RÉSUMÉ
Hyperuricemia (HUA) is characterized by elevated blood uric acid levels, which can increase the risk of erectile dysfunction (ED). Clinical studies have demonstrated satisfactory efficacy of a traditional Chinese medicine formula QYHT decoction in improving ED. Furthermore, the main monomeric components of this formula, linoleyl acetate and mandenol, demonstrate promise in the treatment of ED. This study established an ED rat model induced by HUA and the animals were administered with linoleyl acetate and mandenol. HE and TUNEL were performed to detect tissue changes, ELISA to measure the levels of serum testosterone (T), MDA, NO, CRP, and TNF-α and qPCR and WB to assess the expression levels of NLRP3, ASC, Caspase-1, JAK2, and STAT3 in whole blood. The findings showed that linoleyl acetate and mandenol improved kidney tissue morphology, reduced cell apoptosis in penile tissue, significantly increased T and NO levels, while substantially decreasing levels of MDA, CRP, and TNF-α. Meanwhile, the expression of NLRP3, ASC, and Caspase-1 mRNAs and proteins was markedly reduced, and the phosphorylation of JAK2 and STAT3 was inhibited. These findings were further validated through faecal microbiota transplantation results. Taken together, linoleyl acetate and mandenol could inhibit NLRP3 inflammasome activation, reduce inflammatory and oxidative stress responses, suppress the activity of JAK-STAT signalling pathway, ultimately providing a potential treatment for HUA-induced ED.
Sujet(s)
Dysfonctionnement érectile , Hyperuricémie , Inflammasomes , Kinase Janus-2 , Protéine-3 de la famille des NLR contenant un domaine pyrine , Rat Sprague-Dawley , Facteur de transcription STAT-3 , Transduction du signal , Animaux , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Kinase Janus-2/métabolisme , Mâle , Inflammasomes/métabolisme , Facteur de transcription STAT-3/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Rats , Dysfonctionnement érectile/traitement médicamenteux , Dysfonctionnement érectile/étiologie , Dysfonctionnement érectile/métabolisme , Hyperuricémie/traitement médicamenteux , Hyperuricémie/complications , Apoptose/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaineRÉSUMÉ
BACKGROUND: Febuxostat is recommended for treatment of severe hyperuricemia in chronic kidney disease (CKD). We previously reported a significant positive correlation between fractional excretion of uric acid (FEUA) and estimated excretion of uric acid (eEUA) in patients receiving febuxostat and proposed that the addition of uricosuric agents could further decrease serum uric acid (sUA) levels by enhancing FEUA and eEUA in patients treated with febuxostat. METHODS: This retrospective study included 34 patients with CKD who were categorized into three groups (G3-G5) according to their estimated glomerular filtration rate (eGFR). The effects on sUA, FEUA, and eEUA of adding dotinurad (0.5 mg/day) to febuxostat (10 mg/day) were evaluated in these patients. Specifically, we examined changes in sUA, FEUA, and eEUA in each group after the addition of dotinurad. RESULTS: Dotinurad significantly increased FEUA in all groups and notably decreased sUA in groups G3 and G4 but not in group G5. There was no significant change in eEUA in any group. Dotinurad maintained the significant positive correlation between FEUA and eEUA in patients receiving febuxostat. CONCLUSIONS: This study is the first to show the effect of combining dotinurad with febuxostat in lowering sUA levels in G3 and G4 patients. Additional research is required in order to clarify the pharmacological mechanisms of dotinurad in patients with CKD.
