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ETHNOPHARMACOLOGICAL RELEVANCE: Simiao Pills, a classical traditional Chinese medicine prescription recorded in Cheng Fang Bian Du, has been traditionally used to treat hyperuricemia due to its heat-clearing and diuretic properties. Studies have shown that Simiao Pills effectively reduce uric acid levels. However, further research is needed to elucidate the precise composition of Simiao Pills for treating hyperuricemia and their potential pharmacological mechanism. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of Simiao Pills on hyperuricemia, with a particular focus on evaluating their protective role against hyperuricemia-induced renal injury and elucidating the underlying mechanism of action. MATERIALS AND METHODS: UPLC-MS/MS was used to identify the components of Simiao Pills. The hyperuricemia model mice were established by intraperitoneal injecting potassium oxonate (PO) and oral administrating hypoxanthine (HX). Network pharmacology, transcriptome, and metabolomics analyses were integrated to explore the mechanism of Simiao Pills in reducing uric acid and protecting the kidney. Mechanistic and functional studies were conducted to validate the potential mechanisms. RESULTS: Simiao Pills were found to contain 12 characteristic components. Treatment with Simiao Pills significantly reduced serum uric acid levels and ameliorated hyperuricemia-induced renal injury. Simiao Pills inhibited the enzymatic activities of XOD and XDH, and regulated the uric acid transporters in the kidney and ileum. Transcriptome and network pharmacology analyses highlighted quercetin, berberine, kaempferol, and baicalein as the principal active components of Simiao Pills acting on the kidney during hyperuricemia treatment, primarily impacting fibrosis, apoptosis, and inflammation-related signaling pathways. Metabolomic analysis unveiled 21 differential metabolites and 5 metabolic pathways associated with Simiao Pills against renal injury associated with hyperuricemia. Further experimental results validated that Simiao Pills reduced renal fibrosis, apoptotic renal cells, serum inflammation levels, and inhibited the NF-κB/NLRP3/IL-1ß signaling pathway. CONCLUSION: This study demonstrated that Simiao Pills significantly reduced serum uric acid levels and improved renal injury by regulating inflammation, apoptosis, and renal fibrosis. These findings have provided a robust scientific pharmacological basis for the use of Simiao Pills in treating hyperuricemia patients.
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Medicamentos Herbarios Chinos , Hiperuricemia , Metabolómica , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Ratones , Ácido Úrico/sangre , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Espectrometría de Masas en Tándem , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Farmacología en Red , Enfermedades Renales/tratamiento farmacológico , MultiómicaRESUMEN
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
The development of food-derived antihyperuricemic substances is important for alleviating hyperuricemia (HUA) and associated inflammation. Here, novel peptides fromThunnus albacares (TAP) with strong antihyperuricemic activity were prepared. TAP was prepared by alkaline protease (molecular weight <1000 Da), with an IC50 value of xanthine oxidase inhibitory activity of 2.498 mg/mL, and 5 mg/mL TAP could reduce uric acid (UA) by 33.62% in human kidney-2 (HK-2) cells (P < 0.01). Mice were fed a high-purine diet and injected with potassium oxonate to induce HUA. Oral administration of TAP (600 mg/kg/d) reduced serum UA significantly by 42.22% and increased urine UA by 79.02% (P < 0.01) via regulating urate transporters GLUT9, organic anion transporter 1, and ATP-binding cassette subfamily G2. Meantime, TAP exhibited hepatoprotective and nephroprotective effects, according to histological analysis. Besides, HUA mice treated with TAP showed anti-inflammatory activity by decreasing the levels of toll-like receptor 4, nuclear factors-κB p65, NLRP3, ASC, and Caspase-1 in the kidneys (P < 0.01). According to serum non-targeted metabolomics, 91 differential metabolites between the MC and TAP groups were identified, and purine metabolism was considered to be the main pathway for TAP alleviating HUA. In a word, TAP exhibited strong antihyperuricemic activity both in vitro and in vivo.
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Hiperuricemia , Péptidos , Atún , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Ratones , Humanos , Ácido Úrico/metabolismo , Ácido Úrico/sangre , Péptidos/administración & dosificación , Péptidos/química , Péptidos/farmacología , Masculino , Proteínas de Peces/química , Xantina Oxidasa/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Línea Celular , Riñón/efectos de los fármacos , Riñón/metabolismoRESUMEN
Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.
