Disorder Of Purine Metabolism Research Articles

Metformin improves HPRT1-targeted purine metabolism and repairs NR4A1-mediated autophagic flux by modulating FoxO1 nucleocytoplasmic shuttling to treat postmenopausal osteoporosis.

Osteoporosis is a major degenerative metabolic bone disease that threatens the life and health of postmenopausal women. Owing to limitations in detection methods and prevention strategy awareness, the purpose of osteoporosis treatment is more to delay further deterioration rather than to fundamentally correct bone mass. We aimed to clarify the pathogenesis of postmenopausal osteoporosis and optimize treatment plans. Our experiments were based on previous findings that oxidative stress mediates bone metabolism imbalance after oestrogen deficiency. Through energy metabolism-targeted metabolomics, we revealed that purine metabolism disorder is the main mechanism involved in inducing oxidative damage in bone tissue, which was verified via the use of machine-learning data from human databases. Xanthine and xanthine oxidase were used to treat osteoblasts to construct a purine metabolism disorder model. The activity and differentiation ability of osteoblasts decreased after X/XO treatment. Transcriptomic sequencing indicated that autophagic flux damage was involved in purine metabolism-induced oxidative stress in osteoblasts. Additionally, we performed serum metabolomics combined with network pharmacology to determine the pharmacological mechanism of metformin in the treatment of postmenopausal osteoporosis. HPRT1 was the potential target filtered from the hub genes, and FoxO1 signalling was the key pathway mediating the effect of metformin in osteoblasts. We also revealed that SIRT3-mediated deacetylation promoted the nuclear localization of FoxO1 to increase the expression of HPRT1. HPRT1 upregulation promoted purine anabolism and prevented the accumulation of ROS caused by purine catabolism to reverse oxidative damage in osteoblasts. We propose that purine metabolism disorder-induced oxidative stress is important for the pathogenesis of postmenopausal osteoporosis. The therapeutic mechanism of metformin should be confirmed through subsequent drug optimization and development studies to improve bone health in postmenopausal women.

Structural characterization and anti-hyperuricemic effect of a mannogalactan from Armillariella tabescens mycelium

Hyperuricemia and its complications caused by purine metabolism disorder continue to occur, which require effective drug treatment with fewer side effects. This study explored the positive effects of a natural homogeneous polysaccharide (AT-W) from the mycelium of Armillariella tabescens in a mouse hyperuricemia model. Structural characterization showed that the average molecular weight of AT-W is 25.6 kDa, and it is composed of mannose, galactose, arabinose, and fucose, with molar percentages of 11.46:70.9:4.96:12.67. The main backbone of AT-W is composed of partially 3-O-methylated →6)-α-Galp-(1→, and the branches are mainly composed of α-Manp-(1→, →3)-α-Fucp-(1→. In vivo bioactivity evaluation showed AT-W could not only reduce serum uric acid levels by inhibiting the activity of xanthine oxidase, upregulating the expression of ABCG2 and OAT1, and downregulating the expression of URAT1 but also have a significant protective effect on renal damage caused by hyperuricemia. These findings indicate that AT-W has therapeutic potential for hyperuricemia diseases.

Pediatrics hyperuricemia in clinical practice: A retrospective analysis in 1753 children and adolescents with hyperuricemia

ObjectivesSerum levels of uric acid (S-UA) are influenced by the interaction of genetic and environmental factors; detailed studies of hyperuricemia in children are rare. This retrospective study aimed to analyze the causes, risk factors, and therapeutic approaches associated with the development of hyperuricemia in childhood. MethodsIn a single-center study, serum uric acid levels were analyzed in 33,900 samples from 13,890 children and adolescents˂19 years (6760 girls and 7130 boys) obtained between 2013 and 2023. Hyperuricemia was defined as S-UA>370μmol/L (6.22mg/dL) in girls and>420μmol/L (7.06mg/dL) in boys; mild hyperuricemia was defined as 370–420μmol/L in boys˂13 years. ResultsIn the analyzed group, hyperuricemia was found in 1753 patients (12.6%), including 586 girls and 864 boys; mild hyperuricemia was found in 303 boys˂13 years. The most common associated conditions were obesity with body mass index>95th percentile (27.8% of girls, 26.3% of boys) and chronic kidney disease (18.6% of boys, 11.4% of girls). Hyperuricemia was also relatively common in children with connective tissue disorders (10.6%) or different inherited metabolic disorders (10.7%). Transitory hyperuricemia was found in 19.1% of girls and 10.1% of boys with acute gastroenteritis. Urate-lowering therapy was used in 73 children and adolescents with severe hyperuricemia (S-UA 556±107μmol/L, fraction excretion of UA 3.27±1.98%). Eight treated children had chronic kidney disease, nine were extremely obese, one had combined antiepileptic therapy, and 55 had inherited metabolic diseases, including 26 children with disorders of purine metabolism. The initial daily dose of allopurinol (50–100mg) normalized the S-UA (350±80μmol/L) in a majority of children, except for extremely obese adolescents (weight 98–149kg) where the dose had to be increased to 200–300mg. ConclusionsAsymptomatic hyperuricemia is a relatively common biochemical finding in pediatric clinical practice. The etiology of hyperuricemia should be carefully analyzed, and the value of individualized hyperuricemia management and the eventual benefits of urate-lowering therapy in children must be carefully considered.