Sujet(s)
Fébuxostat , Débit de filtration glomérulaire , Hyperuricémie , Insuffisance rénale chronique , Acide urique , Humains , Fébuxostat/usage thérapeutique , Fébuxostat/administration et posologie , Acide urique/sang , Mâle , Insuffisance rénale chronique/sang , Insuffisance rénale chronique/traitement médicamenteux , Insuffisance rénale chronique/complications , Études rétrospectives , Femelle , Sujet âgé , Adulte d'âge moyen , Hyperuricémie/traitement médicamenteux , Hyperuricémie/sang , Uricosuriques/usage thérapeutique , Uricosuriques/administration et posologie , Benzothiazoles/administration et posologie , Benzothiazoles/usage thérapeutique , Association de médicaments , Sujet âgé de 80 ans ou plus , Marqueurs biologiques/sang , Résultat thérapeutiqueRÉSUMÉ
Plantaginis semen is the dried ripe seed of Plantago asiatica L. or Plantago depressa Willd., which has a long history in alleviating hyperuricemia (HUA) and chronic kidney diseases. While the major chemical ingredients and mechanism remained to be illustrated. Therefore, this work aimed to elucidate the chemicals and working mechanisms of PS for HUA. UPLC-QE-Orbitrap-MS was applied to identify the main components of PS in vitro and in vivo. RNA sequencing (RNA-seq) was conducted to explore the gene expression profile, and the genes involved were further confirmed by real-time quantitative PCR (RT-qPCR). A total of 39 components were identified from PS, and 13 of them were detected in the rat serum after treating the rat with PS. The kidney tissue injury and serum uric acid (UA), xanthine oxidase (XOD), and cytokine levels were reversed by PS. Meanwhile, renal urate anion transporter 1 (Urat1) and glucose transporter 9 (Glut9) levels were reversed with PS treatment. RNA-seq analysis showed that the PPAR signaling pathway; glycine, serine, and threonine metabolism signaling pathway; and fatty acid metabolism signaling pathway were significantly modified by PS treatment. Further, the gene expression of Slc7a8, Pck1, Mgll, and Bhmt were significantly elevated, and Fkbp5 was downregulated, consistent with RNA-seq results. The PPAR signaling pathway involved Pparα, Pparγ, Lpl, Plin5, Atgl, and Hsl were elevated by PS treatment. URAT1 and PPARα proteins levels were confirmed by Western blotting. In conclusion, this study elucidates the chemical profile and working mechanisms of PS for prevention and therapy of HUA and provides a promising traditional Chinese medicine agency for HUA prophylaxis.
Sujet(s)
Hyperuricémie , Acide oxonique , Plantago , Hyperuricémie/traitement médicamenteux , Hyperuricémie/métabolisme , Animaux , Rats , Acide oxonique/effets indésirables , Mâle , Plantago/composition chimique , Acide urique/sang , Extraits de plantes/pharmacologie , Rein/métabolisme , Rein/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Transduction du signal/effets des médicaments et des substances chimiques , Transporteurs de cations organiques/métabolisme , Transporteurs de cations organiques/génétique , Transporteurs d'anions organiques/métabolisme , Transporteurs d'anions organiques/génétique , Xanthine oxidase/métabolismeRÉSUMÉ
The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.
Sujet(s)
Goutte , Hyperuricémie , Transporteurs d'anions organiques , Transporteurs de cations organiques , Xanthine oxidase , Xanthine oxidase/antagonistes et inhibiteurs , Xanthine oxidase/métabolisme , Hyperuricémie/traitement médicamenteux , Animaux , Goutte/traitement médicamenteux , Relation structure-activité , Humains , Transporteurs d'anions organiques/antagonistes et inhibiteurs , Transporteurs d'anions organiques/métabolisme , Rats , Transporteurs de cations organiques/antagonistes et inhibiteurs , Transporteurs de cations organiques/métabolisme , Administration par voie orale , Rat Sprague-Dawley , Mâle , Macaca fascicularis , Fébuxostat/pharmacologie , Fébuxostat/pharmacocinétique , Fébuxostat/usage thérapeutique , Fébuxostat/composition chimique , Découverte de médicament , Antienzymes/pharmacologie , Antienzymes/pharmacocinétique , Antienzymes/usage thérapeutique , Antienzymes/composition chimique , Antienzymes/synthèse chimique , Antigoutteux/pharmacocinétique , Antigoutteux/pharmacologie , Antigoutteux/usage thérapeutique , Antigoutteux/composition chimique , Antigoutteux/synthèse chimique , Biodisponibilité , Probénécide/pharmacologieRÉSUMÉ
BACKGROUND: Hyperuricemia (HUA) is a public health concern that needs to be solved urgently. The lyophilized powder of Poecilobdella manillensis has been shown to significantly alleviate HUA; however, its underlying metabolic regulation remains unclear. AIM: To explore the underlying mechanisms of Poecilobdella manillensis in HUA based on modulation of the gut microbiota and host metabolism. METHODS: A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections. The mice received oral drugs or saline. Additionally, 16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome, respectively. The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay. RESULTS: The protein extract of Poecilobdella manillensis lyophilized powder (49 mg/kg) showed an enhanced anti-trioxypurine ability than that of allopurinol (5 mg/kg) (P < 0.05). A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which included the genera of Prevotella, Delftia, Dialister, Akkermansia, Lactococcus, Escherichia_Shigella, Enterococcus, and Bacteroides. Furthermore, 22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism, sphingolipid metabolism, galactose metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites. CONCLUSION: The proteins in Poecilobdella manillensis powder were effective for HUA. Mechanistically, they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.