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Glicósidos , Hiperuricemia , Proteína con Dominio Pirina 3 de la Familia NLR , Piranos , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico/sangre , Masculino , Glicósidos/farmacología , Glicósidos/uso terapéutico , Piranos/farmacología , Piranos/uso terapéutico , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , FN-kappa B/metabolismo , Ratones Endogámicos C57BLRESUMEN
Hyperuricemia (HUA) is a metabolic disease characterized by the increase of serum uric acid (UA) level. Sargentodoxae Caulis (SC) is a commonly used herbal medicine for the treatment of gouty arthritis, traumatic swelling, and rheumatic arthritis in clinic. In this study, a total of fifteen compounds were identified in SC water extract using UHPLC-Q-TOF-MS/MS, including three phenolic acids, seven phenolic glycosides, four organic acids, and one lignan. Then, to study the hypouricemia effect of SC, a HUA mouse model was induced using a combination of PO, HX, and 20% yeast feed. After 14 days of treatment with the SC water extract, the levels of serum UA, creatinine (CRE), blood urea nitrogen (BUN) were reduced significantly, and the organ indexes were restored, the xanthine oxidase (XOD) activity were inhibited as well. Meanwhile, SC water extract could ameliorate the pathological status of kidneys and intestine of HUA mice. Additionally, quantitative real-time PCR (qRT-PCR) and western blotting results showed that SC water extract could increase the expression of ATP binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3), whereas decrease the expression of glucose transporter 9 (GLUT9). This study provided a data support for the clinical application of SC in the treatment of HUA.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Hiperuricemia , Ácido Úrico , Xantina Oxidasa , Animales , Ratones , Hiperuricemia/tratamiento farmacológico , Masculino , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Ácido Úrico/sangre , Xantina Oxidasa/metabolismo , Modelos Animales de Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Riñón/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Extractos Vegetales/farmacología , Extractos Vegetales/química , Transportadores de Anión Orgánico/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Hidroxibenzoatos/aislamiento & purificación , Hidroxibenzoatos/farmacologíaRESUMEN
BACKGROUND: Hyperuricemia (HUA) is a metabolic disease characterized by a high level of uric acid (UA). The extensive historical application of traditional Chinese medicine (TCM) offers a range of herbs and prescriptions used for the treatment of HUA-related disorders. However, the core herbs in the prescriptions and their mechanisms have not been sufficiently explained. PURPOSE: Our current investigation aimed to estimate the anti-HUA effect and mechanisms of Paeonia veitchii Lynch, an herb with high use frequency identified from data mining of TCM prescriptions. METHODS: Prescriptions for HUA/gout treatment were statistically analyzed through a data mining approach to determine the common nature and use frequency of their composition herbs. The chemical constituents of Paeonia veitchii extract (PVE) were analyzed by UPLC-QTOF-MS/MS, while its UA-lowering effect was further evaluated in adenosine-induced liver cells and potassium oxonate (PO) and hypoxanthine (HX)-induced HUA mice. RESULTS: A total of 225 prescriptions involving 246 herbs were sorted out. The properties, flavors and meridians of the appearing herbs were mainly cold, bitter and liver, respectively, while their efficacy was primarily concentrated on clearing heat and dispelling wind. Further usage frequency analysis yielded the top 20 most commonly used herbs, in which PVE presented significant inhibitory activity (IC50 = 131.33 µg/ml) against xanthine oxidase (XOD), and its constituents showed strong binding with XOD in a molecular docking study and further were experimentally validated through XOD enzymatic inhibition and surface plasmon resonance (SPR). PVE (50 to 200 µg/ml) dose-dependently decreased UA levels by inhibiting XOD expression and activity in BRL 3A liver cells. In HUA mice, oral administration of PVE exhibited a significant UA-lowering effect, which was attributed to the reduction of UA production by inhibiting XOD activity and expression, as well as the enhancement of UA excretion by regulating renal urate transporters (URAT1, GLUT9, OAT1 and ABCG2). Noticeably, all doses of PVE treatment did not cause any liver injury, and displayed a renal protective effect. CONCLUSIONS: Our results first comprehensively clarified the therapeutic effect and mechanisms of PVE against HUA through suppressing UA production and promoting UA excretion with hepatic and renal protection, suggesting that PVE could be a promising UA-lowering candidate with a desirable safety profile for the treatment of HUA and prevention of gout.
