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Ethnopharmacological Relevance: In recent years, in addition to hypertension, hyperglycemia, and hyperlipidemia, the prevalence of hyperuricemia (HUA) has increased considerably. Being the fourth major health risk factor, HUA can affect the kidneys and cardiovascular system. Chrysanthemi Indici Flos is a flavonoid-containing traditional Chinese patent medicine that exhibits a uric acid (UA)-lowering effect. However, the mechanisms underlying Chrysanthemi Indici Flos-enriched flavonoid part (CYM.E) mediated alleviation of HUA remain unelucidated., Aim of the Study: This study aimed to elucidate the efficacy of CYM.E in preventing and treating HUA and its specific effects on UA-related transport proteins, to explore possible mechanism., Methods: The buddleoside content in CYM.E was determined through high-performance liquid chromatography. HUA was induced in mice models using adenine and potassium oxonate. Subsequently, mice were administered 10 mg/kg allopurinol, and 30, 60, and 90 mg/kg CYM.E to evaluate the effects of CYM.E on the of HUA mice model. Herein, plasma uric acid (UA), creatinine (CR), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) contents, along with serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were measured. Additionally, xanthine oxidase (XOD) and adenosine deaminase (ADA) activities in the liver were determined. The histomorphologies of the liver and kidney tissues were examined through hematoxylin and eosin staining. The messenger RNA (mRNA) expression of facilitated glucose transporter 9 (GLUT9), organic anion transporter (OAT)1, OAT3, and adenosine triphosphate binding cassette subfamily G2 (ABCG2) in the kidney was assessed by real-time quantitative polymerase chain reaction. Furthermore, the expression of urate transporter 1 (URAT1), GLUT9, OAT1, and OAT3 in the kidney, OAT4, and ABCG2 proteins was determined by immunohistochemistry and western blotting., Results: The buddleoside content in CYM.E was approximately 32.77%. CYM.E improved body weight and autonomous activity in HUA mice. Additionally, it reduced plasma UA, BUN, and CR levels and serum ALT and AST activities, thus improving hepatic and renal functions, which further reduced the plasma UA content. CYM.E reduced histopathological damage to the kidneys. Furthermore, it lowered plasma TC, TG, and LDL-c levels, thereby improving lipid metabolism disorder. CYM.E administration inhibited hepatic XOD and ADA activities and reduced the mRNA expression of renal GLUT9. CYM.E inhibited the protein expression of renal URAT1, GLUT9, and OAT4, and increased the mRNA and protein expression of renal OAT1, OAT3, and ABCG2. Altogether, these results show that CYM.E could inhibit the production and promote reabsorption of UA and its excretion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Fuling-Zexie (FZ) formula, a traditional Chinese herbal prescription composed of Poria cocos (Schwan.) Wolf. (Poria), Pueraria lobate (Willd.) Howe. (Puerariae Lobatae Radix), Alisma orientale (Sam.) Julep. (Alismatis Rhizoma), and Atractylodes lancea (Thunb.) Dc. (Atractylodis Rhizoma), has been clinically used to ameliorate hyperuricemia (HUA) and its associated renal injury., Aim of Study: This study aims to explore the action and mechanism of FZ on renal inflammation and dysfunction caused by HUA., Materials and Methods: FZ was orally administered to rapid HUA mouse induced by potassium oxonate (PO) and hypoxanthine (HX) for 7 days. Serum levels of uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), xanthine oxidase (XOD), adenosine deaminase (ADA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urine levels of UA, CRE and urinary albumin were determined by biochemical assays. Serum levels of interleukin (IL)-1β and IL-6 were tested by ELISA. Hematoxylin-eosin and Masson staining were used to examine kidney and liver histopathological alterations. The expressions of renal glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), phospho-janus kinase 2 (p-JAK2), p-signal transducer and activator of transcription 3 (p-STAT3), suppression of cytokine signaling 3 (SOCS3), NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cleaved-cysteinyl aspartate specific proteinase-1 (cleaved-Cas-1) were detected by western blots. The potential protein targets and pathways of FZ intervention on HUA were predicted by network pharmacology. The constituents in FZ aqueous extract were analyzed by UPLC-MS., Results: FZ reduced serum UA, CRE, BUN, and urinary albumin and increased urine UA, CRE levels in HUA mice. In addition, the treatment with FZ to HUA mice inhibited the elevated serum levels of XOD and ADA, and regulated renal urate transports including OAT1, GLUT9 and