RESUMEN
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.
Asunto(s)
Hiperuricemia , Ácido Oxónico , Plantago , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Animales , Ratas , Ácido Oxónico/efectos adversos , Masculino , Plantago/química , Ácido Úrico/sangre , Extractos Vegetales/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Xantina Oxidasa/metabolismoRESUMEN
Gout is the second largest metabolic disease worldwide after diabetes, with acute gouty arthritis as most common symptom. Xanthine oxidase (XOD) and the NOD like receptor-3 (NLRP3) inflammasome are the key targets for acute gout treatment. Chlorogenic acid has been reported with a good anti-inflammatory activity, and Apigenin showed an excellent potential in XOD inhibition. Therefore, a series of chlorogenic acid-apigenin (CA) conjugates with varying linkers were designed and synthesized as dual XOD/NLRP3 inhibitors, and their activities both in XOD and NLRP3 inhibition were evaluated. An in vitro study of XOD inhibitory activity revealed that the majority of CA conjugates exhibited favorable XOD inhibitory activity. Particularly, the effects of compounds 10c and 10d, with an alkyl linker on the apigenin moiety, were stronger than that of allopurinol. The selected CA conjugates also demonstrated a favorable anti-inflammatory activity in RAW264.7 cells. Furthermore, compound 10d, which showed the optimal activity both in XOD inhibition and anti-inflammatory, was chosen and its inhibitory ability on NLRP3 and related proinflammatory cytokines was further tested. Compound 10d effectively reduced NLRP3 expression and the secretion of interluekin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) with an activity stronger than the positive control isoliquiritigenin (ISL). Based on these findings, compound 10d exhibits dual XOD/NLRP3 inhibitory activity and, therefore, the therapeutic effects on acute gout is worthy of further study.
Asunto(s)
Apigenina , Ácido Clorogénico , Supresores de la Gota , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Apigenina/farmacología , Apigenina/química , Apigenina/síntesis química , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7 , Ácido Clorogénico/farmacología , Ácido Clorogénico/química , Ácido Clorogénico/síntesis química , Supresores de la Gota/farmacología , Supresores de la Gota/síntesis química , Supresores de la Gota/química , Supresores de la Gota/uso terapéutico , Relación Estructura-Actividad , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Estructura Molecular , Gota/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antiinflamatorios/químicaRESUMEN
Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.
Asunto(s)
Lesión Renal Aguda , Ejercicio Físico , Defectos Congénitos del Transporte Tubular Renal , Humanos , Lesión Renal Aguda/etiología , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Adolescente , Masculino , Recurrencia , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Xantina Oxidasa , Cálculos Urinarios/genética , Cálculos Urinarios/etiología , Cálculos Urinarios/complicaciones , China , Mutación , Pueblos del Este de AsiaRESUMEN
Fabiana punensis S. C. Arroyo is a subshrub or shrub that is indigenous to the arid and semiarid region of northern Argentina and is known to possess several medicinal properties. The objective of this study was to optimize the extraction conditions so as to maximize the yield of bioactive total phenolic compound (TPC) and flavonoids (F) of F. punensis' aerial parts by using non-conventional extraction methods, namely ultrasound-assisted extraction, UAE, and microwave-assisted extraction, MAE, and to compare the biological activities and toxicity of optimized extracts vs. conventional extracts, i.e., those gained by maceration. Response Surface Methodology (RSM) was used to apply factorial designs to optimize the parameters of extraction: solid-to-liquid ratio, extraction time, ultrasound amplitude, and microwave power. The experimental values for TPC and F and antioxidant activity under the optimal extraction conditions were not significantly different from the predicted values, demonstrating the accuracy of the mathematical models. Similar HPLC-DAD patterns were found between conventional and UAE- and MAE-optimized extracts. The main constituents of the extracts correspond to phenolic compounds (flavonoids and phenolic acids) and apigenin was identified. All extracts showed high scavenger capacity on ABTSâ¢+, O2â¢- and H2O2, enabling the inhibition of the pro-inflammatory enzymes xanthine oxidase (XO) and lipoxygenase (LOX). They also showed an antimutagenic effect in Salmonella Typhimurium assay and cytotoxic/anti-proliferative activity on human melanoma cells (SKMEL-28). Toxicological evaluation indicates its safety. The results of this work are important in the development of efficient and sustainable methods for obtaining bioactive compounds from F. punensis for the prevention of chronic degenerative diseases associated with oxidative stress, inflammation, and DNA damage.