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Gota , Hiperuricemia , Paeonia , Ratones , Animales , Hiperuricemia/inducido químicamente , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismo , Simulación del Acoplamiento Molecular , Espectrometría de Masas en Tándem , RiñónRESUMEN
To evaluate the urate-lowering effect and potential drug targets of antihypertensive agent allisartan isoproxil (ALI) and its bioactive metabolite EXP3174, we developed an acute hyperuricemic zebrafish model using potassium oxonate and xanthine sodium salt. Losartan potassium served as the positive control (reference drug). In this model, ALI and losartan potassium exerted a greater urate-lowering effect than EXP3174 indicating that the latter is not the critical substance for elimination of uric acid. The quantitative real-time PCR showed that ALI upregulates the expression of intestinal urate transporters genes ABCG2, PDZK1, and SLC2A9 (p<0.01). Thus, we can suggest that this substance promotes uric acid excretion mainly by interacting with intestinal urate transporters.
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Hiperuricemia , Losartán , Animales , Losartán/farmacología , Losartán/metabolismo , Ácido Úrico/metabolismo , Pez Cebra/metabolismo , Riñón/metabolismo , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/genética , Hiperuricemia/metabolismoRESUMEN
BACKGROUND: Hyperuricemia is an important pathological basis of gout and a distinct hazard factor for metabolic syndromes and cardiovascular and chronic renal disease, but lacks safe and effective treatments currently. Paeonia × suffruticosa Andrews leaf effectively reduced serum uric acid in gout patients; however, the material foundation and the mechanism remain unclear. PURPOSE: To determine the primary active components and mechanism of P. suffruticosa leaf in hyperuricemic mice. METHODS: The chemical constituents of P. suffruticosa leaf was identified using high-performance liquid chromatographic analysis. The anti-hyperuricemic activity of P. suffruticosa leaf extract (12.5, 25, 50, 100, and 200 mg/kg) and its components was evaluated in hyperuricemic mice induced by a high purine diet for 14 days. Then, the urate-lowering effects of apigenin 7-O-glucoside (0.09, 0.18, and 0.36 mg/kg) were assessed in another hyperuricemic mice model built by administrating potassium oxonate and adenine for 4 weeks. The inhibitory effect of apigenin 7-O-glucoside on uric acid production was elucidated by investigating xanthine oxidase activity in vitro and in serum and the liver and through molecular docking. Immunofluorescence and western blot analyses of the expression of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), and ATP-binding cassette G member 2 (ABCG2) proteins elucidated how apigenin 7-O-glucoside promoted uric acid excretion. RESULTS: Six compounds were identified in P. suffruticosa leaf: gallic acid, methyl gallate, oxypaeoniflorin, paeoniflorin, galloylpaeoniflorin, and apigenin 7-O-glucoside. P. suffruticosa leaf extract significantly attenuated increased serum uric acid, creatinine, and xanthine oxidase activity in hyperuricemic mice. Apigenin 7-O-glucoside from P. suffruticosa leaf reduced uric acid, creatinine, and malondialdehyde serum levels, increased superoxide dismutase activity, and partially restored the spleen coefficient in hyperuricemic mice. Apigenin 7-O-glucoside inhibited xanthine oxidase activity in vitro and decreased serum and liver xanthine oxidase activity and liver xanthine oxidase protein expression in hyperuricemic mice. Molecular docking revealed that apigenin 7-O-glucoside bound to xanthine oxidase. Apigenin 7-O-glucoside facilitated uric acid excretion by modulating the renal urate transporters URAT1, GLUT9, OAT1, and ABCG2. Apigenin 7-O-glucoside protected against renal damage and oxidative stress caused by hyperuricemia by reducing serum creatinine, blood urea nitrogen, malondialdehyde, and renal reactive oxygen species levels; increasing serum and renal superoxide dismutase activity; restoring the renal coefficient; and reducing renal pathological injury. CONCLUSION: Apigenin 7-O-glucoside is the main urate-lowering active component of P. suffruticosa leaf extract in the hyperuricemic mice. It suppressed liver xanthine oxidase activity to decrease uric acid synthesis and modulated renal urate transporters to stimulate uric acid excretion, alleviating kidney damage caused by hyperuricemia.
