%w/v. Spectrophotometric assays methods were used for Xanthine Oxidase activity and inhibition studies. Results: The results of the current study showed that all aqueous plant extracts showed the presence of flavonoids. The experimental data showed significant inhibitory effects on XO activity. C. citratum inhibited XO activity by an average of 71%. M. sylvestris exhibited 68%, 61% and 64% at 15, 30 and 45 minutes respectively. V. vinifera exhibited 75%, 66% and 77% XO inhibitory activity at 15, 30 and 45 minutes respectively. Z. Africana exhibited 73%, 65% and 74% at 15, 30 and 45 minutes respectively. M. pudica exhibited 74%, 77% and 78% XO inhibitory activity at 15, 30 and 45 minutes respectively. M. pruriens exhibited 65%, 69% and 71% XO inhibitory activity at 15, 30 and 45 minutes respectively. Conclusion: The results obtained from the current study indicates that the flavonoids present in all plant extracts under study could be potential anti-gout agents by their inhibitory activities on Xanthine Oxidase activity

Celebrating Versatility: Febuxostat's Multifaceted Therapeutic Application.

Febuxostat, initially developed as a xanthine oxidase inhibitor to address hyperuricemia in gout patients, has evolved into a versatile therapeutic agent with multifaceted applications. This review provides a comprehensive overview of febuxostat's mechanism of action, its effectiveness in gout management, its cardiovascular safety profile, renal and hepatic effects, musculoskeletal applications, safety considerations, and emerging research prospects. Febuxostat's primary mechanism involves selective inhibition of xanthine oxidase, resulting in reduced uric acid production. Its pharmacokinetics require personalized dosing strategies based on individual characteristics. In gout management, febuxostat offers a compelling alternative, effectively lowering uric acid levels, relieving symptoms, and supporting long-term control, especially for patients intolerant to allopurinol. Recent studies have demonstrated its cardiovascular safety, and it exhibits minimal hepatotoxicity, making it suitable for those with liver comorbidities. Febuxostat's potential nephroprotective effects and kidney stone prevention properties are noteworthy, particularly for gout patients with renal concerns. Beyond gout, its anti-inflammatory properties hint at applications in musculoskeletal conditions and a broader spectrum of clinical contexts, including metabolic syndrome. Emerging research explores febuxostat's roles in cardiovascular health, neurological disorders, rheumatoid arthritis, and cancer therapy, driven by its anti-inflammatory and antioxidative properties. Future directions include personalized medicine, combination therapies, mechanistic insights, and ongoing long-term safety monitoring, collectively illuminating the promising landscape of febuxostat's multifaceted therapeutic potential.

Synergistic co-catalytic nanozyme system for highly efficient one-pot colorimetric sensing at neutral pH: Combining molybdenum trioxide and Fe(III)-Modified covalent triazine framework

This study investigates the co-catalytic capabilities of MoO3 nanosheets in enhancing the enzyme-like catalytic activity of a two-dimensional ultrathin Fe(III)-modified covalent triazine framework (Fe-CTF) under neutral pH conditions. The unique physicochemical surface properties and two-dimensional structures of Fe-CTF enable the direct immobilization of native enzymes (glucose oxidase (GOD) and xanthine oxidase (XOD)) through adsorption, eliminating the need for chemical processes. Efficient immobilization of the native enzymes within the Fe-CTF/GOD(XOD) hybrid is achieved through multipoint attachment involving various interactions. The Fe-CTF/MoO3 co-catalytic system exhibits enzyme-mimicking activity at neutral pH and, when combined with the high catalytic activity of the immobilized native enzymes, enables the development of a colorimetric method for glucose detection. This method demonstrates excellent facilitation, rapidity, sensitivity, and selectivity, with a linear detection range of 50–1000 μM and a limit of detection of 8.8 μM for glucose. Furthermore, a straightforward one-pot colorimetric method is established for screening XOD inhibitors. The inhibitory potential of a crude extract derived from Chinese water chestnut peel on XOD activity is evaluated using this method. The findings of this study pave the way for the utilization of nanozyme/native enzyme hybrids in pH-neutral conditions for one-pot colorimetric sensing. This work contributes to the advancement of enzyme-based sensing technologies and holds promise for various applications in biosensing and biomedical research.

