Search Results (126)

Background: Myelotoxicity, usually manifested by moderate leukopenia (particularly neutropenia), is a well-known adverse drug reaction to azathioprine (AZA) therapy. Thiopurine methyltransferase (TMPT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genotyping are not routinely performed in patients starting AZA therapy due to their low cost-effectiveness. Additionally, the concomitant use of xanthine oxidase inhibitors and 5-aminosalicylates may slow the metabolism of 6-mercaptopurine. Case Description: We describe a case of a 26-year-old Caucasian man with Crohn’s disease and psoriatic arthritis treated with mesalazine and AZA (100 mg daily) who developed prolonged bone marrow aplasia and neutropenic fever after increasing the daily dose of AZA from 100 to 150 mg (from 44 to 66 mg/m²), without frequent total blood count monitoring. Discontinuation of AZA, multiple transfusions of red blood cells and platelet concentrate, filgrastim, empirical antibiotic therapy, and antiviral and antifungal prophylaxis were obtained after 11 days complete recovery of bone marrow aplasia. Methods: Genomic DNA genotyping of coding regions of TPMT (exons 2–9) and NUDT15 (exons 1–3). Results: Heterozygous alleles in the untranslated region (c.460G>A and c.719A>G) associated with TPMT deficiency and a benign variant (c.*7G>A) in the 3′-UTR of NUDT15 with no effect on enzyme activity were found. Conclusions: This case highlights the importance of monitoring the total blood count frequently during the first weeks of treatment with moderate-to-high doses of AZA. Furthermore, the interaction between AZA and mesalazine may play a significant role in the development of prolonged bone marrow aplasia. Full article

Background: Varicose veins and chronic venous insufficiency are chronic venous disorders involving abnormalities in the venous system. Inflammation, an increase in proteolytic enzymes, and free radicals are important factors that play a role in the varicose vein pathology. Methods: In this study, the antioxidant properties and inhibitor activities of 17 plant extracts used to treat varicose veins in traditional medicine were evaluated against varicose veins-related enzymes (hyaluronidase, elastase, collagenase, lipooxygenase, prolylendopeptidase, and xanthine oxidase). The most effective compounds responsible for the activity of the Helichrysum plicatum subsp. plicatum extract were isolated by open column chromatography techniques. The active compounds were determined to be naringenin, apigenin, and luteolin by spectroscopic methods. In the activity-guided isolation study, the xanthine oxidase enzyme inhibition method was used. Results: The fractions containing naringenin and apigenin (IC₅₀ = 0.269 ± 0.009 µg/mL) and apigenin and luteolin (IC₅₀ = 0.285 ± 0.019 µg/mL) compounds showed synergistic and strong effects against xanthine oxidase and were found to be as active as the positive control allopurinol (IC₅₀ = 0.250 ± 0.006 µg/mL). In the LC-MS/MS analysis of the Helichrysum plicatum extract, quinic acid (22.649 mg compound/g extract), chlorogenic acid (14.573 mg/g extract), isoquercitrin (14.371 mg/g extract), cosmosin (9.885 mg/g extract), and astragalin (11.506 mg/g extract) were detected as the major components. Naringenin, apigenin, and luteolin were detected at concentrations of 1.457, 2.518, and 1.368 mg/g in the extract, respectively. Conclusions: In conclusion, it is predicted that the combination of naringenin, apigenin, and luteolin has a promising use as a conservative treatment option for diseases associated with varicose veins due to their synergistic effects with each other. Full article

Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory condition characterized by hyperuricemia and NLRP3 inflammasome activation, leading to joint damage and systemic inflammation. Although allopurinol (ALP), a xanthine oxidase inhibitor, effectively lowers serum urate levels, it has limited anti-inflammatory effects. This study investigated whether combining disulfiram (DSF), a known NLRP3 inflammasome inhibitor, with ALP enhances therapeutic outcomes in a rat model of gout. Methods: Thirty male Albino Wistar rats (150–200 g) were randomly assigned to five groups (n = 6): control, disease control, ALP-treated, DSF-treated, and ALP + DSF combination. Hyperuricemia was induced using potassium oxonate, followed by MSU crystal injection to trigger acute gout. Treatment lasted 30 days. Efficacy was assessed through clinical scoring, paw swelling, serum uric acid levels, ELISA-based cytokine profiling (IL-1β, TNF-α, IL-6), renal function tests, radiography, and histopathology. Results: Combination therapy with ALP + DSF significantly reduced paw swelling (p < 0.05), inflammation index (p < 0.001), serum uric acid (p < 0.001), and pro-inflammatory cytokines compared to monotherapy. Histopathology revealed preserved synovial architecture and reduced inflammatory infiltration. Radiographic imaging showed attenuated soft tissue swelling and joint erosion. Renal function markers were also improved in the combination group. Conclusions: The combination of ALP and DSF provided superior anti-inflammatory and urate-lowering effects compared to individual treatments. These findings support the potential of disulfiram as an adjunct to conventional ULTs in gout management through dual modulation of urate metabolism and inflammasome-driven inflammation. Full article