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Gota , Hiperuricemia , Transportadores de Anión Orgánico , Paeonia , Ratones , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/inducido químicamente , Ácido Úrico , Xantina Oxidasa/metabolismo , Creatinina , Simulación del Acoplamiento Molecular , Apigenina/farmacología , Riñón , Transportadores de Anión Orgánico/metabolismo , Superóxido Dismutasa/metabolismo , Glucósidos/farmacología , Malondialdehído/metabolismo , Ácido Oxónico/efectos adversosRESUMEN
Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities, including metabolic syndrome, gout with long-term systemic inflammation, chronic kidney disease, urolithiasis, cardiovascular disease, hypertension, rheumatoid arthritis, dyslipidemia, diabetes/insulin resistance and increased oxidative stress. Dysregulation of xanthine oxidoreductase (XOD), the enzyme that catalyzes uric acid biosynthesis primarily in the liver, and urate transporters that reabsorb urate in the renal proximal tubules (URAT1, GLUT9, OAT4 and OAT10) and secrete urate (ABCG2, OAT1, OAT3, NPT1, and NPT4) in the renal tubules and intestine, is a major cause of hyperuricemia, along with variations in the genes encoding these proteins. The first-line therapeutic drugs used to lower serum uric acid levels include XOD inhibitors that limit uric acid biosynthesis and uricosurics that decrease urate reabsorption in the renal proximal tubules and increase urate excretion into the urine and intestine via urate transporters. However, long-term use of high doses of these drugs induces acute kidney disease, chronic kidney disease and liver toxicity. Therefore, there is an urgent need for new nephroprotective drugs with improved safety profiles and tolerance. The current systematic review summarizes the characteristics of major urate transporters, the mechanisms underlying the pathogenesis of hyperuricemia, and the regulation of uric acid biosynthesis and transport. Most importantly, this review highlights the potential mechanisms of action of some naturally occurring bioactive compounds with antihyperuricemic and nephroprotective potential isolated from various medicinal plants.
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The present study aimed to determine the effects of polysaccharides-riched Prunus mume fruit juice concentrate (PFC) on uric acid (UA) excretion and the gut microbiota in mice with chronic kidney disease (CKD). C57BL/6 mice were randomly allocated to four groups: two that were fed AIN93M diet, one of which was administered 500 mg/kg PFC, and two that were fed AIN93M diet containing 0.2% adenine, one of which was administered 500 mg/kg PFC. PFC promoted UA excretion, which may have been mediated through increases in the protein expression of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1), organic carnitine transporter 2 (OCTN2), and reductions in the protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in kidneys of CKD mice. ABCG2 expression in the intestine was also increased by PFC administration. Additionally, PFC significantly increased large intestinal short-chain fatty acids (SCFAs) concentrations, and the number of gut microbial species, and reduced the abundance of the genera Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV and Allobaculum, which have a negative effect on UA excretion. In conclusion, PFC may promote UA excretion in CKD mice by altering the expression of urate transporters and regulating the gut microbiota.
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Hyperuricemia represents a risk factor for the progression of chronic kidney disease. Oxidative stress and inflammation are implicated in the mechanisms underlying hyperuricemia-mediated kidney injury. Monolluma quadrangula possesses several beneficial effects; however, its effect on hyperuricemia has not been investigated. This study evaluated the renoprotective and xanthine oxidase (XO) inhibitory activity of M. quadrangula in hyperuricemic rats. Phytochemical investigation revealed the presence of six known flavonoid isolated for the first time from this species. The rats received M. quadrangula extract (MQE) and potassium oxonate (PO) for 7 days. In vitro assays showed the radical scavenging and XO inhibitory activities of MQE, and in silico molecular docking revealed the inhibitory activity of the isolated flavonoids towards XO. Hyperuricemic rats showed elevated serum uric acid, creatinine, urea, and XO activity, and renal pro-inflammatory cytokines, MDA and NO, and decreased GSH, SOD, and catalase. MQE ameliorated serum uric acid, urea, creatinine, and XO activity, and renal pro-inflammatory cytokines. In addition, MQE attenuated renal oxidative stress, enhanced antioxidants, downregulated URAT-1, and GLUT-9 and upregulated OAT-1 in PO-induced rats. In conclusion, M. quadrangula attenuated hyperuricemia and kidney impairment by suppressing XO activity, oxidative stress and inflammation, and modulating urate transporters.