Xanthine oxidase inhibitors withdrawal syndrome

Abstract Background In humans, uric acid is the final metabolite of adenosine triphosphate, an energy source. Xanthine oxidase (XO) contributes to urate metabolism, and XO inhibitors (XOI) suppress the production of uric acid and could store ATP. However, recent studies showed that discontinuation of XOI may lead to ATP depletion and increased death as a withdrawal syndrome. We examined whether the XOI withdrawal syndrome actually occurs. Methods This study retrospectively analyzed the Japanese Registry Of All cardiac and vascular Diseases (JROAD) database, which included 8,927,858 patients out of 9,825,635 data from April 2014 to March 2020, excluding 330,847 patients younger than 20 years and 566,930 patients older than 90 years. Of these, 356,405 were hospitalized patients with cardiovascular disease who were receiving uric acid-lowering drugs, and 315,388 were on XOI (41,017 were on other uric acid-lowering medications)(Fig). The XOI adherents were divided into the following four groups, and the number of deaths and mortality rates for each were identified as follows. Results (1) Those who were on the drug at admission and continued the drug at discharge: 219,020 cases, of which 59 deaths (0.03%). (2) 89,035 patients were discharged from the hospital on the medication they were on at the time of admission, of which 17,663 died (19.84%). (3) 7,241 patients who were not on any medication at admission (medication was given during hospitalization) and continued on medication at discharge, including 11 deaths (0.15%). (4) No medication at admission (medication was given during hospitalization) and stopped at discharge: 92 cases, of which 11 deaths (11.96%). Continuous medication group: 226,261 cases, including (1) and (3), of which 70 deaths, (0.03%). Withdrawal group: 89,127 cases, including (2) and (4), of which 17,674 deaths (19.8%). The number of deaths in the withdrawal group was 620 times higher than that in the continuation group (p<0.001). Conclusion XOI withdrawal syndrome is detected in our study. However, some of the deaths in the XOI discontinuation group were due to the fact that other medications were also discontinued, which indicate impossible to determine a direct causal relationship between XOI withdrawal and death. Further studies are needed to check the relationship between XOI withdrawal and death in other algorithms.Fig. Flow-chart of the study

Potential of milk-derived bioactive peptides as antidiabetic, antihypertensive, and xanthine oxidase inhibitors: a comprehensive bibliometric analysis and updated review

Potential of milk-derived bioactive peptides as antidiabetic, antihypertensive, and xanthine oxidase inhibitors: a comprehensive bibliometric analysis and updated review

MODERN VIEW ON ANTI-INFLAMMATORY AND URAT-LOWERING THERAPY FOR GOUT

This article provides a thorough analysis of new and promising pharmaceuticals for the treatment of gout, encompassing anti-inflammatory and urate-lowering therapies. It covers drugs that have already received regulatory approval and are in active clinical use, as well as those in various stages of implementation and clinical research, showcasing their notable efficacy and safety. Additionally, the article discusses contemporary gout treatment approaches in alignment with international and domestic clinical guidelines. Emphasis is placed on the safety and efficacy of colchicine in gouty arthritis and its cardioprotective properties for patients with gout and comorbid cardiovascular disease. The article provides the information on the effectiveness of canakinumab, a new anti-inflammatory agent for the symptomatic therapy of gout. The effectiveness and safety of anakinra makes it possible to consider it as a promising alternative to the traditional approach to the anti-inflammatory therapy of gout. Rylonacept allows physicians to develop more effective treatment algorithms for those patients with gout who unsatisfactory respond to conventional therapy. The article provides a historical perspective on the use of adrenocorticotropic hormone as an anti-inflammatory agent for gout. It also highlights existing, new, and potential anti-inflammatory drugs, with a primary focus on the safety and effectiveness of febuxostat, supported by recent large randomized clinical trial results. Additionally, the article describes other medications aimed at reducing uric acid levels in the bloodstream, including uricosuric agents (such as probenecid, benzbromarone, sulfinpyrazone, lesinurad, verinurad, dotinurad, and archalofenate), xanthine oxidase inhibitors (allopurinol and topiroxostat), and pegylated uricase drugs, which may hold promise for future use in combination with primary urate-lowering therapies.