Asunto(s)
Antioxidantes , Microondas , Fenoles , Componentes Aéreos de las Plantas , Extractos Vegetales , Fenoles/química , Fenoles/farmacología , Fenoles/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Componentes Aéreos de las Plantas/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Humanos , Flavonoides/farmacología , Flavonoides/química , Flavonoides/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Ondas Ultrasónicas , Fraccionamiento Químico/métodos , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismoRESUMEN
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.
Asunto(s)
Hiperuricemia , Metabolómica , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Ratas , Metabolómica/métodos , Ácido Úrico/sangre , Masculino , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Ratas Sprague-Dawley , Extractos Vegetales/farmacología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Xantina Oxidasa/metabolismo , Modelos Animales de EnfermedadRESUMEN
Molybdenum (Mo) is an essential element for human life, acting as a cofactor in various enzymes crucial for metabolic homeostasis. This review provides a comprehensive insight into the latest advances in research on molybdenum-containing enzymes and their clinical significance. One of these enzymes is xanthine oxidase (XO), which plays a pivotal role in purine catabolism, generating reactive oxygen species (ROS) capable of inducing oxidative stress and subsequent organ dysfunction. Elevated XO activity is associated with liver pathologies such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Aldehyde oxidases (AOs) are also molybdenum-containing enzymes that, similar to XO, participate in drug metabolism, with notable roles in the oxidation of various substrates. However, beneath its apparent efficacy, AOs' inhibition may impact drug effectiveness and contribute to liver damage induced by hepatotoxins. Another notable molybdenum-enzyme is sulfite oxidase (SOX), which catalyzes the conversion of sulfite to sulfate, crucial for the degradation of sulfur-containing amino acids. Recent research highlights SOX's potential as a diagnostic marker for HCC, offering promising sensitivity and specificity in distinguishing cancerous lesions. The newest member of molybdenum-containing enzymes is mitochondrial amidoxime-reducing component (mARC), involved in drug metabolism and detoxification reactions. Emerging evidence suggests its involvement in liver pathologies such as HCC and NAFLD, indicating its potential as a therapeutic target. Overall, understanding the roles of molybdenum-containing enzymes in human physiology and disease pathology is essential for advancing diagnostic and therapeutic strategies for various health conditions, particularly those related to liver dysfunction. Further research into the molecular mechanisms underlying these enzymes' functions could lead to novel treatments and improved patient outcomes.
Asunto(s)
Aldehído Oxidasa , Molibdeno , Oxidación-Reducción , Sulfito-Oxidasa , Xantina Oxidasa , Humanos , Molibdeno/metabolismo , Xantina Oxidasa/metabolismo , Sulfito-Oxidasa/metabolismo , Aldehído Oxidasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/enzimología , Animales , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/enzimología , Especies Reactivas de Oxígeno/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés OxidativoRESUMEN
Although patients with hyperuricemia and gout often have dyslipidemia, the effects of febuxostat, a xanthine oxidase inhibitor, on their lipid profiles are unclear. Thus, we performed a sub-analysis of the randomized PRIZE study in which the effects of febuxostat on carotid atherosclerosis were investigated in patients with hyperuricemia. The participants were randomized to the febuxostat or control group. The primary endpoint of this sub-analysis was changes in the patients' non-high-density lipoprotein cholesterol (HDL-C) levels from baseline to 6-month follow-up. Correlations between the changes in lipid profiles and cardiometabolic parameters were also evaluated. In total, 456 patients were included. From baseline to 6 months, non-HDL-C levels were significantly reduced in the febuxostat group (-5.9 mg/dL, 95% confidence interval [CI]: -9.1 to -2.8 mg/dL, p < 0.001), but not in the control group (-1.3 mg/dL, 95% CI: -4.4 to 1.8, p = 0.348). The reduction in non-HDL-C levels was more pronounced in women and correlated with changes in serum uric acid and estimated glomerular filtration rate levels only in the febuxostat group. In patients with hyperuricemia, febuxostat treatment was associated with reduced non-HDL-C levels from baseline to the 6-month follow-up compared to the control treatment, suggesting that the lipid-lowering effect of febuxostat should be considered when targeting dyslipidemia.