Sujet(s)
Modèles animaux de maladie humaine , Microbiome gastro-intestinal , Hyperuricémie , Sangsues , Animaux , Hyperuricémie/traitement médicamenteux , Hyperuricémie/sang , Hyperuricémie/microbiologie , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Souris , Mâle , Sangsues/microbiologie , Acide urique/sang , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Rein/microbiologie , Métabolomique/méthodes , ARN ribosomique 16S/génétique , Humains , Dysbiose , Métabolome/effets des médicaments et des substances chimiquesRÉSUMÉ
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.
Sujet(s)
Hyperuricémie , Peptides , Hydrolysats de protéines , Hydrolysats de protéines/composition chimique , Hyperuricémie/traitement médicamenteux , Hyperuricémie/métabolisme , Humains , Peptides/composition chimique , Animaux , Acide urique/métabolisme , Xanthine oxidase/métabolismeRÉSUMÉ
Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
Sujet(s)
Composés benzhydryliques , Fibrose , Glucosides , Hyperuricémie , Inhibiteurs du cotransporteur sodium-glucose de type 2 , Animaux , Glucosides/pharmacologie , Glucosides/usage thérapeutique , Composés benzhydryliques/pharmacologie , Fibrose/traitement médicamenteux , Inhibiteurs du cotransporteur sodium-glucose de type 2/pharmacologie , Hyperuricémie/traitement médicamenteux , Hyperuricémie/complications , Humains , Souris , Mâle , , Maladies du rein/traitement médicamenteux , Maladies du rein/anatomopathologie , Maladies du rein/métabolisme , Rein/anatomopathologie , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Souris de lignée C57BL , Acide urique/sang , Récepteurs des oestrogènes/métabolisme , Protéine-1 de transport d'anions organiques/métabolisme , Protéine-1 de transport d'anions organiques/génétique , Lignée cellulaire , Insuffisance rénale chronique/traitement médicamenteux , Insuffisance rénale chronique/anatomopathologie , Modèles animaux de maladie humaine , FemelleRÉSUMÉ
Previously, we reported a novel natural scaffold compound, isobavachin (4',7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC50 = 0.24 µM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC50 of 4.47 µM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.
Sujet(s)
Conception de médicament , Hyperuricémie , Hyperuricémie/traitement médicamenteux , Animaux , Relation structure-activité , Souris , Humains , Structure moléculaire , Relation dose-effet des médicaments , Mâle , Transporteurs d'anions organiques/antagonistes et inhibiteurs , Transporteurs d'anions organiques/métabolisme , Acide urique/sang , Transporteurs de cations organiques/antagonistes et inhibiteurs , Transporteurs de cations organiques/métabolismeRÉSUMÉ
The incidence of hyperuricemia (HUA) shows a gradually increasing trend towards affecting younger individuals, and it can significantly harm the overall health status of the body. Based on a metabolomics perspective, this study reveals the mechanism of the uric acid-lowering action of Prunus salicina Lindl. cv. "furong" polyphenols (PSLP) on a hyperuricemia mouse model induced by hypoxanthine and potassium oxybutyrate. The results demonstrate that PSLP comprise an effective treatment strategy for reducing the levels of serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) in HUA mice (p < 0.05), wherein the maximum decrease rates are up to 44.50%, 29.46%, and 32.95%, respectively. PSLP are observed to exert a pronounced inhibitory effect on the activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) in the livers of HUA mice, with reductions of up to 16.36% and 20.13%, respectively. These findings illustrate that PSLP exert a significant uric acid-lowering effect. Subsequent metabolomic analysis of mouse serum identified 28 potential biomarkers for hyperuricemia, whose levels were markedly diminished by PSLP. This process involved alterations in purine, glycine, the pentose phosphate pathway, and galactose metabolism. Twenty-eight potential biomarkers were identified for hyperuricemia by subsequent metabolomic analysis of mouse serum, whose levels were markedly reversed by PSLP intervention. The regulation of HUA by PSLP involved alterations in purine metabolism, glycerolipid metabolism, the pentose phosphate pathway, and galactose metabolism. The mechanism of PSLP ameliorated hyperuricemia might be attributed to reduction of the level of the uric acid precursor ribose-5-phosphate in the pentose phosphate pathway, the inhibition of the activities of uric acid synthase XOD and ADA in purine metabolism, and reduction of the synthesis of the end product uric acid. This study provides a theoretical basis for the development of functional foods based on PSLP, which can potentially reduce uric acid levels.