ABCG2. FZ also attenuated kidney inflammation and fibrosis and downregulated the expressions of IL-1β, p-JAK2, p-STAT3, SOCS3, IL-6, NLRP3, ASC, and cleaved-Cas-1. Thirteen compounds were identified in the FG, including L-phenylalanine, D-tryptophan, 3'-hydroxypuerarin, Puerarin, 3'-Methoxy Puerarin, Daidzin, Pueroside A, formononetin-8-C- [xylosyl (1→6)]-glucoside, Ononin, Alisol I 23-acetate, 16-oxo-alisol A, Alisol C and Alisol A., Conclusion: FZ inhibits serum UA generation and promotes urine UA excretion as well as attenuates kidney inflammation and fibrosis in HUA mouse with nephropathy. The underlying mechanism of its action may be associated with suppression of the JAK2/STAT3 signaling pathway and NLRP3 inflammasome activation. This formula may offer a novel source for developing anti-HUA drugs., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Palmatine (Pal) is a major bioactive alkaloid originated from ancient Chinese herbal medicine Cortex Phellodendri Amurensis (CPA), which has long been applied to treat hyperuricemia (HUA)-related diseases. Pal possesses potent anti-inflammatory and anti-oxidant effects against metabolic diseases. However, its potential beneficial effect against PO (potassium oxonate)/HX (hypoxanthine)-induced HUA remains elusive., Aim of the Study: This study aimed to investigate the potential pharmacological effect and mechanism of Pal on PO/HX-induced HUA in mice., Material and Methods: A mouse model of HUA was established by co-administration of PO/HX once daily for 7 consecutive days. The HUA mice were orally given three doses (25, 50 and 100 mg/kg) of Pal daily for a week. Febuxostat (Feb, 5 mg/kg) was given as a positive control. At the scheduled termination of the experiment, the whole blood, liver and kidney were collected for subsequent analyses. The concentrations of uric acid (UA), creatinine (CRE) and blood urea nitrogen (BUN), and activities of adenosine deaminase (ADA) and xanthine oxidase (XOD) were evaluated. Histopathological alterations of the kidney were detected by H&E staining. The inflammatory and oxidative stress status was detected by assay kits. Additionally, key proteins involved in the urate transporter, Keap1-Nrf2 and TXNIP/NLRP3 signaling pathways were evaluated by immunohistochemistry and Western blotting. Finally, molecular docking was employed to probe the binding characteristics of Pal and target proteins Keap1, NLRP3, URAT1 and HO-1., Results: Administration of Pal substantially decreased the elevated kidney weight, lowered UA, CRE and BUN levels, and attenuated abnormal histopathological alterations. Meanwhile, treatment with Pal also dramatically lowered hepatic XOD and ADA activities. Besides, Pal treatment effectively mitigated the renal inflammatory and oxidative stress markers. Further mechanistic investigation indicated Pal distinctly downregulated the protein levels of GLUT9 and URAT1, while up-regulated the expression levels of OAT1 and ABCG2. Pal also restored Nrf2 activation, promoted subsequent expression of anti-oxidative enzymes, and downregulated the expressions of TXNIP, NLRP3, apoptosis-associated speck-like (ASC), caspase-1, IL-1β and IL-18. Molecular docking analysis also indicated Pal firmly bound with Keap1, NLRP3, URAT1 and HO-1., Conclusions: These findings indicated that Pal exhibited favorable anti-HUA effect via modulating the expressions of transporter-related proteins and suppressing XOD activity. Furthermore, Pal also alleviated HUA-induced kidney injury, which was at least partially related to restoring Keap1-Nrf2 pathway and inhibiting TXNIP/NLRP3 inflammasome. Our investigation was envisaged to provide experimental support for the traditional application of CPA and CPA-containing classical herbal formulas in the management of HUA-related diseases and might provide novel dimension to the clinical application of Pal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacology Relevance: One folk use of Alstonia scholaris (L.) R. Br. in "Dai" ethno-medicine system is to treat gouty arthritis, which might be caused by hyperuricemia, but anti-hyperuricemic investigation of A. scholaris were rarely reported., Aim of the Study: To verify anti-hyperuricemic property of A. scholaris, and explore its bioactive compounds in vivo and in vitro., Materials and Methods: The anti-hyperuricemic bioactivity of the non-alkaloids fraction and compounds were evaluated with potassium oxonate (PO) induced hyperuricemia mice model in vivo, and monosodium urate (MSU) induced human renal tubular epithelial cells (HK-2) was selected to test in vitro, respectively, with benzobromarone as the positive control. 