Asunto(s)
Febuxostat , Hiperuricemia , Lípidos , Xantina Oxidasa , Humanos , Febuxostat/uso terapéutico , Febuxostat/farmacología , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/sangre , Xantina Oxidasa/antagonistas & inhibidores , Masculino , Femenino , Persona de Mediana Edad , Lípidos/sangre , Anciano , Ácido Úrico/sangre , Supresores de la Gota/uso terapéutico , Supresores de la Gota/farmacología , HDL-Colesterol/sangre , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/sangre , Dislipidemias/tratamiento farmacológico , Dislipidemias/sangre , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Vietnamese 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 STUDY: The 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. METHODS: According 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. RESULTS: The 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). CONCLUSION: The 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.
Asunto(s)
Antiinflamatorios , Antioxidantes , Artemisia , Edema , Extractos Vegetales , Xantina Oxidasa , Animales , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Ratones , Células RAW 264.7 , Edema/tratamiento farmacológico , Edema/inducido químicamente , Artemisia/química , Masculino , Ácido Úrico , Flavonoides/farmacología , Óxido Nítrico/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , CarrageninaRESUMEN
The discovery of enzyme inhibitors from natural products is a crucial aspect in the development of therapeutic drugs. However, the complexity of natural products presents a challenge in developing simple and efficient methods for inhibitor screening. Herein, we have developed an integrated analytical model for screening xanthine oxidase (XOD) inhibitors that combines simplicity, accuracy, and efficiency. This model utilizes a colorimetric sensor and affinity chromatography technology with immobilized XOD. The colorimetric sensor procedure can quickly identify whether there are active components in complex samples. Subsequently, the active components in the samples identified by the colorimetric sensor procedure were further captured, separated, and identified through affinity chromatography. The integrated analytical model can significantly enhance the efficiency and accuracy of inhibitor screening. The proposed method was applied to screen for an activity inhibitor of XOD in five natural medicines. As a result, a potential active ingredient for XOD, polydatin, was successfully identified from Polygoni Cuspidati Rhizoma et Radix. This work is anticipated to offer new insights for the screening of enzyme inhibitors from natural medicines.
Asunto(s)
Técnicas Biosensibles , Cromatografía de Afinidad , Colorimetría , Inhibidores Enzimáticos , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/química , Cromatografía de Afinidad/métodos , Colorimetría/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/análisis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Técnicas Biosensibles/métodos , Enzimas Inmovilizadas/química , Evaluación Preclínica de Medicamentos , HumanosRESUMEN
Opuntia ficus-indica fruit (OFI) is rich in bioactive compounds, which can promote human health. In this work, the purified OFI extract was prepared from OFI and its bioactivities were investigated. Xanthine oxidase (XOD) and α-glucosidase (α-Glu) inhibitors of the purified OFI extract were screened and identified by bio-affinity ultrafiltration combined with UPLC-QTRAP-MS/MS technology. The inhibitory effect of these inhibitors on enzymes were verified, and the potential mechanism of action and binding sites of inhibitors with enzymes were revealed based on molecular docking. The results showed that the total phenolic content of the purified OFI extract was 355.03 mg GAE/g DW, which had excellent antioxidant activity. Additionally, the extract had a certain inhibitory effect on XOD (IC50 = 199.00 ± 0.14 µg/mL) and α-Glu (IC50 = 159.67 ± 0.01 µg/mL). Seven XOD inhibitors and eight α-Glu inhibitors were identified. Furthermore, XOD and α-Glu inhibition experiments in vitro confirmed that inhibitors such as chlorogenic acid, taxifolin, and naringenin had significant inhibitory effects on XOD and α-Glu. The molecular docking results indicated that inhibitors could bind to the corresponding enzymes and had strong binding force. These findings demonstrate that OFI contains potential substances for the treatment of hyperuricemia and hyperglycemia.