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Hiperuricemia , Animales , Catalasa , Creatinina , Citocinas , Flavonoides/toxicidad , Hiperuricemia/inducido químicamente , Inflamación , Riñón , Simulación del Acoplamiento Molecular , Ácido Oxónico , Extractos Vegetales/farmacología , Ratas , Superóxido Dismutasa , Urea/farmacología , Ácido Úrico , Xantina OxidasaRESUMEN
Objective To investigate the anti-hyperuricemia effects of Bixie deacidification fang on hyperuricemia mice and its mechanism of renal protein transport. Methods The effects of Bixie deacidification fang were investigated on hyperuricemia mice induced by potassium oxonate. Bixie deacidification fang was administered to hyperuricemia mice daily at doses of 220, 440 and 880 mg/kg for 10 days, and allopurinol (5mg/kg) was given as positive control. Serum and urine levels of uric acid and creatinine were determined by colorimetric method. Simultaneously, protein levels of urate transporter 1 (URAT1) and organic anion transporter 1 (OAT1) in the kidney were analyzed by Western blot. Results Compared with the model group, high-dose of Bixie deacidification fang inhibited xanthine oxidase (XOD) activities in serum (18.12±1.33 u/L) and that in liver (70.15±5.20 u/g protein) (P<0.05), decrease levels of serum uric acid (2.04 ± 0.64mg/L) (P<0.05) and serum creatinine (0.35±0.18µmol/L) and blood urea nitrogen (BUN)(8.83±0.71mmol/L) (P<0.05), ncreased levels of urine uric acid (38.34±8.23mg/L), urine creatinine (34.38±1.98mmol/L), down-regulated of URAT1 and up-regulated of OAT1 protein expressions (P<0.05) in the renal tissue of hyperuricemia mice. Conclusion Bixie deacidification fang recipe may promote the excretion of uric acid in the kidney by up-regulating the expression of OAT1 protein to promote the excretion of uric acid, and down-regulating the expression of URAT1 protein to inhibit the reabsorption of uric acid.
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Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1ß, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment.
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Berberina/análogos & derivados , Hiperuricemia/tratamiento farmacológico , Janus Quinasa 2/metabolismo , Transportadores de Anión Orgánico/metabolismo , Sustancias Protectoras/farmacología , Factor de Transcripción STAT3/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Berberina/farmacología , Berberina/uso terapéutico , Nitrógeno de la Urea Sanguínea , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Creatinina/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Hiperuricemia/inducido químicamente , Hipoxantina/toxicidad , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Enfermedades Renales/patología , Enfermedades Renales/prevención & control , Masculino , Ratones , Proteína 1 de Transporte de Anión Orgánico/genética , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ácido Oxónico/toxicidad , Sustancias Protectoras/uso terapéutico , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Ácido Úrico/sangre , Xantina Oxidasa/metabolismoRESUMEN
Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro, DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 µM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1ß, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1ß. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.
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This study was designed to investigate the effects and underlying mechanisms of Astaxanthin (AST) on high-fructose-induced hyperuricemia (HUA) from the perspectives of the uric acid (UA) synthesis and excretion in rat models. Following six weeks of a 10% fructose diet, the level of serum UA effectively decreased in the AST groups as compared to the model group. The enzymatic activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) were significantly inhibited, and the mRNA expression levels of XOD and ADA significantly decreased after the AST administration. These results suggested that the AST reduced UA synthesis by inhibiting the mRNA expressions and enzyme activities of XOD and ADA, thereby contributing to HUA improvement. On the hand, the relative expressions of the mRNA and protein of kidney reabsorption transport proteins (GLUT9 and URAT1) were significantly down-regulated by AST, while that of the kidney secretion proteins (OAT1, OAT3 and ABCG2) were significantly up-regulated by AST. These results indicated that the AST promoted UA excretion by regulating the urate transport proteins, and thus alleviated HUA. This study suggested that the AST could serve as an effective alternative to traditional medicinal drugs for the prevention of fructose-induced HUA.