Front Cover: Design of 3‐Phenylcoumarins and 3‐Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies (ChemMedChem 21/2023)

Front Cover: Design of 3‐Phenylcoumarins and 3‐Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies (ChemMedChem 21/2023)

Antihyperuricemic activity and inhibition mechanism of xanthine oxidase inhibitory peptides derived from whey protein by virtual screening

Xanthine oxidase (XO), a rate-limiting enzyme in uric acid production, is the pivotal therapeutic target for gout and hyperuricemia. In this study, 57 peptides from α-lactalbumin and β-lactoglobulin were obtained via virtual enzymatic hydrolysis, and 10 XO inhibitory peptides were virtually screened using molecular docking. Then toxicity, allergenicity, solubility, and isoelectric point of the obtained 10 novel peptides were evaluated by in silico tools. The XO activity of these synthetic peptides was tested using an in vitro assay by high-performance liquid chromatography. Their inhibitory mechanism was further explored by molecular docking. The results showed that 4 peptides GL, PM, AL, and AM exhibited higher inhibitory activity, and their half maximal inhibitory concentration in vitro was 10.20 ± 0.89, 23.82 ± 0.94, 34.49 ± 0.89, and 40.45 ± 0.92 mM, respectively. The peptides fitted well with XO through hydrogen bond, hydrophobic interaction, and van der Waals forces, and amino acid residues Glu802, Leu873, Arg880, and Pro1076 played an important role in this process. Overall, this study indicated 4 novel peptides GL, PM, AL, and AM from whey protein exhibited XO inhibitory activity, and they might be useful and safe XO inhibitors for hyperuricemia prevention and treatment.

Comparative studies of xanthine oxidase inhibitors viz. allopurinol and febuxostat against induced hyperuricaemia in a poultry model

ABSTRACT In this study, an attempt was made to evaluate the relative efficacy of two important anti-gout agents, viz. allopurinol and febuxostat, in the control of hyperuricaemia/gout using a poultry model. A 21-day study was conducted on 48 Vencobb-400 broiler chicks randomly divided into four groups. In one group hyperuricaemia/gout was induced by the oral administration of diclofenac (group D); in two other groups the ameliorative effect of the two drugs under study was investigated by providing both simultaneously, i.e. diclofenac and allopurinol (group DA), diclofenac and febuxostat (group DF); and the fourth group was kept un-induced and untreated as a control (group C). Both allopurinol and febuxostat inhibit xanthine oxidase enzymes, thereby reducing the production of uric acid. The birds kept on diclofenac alone exhibited the highest level of hyperuricaemia, clinical signs of gout, and overt adverse changes in the visceral organs, whereas these changes were lesser in allopurinol- and febuxostat-treated groups. Furthermore, haematological, biochemical, patho-morphological, and ultra-structural studies using transmission electron microscopy were carried out to evaluate the pathology and, thus, the ameliorative effect of allopurinol and febuxostat. The findings proved that allopurinol and febuxostat carry definite ameliorative potential as anti-hyperuricemic and anti-gout agents in poultry, which was better expressed by febuxostat compared to allopurinol.

Design of 3-Phenylcoumarins and 3-Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies.

Coumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3'-Bromophenyl)-5,7-dihydroxycoumarin (compound 11) proved to be the most potent XO inhibitor, with an IC50 of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound 11 and compound 5 [3-(4'-bromothien-2'-yl)-5,7-dihydroxycoumarin], the second-best compound within the series (IC50 of 280 nM), has been performed, and both compounds showed a mixed-type inhibition. Both compounds present good antioxidant activity (ability to scavenge ABTS radical) and are able to reduce reactive oxygen species (ROS) levels in H2 O2 -treated cells. In addition, they proved to be non-cytotoxic in a Caco-2 cells viability assay. Molecular docking studies have been carried out to correlate the compounds' theoretical and experimental binding affinity to the XO binding pocket.

Andrographolide Reverses Doxorubicin Resistance in Human Breast Cancer Stem Cells by Regulating Apoptotic Gene Expressions

BACKGROUND: Breast cancer stem cells (BCSCs) have been identified as playing a crucial role in therapeutic resistance. This resistance can be attributed to the anti-apoptotic protein survivin and the antioxidant MnSOD high expression. To overcome the resistance to doxorubicin (DOX), this study proposed the utilization of andrographolide (ANDRO), the primary bioactive compound in Andrographis paniculata leaves. The objective was to examine the role of andrographolide in regulating survivin, caspase-9, and caspase-3 gene expressions to reverse doxorubicin resistance in human BCSCs.METHODS: BCSCs were exposed to 0.1 µM DOX every two days or 50 µM rotenone (ROT) for 6 hours, subsequently supplemented with 0.3 mM ANDRO. Superoxide and peroxide levels were measured using DHE and DCFH-DA assay. The MnSOD, survivin, caspase-9, and caspase-3 mRNA expression levels were analyzed using qRT-PCR. Protein expressions were evaluated using Western blotting assay. MnSOD activity was determined using xanthine oxidase inhibition assay. The apoptotic cells were determined using Annexin-V/PI staining.RESULTS: This study indicated that the cytotoxic mechanisms of DOX, similar to ROT, in BCSCs were attributed to oxidative stress, as evidenced by an elevation in superoxide rather than peroxide levels, accompanied by a decrease in MnSOD activity. This study also highlighted that ANDRO reversed DOX resistance in BCSCs subjected to repeated DOX treatment by downregulating survivin and upregulating caspase-9 and caspase-3 mRNA expressions, thereby activating the intrinsic apoptotic pathway.CONCLUSION: This study provides insights into the role of ANDRO in modulating the expression of apoptotic genes, such as survivin, caspase-9, and caspase-3, to overcome DOX resistance in BCSCs.KEYWORDS: breast cancer, breast cancer stem cell, andrographolide, doxorubicin, oxidative stress, apoptosis

New xanthine oxidase inhibitor from white mulberry (Morus alba L.) – anti-gout prospective study

Abstract In recent years, Morus sp. (mulberry) has acquired a special importance due to its phytochemical composition and its beneficial effects on human health, including antioxidant, anticancer, antidiabetic and immuno-modulatory effects. The various parts of Morus sp., such as its fruits, leaves, twigs, and roots, are recognized as abundant sources of secondary metabolites, with the leaves containing significant amounts of glycosylated flavonols like quercetin and kaempferol, along with chlorogenic acid as the primary phenolic compound. Overall, it can be considered a multi utility plant and can be exploited as an alternative therapy in various ailments. Xanthine oxidase (XO) is the key enzyme for high serum urate levels which is the main cause of developing gout. Under the urate lowering therapy, allopurinol and febuxostat are the main XO inhibitors used to treat gout. However, mild to severe side effects of these synthetic XO inhibitors lead to finding an effective natural alternative without having any side effects. The present study was designed to find out phytochemical analysis and antigout properties of leaves of white mulberry plant. The phytochemical analysis was performed on quantitative and qualitative basis. The qualitative basis indicated the presence of alkaloids, glycosides, flavonoids, steroids, tannins, saponins and Anthraquinone. Biochemical regulation of extracts on anti-gout property using XO inhibition study. Microbial XO was isolated from the Bacillus pumilus to study the anti-gout effects of plant extracts qualitatively on xanthine – NBT plate. Additionally, image analysis studies revealed more clear aspects toward the inhibition studies by plant extracts. The XO activity observed varied from 2.89 to 13.80 μM of uric acid formed/min/ml of enzyme used. Ethanolic extract of mulberry leaves (EEML) showed higher XO inhibition than allopurinol. This is associated with its total polyphenol content, which ranged from 81.25 to 103.12 mg GAE/g of dried extract used, as reported in the case of EEML. The present study is the very first report of relating polyphenol content of EEML with the anti-gout property. EEML is a potential candidate for anti-gout property due to the presence of higher amounts of total polyphenol content and B. pumilus is the best source to extract microbial XO.