Medullary Nephrocalcinosis

Medullary nephrocalcinosis is a clinical variant of chronic kidney disease characterized by diffuse deposition of calcium and phosphate salts in the parenchyma, leading to inflammatory-dystrophic changes and the development of chronic renal failure. Medullary nephrocalcinosis is divided into primary (develops in previously unaltered kidneys and initially affects the proximal part of the nephron) and secondary (simultaneously affects all parts of the renal glomeruli, causing nephrosclerosis and increasing the risk of chronic kidney disease). The article describes two clinical cases of medullary nephrocalcinosis with different etiological factors. In the first case, the disease developed against the background of regular use of third-generation cephalosporins (ceftriaxone), while in the second case, it resulted from lipid and purine metabolism disorders. The genetic and etiopathogenetic aspects of medullary nephrocalcinosis are discussed. Given the importance of determining the causes and pathogenetic mechanisms of medullary nephrocalcinosis, the need for thorough diagnostics in adult patients with changes in the renal parenchyma accompanied by hyperparathyroidism, hyper- or normocalcemia, hypophosphatemia, hypomagnesemia, and hypercalciuria is emphasized. Diagnostic workup should include genetic, metabolic, and iatrogenic components of kidney damage.

Mechanism of Biqi capsules in the treatment of gout based on network pharmacology and experimental verification

Ethnopharmacological relevanceGout is a crystal-related arthropathy caused by monosodium urate (MSU) deposition, resulting from purine metabolism disorders and hyperuricemia (HUA). Gout belongs to the traditional medicine category of Bi syndrome. Biqi capsules (BQ) is a traditional Chinese medicine formula used to treat Bi syndrome. The BQ prescription is derived from the ancient prescription of Hua Tuo, a famous physician in the Han Dynasty. Aim of the studyTo study the effect and mechanism of BQ in treating acute gouty arthritis (AGA) and HUA. Materials and methodsAnalyzing BQ's signaling pathways for gout treatment via network pharmacology. The HUA model was induced orally with adenine and potassium oxonate. The rat AGA model was established by MSU injection. In vitro, MH7A and RAW 246.7 cells were treated with LPS and MSU. Serum uric acid, creatinine, and urea nitrogen levels were evaluated. Kidney and ankle joint pathology was observed via HE staining. Inflammatory signaling pathway proteins, epithelial-mesenchymal transition (EMT) pathway proteins, and uric acid metabolism-related proteins were detected by Western blot. Results1780 potential targets for gout treatment were identified, and 1039 target proteins corresponding to BQ's active ingredients were obtained. Pathway enrichment analysis revealed BQ improved gout mainly through inflammatory pathways. Experimental results showed BQ could reduce serum uric acid level and increase uric acid clearance rate by regulating the expression of adenosine deaminase (ADA), and organic anion transporter 1 (OAT1) and glucose transporter 9 (GLUT9) in HUA mice. BQ could improve renal function and injury by inhibiting the NLRP3 pathway in HUA mice' kidneys. Additionally, BQ could alleviate ankle joint swelling and synovial injury, inhibit the TLR4/NLRP3 pathway, and reduce levels of inflammatory factors including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) in AGA rats. The main component of BQ, brucine, could inhibit the activation of NLRP3/NF-κB pathway induced by MSU and reduce the expression level of inflammatory factors (IL-6, IL-1β, and TNF-α) in macrophages. Brucine could inhibit the activation of the EMT pathway and reduce the expression level of inflammatory factors (IL-6, TNF-α) in human fibroblast-like synoviocytes (MH7A cells) induced by MSU. ConclusionsBQ effectively reduced serum uric acid levels, improved kidney and joint damage, and ameliorated the inflammatory response caused by MSU. Its main component, brucine, effectively improved the inflammatory response and reduced the invasive ability of synoviocytes induced by MSU.

