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Ethnopharmacological relevance Lippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling. Aim of the study The present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model. Materials and methods The mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis. Results Oral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7-O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2 mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3 mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200 mg/kg. No toxic effect was observed in rats administered with 5000 mg/kg of methanol extract or F3. Conclusion The potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities.

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 (5 mg/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.

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 2028 mg/kg was orally administered to hyperuricemic and normal mice for 7 days, and allopurinol (5 mg/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.

The Roselle (Hibiscus sabdariffa) was investigated for its uricosuric effect.A human model with nine subjects with no history of renal stones (non-renal stone, NS) and nine with a history of renal stones (RS) was used in this study. A cup of tea made from 1.5 g of dry Roselle calyces was provided to subjects twice daily (morning and evening) for 15 days. A clotted blood and two consecutive 24-h urine samples were collected from each subject three times: (1) at baseline (control); (2) on days 14 and 15 during the tea drinking period; and (3) 15 days after the tea drinking was stopped (washout). Serum and 24-h urinary samples were analyzed for uric acid and other chemical compositions related to urinary stone risk factors.All analyzed serum parameters were within normal ranges and similar; between the two groups of subjects and among the three periods. Vis-à-vis the urinary parameters, most of the baseline values for both groups were similar. After taking the tea, the trend was an increase in oxalate and citrate in both groups and uric acid excretion and clearance in the NS group. In the RS group, both uric acid excretion and clearance were significantly increased (p0.01). When the fractional excretion of uric acid (FEUa) was calculated, the values were clearly increased in both the NS and SF groups after the intake of tea and returned to baseline values in the washout period. These changes were more clearly observed when the data for each subject was presented individually.Our data demonstrate a uricosuric effect of Roselle calyces. Since the various chemical constituents in Roselle calyces have been identified, the one(s) exerting this uricosuric effect need to be identified.

Ethnopharmacological relevance Leaves infusion of Pimenta pseudocaryophyllus (Gomes) Landrum is used in Brazilian folk medicine to treat the predisposition to arthritical and gouty affections of the joints, fever and other diseases. A refreshing drink prepared with the specie is also used due to its diuretic, sedative and aphrodisiac actions. Aim of the study The study was undertaken to investigate the mechanisms of anti-hyperuricemic effect and anti-inflammatory activity of P. pseudocaryophyllus extracts. Materials and methods Anti-hyperuricemic effect was investigated using xanthine oxidase assay and uricosuric studies with rats in which hyperuricemia was induced by potassium oxonate and uric acid. Anti-inflammatory activity was investigated on MSU crystal-induced paw edema model. Ethyl acetate extracts of the leaves (EAL) and branches (EAB), ethanolic extracts of leaves (EEL) and branches (EEB) and aqueous extracts of leaves (AL) and branches (AB) were evaluated. Results The extracts of P. pseudocaryophyllus evaluated showed expressive results regarding the inhibition of xanthine oxidase enzyme in vitro and they were also able to reduce serum uric acid levels in hyperuricemic rats. The investigation of the mechanism of action, it was found that EAL, EAB, EEB, AB (125 and 250 mg/kg) and AL (250 mg/kg) promoted an increase on the urinary excretion of uric acid and EEL, EEB, AB (125 and 250 mg/kg) and EAB (250 mg/kg) were capable to inhibit liver xanthine oxidase. Treatments with EEL (125 and 250 mg/kg) and EEB (250 mg/kg) were able to reduce edema at 48th h. EAL and EAB (125 and 250 mg/kg) showed significant anti-inflammatory activity on monosodium urate crystal-induced paw edema model at all evaluated times. Conclusions The specie P. pseudocaryophyllus showed remarkable anti-hyperuricemic effects through uricosuric effects and inhibition of xanthine oxidase and therefore can be considered as a promise in the treatment of diseases related to hyperuricemia. Moreover, ethyl acetate extracts had significant anti-inflammatory activity.

Ethnopharmacological relevance Shuang-Qi gout capsule, a traditional Chinese medicine prescription, has been used in the treatment of, gout arthritis, arthralgia and inflammation. Since renal urate overload associated with severe disability including gout, elimination of excess renal uric acid is highly essential. Therefore, in this study we evaluated the antihyperuricemic and the renoprotective effect of the Shuang Qi gout capsule (SQ) with elucidation of its mechanism. Materials and methods We assessed the antihyperuricemic activity of SQ on urinary and serum uric acid, creatinine, blood urea nitrogen, fractional excretion of uric acid (FEUA) and glomerular filtration rate of creatinine and uric acid in potassium oxonate (PO) – induced mice as well as in non-induced mice. To illuminate the mechanism of antihyperuricemic activity, we investigated renal transport activity and the expression of mRNA levels in PO-induced and non-induced mice by western blot and RT-PCR methods. Results SQ showed significant reduction in serum uric acid, creatinine and blood urea nitrogen levels and marked elevation of urine uric acid, creatinine and FEUA levels only in hyperuricemic mice. Furthermore, SQ could recover the altered expressions of proteins and mRNA levels of all the main renal transporters significantly in dose dependent manner. Conclusions SQ could effectively regulate the main renal transporters denoted its denote probable antihyperuricemic mechanism of SQ and its dose dependent uricosuric effect. In addition, SQ attenuated the deleterious effects of hyperuricemia with renal dysfunction. Thus SQ could be a potent antihyperuricemic agent which can perform as a safer and effective agent in the management of hyperuricemia via regulating the renal transporters.

Ethnopharmacological relevance Ramulus Mori, the branch of Morus alba , is widely used in traditional Chinese medicine prescriptions to treat gout and hyperuricemia. Aim of this study To evaluate the uricosuric and nephroprotective effects of ethanol extract of Ramulus Mori (ERM) and explore its possible mechanisms in hyperuricemic mice. Materials and methods HPLC analysis was employed to determine the main constituents. Hyperuricemia was induced by potassium oxonate (250 mg/kg) in male mice. ERM (10, 20 and 40 mg/kg) was orally administered to hyperuricemic and normal mice for 7 days. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Simultaneously, renal mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), organic anion transporter 1 (mOAT1) and organic cation/carnitine transporters (mOCT1/2, mOCTN1/2) were analyzed by RT-PCR and Western blotting methods. Results ERM mainly contained mulberroside A, oxyresveratrol, 4-hydroxycinnamic acid, resveratrol, 7-hydroxycumarin and morin. ERM significantly reduced serum urate levels and increased 24 h-urine urate excretion and fractional excretion of uric acid in hyperuricemic mice. It effectively restored oxonate-induced expression alteration of renal mURAT1, mGLUT9 and mOAT1, resulting in urate excretion enhancement. Moreover, ERM decreased serum creatinine and BUN levels and increased creatinine clearance, and up-regulated expression of mOCT1/2 and mOCTN1/2, contributing to kidney function improvement in this model. Conclusion These results suggest that ERM exerts the uricosuric and nephroprotective actions by the regulation of these renal organic ion transporters in hyperuricemic mice, and provide scientific support for the empirical use of Ramulus Mori.

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 IC 50 of 39.39 μg/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 10 mg/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.