Uric Acid Production Research Articles

Analysis of a family with hypouricemia due to type Ⅰ xanthinuria

This article reports a patient presenting with"extremely low uric acid levels in blood and urine"clinically along with reviewing relevant literature to consider a diagnosis of xanthinuria. Peripheral blood samples of the patient and her family were further collected for xanthine dehydrogenase(XDH) gene sequencing, showing that the patient had compound heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del) and exon 10:c.871G>T(p.Glu291*), however no mutations were found in the gene encoding MOCOS on chromosome 18, confirming the diagnosis of hereditary xanthinuria type Ⅰ.The patient's father, son and daughter carried heterozygous mutations in exon 19:c.1995_2006del12(p.His666_Gly669del), and the mother carried heterozygous mutations in exon 10:c.871G>T(p.Glu291*).Mutations in the XDH gene cause a lack of xanthine oxidoreductase function, which hinders the production of uric acid, leading to very low or undetectable levels in blood and urine. Patients present clinically with hematuria, renal colic, urolithiasis, and even acute renal failure. Through the diagnosis and treatment of this patient and literature review, the article aims to deepen the understanding of purine metabolism and uric acid production process, and improve the clinicians' diagnosis and treatment ability of hypouricemia.

Reduction Rate of Uric Acid in Blood During Continuous Renal Replacement Therapy for Acute Kidney Injury: A Multicenter Retrospective Observational Study

Introduction: Continuous renal replacement therapy (CRRT) eliminates these small solutes with equal efficacy under the same conditions. However, variations in the reduction rates of these solutes observed in patients with CRRT are likely influenced by factors other than removal through CRRT. This study evaluated the reduction rates of these small solutes during CRRT and their possible association with mortality. Methods: This study used the data of limited patients registered in the CHANGE study, which is a large retrospective observational study on CRRT management across 18 Japanese ICUs. Reduction rates of three solutes in blood, calculated on the 1st and 2nd days, were compared in patients with acute kidney injury (AKI) treated by CRRT. The potential association between solute reduction rates and mortality during CRRT or within 7 days after the termination of CRRT was evaluated. Results: In total, 163 patients with AKI were included in the analysis. The reductuin rates of uric acid (UA) were significantly higher than those of urea and creatinine for the 1st and 2nd tests in the entire cohort. Receiver operating curve (ROC) analysis revealed that lower UA reduction rates were significantly associated with mortality during CRRT or within 7 days after CRRT termination (area under the ROC curve: 0.62 [95% confidence interval {CI} 0.52–0.71] for the 1st test and 0.63 [95%CI 0.54–0.72] for the 2nd test). After adjusting for age and SOFA score, a significant association was observed between lower UA reduction rates and hospital mortality for both tests. Conclusion: Among the small solutes, UA reduction rates in patients with AKI treated with CRRT were notably higher than those of creatinine and urea. Furthermore, the significant association between lower UA reduction rates and mortality suggests that UA reduction rate may serve as a valuable indicator of insufficient removal of uremic solutes by CRRT, although the decline in UA production must be taken into account.

Pharmacotherapy for patients with calcium oxalate stones and abnormal urine chemistry: A systematic review and meta-analysis for the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition.

We performed a systematic review and meta-analysis to evaluate the benefits and harms of pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry. This article is a modified and detailed version of the commentary on Clinical Question 10 described in the Japanese Clinical Practice Guidelines for the Management of Urinary Stones, Third Edition. PubMed and Ichushi Web were searched through August 2020 for articles on pharmacotherapies for calcium oxalate stones (thiazides, citrate preparations, uric acid production inhibitors, and magnesium preparations). Two reviewers independently selected randomized controlled trials reporting reduction of stone recurrence and adverse drug reactions as outcomes and performed data extraction and quality assessment. Meta-analyses with random effects models and rating of the strength of evidence were performed. Pharmacotherapies were shown to significantly reduce stone recurrence (risk ratio 0.47, 95% confidence interval 0.35-0.63). Meanwhile, the pharmacotherapies increased adverse drug reactions leading to study dropout (risk ratio 2.51, 95% confidence interval 1.09-5.75) and adverse drug reactions/adverse events (risk ratio 1.95, 95% confidence interval 1.07-3.56). The reported adverse drug reactions were, however, mainly minor and did not frequently require discontinuation of medication (2%-16%). The strengths of evidence for both outcomes were rated as moderate, because the risk of bias, indirectness, inconsistency, imprecision, and publication bias were all serious except for one item. The overall strength of evidence across outcomes was therefore determined to be moderate. These results support the conditional recommendation to initiate pharmacotherapies for patients with calcium oxalate stones and abnormal urine chemistry.