DaiTongXiao improves gout nephropathy by inhibiting inflammatory response through the TLR4/MyD88/NF-κB pathway.

Introduction: Gouty nephropathy (GN) arises from factors like excessive purine intake, metabolic disorders or abnormal synthesis, and uric acid hypersaturation in the blood, leading to urate crystal deposition in kidney tissue. DaiTongXiao (DTX) is a remedy used by the Dai people of China. It shows efficacy in lowering uric acid levels and exhibits anti-inflammatory and kidney-protective properties. Methods: A GN rat model was induced using adenine and potassium oxonate. Following DTX administration, various parameters were assessed in urine, serum, and kidney tissue. Western blot analysis evaluated TLR4/MyD88/NF-κB signaling proteins, while immunofluorescence examined NF-κB nuclear expression. Results: DTX treatment improved kidney morphology, increased body weight, and kidney index and enhanced urinary levels of blood urea nitrogen (Bun), 24-h urinary protein, uric acid (UA), and allantoin in GN rats, reducing UA, Bun, creatinine (Cre), cystatin C (CysC), serum amyloid A (SAA), α1-microglobulin (MG), and β2-MG in serum analysis. Renal tissue assessments showed decreased xanthine oxidase (XOD), hydroxyproline (Hyp), α-smooth muscle actin (α-SMA), and collage type Ⅳ (COL-Ⅳ). Kidney damage severity was notably reduced. DTX lowered serum inflammatory factors like interleukin (IL) -18, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), transforming growth factor-β1 (TGF-β1), and IL-1β in the rat serum, reducing chemokine monocyte chemoattractant protein-1 (MCP-1) and adhesion factor vascular cell adhesion molecule-1(VCAM-1). Western blotting demonstrated the downregulation of TLR4/MyD88/NF-κB pathway proteins, and immunofluorescence revealed reduced NF-κB expression in renal tissue. Discussion: DTX exhibits significant anti-GN effects by modulating TLR4/MyD88/ NF-κB pathway protein expression, reducing inflammatory factor release, and inhibiting GN progression.

КАРДИОМЕТАБОЛИЧЕСКИЙ ПРОФИЛЬ С УЧЕТОМ СТАДИРОВАНИЯ ПО CMDS У ЛИЦ МОЛОДОГО ВОЗРАСТА

Abstract. Introduction. The burden of cardiovascular disease, diabetes mellitus, and the associated mortality remains high. One classification system that predicts the development of cardiovascular events and type 2 diabetes mellitus is Cardiometabolic Disease Staging (CMDS). The study of new cardiometabolic profile parameters is relevant in the context of their association with residual cardiovascular risk. The aim of the study was to evaluate the cardiometabolic profile, including extended parameters, in young adults, while taking into account the CMDS. Materials and Methods. 185 male and female subjects aged 35.0 [30.0–39.0] years were examined. The participants were divided into groups according to the CMDS classification: Stage 0, metabolically healthy; Stage 1 (low risk), one or two risk factors (RFs) other than prediabetes; Stage 2 (intermediate risk), presence of ≥3 risk factors or prediabetes; Stage 3 (high risk), presence of ≥3 risk factors and prediabetes. The study examined visceral adiposity index, visceral fat level, insulin resistance, leptinemia, hyperuricemia, glomerular filtration rate, C–reactive protein, and N–terminal brain natriuretic peptide concentrations. The data were processed in SPSS Statistics 26. Results and Discussion. The cardiometabolic profile demonstrated unfavorable alterations with the progression of CMDS stages. Across the spectrum from CMDS 0 to CMDS 3, we observed a significant rise in the prevalence of abdominal obesity (0% to 100%, p<0,001), body mass index ≥25 kg/m2 (16.2% to 100%, p<0.001), and excess visceral fat level (0% to 23.8%, p<0.001). Simultaneously, the prevalence of hypercholesterolemia demonstrated a significant rise (24.3% to 52.4%, p=0.025), as did elevated low–density lipoprotein cholesterol (32.4% to 76.1%, p=0.014), insulin resistance (2.7% to 66.7%, p<0.001), leptinemia (45.9% to 90.5%, p=0.009), C–reactive protein (2.7% to 57.1%, p<0.001) and hyperuricemia (16.2% to 61.9%, p<0.001). The median values of these parameters also increased. Conclusions. Our data confirm the simultaneous increase in both the quantity and intensity of risk factors, manifestations of adiposopathy associated with increasing residual cardiovascular risk. Our results substantiate the feasibility of using the CMDS classification at the stage of primary prevention of cardiometabolic diseases to identify groups with the most significant metabolism disorders of lipid, carbohydrate and purine metabolism in young adults.