11 triterpenoids were isolated by phytochemical methods and their structures were elucidated by spectroscopic analysis and ECD calculation., Results: The non-alkaloids fraction of A. scholaris decreased the serum uric acid (UA) level in mice model significantly at the doses of 100 mg/kg and 200 mg/kg, and then nine ursane- and two oleanane-triterpenoids including four new compounds (1-3 and 10) were isolated from the bioactive fraction, in which compounds 1, 4, 5, 6 and 10 exhibited better anti-hyperuricemic tendency in vitro by promoting the excretion of UA in MSU-induced HK-2 cell model at a concentration of 5 μM. Furthermore, compounds 1 and 4 were proved to reduce the serum UA level in mice significantly at 5 mg/kg in vivo., Conclusions: The results supported the traditional use of A. scholaris in treating gouty arthritis, and also provided new bioactive triterpenoids for further chemical and pharmacological investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Moringa oleifera Lam. leaf (MOL), a rich source of protein and phenolics, was traditionally used to treat various diseases including headaches, fevers, sore throat and dyslipidemia. Recently, MOL was reported to possess antioxidant, anti-dyslipidemia and hepato-renal protective activities, indicating that MOL could become a potential agent to improve metabolic disorders associated with hyperuricemia. The antihyperuricemic effect of MOL hydrolysate (MOLH) with high contents of phenolics and peptides remains unknown., Aim of the Study: The aim of this study is to investigate xanthine oxidase (XO) inhibitory activity of MOLH, to clarify phenolic and peptide profiles of MOLH, and to evaluate possible mechanism underlying the antihyperuricemic effect of MOLH., Materials and Methods: MOLH was prepared by enzymatic hydrolysis using commercial trypsin. XO inhibitory activity was determined by XO reaction-UPLC-MS coupling method. The chemical profiles of the phenolic and peptide fractions of MOLH were determined by UPLC-QTOF-MS/MS. The antihyperuricemic effect of MOLH was evaluated in a potassium oxonate-induced hyperuricemic rat model at doses of 200 and 500 mg/kg. Serum uric acid (UA), urea nitrogen, creatinine (CRE), triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels, serum XO activity, liver malondialdehyde (MDA) equivalent level, renal tumor necrosis factor-α and interleukin-1β levels, and protein expression of renal urate-anion transporter 1, glucose transporter 9 and ATP-binding cassette transporter G2 were determined., Results: The phenolic and peptide fractions played key roles in inhibiting XO activity and blocking uric acid production. Five flavonoids and sixteen polypeptides were identified in the phenolic and peptide fractions of MOLH, respectively. MOLH (200 and 500 mg/kg) could effectively reduce the serum UA level of hyperuricemic rats (p < 0.001) by regulation of serum XO activity (p < 0.05 at 200 mg/kg, p < 0.01 at 500 mg/kg) and renal urate transporters. Besides, MOLH could improve metabolic disorders associated with hyperuricemia by its multiple actions on liver MDA (p < 0.001), serum CRE (p < 0.05 at 500 mg/kg) and serum TG (p < 0.001)., Conclusion: The results provided scientific evidence that MOLH rich in phenolics and peptides ameliorated hyperuricemia and metabolic disorders. This study validated the potential use of MOLH for regulation of hyperuricemia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Herbaceous peony (Paeonia lactiflora Pall.) flower has been used widely in dietotherapy in China and other countries. It has good ethnopharmacological value in the treatment of various metabolic diseases. However, the molecular mechanisms by which it lowers serum uric acid are unknown. The development of pharmaceutical resources is very important. Here, we sought to elucidate the mode of action of herbaceous peony in terms of reducing uric acid levels., Aim of the Study: In the present research, the effects of the total glucosides of herbaceous peony flower were investigated in a rat hyperuricaemia model. Another aim of the study was to clarify the mechanism by which herbaceous peony flower (TGPF) lowers serum uric acid levels., Materials and Methods: A hyperuricaemic rat model was induced via intragastric administration of 100 mg/kg adenine and 250 mg/kg ethambutol hydrochloride (EH) for 23 d. Then TongFengShu 600 mg/kg, allopurinol 42 mg/kg, or TGPF (50 mg/kg, 100 mg/kg, or 200 mg/kg) was administered 1 h after the adenine and EH treatments., Results: TGPF improved weight loss and decreased serum UA, XOD, MCP-1, TNF-α, Cr, and BUN in the rats with hyperuricaemic nephropathy. TGPF downregulated renal URAT1 and GLUT9, upregulated renal OAT1, and ameliorated histopathological changes in the thymus, spleen, and kidney., Conclusion: TGPF is promising as a therapeutic agent against hyperuricaemia. It regulates