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies

ObjectiveRenal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. MethodsA systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. ResultsThe overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose–exposure–effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. ConclusionUric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.

Rapid screening, isolation, and activity evaluation of potential xanthine oxidase inhibitors in Polyporus umbellatus and mechanism of action in the treatment of gout.

Studies show that Polyporus umbellatus has some pharmacological effects in enhancing immunity and against gout. We aimed to establish new techniques for extraction, biological activity screening, and preparation of xanthine oxidase inhibitors (XODIs) from P.umbellatus. First, the extraction of P.umbellatus was investigated using the back propagation (BP) neural network genetic algorithm mathematical regression model, and the extraction variables were optimised to maximise P.umbellatus yield. Second, XODIs were rapidly screened using ultrafiltration, and the change of XOD activity was tested by enzymatic reaction kinetics experiment to reflect the inhibitory effect of active compounds on XOD. Meanwhile, the potential anti-gout effects of the obtained active substances were verified using molecular docking, molecular dynamics simulations, and network pharmacology analysis. Finally, with activity screening as guide, a high-speed countercurrent chromatography (HSCCC) method combined with consecutive injection and two-phase solvent system preparation using the UNIFAC mathematical model was successfully developed for separation and purification of XODIs, and the XODIs were identified using MS and NMR. The results verified that polyporusterone A, polyporusterone B, ergosta-4,6,8(14),22-tetraen-3-one, and ergosta-7,22-dien-3-one of P.umbellatus exhibited high biological affinity towards XOD. Their structures have been further identified by NMR, indicating that the method is effective and applicable for rapid screening and identification of XODIs. This study provides new ideas for the search for natural XODIs active ingredients, and the study provide valuable support for the further development of functional foods with potential therapeutic benefits.

In vitro and In vivo Investigations on Anti-Hyperuricemic Activity of Commercial Preparations of Persicaria minor (Biokesum®) and Eurycoma longifolia (Physta®)

Background: Eurycoma longifolia Jack (Simaroubaceae) root extracts and Persicaria minor Huds. (Polygonaceae) leaf extracts are known to exhibit antioxidant activity, while their antihyperuricemic effects remain unclear. Objective: The objective of this study is to investigate the anti-hyperuricemic activity of Biokesum® (extract of P. minor) and Physta® (extract of E. longifolia). Methods: In vitro anti-hyperuricemic activity for Biokesum® and Physta® was measured by xanthine oxidase inhibition based on a biochemical enzymatic assay at concentrations of 1, 10, and 100 μg/mL. In vivo anti-hyperuricemic activity was assessed in potassium oxonate-induced hyperuricemia Sprague-Dawley rat model. Biokesum® at doses of 100, 300, and 500 mg/kg and Physta® at doses of 300 and 500 mg/kg were administered for 7 days to the hyperuricemic rats. Serum uric acid was measured on days 0, 1, 3, and 7, and liver xanthine oxidase activity was measured on day 8. Allopurinol was used as positive control in both in vitro and in vivo investigations. Results: Based on xanthine oxidase biochemical enzymatic assay, IC50 of Biokesum® and Physta® were 88.6 μg/mL and > 100 μg/mL respectively. In hyperuricemic rats, Biokesum® and Physta® significantly reduced the serum uric acid by 5.6% and 5.5% respectively at 300 mg/kg (p < 0.05) and 9.8% and 9.0% respectively at 500mg/kg (p < 0.001) compared to untreated rats. Significant liver xanthine oxidase inhibition at 37.5% and 34.1% were observed in rats treated with Biokesum® and Physta® respectively. Conclusion: The study has demonstrated hyperuricemic activity of Biokesum® and Physta®, clinical studies in hyperuricemia-related diseases population are required to further confirm the activity.