Ischemic stroke: focus on hyperuricemia

Uric acid is a weak organic acid with a molecular weight of 168.112 g/mol. Most uric acid at normal blood pH circulates as urates, negatively charged weak salts derived from uric acid. Being the end product of the process of purine catabolism, uric acid is excreted from the human body in urine until kidney function is impaired. Hyperuricemia may occur due to decreased excretion, increased production, or a combination of both mechanisms. Over the past decades, several studies in the adult population have attempted to establish the correlation between the risk of stroke and serum uric acid concentrations, and how these levels influence the patient's neurological outcome after stroke. Our review is devoted to the study of the mechanisms of normal purine metabolism, disorders of purine metabolism and pathogenetic mechanisms of the development of ischemic stroke in hyperuricemia.

#2556 Therapeutic monitoring in patients with APRT deficiency using UPLC-MS/MS-based plasma assay

Abstract Background and Aims Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder of purine metabolism, characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to nephrolithiasis and chronic kidney disease (CKD). Treatment with xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces DHA excretion and slows or halts CKD progression. The aim of the study was to optimize and validate an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based assay for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma, for monitoring of pharmacotherapy in patients with APRT deficiency. Method The UPLC-MS/MS-based assay was optimized employing the chemometric approach design of experiments, using the software Modde Pro 13 (Sartorius, Umeå, Sweden). The assay was validated and used for absolute quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in plasma samples from both untreated and treated APRTd patients and healthy controls. Results Accuracy and precision were within ±15% for all analytes, and the analytes were stable in plasma for 12 months at −80°C. The median (range) concentration of DHA in plasma samples from six APRT deficiency patients was 204.0 (187.2–315.8) ng/mL when they were untreated and 69.2 (below the limit of quantification [BLQ]–131.6) ng/mL when treated with allopurinol (400 mg/day), and BLQ when febuxostat (80 mg/day) was the therapeutic agent. The median (range) plasma adenine concentration was 238.1 (218–502) ng/mL in the untreated patients, and 561.1 (418–2104) and 856.0 (726–1711) ng/mL in those on treatment with allopurinol and febuxostat, respectively. DHA was not detected in plasma samples from healthy controls. The median (range) plasma concentration of allopurinol, oxypurinol and febuxostat in patients receiving XOR inhibitor therapy was 1657 (BLQ-3266) ng/mL, 8102 (4778–34906) ng/mL and 109 (BLQ-1657) ng/mL, respectively. Conclusion The UPLC-MS/MS-based assay provides accurate and precise quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma. Measurement of plasma DHA is being implemented as a diagnostic test for APRT deficiency and the full assay for monitoring of XOR inhibitor treatment in patients with the disorder.

Shexiang Baoxin Pill enriches Lactobacillus to regulate purine metabolism in patients with stable coronary artery disease

BackgroundIt has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored. PurposeThe study explored the therapeutic mechanism of SBP in the treatment of SCAD patients. MethodsWe examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing. ResultsSBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota. ConclusionOur study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.

Hospital Length of Stay and Associated Factors in Patients with Osteoarthritis from Germany: A Cross-Sectional Study.

Objective: There is a scarcity of data on hospital length of stay (LOS) in the osteoarthritis population. Therefore, this study aimed to investigate hospital LOS and associated factors in patients with osteoarthritis from Germany. Methods: The present cross-sectional study included patients hospitalized for osteoarthritis in one of fourteen hospitals in Germany between 2018 and 2023 (hospital database; IQVIA). The study outcome was the duration of hospital stay in days. Study covariables included age, sex, hospital department, osteoarthritis type, co-diagnosis, and hospitalization-related procedure. Associations between covariables and hospital LOS were analyzed using hierarchical linear regression models. Results: There were 8770 patients included in the study (mean [standard deviation] age 68.7 [10.8] years; 60.2% women). The mean (standard deviation) hospital LOS was 8.5 (5.0) days. Factors positively and significantly associated with hospital LOS were older age, female sex, orthopedic surgery and other medical specialty departments (compared with other surgery departments), knee and other and unspecified osteoarthritis (compared with hip osteoarthritis), multiple co-diagnoses (e.g., acute posthemorrhagic anemia, other disorders of fluid, electrolyte, and acid-base balance, and disorders of purine and pyrimidine metabolism), and several hospitalization-related procedures (i.e., geriatric rehabilitation, hip arthroplasty, and knee arthroplasty). Conclusions: The mean hospital LOS was higher than eight days in this osteoarthritis population from Germany, with a spectrum of demographic, clinical, and hospitalization-related factors associated with this hospital LOS. In this context, interventions are needed to reduce the LOS of hospitalizations for osteoarthritis in Germany.