We used molecular docking to determine the binding energy and interactions of apigenin and 16 related flavonoids, with 24 distinct proteins having diverse biological functions. We aimed to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids impacting their binding energy. Our results demonstrate that apigenin exhibits high binding energies (a surrogate for binding affinity or inhibitory potential) to all tested proteins. The strongest binding energy was −8.21 kcal/mol for p38 mitogen-activated protein kinases, while the weakest was −5.34 kcal/mol for cyclin-dependent kinase 4. Apigenin and many other flavonoids showed high binding energies on xanthine oxidase (1.1–1.5 fold of febuxostat) and DNA methyltransferases (1.1–1.2 fold of azacytidine). We uncovered high binding energies of apigenin and certain flavonoids with mutated Kirsten rat sarcoma viral oncogene homolog at G12D (KRAS G12D), G12V, and G12C. Consequently, apigenin and certain flavonoids have the potential to effectively inhibit pan-KRAS oncogenic activity, not just on specific KRAS mutations. Apigenin and certain flavonoids also have high binding energies with aromatase (involved in estrogen production) and bacterial infections, i.e., DNA gyrase B and 3R-hydroxy acyl-ACP dehydratase (FABZ). Our findings are pivotal in identifying specific flavonoids that can effectively inhibit targeted proteins, paving the way for the development of innovative flavonoid-based drugs. Full article

Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that catalyzes hypoxanthine and xanthine to produce urate and is accompanied by the generation of reactive oxygen species (ROS) in purine catabolism. Considerable preclinical and clinical studies have been conducted over many decades to investigate the role of XO in the pathogenesis of AP and its potential targeting therapeutic value. There is no doubt that the ROS generated by irreversibly activated XO participates in the local pancreas and multiple organ failure during AP. However, the optimal timing and doses for therapeutic interventions targeting XO in animal studies and the clinic, as well as the additional molecular mechanisms through which XO contributes to disease onset and progression, including metabolic regulation, remain to be elucidated. This review summarized the benefits and contradictions of using XO inhibitors in animal models, offered mechanisms other than ROS, and discussed the difficulties faced in clinical trials. We hope to provide a perspective on the future worthwhile basic and clinical research on XO by analyzing its chemical and biological characteristics, as well as the progress of its regulatory mechanisms in AP. Full article

Introduction: Hyperuricemia is characterized by increased uric acid (UA) in the body. The ability to block xanthine oxidase (XO) is a useful way to check how different bioactive molecules affect hyperuricemia. Previous reports showed the significant effect of corn against hyperuricemia disorder with its anti-XO activity. The identification of stable Zea mays miRNA (zma-miR) in humans has opened up a new avenue for speculation about its part in regulating novel human gene targets. Aims: The aim of this study was to investigate the prospects of zma-miRs in XO gene regulation, the possible mechanism, and the interaction analysis of the zma-miR-XO mRNA transcript. Method: Significant features of miRNA-mRNA interaction were revealed using two popular miRNA target prediction software—intaRNA (version 3.3.1) and RNA hybrid (version 2.2.1) Results: Only 12 zma-miR-156 variants, out of the 325 zma-miR’s sequences reported in the miRNA database, efficiently interact with the 3′UTR of the XO gene. Characteristics of miRNA-mRNA interaction were as follows: the positioning of zma-miR-156 variants shows that they all have the same 11-mer binding sites, guanine (G), and uracil (U) loops at the 13th and 14th positions from the 5′ end, and no G: U wobble pairing. These factors are related to the inhibition of functional mRNA expression. Additionally, the zma-miR-156 variants exhibit a single-base variation (SBV), which leads to distinct yet highly effective alterations in their interaction pattern with the XO mRNA transcript and the corresponding free energy values. Conclusion: Therefore, we propose that zma-miR-156 variants may be a promising new bioactive compound against hyperuricemia and related diseases. Full article