Sujet(s)
Hyperuricémie , Hypoxanthine , Métabolomique , Polyphénols , Prunus , Acide urique , Animaux , Hyperuricémie/traitement médicamenteux , Hyperuricémie/métabolisme , Hyperuricémie/induit chimiquement , Souris , Acide urique/sang , Acide urique/métabolisme , Mâle , Prunus/composition chimique , Polyphénols/pharmacologie , Hypoxanthine/métabolisme , Extraits de plantes/pharmacologie , Modèles animaux de maladie humaine , Hydroxy-butyrates , Créatinine/sang , Marqueurs biologiques/sang , Acide oxoniqueRÉSUMÉ
Hyperuricemia is with growing incidence and of high risk to develop into gout and other metabolic diseases. The key enzyme catalyzing uric acid synthesis, xanthine oxidoreductase (XOR) is a vital target for anti-hyperuricemic drugs, while XOR inhibitors characterized as both potent and safe are currently in urgent need. In this study, a novel small molecule compound, CC15009, was identified as a specific XOR inhibitor. CC15009 exerted strongest in vitro XOR inhibitory activity among current XOR inhibitors. It also showed favorable dose-dependent uric acid-lowering effects in two different XOR substrate-induced hyperuricemic mouse models, which was significantly superior than the current first-line drug, allopurinol. Mechanically, the direct binding of CC15009 against XOR was confirmed by molecular docking and SPR analysis. The inhibition mode was competitive and reversible. Besides, the potential antioxidant activity of CC15009 was indicated by its strong inhibitory activity against the oxidized isoform of XOR, which reduced ROS generation as the byproduct. Regarding the safety concerns of current XOR inhibitors, especially in cardiovascular risks, the safety of CC15009 was comprehensively evaluated. No significant abnormality was observed in the acute, subacute toxicity tests and mini-AMES test. Notably, there was no obvious inhibition of CC15009 against cardiac ion channels, including hERG, Nav1.5, Cav1.2 at the concentration of 30⯵M, indicating its lower cardiovascular risk. Taken together, our results supported CC15009 as a candidate of high efficacy and safety profile to treat hyperuricemia through direct XOR inhibition.
Sujet(s)
Antienzymes , Hyperuricémie , Acide urique , Xanthine dehydrogenase , Animaux , Humains , Mâle , Souris , Allopurinol/pharmacologie , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Antienzymes/pharmacologie , Antienzymes/composition chimique , Antienzymes/effets indésirables , Antienzymes/usage thérapeutique , Hyperuricémie/traitement médicamenteux , Souris de lignée C57BL , Simulation de docking moléculaire , Acide urique/sang , Xanthine dehydrogenase/antagonistes et inhibiteurs , Xanthine dehydrogenase/métabolismeRÉSUMÉ
The abnormal production and/or excretion of uric acid can lead to a disorder in uric acid metabolism, resulting in hyperuricemia, uric acid nephropathy, gouty arthritis, and other diseases related to uric acid metabolism disorder. The clinical incidence of these diseases is increasing year after year, posing a significant threat to public health. In the past, hyperuricemia and gouty arthritis were often considered different diseases, with uric acid nephropathy being a complication of hyperuricemia. However, recent research has challenged this perspective, suggesting that hyperuricemia, uric acid nephropathy, and gouty arthritis are different stages of the same disease, with urate deposition as the common pathological feature. This article offered a comprehensive overview of the current understanding of hyperuricemia, uric acid nephropathy, and gouty arthritis in both traditional Chinese medicine(TCM) and western medicine. It delved into the most up-to-date insights into the involvement of urate deposition in the pathogenesis of uric acid metabolism disorders and highlighted the dominant role of TCM in the prevention and treatment of uric acid metabolism disorders, so as to provide a reference for effective intervention strategies and drug development in uric acid metabolism disorder-related diseases.