the uric acid transporters and diminished serum uric acid levels, and alleviates renal pathology associated with hyperuricaemia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacology Relevance: Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels., Aim of the Study: The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity., Materials and Methods: After oral administration of Dioscin in potassium oxonate (PO) induced hyperuricemia rats and adenine-PO induced hyperuricemia mice models, serum uric acid and creatinine levels, clearance of uric acid and creatinine, fractional excretion of uric acid, and renal pathological lesions were determined were used to evaluate the antihyperuricemic effects. Renal glucose transporter-9 (GLUT-9) and organic anion transporter-1 (OAT-1) expressions were analyzed by western blotting method. Renal uric acid excretion was evaluated using stably urate transporter-1 (URAT-1) transfected human epithelial kidney cell line. Intestinal uric acid excretion was evaluated by measuring the transcellular transport of uric acid in HCT116 cells., Results: In hyperuricemia rats, both 25 and 50mg/kg of oral Dioscin decreased serum uric acid levels over 4h. In the hyperuricemia mice, two weeks treatment of Dioscin significantly decreased serum uric acid and creatinine levels, increased clearance of uric acid and creatinine, increased fractional excretion of uric acid, and reduced renal pathological lesions caused by hyperuricemia. In addition, renal GLUT -9 was significantly down-regulated and OAT-1 was up-regulated in Dioscin treated hyperuricemia mice. Dioscin's metabolite Tigogenin significantly inhibited uric acid re-absorption via URAT1 from 10 to 100μM. Diosgenin and Tigogenin increased uric acid excretion via ATP binding cassette subfamily G member 2 (ABCG2)., Conclusion: Decreasing effect of Dioscin on serum uric acid level and enhancing effect on urate excretion were confirmed in hyperuricemia animal models. Tigogenin, a metabolite of Dioscin, was identified as an active substance with antihyperuricemic activity in vivo, through inhibition of URAT1 and promotion of ABCG2., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Cordyceps militaris was recorded in the classic traditional Chinese medicine book with the main functions of "protecting liver and enhancing kidney functions", influencing serum uric acid levels., Aim of Study: The aim is to investigate the hypouricemic effects and possible mechanism of C. militaris in hyperuricemic mice., Materials and Methods: A water extract (WECM) was prepared by decocting C. militaris directly at 80 °C in water bath, followed by lyophilization. WECM at 50, 100 and 200mg/kg was orally administered to hyperuricemic mice induced by potassium oxonate and hypoxanthine combinedly and allopurinol (5mg/kg) was served as a positive control., Results: WECM exhibited excellent hypouricemic activity, which could decrease the serum uric acid levels of the hyperuricemic mice (306μmol/L) to 189, 184 and 162μmol/L at different doses respectively (P<0.01), approaching the levels of normal mice (184μmol/L). The urate transporter 1 (URAT1) protein levels of kidney at different doses of WECM were 28.15, 17.43, 9.03pg/mL respectively, much lower than that in the hyperuricemia group (93.45pg/mL, P<0.01); and suggested WECM may interact with URAT1. Docking simulations using modeled structure of URAT1 suggested that LYS145, ARG325, ARG477 and ASP168 of URAT1 are key functional residues of URAT1. Four active compounds in C. militaris were identified and their interaction energies with target were estimated between -200 and -400kcal/mol., Conclusions: These findings suggested that C. militaris produced significant hypouricemic actions and the hypouricemic effects of WECM may be attributed to the inhibitive effect of WECM on URAT1 protein levels. The results of blood urine nitrogen and serum creatinine levels and liver, kidney and spleen coefficients showed that WECM have no negative impacts on liver, renal and spleen functions. The screened four active compounds using molecular docking method deserve further investigation in other work., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Green tea is a Chinese materia medica with the main functions of "inducing urination and quenching thirst". Green tea polyphenols (GTP) are generally acknowledged as the main active fraction with multiple pharmacological functions in green tea. However, the effect of GTP on hyperuricemia is not clear till now., Aim of Study: The present study was carried out to investigate the effect of GTP on serum level of uric acid in potassium oxonate (PO)-induced hyperuricemic mice, and explore the underlying mechanisms from two aspects of production and excretion of