A rare occurrence of xanthine urolithiasis in siblings with Lesch–Nyhan syndrome treated with Allopurinol—a case report

Abstract Introduction Lesch–Nyhan syndrome (LNS) is an X-linked disorder affecting the metabolism of the purine salvage pathway leading to excessive serum uric acid production. Treatment of hyperuricemia with Allopurinol is usually effective to lower serum uric acid concentration to acceptable levels. Allopurinol blocks the conversion of hypoxanthine and xanthine to serum uric acid in the purine degradation pathway. The effect of Allopurinol may result in excessive buildup of xanthine, potentially resulting in urolithiasis composed of xanthine. This rare occurrence poses a unique challenge maintaining a balance between lowering hyperuricemia and preventing the development of xanthine urolithiasis. This case report includes two siblings with LNS treated with Allopurinol who developed xanthine urolithiasis. Case description Patients are siblings, a 22-year-old male and a 21-year-old female, with LNS diagnosed in early childhood. They both share similar manifestations of the disease and were treated with Allopurinol with an intended therapeutic window of serum uric acid levels since diagnosis. Both were prone to developing urolithiasis and nephrolithiasis, the male more than the female, regardless of the medical regimen. Uric acid and calcium levels were normal in the serum and urine. Chemical analysis of calculi eliminated by both siblings revealed xanthine stones. Conclusions Patients with LNS tend to develop stones composed of urate. Rarely, they can also precipitate stones composed of xanthine resulting from its buildup in serum and urine by Allopurinol. This complication should be considered in all patients undergoing treatment with Allopurinol. Careful clinical monitoring and dose adjustments of Allopurinol must balance the need to control hyperuricemia with avoiding excessive blockade of hypoxanthine.

Influence of Various Methods of Processing Soybeans on Protein Digestibility and Reduction of Nitrogen Deposits in the Natural Environment – A Review

Abstract Soybean meal (SBM) is a significant source of protein for poultry due to its high concentration of protein and amino acids profile. The primary objective of SBM processing is the reduction and deactivation of anti-nutritional factors (ANFs) to enhance nutrient digestibility. However, eliminating ANFs does not necessarily correlate with increased protein and amino acid content. Several processing methods, such as soaking, cooking, and commercial techniques, improve SBM protein digestibility. To sustain feeding qualities, soybeans must undergo heating to remove inherent chemicals that interfere with poultry digestion. However, both under and over-processing can impair meal digestibility. Extrusion heating significantly contributes to protein and starch digestibility while reducing certain ANFs. Thermomechanical and enzyme-assisted procedures reduce heat-resistant proteins more efficiently than extraction methods, producing soy protein concentrate (SPC) and fermentation. These techniques reduce ANFs in SBM, activating digestive enzymes and alleviating digestive tract pressure, leading to decreased endogenous protein deficits. Exogenous enzyme supplementation is a biotechnological approach for enhancing the nutritional content of SBM and certain other protein-rich products. However, different processing methods not only affect protein digestibility but also impact poultry production, gastrointestinal health, and the environment due to higher nitrogen excrement. Ammonia (NH3) emissions are a significant environmental concern in chicken farming, resulting from uric acid production during protein consumption. It has a negative impact on the environment and the health of birds/humans. This review investigates the impact of several processing techniques on the digestibility of SBM protein and the reduction of N2 regarding one health concept. Future research should focus on identifying optimal processing methods maximizing protein digestibility while minimizing environmental nitrogen impacts.

Alterations of Hepatic Lipidome Occur in a Gouty Model: A Shotgun Lipidomics Study.