Sujet(s)
Médicaments issus de plantes chinoises , Hyperuricémie , Médecine traditionnelle chinoise , Acide urique , Humains , Acide urique/métabolisme , Hyperuricémie/traitement médicamenteux , Hyperuricémie/métabolisme , Médicaments issus de plantes chinoises/usage thérapeutique , Goutte articulaire/métabolisme , Goutte articulaire/traitement médicamenteux , Goutte articulaire/prévention et contrôle , AnimauxRÉSUMÉ
Hyperuricemia is an objective risk factor of derangement of fasting serum glucose and type 2 diabetes (T2D), yet whether hyperuricemia has a causative influence on insulin resistance is still debatable. In this study, we tested the hypothesis that lowering uric acid in hyperuricemic nondiabetic subjects might improve insulin resistance. Patients with renal stone and hyperuricemia (n=15) were recruited from the private clinic of Ib-Sina Local Teaching Hospital in Mosul city and prospectively placed on allopurinol (300mg/day) for 6 months. Serum uric acid (SUA), fasting serum glucose (FSG), fasting insulin, and C-peptide were measured using commercial kits. Results confirmed that allopurinol has significantly (P<0.05) reduced c-peptide and insulin together with a non-significant (p>0.05) reduction of serum glucose levels. In conclusion, allopurinol has improved insulin level and glycemic control in a healthy individual, these findings could be used as a template for using allopurinol in diabetic patients to improve glycemic control or future studies could be directed toward structural modification of allopurinol which hopefully might lead to innovation of new antidiabetic drugs.
Sujet(s)
Allopurinol , Glycémie , Hyperuricémie , Insulinorésistance , Insuline , Calculs rénaux , Acide urique , Humains , Allopurinol/usage thérapeutique , Calculs rénaux/traitement médicamenteux , Acide urique/sang , Insuline/sang , Mâle , Glycémie/effets des médicaments et des substances chimiques , Glycémie/métabolisme , Adulte d'âge moyen , Hyperuricémie/traitement médicamenteux , Hyperuricémie/sang , Hyperuricémie/complications , Femelle , Adulte , Peptide C/sang , Diabète de type 2/traitement médicamenteux , Diabète de type 2/complications , Diabète de type 2/sangRÉSUMÉ
Hyperuricemia (HUA), a metabolic disease caused by excessive production or decreased excretion of uric acid (UA), has been reported to be closely associated with a variety of UA transporters. Clerodendranthus spicatus (C. spicatus) is an herbal widely used in China for the treatment of HUA. However, the mechanism has not been clarified. Here, the rat model of HUA was induced via 10% fructose. The levels of biochemical indicators, including UA, xanthine oxidase (XOD), adenosine deaminase (ADA), blood urea nitrogen (BUN), and creatinine (Cre), were measured. Western blotting was applied to explore its effect on renal UA transporters, such as urate transporter1 (URAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette super-family G member 2 (ABCG2). Furthermore, the effect of C. spicatus on plasma metabolites was identified by metabolomics. Our results showed that C. spicatus could significantly reduce the serum levels of UA, XOD, ADA and Cre, and improve the renal pathological changes in HUA rats. Meanwhile, C. spicatus significantly inhibited the expression of URAT1 and GLUT9, while increased the expression of ABCG2 in a dose-dependent manner. Metabolomics showed that 13 components, including 1-Palmitoyl-2-Arachidonoyl-sn-glycero-3-PE, Tyr-Leu and N-cis-15-Tetracosenoyl-C18-sphingosine, were identified as potential biomarkers for the UA-lowering effect of C. spicatus. In addition, pathway enrichment analysis revealed that arginine biosynthesis, biosynthesis of amino acids, pyrimidine metabolism and other metabolic pathways might be involved in the protection of C. spicatus against HUA. This study is the first to explore the mechanism of anti-HUA of C. spicatus through molecular biology and metabolomics analysis, which provides new ideas for the treatment of HUA.