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Inhibidores de la Adenosina Desaminasa/farmacología , Adenosina Desaminasa/metabolismo , Hiperuricemia/prevención & control , Proteínas de Transporte de Membrana/efectos de los fármacos , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores , Adenosina Desaminasa/genética , Animales , Biomarcadores/sangre , Biomarcadores/orina , Modelos Animales de Enfermedad , Fructosa , Hiperuricemia/inducido químicamente , Hiperuricemia/enzimología , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratas Sprague-Dawley , Reabsorción Renal/efectos de los fármacos , Ácido Úrico/orina , Xantina Oxidasa/genética , Xantina Oxidasa/metabolismo , Xantófilas/farmacologíaRESUMEN
Urate transporters, which are located in the kidneys, significantly affect the level of uric acid in the body. We looked at genetic variants of genes encoding the major reabsorption proteins GLUT9 (SLC2A9) and URAT1 (SLC22A12) and their association with hyperuricemia and gout. In a cohort of 250 individuals with primary hyperuricemia and gout, we used direct sequencing to examine the SLC22A12 and SLC2A9 genes. Identified variants were evaluated in relation to clinical data, biochemical parameters, metabolic syndrome criteria, and our previous analysis of the major secretory urate transporter ABCG2. We detected seven nonsynonymous variants of SLC2A9. There were no nonsynonymous variants of SLC22A12. Eleven variants of SLC2A9 and two variants of SLC22A12 were significantly more common in our cohort than in the European population (p = 0), while variants p.V282I and c.1002+78A>G had a low frequency in our cohort (p = 0). Since the association between variants and the level of uric acid was not demonstrated, the influence of variants on the development of hyperuricemia and gout should be evaluated with caution. However, consistent with the findings of other studies, our data suggest that p.V282I and c.1002+78A>G (SLC2A9) reduce the risk of gout, while p.N82N (SLC22A12) increases the risk.
RESUMEN
OBJECTIVES: To investigate the antihyperuricemia and nephroprotective effects of Orthosiphon stamineus extracts on hyperuricemia (HUA) mice and explore the potential mechanisms. METHODS: Orthosiphon stamineus extracts were extracted using 50% ethanol and enriched using ethyl acetate, and characterised utilising UPLC/ESI-MS. A potassium oxonate (PO) induced hyperuricemic mouse model was used to evaluate antihyperuricemia and nephroprotective effects of O. stamineus ethyl acetate extracts (OSE). KEY FINDINGS: Eight constituents from OSE were identified and OSE treatment ameliorated HUA by regulating key indicators of kidney dysfunction and xanthine oxidase, adenosine deaminase activity and urate transporters in hyperuricemic mice. Moreover, in renal histopathology analysis, OSE significantly alleviated kidney injury. CONCLUSIONS: These findings demonstrate that OSE has antihyperuricemic and nephroprotective effects on PO-induced HUA mice and those results indicate that OSE could be a safe and effective agent or functional ingredient for treating HUA.