Liver injury, such as nonalcoholic fatty liver disease, is a common symptom observed in patients with gout/hyperuricaemia. However, the exact mechanisms are still unclear. There is ongoing controversy about whether representative agents like colchicine and febuxostat, commonly used to manage gout, could also help prevent the liver injury. Liver plays a crucial role in uric acid (UA) production and lipid metabolism. Thus, the study aimed to investigate the aberrant lipid metabolism in the liver during injury and the effects of these drugs. An advanced multi-dimensional mass spectrometry-based shotgun lipidomics technology was employed for class-targeted lipid analysis of cellular lipidomes in hepatic tissue of a gouty model induced by a combination of monosodium urate crystals and high-fat diet with or without treatment with colchicine and febuxostat. Serum UA, blood urea nitrogen, creatinine, proinflammatory cytokines, expression of AMP-activated protein kinase protein, footpad histopathology, and footpad swelling and pain threshold of these mice were assessed to evaluate the progression of gout. Lipidomics analysis clearly demonstrated that the ectopic fat accumulation as well as changes in fatty acyls composition in TAG pool, impaired mitochondrial function resulted by decreased tetra 18:2 cardiolipin, and reduced 4-hydroxyalkenal bioavailability in liver tissue could contribute to liver damage to the gouty model. Treatment with colchicine or febuxostat not only ameliorated gouty symptoms but also corrected these abnormal hepatic lipid metabolism patterns. This study shed light on underlying mechanism(s) for liver injury in gout/hyperuricaemia and suggested that administration of drugs like colchicine and febuxostat could prevent liver injury.

Serum creatinine is more strongly associated with hyperuricemia than eGFR in males but not in females.

Serum creatinine and estimated glomerular filtration ratio (eGFR) are factors associated with hyperuricemia, though which is more closely associated with hyperuricemia remains unclear. This retrospective cross-sectional study examined the associations of serum creatinine and eGFR with hyperuricemia using health check-up findings. Enrolled were 6020 individuals (3509 males, 2511 females) who underwent health check-ups from 2017 to 2021. The subjects were divided based on serum uric acid level into the normuricemia (males 1.5-7.0 mg/dl, females 1.5-< 6.0 mg/dl) and hyperuricemia (males >7.0 mg/dl, female ≥ 6.0 mg/dl) groups. Matched-pair analysis was used to evaluate the association between hyperuricemia and variables related to serum uric acid. Matched-pair analysis results showed a significant association of serum creatinine with hyperuricemia in male subjects but not in females. Furthermore, propensity score obtained by binominal logistic regression demonstrated that serum creatinine had a greater association with hyperuricemia than eGFR in the males but not in females. The present findings indicate an association of serum creatinine with hyperuricemia in males not only because of reduced renal function but other factors related to greater muscle mass, such as increased intake of protein-rich foods containing purines and increased uric acid production induced by accelerated creatinine metabolism.

Evaluating renal injury characteristics in different rat models of hyperuricemia and elucidating pathological molecular mechanisms via serum metabolomics.

Hyperuricemia has emerged as a significant global health concern, closely associated with various metabolic disorders. The adverse effects frequently observed with current pharmacological treatments for hyperuricemia highlight the urgent need for reliable animal models to elucidate the disease's pathophysiological mechanisms, thereby facilitating the development of safer and more effective therapies. In this study, we established three rat models of hyperuricemia using potassium oxonate, either alone or in combination with fructose and adenine. Each model exhibited distinct pathological changes, with the combination of potassium oxonate, fructose, and adenine causing significantly more severe damage to liver and kidney functions than potassium oxonate alone. Serum metabolomics analyses revealed profound dysregulation in the metabolic pathways of purine, pyrimidines, and glutathione, underscoring the pivotal role of oxidative stress in the progression of hyperuricemia. We identified key biomarkers such as orotidine, ureidosuccinic acid, uracil, and pseudouridine, which are associated with uric acid-induced damage to hepatic and renal systems. MetOrigin tracing analysis further revealed that differential metabolites related to hyperuricemia are primarily involved in host-microbiome co-metabolic pathways, particularly in purine metabolism, with bacterial phyla such as Pseudomonadota, Actinomycetota, and Ascomycota being closely linked to the critical metabolic processes of uric acid production. These findings not only enhance our understanding of the pathogenic mechanisms underlying hyperuricemia but also provide a robust experimental model foundation for the development of innovative treatment strategies.