Sujet(s)
Hyperuricémie , Métabolomique , Acide urique , Animaux , Hyperuricémie/traitement médicamenteux , Hyperuricémie/métabolisme , Rats , Métabolomique/méthodes , Acide urique/sang , Mâle , Rein/métabolisme , Rein/effets des médicaments et des substances chimiques , Rein/anatomopathologie , Transporteurs d'anions organiques/métabolisme , Transporteurs d'anions organiques/génétique , Rat Sprague-Dawley , Extraits de plantes/pharmacologie , Médicaments issus de plantes chinoises/pharmacologie , Médicaments issus de plantes chinoises/usage thérapeutique , Xanthine oxidase/métabolisme , Modèles animaux de maladie humaineRÉSUMÉ
Gout is characterized by monosodium urate (MSU) crystal deposition secondary to hyperuricemia. Gout is associated with metabolic syndrome (MetS) and its related comorbid conditions such as cardiovascular disease (CVD). Major advances have been made in the comprehension of the link between MetS and gout. Despite observational studies suggesting an association between MetS-related conditions and hyperuricemia, there is no proof of causality. Most studies using Mendelian randomization did not find hyperuricemia as a causal factor for MetS-related conditions. In contrast, these conditions were found associated with hyperuricemia, which suggests a reverse causality. Among patients with gout, this high CVD risk profile implies the need for systematic screening for MetS-related conditions. Most international guidelines recommend systematic screening for and care of CVD and related risk factors in patients with gout. Some anti-hypertensive agents, such as losartan and calcium channel blockers, are able to decrease serum urate (SU) levels. However, there are potential interactions between gout management therapies and the treatment of metabolic diseases. Some data suggest that anti-inflammatory drugs used for gout flare treatment, such as colchicine or canakinumab, might have benefits for CVD. Regarding the impact of urate-lowering therapies on CVD risk, recent studies found a similar CVD safety profile for allopurinol and febuxostat. Finally, sodium-glucose cotransporter-2 inhibitors are promising for gout because of their ability to decrease SU levels and risk of recurrent flares. In this review, we focus on the clinical challenge of managing MetS in patients with gout, particularly older patients with co-medications.
Sujet(s)
Goutte , Syndrome métabolique X , Humains , Goutte/traitement médicamenteux , Goutte/complications , Syndrome métabolique X/complications , Antigoutteux/usage thérapeutique , Maladies cardiovasculaires/étiologie , Hyperuricémie/traitement médicamenteux , Hyperuricémie/complicationsRÉSUMÉ
Uric acid nephropathy (UAN), caused by a common metabolic disorder resulting from hyperuricemia (HUA), has an increasing incidence. Previous studies have shown that berberine (BBR) has clear urate-lowering and anti-inflammatory effects in UAN mice, but its mechanism needs to be further clarified. Therefore, Potassium Oxonate (PO) combined with hypoxanthine (HX) induced UAN mice model and MSU induced THP-1 cells polarization model were adopted to investigate the mechanism of BBR on UAN in terms of tissue distribution and molecular pharmacology. Study unveiled that BBR was first found to bind to red blood cells (RBCs), which were recognized and phagocytosed by monocytes, then recruited by the injured kidney. Subsequently, BBR was enriched and functional in damaged kidney. The results of in vivo experiments revealed that, BBR reduced UA, BUN, CRE levels as well as the release of TNF-α, IL-1ß, IL-18 and IL-6, and alleviated renal injury in UAN mice, as consistent with previous studies. Additionally, BBR decreased MCP-1 expression, while diminishing macrophage infiltration and decreasing M1 proportion as determined by RT-qPCR. In vitro experiments, demonstrated that MSU promoted inflammatory polarization of THP-1 cells, while BBR reduced synthesis of inflammatory factors and inhibited MSU-induced inflammatory polarization. These effects of BBR were dependent on AMPK activation along with indirect inhibition of NF-κB signaling pathway mediated. However, the anti-inflammatory and macrophage polarization regulation effects of BBR were completely reversed upon administration of Compound C, an AMPK inhibitor. Therefore, BBR ameliorated kidney injury via regulating macrophage polarization through AMPK, which has therapeutic potential for UAN patients.
Sujet(s)
AMP-Activated Protein Kinases , Berbérine , Cytokines , Rein , Macrophages , Transduction du signal , Acide urique , Animaux , Humains , Mâle , Souris , AMP-Activated Protein Kinases/métabolisme , Anti-inflammatoires/pharmacologie , Berbérine/pharmacologie , Cytokines/métabolisme , Modèles animaux de maladie humaine , Hyperuricémie/traitement médicamenteux , Rein/anatomopathologie , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Maladies du rein/traitement médicamenteux , Maladies du rein/métabolisme , Maladies du rein/anatomopathologie , Macrophages/effets des médicaments et des substances chimiques , Macrophages/immunologie , Macrophages/métabolisme , Souris de lignée C57BL , Transduction du signal/effets des médicaments et des substances chimiques , Cellules THP-1RÉSUMÉ
Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.