uric acid., Materials and Methods: PO and GTP were intragastricly administered to mice for consecutive 7 days. Serum level of uric acid, and xanthine oxidase (XOD) activity in serum and liver were examined. Simultaneously, expression of XOD protein in liver was analyzed by Western blot assay. Expressions of urate transporters including urate-anion transporter (URAT) 1, organic anion transporter (OAT) 1 and 3 in kidney were analyzed by immunohistochemistry staining method., Results: 300 and 600 mg/kg GTP significantly decreased serum level of uric acid of hyperuricemic mice in a dose-dependent manner (p<0.05 or p<0.01). Besides, 300 and 600 mg/kg GTP markedly reduced XOD activity in serum and liver of hyperuricemic mice (both p<0.01). Furthermore, 300 and 600 mg/kg GTP clearly reduced XOD expression in liver, as well as reduced URAT1 expression and increased OAT1 and OAT3 expressions in kidney of hyperuricemic mice (p<0.05 or p<0.01)., Conclusions: These results demonstrated that GTP had the effect of lowering uric acid through decreasing the uric acid production and increasing uric acid excretion. Our study suggested that GTP would be a promising candidate as a novel hypouricaemic agent for further investigation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Simiao pill is one of the most frequently prescriptions in traditional Chinese medicine to treat hyperuricemia and gout. This study was to investigate the protective effects of Simiao pill on renal glomerular injury in a rat model of high fructose intake., Materials and Methods: Sprague-Dawley male rats were given 10% fructose in drinking water and standard laboratory chow for 4 weeks to induce hyperuricemia and metabolic syndrome. Then fructose-fed animals were randomly divided into four groups receiving water, Simiao pill (78.87 and 157.74 mg/kg) and allopurinol (5mg/kg) daily for next 6 weeks, respectively. Serum levels of uric acid, creatinine, triglyceride, total cholesterol, low density lipoprotein, blood urea nitrogen, insulin, as well as urinary albumin were measured. Oral glucose tolerance test (OGTT) was carried out. Kidney pathological changes were detected using periodic-acid schiff-stained (PAS) staining and transmission electron microscopy (TEM) analysis. Glomerular protein levels of nephrin, podocin, CD2-associated protein (CD2AP), interleukin (IL)-1β, sirtuin 1 (Sirt1), nuclear factor kappaB (NF-κB) and pyrin domain containing 3 (NLRP3) inflammasome were measured by Western blot., Results: Simiao pill effectively restored high fructose-induced hyperuricemia and metabolic syndrome in rats. Simiao pill significantly increased protein levels of nephrin, podocin and CD2AP in renal glomeruli, improved renal inflammatory cell infiltration into interstitium and glomerular injury in high fructose-fed rats with reduction of urine albumin levels. Furthermore, Simiao pill up-regulated Sirt1 protein levels and suppressed NF-κB/NLRP3 inflammasome activation to reduce IL-1β in renal glomeruli of high fructose-fed rats., Conclusions: The renal protective effects of Simiao pill may be associated with up-regulation of Sirt1 expression and suppression of NF-κB/NLRP3 inflammasome activation to reduce renal glomerular injury in high fructose-fed rats with metabolic syndrome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Wuling San, a famous prescription in Chinese medicine, is composed of Polyporus, Poria, Alismatis rhizoma, Cinnamomi cortex and Atractylodis macrocephalae rhizoma, and promotes kidney function and diuresis. The main purpose of this study was to investigate its renal protective effect in high fructose-induced hyperuricemic mice., Materials and Methods: ICR mice were fed with 30% fructose in drinking water for 6 weeks to induce hyperuricemia and renal dysfunction. Then mice were orally administrated for other 6 weeks with Wuling San (987, 1316, 1755 and 2340mg/kg), allopurinol (5mg/kg) and water daily, respectively. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Hematoxylin and eosin staining was used to assess renal histological changes. Renal interleukin (IL)-1β concentrations were measured using ELISA kit. Renal protein levels of organic ion transporters, as well as toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling and pyrin domain containing 3 (NLRP3) inflammasome were determined by Western blot assay., Results: Wuling San significantly decreased serum uric acid, creatinine and BUN levels, increased fractional excretion of uric acid (FEUA) in fructose-fed mice. It restored fructose-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 1 (OAT1), as well as organic cation transporter 1 (OCT1) and OCT2 in mice. Wuling San obviously alleviated infiltration of inflammation cells in kidney glomerulus