Asunto(s)
Frutas , Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , Opuntia , Extractos Vegetales , Xantina Oxidasa , alfa-Glucosidasas , Xantina Oxidasa/antagonistas & inhibidores , Inhibidores de Glicósido Hidrolasas/farmacología , Frutas/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Opuntia/química , Antioxidantes/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Espectrometría de Masas en Tándem/métodos , Fenoles/farmacología , Fenoles/química , Flavanonas/farmacologíaRESUMEN
Hyperuricemia (HUA) is characterized by abnormally elevated levels of serum uric acid, the product of purine metabolism. The primary symptom of HUA is gout; however, asymptomatic HUA is associated with complications such as hypertension, kidney disease, cardiovascular disease, and metabolic syndrome. The activation of xanthine oxidase (XO), a pivotal enzyme in uric acid biosynthesis, is coupled with extensive reactive oxygen species generation, leading to inflammatory responses, and triggers the development of HUA and its complications. In clinical practice, XO inhibitors are primarily used to treat HUA; however, their prolonged use is accompanied by serious adverse effects. Mushrooms and their bioactive constituents have shown promising anti-HUA activities in both in vitro and in vivo studies, including inhibition of urate production, modulation of renal urate transporters, enhancement of intestinal uric acid excretion, and antioxidant, anti-inflammatory, and antimetabolic syndrome properties. Clinical trials are necessary to validate the beneficial effects and safety of mushrooms in preventing or alleviating HUA and attenuating the associated complications. This review presents contemporary insights into the pathogenesis of HUA, the bioactive components of mushrooms, their therapeutic potential, and the underlying mechanisms involved in ameliorating HUA.
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Agaricales , Hiperuricemia , Ácido Úrico , Hiperuricemia/tratamiento farmacológico , Humanos , Agaricales/química , Ácido Úrico/metabolismo , Animales , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Hyperuricemia (HUA) is a metabolic disorder caused by excessive production of uric acid (UA) or impaired uric acid metabolism. Smilax China L. has a wide range of pharmacological activities such as immunomodulatory, anti-inflammatory, and antioxidant. Its roots and rhizomes have been widely used for the treatment of HUA. However, its mechanisms for treating HUA and reducing renal impairment have not been fully elucidated. In the present study, we evaluated the effect of Smilax China L. extract (SC) on UA metabolism and further explored its mechanism of action by feeding a high-calcium and high-protein diet to chickens to induce a model of HUA in chickens. SC significantly reduced serum UA levels and improved renal function in hyperuricemic chickens. Meanwhile, SC was able to inhibit the activity of xanthine oxidase (XOD) in vivo and in vitro, reducing the production of uric acid. In addition, SC was able to increase the expression of Breast Cancer Resistance Protein (BCRP) in the kidney and ileum and increase uric acid excretion. Therefore, our results suggest that SC may be a candidate for anti-hyperuricemia.
Asunto(s)
Pollos , Hiperuricemia , Extractos Vegetales , Smilax , Ácido Úrico , Xantina Oxidasa , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/veterinaria , Smilax/química , Xantina Oxidasa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Enfermedades de las Aves de Corral/tratamiento farmacológico , Dieta/veterinaria , Masculino , Alimentación Animal/análisis , Distribución AleatoriaRESUMEN
Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4â¯%), followed by total flavonoids (9.1â¯%), and total triterpenoids (3.5â¯%). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.