Mechanisms of levan in ameliorating hyperuricemia: Insight into levan on serum metabolites, gut microbiota, and function in hyperuricemia rats

This study aims to investigate the effects of levan on the progression of hyperuricemia (HUA) rats and elucidate its underlying mechanisms. After levan intervention, both low and high-dose groups exhibited a significant decrease in serum uric acid (UA) levels, reaching 71.0 % and 77.5 %, respectively, compared to the model group. Furthermore, levan could alleviate renal pathological damage caused by glomerular cell vacuolation, inflammatory infiltration and collagen deposition. The results of enzyme activity assay and real-time fluorescence quantitative PCR showed that levan decreased UA production by inhibiting adenosine deaminase (ADA) activity and gene expression in liver; it upregulated ATP-binding cassette subfamily G member 2 protein (ABCG2) and organic anion transporter 1 (OAT1) transporter gene expression in the kidney, promoting UA excretion. Gut microbiome analysis indicated that levan regulated gut flora dysbiosis induced by HUA, resulting in up-regulated the abundance of beneficial bacteria (Muribaculaceae, Faecalibaculum, Bifidobacterium, and Lactobacillus) and decreased conditioned pathogenic bacteria (Escherichia_Shigella and Proteus). Non-targeted metabolomics showed changes in various serum metabolites associated with glycerophospholipid metabolism, lipid metabolism, and inflammation following oral administration of levan. Therefore, levan may be a promising functional dietary supplement for regulating the gut flora and remodeling of metabolic disorders in individuals with HUA.

Harnessing Protein Hydrolysates and Peptides for Hyperuricemia Management: Insights into Sources, Mechanisms, Techniques, and Future Directions.

Hyperuricemia (HUA) is a metabolic disorder characterized by an imbalance in uric acid production and excretion, frequently leading to gout and various chronic conditions. Novel bioactive compounds offer effective alternatives for managing HUA, reducing side effects of traditional medications. Recent studies have highlighted the therapeutic potential of protein hydrolysates and peptides in managing HUA. This review focuses on preparing and applying protein hydrolysates to treat HUA and explores peptides for xanthine oxidase inhibition. Particularly, we discuss their origins, enzymatic approaches, and mechanisms of action in detail. The review provides an updated understanding of HUA pathogenesis, current pharmacological interventions, and methodologies for the preparation, purification, identification, and assessment of these compounds. Furthermore, to explore the application of protein hydrolysates and peptides in the food industry, we also address challenges and propose solutions related to the safety, bitterness, oral delivery, and the integration of artificial intelligence in peptide discovery. Bridging traditional pharmacological approaches and innovative dietary interventions, this study paves the way for future research and development in HUA management, contributing to the utilization of proteins from different food sources. In conclusion, protein hydrolysates and peptides show significant promise as safe agents and dietary interventions for preventing and treating HUA.

Polysaccharides from Alpinia oxyphylla fruit prevent hyperuricemia by inhibiting uric acid synthesis, modulating intestinal flora and reducing renal inflammation

Hyperuricemia (HUA) is one of the most common chronic diseases today, with a prevalence exceeding 14 % in both the United States and China. Current clinical treatments for HUA focus on promoting uric acid (UA) excretion and inhibiting UA production, but often neglect the strain on the liver and kidneys. The fruit of Alpinia oxyphylla (A. oxyphylla) is known to improve renal function, regulate metabolism, and exhibit anti-inflammatory effects; however, its effectiveness and mechanisms in treating HUA are not well understood. In this study, HUA mice induced by potassium oxonate and adenine were treated with A. oxyphylla polysaccharide (AFP) for 21 days. The levels associated with HUA were quantified using assay kits to evaluate the impact of AFP on HUA. Serum metabolomics and 16S rRNA sequencing were used to investigate the mechanisms by which AFP ameliorates HUA. The results showed that AFP treatment reduced abnormal biochemical levels, including UA, blood urea nitrogen, and creatinine, in HUA mice. AFP inhibited UA synthesis by regulating pyrimidine metabolism and the metabolism of alanine, aspartate and glutamate, reduced kidney inflammation, and promoted UA excretion by regulating intestinal flora. Thus, AFP appears to be an effective agent for alleviating HUA symptoms.

Comprehensive Screening and Evaluation of Anti-gout Activity of Plantago asiatica L. through Integrated In vivo and In vitro Methodologies