Free radical scavenging effect of extracts from \(\textit{Isaria cicadae}\) F0004 in Vietnam

Isaria cicadae, currently identified as Paecilomyces cicadae (Miq.) Samson (Cordycipitaceae, Hypocreales, Ascomycetes), is a parasitic fungus on cicadas and is considered a folk medicine in traditional medicine. In this research, the antioxidant activity of some extracts from the biomass and fruit bodies of Isaria cicadae F0004 isolated in Vietnam was investigated. The results showed that the Ethyl acetate (EA) fraction extract of the biomass of Isaria cicadae F0004 exhibited the best antioxidant activity in vitro, with IC50 values of 159.73 ± 7.33 μg/mL (DPPH assay) and 379.25 ± 7.33 μg/mL (ABTS assay). Meanwhile, the EA fraction extract of the fruit bodies of I. cicadae F0004 showed antioxidant activity with IC50 values of 90.8 ± 2.36 μg/mL (xanthine oxidase inhibition), 68.631 ± 0.632 μg/mL (protein membrane protection), 19.042 ± 1.072 μg/mL (lipid membrane protection). Furthermore, the EA fraction extract of the fruit bodies of I. cicadae F0004 exhibited a strong capability for DNA damage protection at 100 μg/mL concentration and ∆OD4000 μg/mL = 0.422 ± 0.014 (reducing power). Therefore, the EA fraction extract of I. cicadae F0004 serves as an effective free radical scavenger and a potential source of natural antioxidants, and this study contributes more information on the biological activities of I. cicadae F0004 from local raw materials.

Effects of Allopurinol in the Prevention of Periprocedural Myocardial Injury Following Elective Percutaneous Coronary Intervention: A Randomized Clinical Trial

Background: Periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) is a substantial health issue with a high mortality rate. Inflammation and oxidative stress are major contributing factors to PMI. Allopurinol inhibits xanthine oxidase (XO)-induced oxidative stress and has potential cardiovascular benefits. Methods: This randomized clinical trial evaluated 110 patients admitted to elective PCI. Patients were assigned to receive either a 1200 mg loading dose of allopurinol 2 hours before the procedure (n = 55) or the standard pretreatment (n = 55). The creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) levels were measured in both groups at the baseline, 8, and 24 hours after PCI. Results: There were no significant differences in the CK-MB levels at baseline (P = 0.71), 8 (P = 0.26), and 24 hours (P = 0.88) after PCI between the two groups. No significant changes in the cTnI levels at baseline (P = 0.26), 8 (P = 0.80), and 24 hours (P = 0.89) after the PCI were also noted. The mean difference for CK-MB and cTnI changes was not different between the two groups. Conclusion: Our study revealed that allopurinol did not reduce cardiac-specific enzymes. Further studies are required to evaluate the impact of allopurinol on preventing PCI-related myocardial injury.

Mining Xanthine Oxidase Inhibitors from an Edible Seaweed Pterocladiella capillacea by Using In Vitro Bioassays, Affinity Ultrafiltration LC-MS/MS, Metabolomics Tools, and In Silico Prediction.