Background: Xanthine oxidase inhibitors (XOIs) may help prevent stroke. However, heterogeneity can be found in the conclusions of different studies. The relevant evidence was summarized in this systematic review and meta-analysis to further clarify the role of XOIs in the prevention and treatment of stroke, with a focus on evaluating the effects of XOIs in primary and secondary prevention of stroke, acute stroke treatment, and reduction of post-stroke complications. Methods: Randomized controlled trials (RCTs) or cohort studies on the effect of XOIs in the prevention and treatment of stroke were searched in PubMed, EMBASE, and Cochrane Library from inception to 3 March 2024, along with hand searching. The analyses were carried out using Review Manager 5.4. Results: The analysis included 14 studies (115,579 patients). While XOIs did not significantly reduce the risk of stroke (RR: 0.89; 95% CI: 0.59–1.34), they improved post-stroke functional outcomes, with a reduction in the modified Rankin scale scores (mean difference: −0.6; 95% CI: −0.8 to −0.4), decreased intercellular adhesion molecule-1 levels (mean difference: −15.2 ng/mL; 95% CI: −22.3 to −8.1), improved augmentation index (AIx) by 4.2% (95% CI: 2.5–5.9%), reduced central blood pressure (mean reduction: 4.8 mmHg; 95% CI: 2.6–6.9), and delayed carotid intima-media thickness progression (mean difference: −0.05 mm/year; 95% CI: −0.08 to −0.02). Full article

Marine-derived foods, often called blue foods, are promising sustainable alternatives to conventional food sources owing to their abundant amino acids and high protein content. Current treatments for hyperuricemia, a chronic condition attributed to purine metabolism disorders, are associated with various side effects. Novel peptide xanthine oxidase inhibitors have been discovered in the hydrolyzed products of marine fish and invertebrate proteins, which have demonstrated promising therapeutic potential by reducing uric acid levels in vitro and in vivo. This review explores the potential therapeutic effects of xanthine oxidase inhibitors derived from marine fish and invertebrates, summarizes the methods for extracting bioactive peptides from marine organisms, and emphasizes the impact of different proteases on the structure–activity relationship of bioactive peptides. The hypouricemic effects of these bioactive peptides warrant further verification. There is consensus on the in vitro chemical methods used to verify the xanthine oxidase inhibitory effects of these peptides. Considering several cell and animal model development strategies, this review summarizes several highly recognized modeling methods, proposes strategies to improve the bioavailability of bioactive peptides, and advocates for a diversified evaluation system. Although the screening and evaluation methods for antihyperuricemic peptides have been shown to be feasible across numerous studies, they are not optimal. This review examines the deficiencies in bioavailability, synthesis efficiency, and evaluation mechanisms in terms of their future development and proposes potential solutions to address these issues. This review provides a novel perspective for the exploration and application of marine-derived hypouricemic bioactive peptides. Full article

Although patients with hyperuricemia and gout often have dyslipidemia, the effects of febuxostat, a xanthine oxidase inhibitor, on their lipid profiles are unclear. Thus, we performed a sub-analysis of the randomized PRIZE study in which the effects of febuxostat on carotid atherosclerosis were investigated in patients with hyperuricemia. The participants were randomized to the febuxostat or control group. The primary endpoint of this sub-analysis was changes in the patients’ non-high-density lipoprotein cholesterol (HDL-C) levels from baseline to 6-month follow-up. Correlations between the changes in lipid profiles and cardiometabolic parameters were also evaluated. In total, 456 patients were included. From baseline to 6 months, non-HDL-C levels were significantly reduced in the febuxostat group (−5.9 mg/dL, 95% confidence interval [CI]: −9.1 to −2.8 mg/dL, p < 0.001), but not in the control group (−1.3 mg/dL, 95% CI: −4.4 to 1.8, p = 0.348). The reduction in non-HDL-C levels was more pronounced in women and correlated with changes in serum uric acid and estimated glomerular filtration rate levels only in the febuxostat group. In patients with hyperuricemia, febuxostat treatment was associated with reduced non-HDL-C levels from baseline to the 6-month follow-up compared to the control treatment, suggesting that the lipid-lowering effect of febuxostat should be considered when targeting dyslipidemia. Full article