Abstract Objective: This study aimed to elucidate the active components and mechanisms of Plantago asiatica L. (PAL) in the treatment of gout. Materials and Methods: Based on its polarity, PAL was partitioned into three parts, P1, P2, and P3, through gradient elution using AB-8 macroporous resin columns. The primary constituents of these fractions include iridoids, phenylethanoid glucosides, and flavonoids. Subsequently, a comprehensive in vitro and in vivo screening and evaluation model was developed considering the fundamental pathological processes of gout, including the inhibition of uric acid (UA) production, augmentation of UA excretion, and anti-inflammatory effects. This model was used to analyze the anti-gout activity of P1, P2, P3, and the overall extracts derived from PAL. Results: All the PAL parts exhibited specific therapeutic properties as part of gout therapy. Specifically, the P2 part demonstrated the ability to diminish interleukin-1 beta levels, lower UA concentrations, suppress joint inflammation in rats, and restore abnormal parameters associated with gout, such as creatinine and urea nitrogen. These findings highlight the significant effect of P2 on gout treatment. Conclusions: Following a thorough assessment of the outcomes derived from diverse anti-gout experiments, P2 exhibited superior anti-gout properties compared to the remaining parts. P2 demonstrated a restorative effect on the aberrant parameters associated with gout, thereby comprehensively elucidating the therapeutic mechanism of P2 against gout. This study provides substantial evidence and serves as a reference for future investigations regarding the material foundation of PAL in gout treatment.

Lipidomics and metabolomics investigation into the effect of DAG dietary intervention on hyperuricemia in athletes

The occurrence of hyperuricemia (HUA; elevated serum uric acid) in athletes is relatively high despite that exercise can potentially reduce the risk of developing this condition. Although recent studies have shown the beneficial properties of DAG in improving overall metabolic profiles, a comprehensive understanding of the effect of DAG in modulating HUA in athletes is still lacking. In this study, we leveraged combinatorial lipidomics and metabolomics to investigate the effect of replacing TAG with DAG in the diet of athletes with HUA. A total of 1,074 lipids and metabolites from 94 classes were quantitated in serum from 33 athletes, who were categorized into responders and non-responders based on whether serum uric acid levels returned to healthy levels after the DAG diet intervention. Lipidomics and metabolomics analyses revealed lower levels of xanthine and uric acid in responders, accompanied by elevated plasmalogen phosphatidylcholines and diminished acylcarnitine levels. Our results highlighted the mechanisms behind how the DAG diet circumvented the risk and effects associated with high uric acid via lowered triglycerides at baseline influencing the absorption of DAG resulting in a decline in ROS and uric acid production, increased phospholipid levels associated with reduced p-Cresol metabolism potentially impacting on intestinal excretion of uric acid as well as improved ammonia recycling contributing to decreased serum uric acid levels in responders. These observed alterations might be suggestive that successful implementation of the DAG diet can potentially minimize the likelihood of a potentially vicious cycle occurring in high uric acid, elevated ROS, and impaired mitochondrial metabolism environment.

Spike lavender essential oil attenuates hyperuricemia and induced renal injury by modulating the TLR4/NF-κB/NLRP3 signalling pathway

Hyperuricemia (HUA), recognized as the fourth “high” condition following hypertension, hyperlipidemia, and hyperglycemia, is a metabolic disorder that severely impairs renal function. Spike lavender essential oil (SLEO) exhibits substantial anti-inflammatory and antioxidant activities and can inhibit xanthine oxidase (XOD), suggesting its potential therapeutic potential against HUA. This of this study aimed to analyze the chemical constituents of SLEO with potential efficacy in treating HUA and to explore their mechanisms of action. Gas chromatography-mass spectrometry (GC–MS) combined with a greedy algorithm identified linalool, β-pinene, and β-caryophyllene as key active components of SLEO. Through network pharmacology “weight coefficient” method, the NOD-like signaling pathway emerged as a significant mechanism for SLEO in treating HUA. Investigating an in vitro uric acid (UA)-induced HK-2 cell model revealed that SLEO effectively inhibited the production of IL-1β and IL-18 in the supernatant of HK-2 cells compared to the NLRP3 (antagonist MCC950). Additionally, a HUA rat model demonstrated that SLEO administration significantly reduced hyperuricemia pathological indicators, such as UA, XOD, and blood urea nitrogen (BUN) levels, with renal histopathological sections showing a marked reduction in following SLEO treatment. Metabolomics and transcriptomics analyses further highlighted significant changes in differential metabolites such as arachidonic acid and glycine, as well as the regulation of differential genes such as pycard and PTGS2 in rats.Immunohistochemistry, Western blotting, molecular docking and in vitro XOD activity inhibition assays elucidated the active components mechanisms of SLEO in treating HUA and associated renal inflammation. The findings concluded that SLEO mitigates HUA and renal inflammation by modulating the arachidonic acid metabolic pathway and the NF-κB signaling pathway. Moreover, linalool, β-pinene and β-caryophyllene in SLEO were shown to reduce UA production and lower UA levels in vivo by inhibiting the TLR4/NF-κB/NLRP3 pathway, thereby alleviating HUA-induced renal injury.