of fructose-fed mice. Moreover, Wuling San suppressed the activation of TLR4/ MyD88 signaling to inhibit nuclear factor κB (NF-κB) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1β secretion in the kidney of fructose-fed mice., Conclusion: Wuling San exerts renal protective effect by modulating renal organic ion transporters in fructose-induced hyperuricemic mice. The molecular mechanism of its action may be associated with the suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β production in high fructose-induced hyperuricemic mice., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: The species Sparattosperma leucanthum (Vell.) K. Schum is used in Brazilian folk medicine to treat rheumatism, throat ulcers, stomatitis, syphilis, bladder stones and as blood cleanser. The aim of this study was to evaluate the potential, in vitro and in vivo, of the extracts of leaves from Sparattosperma leucanthum to treat hyperuricemia and inflammation in the gouty arthritis model., Materials and Methods: Ethyl acetate extract (SLE), methanolic extract (SLM) and aqueous extract (SLW) were evaluated in vitro on XO inhibitory activity and in vivo in an experimental model with oxonate-induced hyperuricemia in mice which was used to evaluate anti-hyperuricemic activity and liver xanthine oxidase (XOD) inhibition. Anti-inflammatory activity was also investigated on MSU crystal-induced paw edema model., Results: Sparattosperma leucanthum crude extracts showed expressive results on urate-lowering activity in blood. SLW at the dose of 125 mg/kg has proved to be active in reducing hyperuricemia and was capable to inhibit the hepatic xanthine oxidase enzyme (XOD). SLM showed anti-hyperuricemic activity on all doses tested; however, this extract showed activity on the XOD only at the dose of 500 mg/kg. SLE, at the three evaluated doses, has proved to be active in reducing hyperuricemia in vivo and was able to inhibit XO activity in vitro at the concentration of 100 µg/mL. This extract was also able to inhibit XOD activity in vivo at the doses of 250 mg/kg and 500 mg/kg. SLE (125 and 250 mg/kg) and SLW (500 mg/kg) showed significant anti-inflammatory activity on monosodium urate crystal-induced paw edema model., Conclusions: The ethyl acetate, methanolic and aqueous extracts of Sparattosperma leucanthum showed significant results on evaluated models and therefore may be important agents for the treatment of gouty arthritis and hyperuricemia., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Jatropha isabellei Müll Arg. (Euphorbiaceae) is a medicinal plant that has been used in South American folk medicine for the treatment of arthritic diseases, particularly gout., Aim of the Study: This study was designed to verify the antinociceptive, anti-inflammatory and hypouricemic potential of Jatropha isabellei., Materials and Methods: Rats were orally administered with the crude extract (100-300 mg/kg) or a fraction that is rich in alkaloids (0.15 mg/kg) of Jatropha isabellei. An intra-articular (i.a.) injection of 50 μl of monosodium urate (MSU) crystals (1.25mg/site) was used to generate the gout model to assess the effect of the treatment on nociception (thermal and mechanical hyperalgesia) and inflammation (oedema and neutrophil infiltration). The effect of Jatropha isabellei on the serum levels of uric acid was evaluated in a model of hyperuricaemia induced by the intraperitoneal injection of potassium oxonate (250 mg/kg). The side effects were analysed using an open-field test, gastric lesion assessment and by measuring the levels of the ALT and AST enzymes., Results: Our study demonstrated that the crude extract of Jatropha isabellei and a fraction rich in alkaloids were able to prevent the thermal hyperalgesia, mechanical allodynia, oedema and neutrophil infiltration induced by intra-articular MSU injection in rats. On the other hand, treatment with Jatropha isabellei did not alter the uric acid levels increased by potassium oxonate in the hyperuricaemia model. In addition, Jatropha isabellei did not induce gastric lesions or liver damage and did not alter spontaneous locomotor activity., Conclusion: The crude extract of Jatropha isabellei and its fraction rich in alkaloid presents antinociceptive and anti-inflammatory effects in a rat gout model, similar to that observed after treatment with colchicine, supporting the traditional use of this plant in gouty patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: The ethanolic extract of Lychnophora trichocarpha Spreng. is used in Brazilian folk medicine to treat bruise, pain and inflammatory diseases., Aim of the Study: The present study aimed at investigating whether ethanolic extract of L. trichocarpha, its ethyl acetate fraction and its main bioactive