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Hiperuricemia/tratamiento farmacológico , Riñón/efectos de los fármacos , Orthosiphon/química , Extractos Vegetales/farmacología , Animales , Creatinina/sangre , Hiperuricemia/inducido químicamente , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Masculino , Ratones , Transportadores de Anión Orgánico/metabolismo , Ácido Oxónico , Ácido Úrico/sangre , Xantina Oxidasa/metabolismoRESUMEN
We presented an update in the field of hypouricemia, which is defined as a serum urate concentration of < 2 mg/dL (119 µmol/L), for the practicing rheumatologist, who usually is the consulting physician in cases of disorders of urate metabolism. We performed a narrative review through a literature search for original and review articles in the field of human hypouricemia published between January 1950 and July 2018. We divided the etiology of hypouricemia into two main categories: those associated with a decrease in urate production and those promoting the elimination of urate via the kidneys. The most common conditions associated with these categories are discussed. Furthermore, the etiology of hypouricemia may be associated with certain medications prescribed by the practicing rheumatologists, such as the following: urate-lowering drugs (allopurinol and febuxostat); recombinant uricase (pegloticase); uricosuric agents (probenecid, benzbromarone); urate transporter URAT1 inhibitor (lesinurad); angiotensin II receptor blocker (losartan); fenofibrate; high-dose trimethoprim-sulfamethoxazole; some NSAID; and high-dose salicylate therapy. The rheumatologist is considered an expert in the metabolism of urate and its associated pathological conditions. Therefore, specialists must recognize hypouricemia as a biomarker of various pathological and potentially harmful conditions, highlighting the importance of conducting a deeper clinical investigation to reach a more accurate diagnosis and treatment.
Asunto(s)
Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/tratamiento farmacológico , Uricosúricos/uso terapéutico , Cálculos Urinarios/diagnóstico , Cálculos Urinarios/tratamiento farmacológico , Biomarcadores , Humanos , ReumatólogosRESUMEN
Chrysanthemum indicum Linne flower (CF) and Cinnamomum cassia (L.) J. Presl bark (CB) extracts have been used as the main ingredients in several prescriptions to treat the hyperuricemia and gout in traditional medicine. In the present study, we investigated the antihyperuricemic effects of DKB114, a CF, and CB mixture, and the underlying mechanisms in vitro and in vivo. DKB114 markedly reduced serum uric acid levels in normal rats and rats with PO-induced hyperuricemia, while increasing renal uric acid excretion. Furthermore, it inhibited the activity of xanthine oxidase (XOD) in vitro and in the liver in addition to reducing hepatic uric acid production. DKB114 decreased cellular uric acid uptake in oocytes and HEK293 cells expressing human urate transporter (hURAT)1 and decreased the protein expression levels of urate transporters, URAT1, and glucose transporter, GLUT9, associated with the reabsorption of uric acid in the kidney. DKB114 exerts antihyperuricemic effects and uricosuric effects, which are accompanied, partially, by a reduction in the production of uric acid and promotion of uric acid excretion via the inhibition of XOD activity and reabsorption of uric acid. Therefore, it may have potential as a treatment for hyperuricemia and gout.
Asunto(s)
Chrysanthemum/química , Cinnamomum/química , Hiperuricemia/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Ácido Úrico/orina , Xantina Oxidasa/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/farmacología , Flores/química , Expresión Génica , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/fisiología , Células HEK293 , Células Hep G2 , Humanos , Hígado/química , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/fisiología , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/fisiología , Corteza de la Planta/química , Extractos Vegetales/toxicidad , Ratas , Ratas Sprague-Dawley , Transfección , Urato Oxidasa/antagonistas & inhibidores , Ácido Úrico/análisis , Ácido Úrico/metabolismoRESUMEN
After a "silence" period for decades, a great body of new information has become available about the pathogenesis, diagnosis and treatment of gout. New data on purine metabolism and urate transporters have been published. It has become evident that gout is an autoinflammatory disease involving the inflammasome and interleukin-1. With respect to diagnosis, microscopic evaluation of the urate crystal is still the gold standard, however, sensitive imaging techniques (ultrasound, modern computed tomography methods) are able to visualize crystal deposition and tophus formation. Tophus size may also be monitored over time. We see a renaissance of non-pharmacological, lifestyle-related treatment modalities. Pharmacotherapy includes the resolution of attacks and urate-lowering maintenance therapy. In 2016, two recent series of recommendations have been published. Treat-to-target therapy aiming at urate levels ≤360 µmol/l is crucial. Urate-lowering therapy includes xanthine oxidase inhibitors (allopurinol, febuxostat). However, a number of novel compounds (urate transporter inhibitors, recombinant uricase, interleukin-1 inhibitors) are under development or before introduction to gout treatment. Comorbidites should be considered throughout the follow-up of gout patients. Orv Hetil. 2018; 159(40): 1625-1636.