A Multimorbidity Analysis of Hospitalized Patients With COVID-19 in Northwest Italy: Longitudinal Study Using Evolutionary Machine Learning and Health Administrative Data.

Multimorbidity is a significant public health concern, characterized by the coexistence and interaction of multiple preexisting medical conditions. This complex condition has been associated with an increased risk of COVID-19. Individuals with multimorbidity who contract COVID-19 often face a significant reduction in life expectancy. The postpandemic period has also highlighted an increase in frailty, emphasizing the importance of integrating existing multimorbidity details into epidemiological risk assessments. Managing clinical data that include medical histories presents significant challenges, particularly due to the sparsity of data arising from the rarity of multimorbidity conditions. Also, the complex enumeration of combinatorial multimorbidity features introduces challenges associated with combinatorial explosions. This study aims to assess the severity of COVID-19 in individuals with multiple medical conditions, considering their demographic characteristics such as age and sex. We propose an evolutionary machine learning model designed to handle sparsity, analyzing preexisting multimorbidity profiles of patients hospitalized with COVID-19 based on their medical history. Our objective is to identify the optimal set of multimorbidity feature combinations strongly associated with COVID-19 severity. We also apply the Apriori algorithm to these evolutionarily derived predictive feature combinations to identify those with high support. We used data from 3 administrative sources in Piedmont, Italy, involving 12,793 individuals aged 45-74 years who tested positive for COVID-19 between February and May 2020. From their 5-year pre-COVID-19 medical histories, we extracted multimorbidity features, including drug prescriptions, disease diagnoses, sex, and age. Focusing on COVID-19 hospitalization, we segmented the data into 4 cohorts based on age and sex. Addressing data imbalance through random resampling, we compared various machine learning algorithms to identify the optimal classification model for our evolutionary approach. Using 5-fold cross-validation, we evaluated each model's performance. Our evolutionary algorithm, utilizing a deep learning classifier, generated prediction-based fitness scores to pinpoint multimorbidity combinations associated with COVID-19 hospitalization risk. Eventually, the Apriori algorithm was applied to identify frequent combinations with high support. We identified multimorbidity predictors associated with COVID-19 hospitalization, indicating more severe COVID-19 outcomes. Frequently occurring morbidity features in the final evolved combinations were age>53, R03BA (glucocorticoid inhalants), and N03AX (other antiepileptics) in cohort 1; A10BA (biguanide or metformin) and N02BE (anilides) in cohort 2; N02AX (other opioids) and M04AA (preparations inhibiting uric acid production) in cohort 3; and G04CA (Alpha-adrenoreceptor antagonists) in cohort 4. When combined with other multimorbidity features, even less prevalent medical conditions show associations with the outcome. This study provides insights beyond COVID-19, demonstrating how repurposed administrative data can be adapted and contribute to enhanced risk assessment for vulnerable populations.

D-glucaro-1,4-lactone improves Diethylnitrosamine induced hepatocellular carcinoma in rats via the uric acid-ROS pathway