Sujet(s)
Hyperuricémie , Liposomes , ARN messager , Urate oxidase , Acide urique , Hyperuricémie/traitement médicamenteux , Hyperuricémie/génétique , Hyperuricémie/métabolisme , Animaux , ARN messager/métabolisme , ARN messager/génétique , Urate oxidase/métabolisme , Urate oxidase/génétique , Femelle , Souris , Humains , Acide urique/métabolisme , Acide urique/sang , Liposomes/composition chimique , Nanoparticules/composition chimique , Hépatocytes/métabolisme , Modèles animaux de maladie humaine , Souris de lignée C57BLRÉSUMÉ
Hyperuricemia (HUA) may lead to myocardial cell damage, thereby promoting the occurrence and adverse outcomes of heart diseases. In this review, we discuss the latest clinical research progress, and explore the impact of HUA on myocardial damage-related diseases such as myocardial infarction, arrhythmias, and heart failure. We also combined recent findings from basic research to analyze potential mechanisms linking HUA with myocardial injury. In different pathological models (such as direct action of high uric acid on myocardial cells or combined with myocardial ischemia-reperfusion model), HUA may cause damage by activating the NOD-like receptor protein 3 inflammasome-induced inflammatory response, interfering with cardiac cell energy metabolism, affecting antioxidant defense systems, and stimulating reactive oxygen species production to enhance the oxidative stress response, ultimately resulting in decreased cardiac function. Additionally, we discuss the impact of lowering uric acid intervention therapy and potential safety issues that may arise. However, as the mechanism underlying HUA-induced myocardial injury is poorly defined, further research is warranted to aid in the development novel therapeutic strategies for HUA-related cardiovascular diseases.
Sujet(s)
Cardiopathies , Hyperuricémie , Stress oxydatif , Acide urique , Humains , Hyperuricémie/métabolisme , Hyperuricémie/traitement médicamenteux , Hyperuricémie/complications , Animaux , Cardiopathies/métabolisme , Acide urique/métabolisme , Espèces réactives de l'oxygène/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Inflammasomes/métabolismeRÉSUMÉ
In this study, we first screened and evaluated the inhibitory effects of seven medicinal fungi on diseases such as hyperuricemia (HUA). Then, using metabolomics and gut microbiome methods, the focus was on analyzing and evaluating the effects of the aqueous extract of Cordyceps. militaris (CME) and cordycepin on potassium oxyzinate induced HUA mice. It was found that CME exhibits good uric acid lowering activity in both in vivo and in vitro experiments. It can relieve hyperuricemia by inhibiting xanthine oxidase enzyme activity, reducing the production of xanthine precursors, and inhibiting insulin resistance. The uric acid-lowering efficacy of cordycepin in vivo is comparable to that of CME. The species abundance of Oscillibacter, Alistipes, Prevotellaaceae_NK3B31, Lachnospiraceae_NK4A136 were decreased after treatment with CME and cordycepin. The metabolomics analysis of cecal contents and fecal samples elucidated the mechanism of intervention of CME on hyperuricemia from different perspectives. This suggests that we should consider carefully when selecting samples. This current research provides the scientific foundation for the medicinal research of C. militaris and the maintenance of human health.