compounds could be useful to treat gouty arthritis by countering hyperuricemia and inflammation., Materials and Methods: L. trichocarpha ethanolic extract (LTE), ethyl acetate fraction from ethanolic extract (LTA) and isolated compounds were evaluated for urate-lowering activity and liver xanthine oxidase (XOD) inhibition in oxonate-induced hyperuricemic mice. Anti-inflammatory activity in monosodium urate crystal-induced paw oedema, an experimental model of gouty arthritis, was also investigated., Results: Crude ethanolic extract and its ethyl acetate fraction showed significant urate-lowering effects. LTE was also able to significantly inhibit liver xantine oxidase (XOD) activity in vivo at the dose of 250mg/kg. Luteolin, apigenin, lupeol, lychnopholide and eremantholide C showed the anti-hyperuricemic activities among tested compounds. Apigenin also showed XOD inhibitory activity in vivo. Luteolin, lychnopholide, lupeol and eremantholide C, in turn, did not shown significant inhibitory activity towards this enzyme, indicating that this mechanism is not likely to be involved in urate-lowering effects of those compounds. LTE, LTA, lupeol, β-sitosterol, lychnopholide, eremantholide, luteolin and apigenin were also found to inhibit monosodium urate crystals-induced paw oedema in mice., Conclusions: Ethanolic extract of Lychnophora trichocarpha and some of its bioactive compounds may be promising agents for the treatment of gouty arthritis since they possesses both anti-hiperuricemic and anti-inflammatory properties., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Modified Simiao Decoction (MSD), based on clinical experience, has been used for decades and famous for its efficiency in treating hyperuricemic and gouty diseases., Aim of the Study: To investigate the effects of MSD on anti-hyperuricemic and nephroprotective effects are involved in potassium oxonate-induced hyperuricemic mice., Materials and Methods: The effects of MSD were investigated in hyperuricemic mice induced by potassium oxonate. MSD were fed to hyperuricemic mice daily at a dose of 0.45, 0.90, 1.80 g/kg for 10 days, and allopurinol (5mg/kg) was given as a positive control. Serum and urine levels of uric acid and creatinine, and fractional excretion of uric acid (FEUA) were determined by colorimetric method. Its nephroprotective effects were evaluated by determining a panel of oxidative stress markers after the intervention in hyperuricemic mice. Simultaneously, protein levels of urate transporter 1 (URAT1) and organic anion transporter 1 (OAT1) in the kidney were analyzed by Western blotting., Results: MSD could inhibit XOD activities in serum and liver, decrease levels of serum uric acid, serum creatinine and BUN, and increased levels of urine uric acid, urine creatinine, FEUA dose-dependently through down-regulation of URAT1 and up-regulation of OAT1 protein expressions in the renal tissue of hyperuricemic mice. It also effectively reversed oxonate-induced alterations on renal MDA levels and SOD activities in this model., Conclusion: MSD processes uricosuric and nephroprotective actions by regulating renal urate transporters and enhancing antioxidant enzymes activities to improve renal dysfunction in hyperuricemic mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Simiao pill is one of the most frequently prescription in traditional Chinese medicine to treat gout and hyperuricemia., Aim of the Study: We investigated the effects of Simiao pill on urate excretion and renal function and examined whether renal organic ion transporters are involved in potassium oxonate-induced hyperuricemic mice., Materials and Methods: Water extract of Simiao pill at 507, 1014 and 2028mg/kg was orally administered to hyperuricemic and normal mice for 7 days, and allopurinol (5mg/kg) was given as a positive control. Serum and urine levels of uric acid and creatinine, and fractional excretion of uric acid (FEUA) were measured in hyperuricemic and normal mice treated with Simiao pill and allopurinol. Simultaneously, the mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9) and organic anion transporter 1 (mOAT1) and organic cation/carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in the kidney were analyzed by semi-quantitative RT-PCR and Western blotting methods, respectively., Results: Simiao pill significantly reduced serum uric acid levels and increased FEUA dose-dependently in hyperuricemic mice. And it effectively reversed oxonate-induced alterations in renal mURAT1, mGLUT9 and mOAT1 mRNA and protein levels, resulting in the enhancement of renal urate excretion in mice. Moreover, Simiao pill decreased serum creatinine levels, as well as increased renal mOCT1, mOCT2, mOCTN1 and mOCTN2 mRNA and protein levels, leading