Ethnopharmacological relevanceLiuwei dihuang pills is a famous Traditional Chinese Medicine with various anti-cancer properties. Over 50 pharmaceutical manufacturers produce Liuwei dihuang pills in China and an estimated millions of people around the world orally take it every day. D-glucaro-1,4-lactone (1,4-GL) was quantified to be about 12.0 mg/g in Liuwei dihuang pills and a primary bioactive component of it inhibiting the activity of β-glucuronidase in vivo. 1,4-GL can prevent and effectively inhibit various types of cancer. However, its exact mechanism of action remains unknown. The study would justify the traditional usage of Liuwei dihuang pills against cancers. Aim of the study1,4-GL, a bioactive ingredient derived from Liuwei dihuang pills, a famous Traditional Chinese Medicine, could delay the progression of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The mechanism underpinning the effect, however, remains poorly understood. Materials and methodsHealthy and HCC rats were treated with or without 1,4-GL (40.0 mg/kg) and 1HNMR-based metabonomic analysis was employed. 10 metabolites in uric acid pathway were quantitatively determined by UPLC-MS/MS. The expression of xanthine dehydrogenase (XDH), SLC2A9 mRNA, and SLC2A9 protein was determined using RT-qPCR and Western Blot. The effect of 1,4-GL on HCC-LM3 cells was verified in vitro. The alterations of ROS activity, SLC2A9 and XDH gene levels were observed in NCTC-1469 cells induced by lipopolysaccharide (LPS) after 1,4-GL treatment. ResultsAfter the intervention of 1,4-GL, improved pathological morphology, liver lesions in HCC rats was observed with restored serum levels of AFP, AST, ALP, γ-GGT and Fisher's ratio. Hepatic metabonomics revealed that puring metabolism were significantly regulated by 1,4-GL in HCC rats. Uric acid, xanthine and hypoxanthine levels were quantified by UPLC-MS/MS and found to be nearly restored to control levels after 1,4-GL treatment in HCC rats. Changes in xanthine oxidase activity, XDH mRNA expression, and SLC2A9 mRNA and protein expression were also reversed. 1,4-GL treatment in LM3 HCC cells were consistent with the results in vivo. Furthermore, oxidative stress indicators such as T-SOD, GSH, CAT and MDA in serum and liver were improved after HCC rats treated with 1,4-GL. In vitro, 1,4-GL was observed to reduce lipopolysaccharide-induced ROS levels in NCTC-1469 cells with enhanced mRNA and protein expression of SLC2A9 and decreased mRNA level of XDH. ConclusionThe protective effects of 1,4-GL against DEN-induced HCC by reducing uric acid and ROS levels due to down-regulation of uric acid production and up-regulation of SLC2A9 expressions. 1,4-GL may represent a novel treatment that improves recovery from HCC by targeting uric acid-ROS pathway.

A study on the antioxidant, anti-inflammatory, and xanthine oxidase inhibitory activity of the Artemisia vulgaris L. extract and its fractions

Ethnopharmacological relevanceVietnamese people use mugwort (Artemisia vulgaris L.) to treat arthritis and gout. Our previous research shows that mugwort contains flavonoids, and its extract possesses antibacterial and anti-inflammatory activities. However, no publications have been on the xanthine oxidase inhibitory activity of mugwort and acute anti-inflammatory activity in vivo. Aim of the studyThe study aimed to verify the antioxidant, xanthine oxidase inhibitory, and anti-inflammatory capabilities of mugwort extract in vitro and in vivo, isolate phyto-compounds from potential bioactive fractions, and then evaluate their potential in inhibiting xanthine oxidase. MethodsAccording to established methods, the extract and the active flavonoids were obtained using different chromatographic techniques. DPPH, ABTS, reducing power, and H2O2 elimination were used to evaluate antioxidant activity. The model of LPS-induced RAW264.7 cells was used to measure the inhibition of NO production. The carrageenan-induced paw oedema model was used to assess acute inflammation in mice. In vitro, xanthine oxidase inhibition assay was applied to investigate the effects of extract/compounds on uric acid production. Chemical structures were identified by spectral analysis. ResultsThe assessment of the acute inflammatory model in mice revealed that both the 96% ethanol and the 50% ethanol extracts significantly decreased oedema in the mice's feet following carrageenan-induced inflammation. 96% ethanol extract exhibited a better reduction in oedema at the low dose. The analysis revealed that the ethyl acetate fraction had the highest levels of total polyphenols and flavonoids. Additionally, this fraction demonstrated significant antioxidant activity in various assays, such as DPPH, ABTS, reducing power, and H2O2 removal. Furthermore, it displayed the most potent inhibition of xanthine oxidase, an anti-inflammatory activity. Five phytochemicals were isolated and determined from the active fraction such as luteolin (1), rutin (2), apigenin (3), myricetin (4), and quercetin (5). Except for rutin, the other compounds demonstrated the ability to inhibit effective xanthine oxidase compared to standard (allopurinol). Moreover, quercetin (5) inhibited NO production (IC50 21.87 μM). ConclusionThe results indicate that extracts from A. vulgaris effectively suppressed the activity of xanthine oxidase and exhibited antioxidant and anti-inflammatory properties, potentially leading to a reduction in the production of uric acid in the body and eliminating ROS. The study identified mugwort extract and bioactive compounds derived from Artemisia vulgaris, specifically luteolin, apigenin, and quercetin, as promising xanthine oxidase inhibitors. These findings suggest that further development of these compounds is warranted. At the same time, the above results also strengthen the use of mugwort to treat gout disease in Vietnam.