Sujet(s)
Cordyceps , Désoxyadénosine , Microbiome gastro-intestinal , Hyperuricémie , Animaux , Désoxyadénosine/pharmacologie , Hyperuricémie/traitement médicamenteux , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Souris , Cordyceps/composition chimique , Mâle , Métabolomique/méthodes , Acide urique/métabolisme , Métabolome/effets des médicaments et des substances chimiques , Xanthine oxidase/métabolisme , Xanthine oxidase/antagonistes et inhibiteurs , Modèles animaux de maladie humaine , Acide oxoniqueRÉSUMÉ
Asymptomatic hyperuricemia is defined by serum uric acid levels above 6.2âmg/dl in women and 7âmg/dl in men. In the presence of monosodium urate crystal formation and articular inflammation, hyperuricemia may become symptomatic (namely nephrolithiasis and gout). Uric acid results from purine catabolism and is at the centre of a complex metabolic interplay that involves oxidative stress, inflammation, renin-angiotensin-aldosterone system (RAAS) activation and insulin resistance. Uric acid levels present a continuous relation with conditions like hypertension and chronic kidney disease (CKD) and are reported to have an impact on risk of cardiovascular events. However, whether elevated uric acid is a causal agent and thus a possible therapeutic target is still uncertain and matter of further investigation. Treating symptomatic hyperuricemia involves lowering uric acid drugs and controlling inflammation. Urate-lowering agents are well tolerated but show minimal impact on cardiovascular events in patients with gout. Use of direct-acting urate-lowering agents in asymptomatic hyperuricemia associated with cardiovascular diseases does not warrant a clear benefit, whereas addressing cardiovascular issues with guideline-recommended therapies lowers uric acid and reduces the occurrence of cardiovascular events. Regular assessment of uric acid and clinical symptoms is advised before starting and renewing a urate-lowering treatment.
Sujet(s)
Maladies cardiovasculaires , Hyperuricémie , Acide urique , Hyperuricémie/complications , Hyperuricémie/traitement médicamenteux , Hyperuricémie/sang , Humains , Maladies cardiovasculaires/étiologie , Acide urique/sang , Médecine factuelle , Antigoutteux/usage thérapeutique , Mâle , Maladies asymptomatiques , FemelleRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Palmatine is a main bioactive alkaloid of Cortex Phellodendri, which has been commonly prescribed for the treatment of hyperuricemia (HUA) in China. The metabolites of palmatine were crucial to its prominent biological activity. 9-Hydroxy-8-oxypalmatine (9-OPAL) is a novel liver-mediated secondary oxymetabolite of palmatine. AIM OF THE STUDY: The current study was to assess the efficacy of 9-OPAL, a novel liver-mediated secondary oxymetabolite of palmatine derived from Cortex Phellodendri, in experimental HUA mouse model and further explore its underlying mechanism. MATERIALS AND METHODS: An in vitro metabolic experiment with oxypalmatine was carried out using liver samples. We separated and identified a novel liver metabolite, and investigated its anti-HUA effect in mice. HUA mice were induced by potassium oxonate and hypoxanthine daily for one week. After 1 h of modeling, mice were orally administered with different doses of 9-OPAL (5, 10 and 20 mg/kg). The pathological changes of the kidneys were evaluated using hematoxylin-eosin staining (H&E). The acute toxicity of 9-OPAL was assessed. The effects of 9-OPAL on serum levels of uric acid (UA), adenosine deaminase (ADA), xanthine oxidase (XOD), creatinine (CRE), blood urea nitrogen (BUN) and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) or biochemical method. Furthermore, Western blot, quantitative real-time PCR (qRT-PCR) and molecular docking were used to investigate the effect of 9-OPAL on the expression of renal urate transporters and NLRP3 signaling pathway in HUA mice. RESULTS: 9-OPAL had been discovered to be a novel liver-mediated oxymetabolite of palmatine for the first time. Treatment with 9-OPAL significantly reduced the UA, CRE as well as BUN levels, and also effectively attenuated abnormal renal histopathological deterioration with favorable safety profile. Besides, 9-OPAL significantly decreased the serum and hepatic activities of XOD and ADA, dramatically inhibited the up-regulation of UA transporter protein 1 (URAT1) and glucose transporter protein 9 (GLUT9), and reversed the down-regulation of organic anion transporter protein 1 (OAT1). Additionally, 9-OPAL effectively mitigated the renal inflammatory markers (TNF-α, IL-1ß, IL-6 and IL-18), and downregulated the transcriptional and translational expressions of renal Nod-like receptor family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like (ASC) and IL-1ß in HUA mice. Molecular docking results revealed 9-OPAL bound firmly with XOD, OAT1, GLUT9, URAT1, NLRP3, caspase-1, ASC and IL-1ß. CONCLUSIONS: 9-OPAL was found to be a novel liver-mediated secondary metabolite of palmatine with favorable safety profile. 9-OPAL had eminent anti-hyperuricemic and renal-protective effects, and the mechanisms might be intimately associated with repressing XOD activities, modulating renal urate transporter expression and suppressing the NLRP3 inflammasome activation. Our investigation might also provide further experimental evidence for the traditional application of Cortex Phellodendri in the treatment of HUA.