to improve renal dysfunction in this model., Conclusion: These findings suggest that Simiao pill processes uricosuric and nephroprotective actions by regulating renal organic ion transporters in hyperuricemic animals., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Phyllanthus niruri Linn. (Euphorbiaceae) is used as folk medicine in South America to treat excess uric acid. Our initial study showed that the methanol extract of Phyllanthus niruri and its lignans were able to reverse the plasma uric acid of hyperuricemic animals., Aim of the Study: The study was undertaken to investigate the mechanisms of antihyperuricemic effect of Phyllanthus niruri and its lignan constituents., Material and Methods: The mechanisms were investigated using xanthine oxidase assay and uricosuric studies in potassium oxonate- and uric acid-induced hyperuricemic rats., Results: Phyllanthus niruri methanol extract exhibited in vitro xanthine oxidase inhibition with an IC50 of 39.39 microg/mL and a moderate in vivo xanthine oxidase inhibitory activity. However, the lignans display poor xanthine oxidase inhibition in vitro and a relatively weak in vivo inhibitory activity at 10mg/kg. On the other hand, intraperitoneal treatment with Phyllanthus niruri methanol extract showed 1.69 folds increase in urinary uric acid excretion when compared to the hyperuricemic control animals. Likewise, the lignans, phyllanthin, hypophyllanthin and phyltetralin exhibited up to 2.51 and 11.0 folds higher in urinary uric acid excretion and clearance, respectively. The co-administration of pyrazinamide with phyllanthin exhibited a significant suppression of phyllanthin's uricosuric activity resembling that of pyrazinamide with benzbromarone., Conclusions: The present study showed that the antihyperuricemic effect of Phyllanthus niruri methanol extract may be mainly due to its uricosuric action and partly through xanthine oxidase inhibition, whereas the antihyperuricemic effect of the lignans was attributed to their uricosuric action.

Xanthine oxidase inhibitory activity was assayed from six species belonging to different families traditionally used for the treatment of gout and related symptoms by indigenous people of India. The aqueous, methanol-water mixture and methanolic extract of these plants were used for the experiment. Of the 18 extracts assayed, 14 extracts demonstrated xanthine oxidase inhibitory activity at 100 microg/ml, among which 10 extracts showed an inhibition greater than 50% and IC(50) values below 100 microg/ml. The methanolic extracts of Coccinia grandis, Datura metel, Strychnos nux-vomica and Vitex negundo showed more than 50% inhibition, hence, they were screened for their in vivo hypouricaemic activity against potassium oxonate-induced hyperuricaemia in mice. Methanolic extracts of Coccinia grandis and Vitex negundo showed a significant decrease in the serum urate level (3.90+/-0.07 mg/dl, P<0.001) and (6.26+/-0.06 mg/dl, P<0.01), respectively, when compared to hyperuricaemic control (11.42+/-0.14 mg/dl). This effect is almost similar to the serum urate level of allopurinol (3.89+/-0.07 mg/dl).

We investigated the hypouricemic effects of cassia oil extracted from Cinnamomum cassia using hyperuricemic mice induced by potassium oxonate, and its inhibitory actions against liver xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) activities. Oral administration of cassia oil significantly reduced serum and hepatic urate levels in hyperuricemic mice in a time- and dose-dependent manner. At doses of 450 mg/kg of cassia oil or above, serum urate levels of the oxonate-pretreated mice were not different from the normal control mice. Cassia oil at 600 mg/kg was found to be as potent as allopurinol, which reduced hepatic urate levels to lower than normal. In normal mice, urate levels in liver, but not in serum, were altered with dose-dependent decrease after cassia oil treatment. Furthermore, the ratio, liver uric acid/serum uric acid, was determined after cassia oil administration with time- and dose-dependent decreases in hyperuricemic mice. The positive dose-dependent decrease ratio was also observed after cassia oil treatment in the normal animals. The decreased extent of ratio elicited by cassia oil in normal mice appeared to be greater than that in the hyperuricemic animal. In addition, cassia oil significantly exhibited marked reductions in liver XDH/XOD activities, with an apparent dose-dependence in the normal and hyperuricemic mice. The onset of inhibition in enzyme activities elicited by allopurinol was much higher than that elicited by cassia oil. These results suggested that hypouricemic effects of cassia oil could be explained, at least partly, by inhibiting liver in vivo activities of XDH/XOD.