The prevalence of gout and the adverse effects of current synthetic anti-gout drugs call for new natural and effective xanthine oxidase (XOD) inhibitors to target this disease. Based on our previous finding that an edible seaweed Pterocladiella capillacea extract inhibits XOD, XOD-inhibitory and anti-inflammatory activities were used to evaluate the anti-gout potential of different P. capillacea extract fractions. Through affinity ultrafiltration coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS), feature-based molecular networking (FBMN), and database mining of multiple natural products, the extract's bioactive components were traced and annotated. Through molecular docking and ADMET analysis, the possibility and drug-likeness of the annotated XOD inhibitors were predicted. The results showed that fractions F4, F6, F4-2, and F4-3 exhibited strong XOD inhibition activity, among which F4-3 reached an inhibition ratio of 77.96% ± 4.91% to XOD at a concentration of 0.14 mg/mL. In addition, the P. capillacea extract and fractions also displayed anti-inflammatory activity. Affinity ultrafiltration LC-MS/MS analysis and molecular networking showed that out of the 20 annotated compounds, 8 compounds have been previously directly or indirectly reported from seaweeds, and 4 compounds have been reported to exhibit anti-gout activity. Molecular docking and ADMET showed that six seaweed-derived compounds can dock with the XOD activity pocket and follow the Lipinski drug-like rule. These results support the value of further investigating P. capillacea as part of the development of anti-gout drugs or related functional foods.

Inhibition of xanthine oxidase-catalyzed xanthine and 6-mercaptopurine oxidation by luteolin, naringenin, myricetin, ampelopsin and their conjugated metabolites

Luteolin, naringenin, myricetin, and ampelopsin are abundant flavonoids in nature, and several dietary supplements also contain them at very high doses. After the peroral intake, flavonoids go through extensive presystemic biotransformation; therefore, typically their sulfate/glucuronic acid conjugates reach high concentrations in the circulation. Xanthine oxidase (XO) enzyme is involved in uric acid production, and it also takes part in the elimination of certain drugs (e.g., 6-mercaptopurine). The inhibitory effects of flavonoid aglycones on XO have been widely studied; however, only limited data are available regarding their sulfate and glucuronic acid conjugates. In this study, we examined the impacts of luteolin, naringenin, myricetin, ampelopsin, and their sulfate/glucuronide derivatives on XO-catalyzed xanthine and 6-mercaptopurine oxidations employing in vitro enzyme incubation assays and molecular modeling studies. Our major results/conclusions are the following: (1) Sulfate metabolites were stronger while glucuronic acid derivatives were weaker inhibitors of XO compared to the parent flavonoids. (2) Naringenin, ampelopsin, and their metabolites were weak inhibitors of the enzyme. (3) Luteolin, myricetin, and their sulfates were highly potent inhibitors of XO, and the glucuronides of luteolin showed moderate inhibitory impacts. (4) Conjugated metabolites of luteolin and myricetin can be involved in the inhibitory effects of these flavonoids on XO enzyme.

Antigout Activity of The Spatholobus littoralis Hassk. Extract Fractions Against Xanthine Oxidase: Its Metabolite Profile and Inhibition Kinetics

The Spatholobus littoralis Hassk. (S. littoralis Hassk.) is a native plant in Indonesia and has been widely used in traditional Dayaknese medicine for non-communicable degenerative diseases. One of these illnesses, known as gout, is caused by excessive uric acid in the blood, which is the catalytic byproduct of a xanthine oxidase (XO) enzyme. In this work, we investigated the inhibition kinetics of XO and identified bioactive compounds from the stem extract fractions of S. littoralis Hassk. using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Fractionation was carried out to obtain n-hexane, dichloromethane, and 1-butanol fractions from the water and 70% ethanol extracts. Fraction of 1-butanol from 70% ethanol and water extract displayed potent inhibitors of XO with IC50 value 116.91±3.51 and 137.15±5.00 mg/L, respectively. Lineweaver-Burk plot analysis showed that the 1-butanol fraction from the two extracts inhibited XO competitively. The 1-butanol fraction from the two extracts has been further identified as a bioactive fraction. The majority of the compounds in the two active fractions were phenolics. These findings revealed that the 1-butanol fraction from the two extracts is promising as an antigout treatment in the future.