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Adenina , Hiperuricemia , Riñón , Ácido Oxónico , Xantina Oxidasa , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/inducido químicamente , Masculino , Ratones , Adenina/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Xantina Oxidasa/metabolismo , Basidiomycota/química , Ácido Úrico/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismoRESUMEN
About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1ß and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.
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Hiperuricemia , Hipoxia , Riñón , Hígado , Estrés Oxidativo , Hiperuricemia/metabolismo , Animales , Masculino , Ratas , Hígado/metabolismo , Hígado/patología , Hipoxia/metabolismo , Hipoxia/complicaciones , Riñón/metabolismo , Riñón/patología , Altitud , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Ratas Sprague-Dawley , Xantina Oxidasa/metabolismo , Mal de Altura/metabolismo , Mal de Altura/complicaciones , Mal de Altura/fisiopatologíaRESUMEN
Xanthine oxidase (XO) is a typical target for hyperuricemia and gout, for which there are only three commercial xanthine oxidase inhibitors (XOIs): febuxostat, topiroxostat and allopurinol. However, these inhibitors have problems such as low bioactivity and several side effects. Therefore, the development of novel XOIs with high bioactivity for the treatment of hyperuricemia and gout is urgently needed. In this work we constructed a XO immobilized cellulose membrane colorimetric biosensor (XNCM) by the TEMPO oxidation, amide bond coupling and nitro blue tetrazolium chloride (NBT) loading method. As expected, the XNCM was able to detect xanthine, with high selectivity and sensitivity by colorimetric method with a distinctive color change from yellow to purple, which can be easily observed by the naked-eye in just 8 min without any complex instrumentation. In addition, the XNCM sensor performed screening of 21 different compounds and have been successfully pre-screened out XOIs with biological activity. Most importantly, the XNCM was able to quantitatively detect the IC50 values of two commercial inhibitors (febuxostat and allopurinol). All the results confirmed that the XNCM is a simple and effective tool which can be used for the accelerated screening of XOIs and has the potential to uncover additional XOIs.
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Técnicas Biosensibles , Celulosa , Colorimetría , Inhibidores Enzimáticos , Enzimas Inmovilizadas , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Colorimetría/métodos , Técnicas Biosensibles/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/análisis , Celulosa/química , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/antagonistas & inhibidores , Membranas Artificiales , Alopurinol/farmacología , Humanos , Evaluación Preclínica de MedicamentosRESUMEN
Coptis teeta Wall., an endangered but valuable medicinal species having various folklore uses in Indian and Chinese Traditional system of medicine. Its distribution is restricted to India, China and Tibet. In India, C. teeta is traditionally used in joint disorders, urinary infections and inflammatory diseases, however the scientific validation is missing. Thus, the present study aims to validate the anti-lithiatic and anti-gout activity of C. teeta rhizome extract (CTME) through in-vitro biological assays. The metabolic fingerprinting of CTME through reverse phase-high performance liquid chromatography-photodiode array (RP-HPLC-PDA) showed the presence of five benzyl-isoquinoline alkaloids, namely berberine (2.59%), coptisine (0.746%) jatrorrhizine (0.133%), palmatine (0.03%) and tetrahydropalmatine (0.003%). The anti-gout potency analysed via in-vitro xanthine oxidase (XOD) inhibition assay, followed by HPTLC (High performance thin layer chromatography) mediated bio-autographic inhibition of XOD signifies that CTME exhibit strong inhibition of XOD (IC50: 3.014 µg/ml), insignificantly different (p > 0.05) from allopurinol (IC50: 2.47 µg/ml). The XOD bioautographic assay advocates that the efficacy is primarily due to berberine and coptisine alkaloids. The CTME has significant anti-lithiatic activity, and thereby limiting the progression of crystal nidus formation, mediated via inhibition of calcium oxalate crystals nucleation and aggregation. Additionally, the extract also exhibits potential effect on inhibition of oxidative stress associated inflammation, which plays crucial role in alleviating urolithiasis and gouty conditions. Validating the traditional claims of C. teeta will not only confirm its medicinal benefits for targeted pathological conditions but also enhance its industrial demand.