Prospective evaluation of the clinical, laboratory, and dietary determinates of outcomes in purine and pyrimidine metabolism disorders: Considerations for the study design

Prospective evaluation of the clinical, laboratory, and dietary determinates of outcomes in purine and pyrimidine metabolism disorders: Considerations for the study design

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 μM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

Retinol dehydrogenase 12 (RDH12) knock out may cause hyperuricemia phenotype in mice

Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder. And several gene loci and transporter proteins that associated with uric acid transport functions have been identified. Retinol Dehydrogenase 12 (RDH12), recognized for its role in safeguarding photoreceptors, and our study investigated the potential impact of Rdh12 mutations on other organs and diseases, particularly hyperuricemia. We assessed Rdh12 mRNA expression levels in various tissues and conducted serum biochemical analyses in Rdh12−/− mice. Compared with the wild type, significant alterations in serum uric acid levels and kidney-related biochemical indicators have been revealed. Then further analysis, including quantitative RT-PCR of gene expression in the liver and kidney, highlighted variations in the expression levels of specific genes linked to hyperuricemia. And renal histology assessment exposed mild pathological lesions in the kidneys of Rdh12−/− mice.In summary, our study suggests that Rdh12 mutations impact not only retinal function but also contribute to hyperuricemia and renal disease phenotypes in mice. Our finding implies that individuals with Rdh12 mutations may be prone to hyperuricemia and gout, emphasizing the significance of preventive measures and regular examinations in daily life.

Postbiotic of Pediococcus acidilactici GQ01, a Novel Probiotic Strain Isolated from Natural Fermented Wolfberry, Attenuates Hyperuricaemia in Mice through Modulating Uric Acid Metabolism and Gut Microbiota.

Hyperuricaemia (HUA) is a disorder of purine metabolism, which manifests itself as an increase in uric acid production and a decrease in uric acid excretion, as well as a change in the structure of the intestinal microbiota. Most of the drugs currently used to treat HUA have significant side effects, and it is essential to find a treatment for HUA that is free of side effects. In this study, a novel strain, Pediococcus acidilactici GQ01, was screened from natural fermented wolfberry. The effects of both live bacteria GQ01 and its heat-killed G1PB postbiotic on HUA were investigated. The results showed that both probiotic GQ01 and G1PB postbiotics could effectively decrease blood uric acid, creatinine, and urea nitrogen levels in the HUA mice model. P. acidilactici GQ01 was more effective in inhibiting ADA activity, while G1PB postbiotics was more effective in inhibiting XOD activity. Meanwhile, GQ01 and G1PB were able to ameliorate liver and kidney tissue injury, upregulate the expression of ABCG2 in kidney and XOD gene in liver, downregulate the protein expression of URAT1 and GLUT9 in kidney, and therefore reduce the value of blood uric acid by decreasing the uric acid reabsorption and increasing the excretion of uric acid. Additionally, both probiotics and postbiotics could regulate the intestinal microbiota structure of HUA mice, so as to bring the dysfunctional intestinal composition back to normal. Furthermore, P. acidilactici GQ01 and G1PB postbiotics can increase the levels of acetic acid, propionic acid, and butyric acid in the intestinal tract, improve the intestinal function, and maintain the healthy homeostatic state of the intestinal tract. In summary, P. acidilactici GQ01 and its G1PB postbiotics may be developed as functional food or drug materials capable of treating HUA.