There is a growing interest in the discovery of novel xanthine oxidase inhibitors for gout prevention and treatment with fewer side effects. This study aimed to identify the xanthine oxidase (XO) inhibitory potential and drug-likeness of the metabolites present in the methanolic leaf extract of Anastatica (A.) hierochuntica L. using in vitro and in silico models. The extract-derived metabolites were identified by liquid-chromatography–quadrupole-time-of-flight-mass-spectrometry (LC-QTOF-MS). Molecular docking predicted the XO inhibitory activity of the identified metabolites and validated the best scored in vitro XO inhibitory activities for experimental verification, as well as predictions of their anticancer, pharmacokinetic, and toxic properties; oral bioavailability; and endocrine disruption using SwissADMET, PASS, ProTox-II, and Endocrine Disruptome web servers. A total of 12 metabolites, with a majority of flavonoids, were identified. Rutin, quercetin, and luteolin flavonoids demonstrated the highest ranked docking scores of −12.39, −11.15, and −10.43, respectively, while the half-maximal inhibitory concentration (IC₅₀) values of these metabolites against XO activity were 11.35 µM, 11.1 µM, and 21.58 µM, respectively. In addition, SwissADMET generated data related to the physicochemical properties and drug-likeness of the metabolites. Similarly, the PASS, ProTox-II, and Endocrine Disruptome prediction models stated the safe and potential use of these natural compounds. However, in vivo studies are necessary to support the development of the prominent and promising therapeutic use of A. hierochuntica methanolic-leaf-extract-derived metabolites as XO inhibitors for the prevention and treatment of hyperuricemic and gout patients. Furthermore, the predicted findings of the present study open a new paradigm for these extract-derived metabolites by revealing novel oncogenic targets for the potential treatment of human malignancies. Full article

Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant–antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration. Full article

Gout is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), owing to impaired uric acid excretion. However, treating gout in this population is challenging due to concerns about medication safety and efficacy with reduced kidney function. This review examines the evidence of various pharmacologic and non-pharmacologic approaches to managing gout in CKD/ESRD. For acute gout flares, there is insufficient evidence to guide optimal dosing of NSAIDs, colchicine, and corticosteroids in advanced CKD. The risks generally outweigh the benefits of NSAIDs and colchicine. Corticosteroids appear safer but require individual risk-benefit assessments. Interleukin-1 inhibitors show promise, but larger studies are needed. For long-term urate lowering, xanthine oxidase inhibitors like allopurinol and febuxostat are preferred over probenecid and other uricosurics. However, studies specifically evaluating urate-lowering therapies in CKD are scarce, resulting in conflicting expert guidelines. Starting with low allopurinol doses and gradual titration can mitigate the risks. Higher allopurinol doses may be needed to reach urate targets in some CKD patients. Febuxostat’s safety in advanced CKD remains debated. Optimal gout management in dialysis patients is also unclear, including when to continue urate-lowering therapy. Overall, gout is often suboptimally treated in CKD/ESRD, highlighting the need for more research to guide therapy in this population. Improving management can significantly reduce the burden of these comorbid diseases. Full article

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer’s disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress. Full article

Dioscoreae hypoglaucae Rhizoma (DH) and Dioscoreae spongiosae Rhizoma (DS) are two similar Chinese herbal medicines derived from the Dioscorea family. DH and DS have been used as medicines in China and other Asian countries for a long time, but study on their phytochemicals and bioactive composition is limited. This present study aimed to compare the chemical compositions of DH and DS, and explore the anti-xanthine oxidase components based on chemometric analysis and spectrum–effect relationship. Firstly, an HPLC method was used to establish the chemical fingerprints of DH and DS samples, and nine common peaks were selected. Then, hierarchical clustering analysis, principal component analysis and orthogonal partial least squares discriminant analysis were employed to compare and discriminate DH and DS samples based on the fingerprints data, and four steroidal saponins compounds (protodioscin, protogracillin, dioscin, gracillin) could be chemical markers responsible for the differences between DH and DS. Meanwhile, the anti-xanthine oxidase activities of these two herbal medicines were evaluated by xanthine oxidase inhibitory assay in vitro. Pearson correlation analysis and partial least squares regression analysis were subsequently used to investigate the spectrum–effect relationship between chemical fingerprints and xanthine oxidase inhibitory activities. The results showed that four steroidal saponins, including protodioscin, protogracillin, methyl protodioscin and pseudoprogracillin could be potential anti-xanthine oxidase compounds in DH and DS. Furthermore, the xanthine oxidase inhibitory activities of the four selected inhibitors were validated by anti-xanthine oxidase inhibitory assessment and molecular docking experiments. The present work provided evidence for understanding of the chemical differences and the discovery of the anti-xanthine oxidase constituent of DH and DS, which could be useful for quality evaluation and bioactive components screening of these two herbal medicines. Full article