Recent Advances in Xanthine Oxidase Inhibitors.

Uric acid is a product of purine nucleotide metabolism, and high concentrations of uric acid can lead to hyperuricemia, gout and other related diseases. Xanthine oxidase, the only enzyme that catalyzes xanthine and hypoxanthine into uric acid, has become a target for drug development against hyperuricemia and gout. Inhibition of xanthine oxidase can reduce the production of uric acid, so xanthine oxidase inhibitors are used to treat hyperuricemia and related diseases, including gout. In recent years, researchers have obtained new xanthine oxidase inhibitors through drug design, synthesis, or separation of natural products. This paper summarizes the research on xanthine oxidase inhibitors since 2015, mainly including natural products, pyrimidine derivatives, triazole derivatives, isonicotinamide derivatives, chalcone derivatives, furan derivatives, coumarin derivatives, pyrazole derivatives, and imidazole derivatives, hoping to provide valuable information for the research and development of novel xanthine oxidase inhibitors.

Relationship Between Physical Activity and Body Mass Index with Uric Acid Levels in The Community

Physical activity is related to uric acid levels in the blood, and an increase in body mass index (BMI) is associated with an increase in uric acid levels due to increased triglyceride synthesis in the liver associated with increased purine synthesis by new routes, thereby accelerating uric acid production. The results of Riskesdas in 2018 showed the number of joint diseases from the weighted average results in Ogan Komering Ulu Regency was 1,040. This study aims to determine whether there is a relationship between BMI, physical activity, and uric acid levels in the community in Sukaraya Village, East Baturaja District, Ogan Komering Ulu Regency in 2023. This study used an accidental sampling method with a cross-sectional approach and involved 67 respondents with criteria aged between 26 and 45 years, living in Sukaraya Village, being able to read and communicate well, and being willing to be respondents, while the exclusion criteria in this study were not willing to be respondents and could not communicate, and willing to be a respondent, while the exclusion criteria in this study are not willing to be a respondent and cannot be communicated with. The instruments used were the International Physical Activity Quitioner (IPAQ) questionnaire to measure physical activity, scales to measure body weight and height, and uric acid sticks and digital devices (easytouch) to measure uric acid levels. Data were processed using SPSS and chi-square analysis to determine the relationship between the independent variable and the dependent variable. The results of chi-square data analysis showed a relationship between physical activity and uric acid levels (p-value 0.005) and a relationship between BMI and uric acid levels (p-value 0.000). Physical activity and BMI index correlate with uric acid levels in residents in Sukaraya Village, East Baturaja District, Ogan Komering Ulu Regency. It is necessary to increase knowledge about joint health for the community by providing counseling on joint health and also holding activities such as gymnastics so that physical activity and body mass index can be controlled so as to reduce the risk of high uric acid levels.

Development and Validation of an RP-HPLC Method for the Estimation of the Selective Xanthine Oxidase Inhibitor Topiroxostat in Tablets: Greenness Analysis Using AGREE Score

ABSTRACT Background: Xanthine oxidoreductase (XOR) is a key enzyme in the breakdown of purines. It converts hypoxanthine to xanthine and then xanthine to uric acid. Excess uric acid can lead to gout, a painful type of arthritis. XOR inhibitors such as topiroxostat are used to treat gout by reducing uric acid production, preventing the formation of uric acid crystals. Aim and Objectives: A simple and sensitive analytical method was developed to quantify the xanthine oxidase inhibitor topiroxostat in tablet formulation. Materials and Methods: The analyte was seperated on a Phenomenex Luna C18 column (250 mm × 4.6 mm × 5 μm particle size) using a mobile phase of potassium dihydrogen orthophosphate pH 2.5 adjusted with orthophosphoric acid and acetonitrile (60:40 % v/v) pumped at 1.0 mL/min. Detection of the effluent was done using a UV detector at a wavelength of 215 nm. Results: The retention time for topiroxostat was 3.81 min. The drug showed linearity within the concentration range of 18–42 μg/mL. The accuracy of the method was considered satisfactory and the mean recovery percentage in the acceptable range of 99.33-100.45 %. Conclusion: The RP-HPLC method was successfully developed and validated according to ICH guidelines. The AGREE software was used to assess the environmental friendliness score of the proposed method, which was determined to be 0.79. The proposed method was simple, precise, sensitive, rapid, and robust for estimating topiroxostat in tablets.