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Bencilisoquinolinas , Oxalato de Calcio , Coptis , Extractos Vegetales , Ácido Úrico , Coptis/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/aislamiento & purificación , Rizoma/química , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , India , Supresores de la Gota/farmacología , Supresores de la Gota/aislamiento & purificación , Enfermedades Metabólicas/tratamiento farmacológico , Estructura MolecularRESUMEN
Xanthine oxidase (XO) plays a critical role in purine catabolism, catalyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid, contributing to superoxide anion production. This process is implicated in various human diseases, particularly gout. Traditional XO inhibitors, such as allopurinol and febuxostat, while effective, may present side effects. Our study focuses on Asphodelus microcarpus, a plant renowned for traditional anti-inflammatory uses. Recent investigations into its phenolic-rich flowers, notably abundant in luteolin derivatives, reveal its potential as a natural source of XO inhibitors. In the present research, XO inhibition by an ethanolic flowers extract from A. microcarpus is reported. In silico docking studies have highlighted luteolin derivatives as potential XO inhibitors, and molecular dynamics support that luteolin 7-O-glucoside has the highest binding stability compared to other compounds and controls. In vitro studies confirm that luteolin 7-O-glucoside inhibits XO more effectively than the standard inhibitor allopurinol, with an IC50 value of 4.8 µg/mL compared to 11.5 µg/mL, respectively. These findings underscore the potential therapeutic significance of A. microcarpus in managing conditions related to XO activity. The research contributes valuable insights into the health-promoting properties of A. microcarpus and its potential application in natural medicine, presenting a promising avenue for further exploration in disease management.
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Inhibidores Enzimáticos , Luteolina , Simulación del Acoplamiento Molecular , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Luteolina/química , Luteolina/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Glucósidos/química , Glucósidos/farmacología , Simulación de Dinámica Molecular , Flores/química , Alopurinol/farmacología , Alopurinol/química , Humanos , Sitios de UniónRESUMEN
Continued interest in the bioactive alkaloids led to the isolation of five undescribed alkaloids (1-5), ophiorglucidines A-E, and seven known analogues (6-12) from the water-soluble fraction of Ophiorrhiza japonica. The structures were elucidated based on spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. The structure of 1 was characterized as a hexacyclic skeleton including a double bridge linking the indole and the monoterpene moieties, which is the first report of a single crystal with this type of structure. Moreover, the inhibitory effect of zwitterionic indole alkaloid glycosides on xanthine oxidase was found for the first time. The alkaloids 2 and 3, both of which have a pentacyclic zwitterionic system, were more active than the reference inhibitor, allopurinol (IC50 = 11.1 µM) with IC50 values of 1.0 µM, and 2.5 µM, respectively. Structure-activity relationships analyses confirmed that the carbonyl group at C-14 was a key functional group responsible for the inhibitory effects of these alkaloids.