Gout: physical activity in therapy and prevention of the disease

Gout is a systemic chronic inflammatory disease associated with purine metabolism disorders. Risk factors for gout are a combination of genetic and environmental factors. Taking into account such features of the pathogenesis of gout as hyperuricemia and the deposition of monosodium urate crystals in tissues and joints, the development of the inflammatory, researchers studied the effect of physical activity on its main links. The intensity of the load and the type of physical exercise were taken into account due to their possible effect on metabolic processes. There is currently no reliable evidence on the importance of physical activity in reducing serum uric acid levels. Research has shown that physical activity has a positive effect on inflammation between gout attacks. The use of physical exercise can indirectly affect uric acid levels by reducing body weight in comorbid pathologies. EULAR emphasizes physical activity to prevent cardiovascular risks, which is also important for gout. Conclusions. Physical activity as one of the components of lifestyle is important for gout due to its effect on the inflammatory process and the prevention of relapses, a general strengthening effect on the body, an effect on hyperuricemia due to the positive effect associated with comorbid pathology, and a decrease in cardiovascular risk and associated him premature death. Physical activity of low and moderate intensity is effective for gout. Preference is given to aerobic exercise, taking into account the nature of metabolism and the possible impact on the occurrence of gout attacks. Further study and development of the characteristics of physical activity in gout are necessary to improve the prevention and treatment of the disease, and the development of individual recommendations for patients (for the management of gout).

Multi-omics analyses reveal interactions between the skin microbiota and skin metabolites in atopic dermatitis.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. Skin microecological imbalance is an important factor in the pathogenesis of AD, but the underlying mechanism of its interaction with humans remains unclear. 16S rRNA gene sequencing was conducted to reveal the skin microbiota dynamics. Changes in skin metabolites were tracked by LC-MS metabolomics. We then explored the potential mechanism of interaction by analyzing the correlation between skin bacterial communities and metabolites in corresponding skin-associated samples. Samples from 18 AD patients and 18 healthy volunteers (HVs) were subjected to 16S rRNA gene sequencing and LC-MS metabolomics. AD patients had dysbiosis of the skin bacterial community with decreased species richness and evenness. The relative abundance of the genus Staphylococcus increased significantly in AD, while the abundances of the genera Propionibacterium and Brevundimonas decreased significantly. The relative abundance of the genera Staphylococcus in healthy females was significantly higher than those in healthy males, while it showed no difference in AD patients with or without lesions. The effects of AD status, sex and the presence or absence of rashes on the number of differentially abundant metabolites per capita were successively reduced. Multiple metabolites involved in purine metabolism and phenylalanine metabolism pathways (such as xanthosine/xanthine and L-phenylalanine/trans-cinnamate) were increased in AD patients. These trends were much more obvious between female AD patients and female HVs. Spearman correlation analysis revealed that the genus Staphylococcus was positively correlated with various compounds involved in phenylalanine metabolism and purine metabolic pathways. The genera Brevundimonas and Lactobacillus were negatively correlated with various compounds involved in purine metabolism, phenylalanine metabolism and sphingolipid signaling pathways. We suggest that purine metabolism and phenylalanine metabolism pathway disorders may play a certain role in the pathogenic mechanism of Staphylococcus aureus in AD. We also found that females are more likely to be colonized by the genus Staphylococcus than males. Differentially abundant metabolites involved in purine metabolism and phenylalanine metabolism pathways were more obvious in female. However, we should notice that the metabolites we detected do not necessarily derived from microbes, they may also origin from the host.

Hyperuricemia research progress in model construction and traditional Chinese medicine interventions.

Hyperuricemia (HUA), a severe metabolic disease derived from purine metabolism disorder, will lead to abnormally increased serum uric acid (SUA) levels in the body. Studies have shown that HUA is highly related to gout, hypertension, diabetes, coronary heart disease, chronic kidney diseases, and so on. Traditional Chinese medicine (TCM) shows excellent results in treating HUA because of its unique advantages of multi-metabolites and multi-targets. This article reports on the use of TCM components for uric acid (UA)-lowering activity with excellent efficacy and low side effects based on established HUA models. This work summarizes the advantages and limitations of various HUA disease models for efficacy evaluation. Applications of TCM in HUA treatment have also been discussed in detail. This paper reveals recent research progress on HUA in constructing evaluation models and systematic TCM interventions. It will provide a scientific reference for establishing the HUA model and suggest future TCM-related HUA studies.

Hesperitin-Copper(II) Complex Regulates the NLRP3 Pathway and Attenuates Hyperuricemia and Renal Inflammation.

Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex's UA-lowering and nephroprotective effects in vivo. A mouse with HUA was used to investigate the complex's hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.

Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway

BackgroundDiabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear. AimThis study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved. MethodsC57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses. ResultsAfter a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels. ConclusionTreatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.