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Inhibidores Enzimáticos , Alcaloides Indólicos , Monoterpenos , Rubiaceae , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Rubiaceae/química , Relación Estructura-Actividad , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Monoterpenos/química , Monoterpenos/farmacología , Monoterpenos/aislamiento & purificación , Estructura Molecular , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Cristalografía por Rayos XRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Qiling granules (FQG), derived from the traditional Qiling Decoction with a longstanding clinical history, is utilized for the treatment of hyperuricemia (HUA). FQG is formulated with a combination of seven Chinese herbs based on the principles of traditional Chinese medicine (TCM) theories. Clinical evidence indicates that FQG exhibits favorable therapeutic effects in reducing uric acid (UA) levels and attenuating renal damage. AIM OF THIS STUDY: To elucidate the potential active components and pharmacological mechanism of FQG in the treatment of HUA, and to provide an experimental basis for the development of efficient and low-toxicity TCM for HUA treatment. MATERIALS AND METHODS: A HUA rat model induced by potassium oxonate and adenine was established to initially evaluate the hypouricemic effects of FQG. Chemical analyses were conducted using an ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Network pharmacology was used to investigate the active components and mechanism of FQG in the treatment of HUA. Potential Xanthine oxidase (XOD) inhibitors were screened from FQG based on ultrafiltration liquid chromatography and mass spectrometry (UF-LC-MS). Molecular docking, surface plasmon resonance (SPR) and circular dichroism (CD) spectroscopy were applied to validate the interactions between the active components and XOD. RESULTS: In comparison to the model group, treatment with FQG significantly decreased serum UA, serum creatinine (CREA), serum blood urea nitrogen (BUN), and liver XOD activity. Additionally, the FQG administration notably ameliorated HUA-induced renal injury in rats. Through the pharmacodynamics of the HUA rat models and network pharmacology, it was found that XOD was a key pathway enzyme in UA metabolism. 18 XOD inhibitors were screened from FQG by UF-LC-MS, and 11 compounds with strong affinity were verified by SPR, molecular docking and CD spectroscopy. CONCLUSION: In summary, flavonoids, organic acids and saponins may be the active components in FQG that alleviate HUA. The primary mechanism of FQG involves inhibiting XOD enzyme activity in the plasma to reduce UA production, alleviating renal tubular epithelial cell necrosis, tubulointerstitial injury, fibrosis, and urate deposition, ultimately exerting a therapeutic effect on HUA.
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Medicamentos Herbarios Chinos , Hiperuricemia , Xantina Oxidasa , Animales , Masculino , Ratas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Inhibidores Enzimáticos/farmacología , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/inducido químicamente , Simulación del Acoplamiento Molecular , Farmacología en Red , Ácido Oxónico , Ratas Sprague-Dawley , Ácido Úrico/sangre , Xantina Oxidasa/metabolismo , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
This study aimed to explore the antioxidant and prooxidative activity of two natural furanocoumarin derivatives, Bergaptol (4-Hydroxy-7H-furo [3,2-g] [1]benzopyran-7-one, BER) and Xanthotoxol (9-Hydroxy-7H-furo [3,2-g] [1]benzopyran-7-one, XAN). The collected thermodynamic and kinetic data demonstrate that both compounds possess substantial antiradical activity against HO⢠and CCl3OO⢠radicals in physiological conditions. BER exhibited better antiradical activity in comparison to XAN, which can be attributed to the enhanced deprotonation caused by the positioning of the -OH group on the psoralen ring. In contrast to highly reactive radical species, newly formed radical species BER⢠and XAN⢠exhibited negligible reactivity towards the chosen constitutive elements of macromolecules (fatty acids, amino acids, nucleobases). Furthermore, in the presence of O2â¢â, the ability to regenerate newly formed radicals BER⢠and XAN⢠was observed. Conversely, in physiological conditions in the presence of Cu(II) ions, both compounds exhibit prooxidative activity. Nevertheless, the prooxidative activity of both compounds is less prominent than their antioxidant activity. Furthermore, it has been demonstrated that anionic species can engage in the creation of a chelate complex, which restricts the reduction of metal ions when reducing agents are present (O2â¢â and Ascâ). Moreover, studies have demonstrated that these chelating complexes can be coupled with other radical species, hence enhancing their ability to inactivate radicals. Both compounds exhibited substantial inhibitory effects against enzymes involved in the direct or indirect generation of ROS: Xanthine Oxidase (XOD), Lipoxygenase (LOX), Myeloperoxidase (MPO), NADPH oxidase (NOX).