Eggshell Membrane Ameliorates Hyperuricemia by Increasing Urate Excretion in Potassium Oxonate-Injected Rats.

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1ß levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.

Health properties of the Italian San Martino® mineral-rich water: A self-controlled pilot study.

The effect of hyper-mineral waters on human health has long been debated. This pilot study evaluated the influence of San Martino® water (Sardinia, Italy), on clinical and biological parameters, following the treatment of 10 hospitalized patients. Crenotherapy consisted of 1-2 L of the water daily for 10 days. A complete blood count, serum electrolytes, liver and kidney function tests, fasting lipid profile and plasma glucose, and abdominal ultrasound imaging were assessed before and at the end of treatment. In addition, body weight, dyspeptic symptoms, bowel movements, diuresis, uricuria and blood pressure were evaluated daily. According to its physico-chemical properties, the water is hyper-mineral (TDS 2808 mg/L) with a high content of bicarbonate and iron. At the end of the study, diuresis increased by 60% (850 vs 1295 ml/24 h, P = 0.009) and uricuria by 41% (362 vs 490 mg/24 h, P = 0.022) respectively, whereas plasma uric acid level decreased by 7% (4.7 vs 4.3 mg/dL, P = 0.043). Compared to the basal values, serum gamma-glutamyl transferase, alkaline phosphatase and total bilirubin levels, showed a reduction of 65% (31 vs 18 U/L, P = 0.022), 15% (96 vs 90 U/L, P = 0.041), and 11% (0.53 vs 0.45 g/dL, P = 0.041), respectively. Bowel movements improved in 62.5% of patients with constipation, and 80% of dyspeptic patients experienced symptoms relief. Compliance to the treatment reached 100%. Mild differences were observed in body weight and blood pressure, although not in ultrasound imaging during crenotherapy. These findings suggest that the San Martino® hyper-mineral water may have some benefits to human health. Additional studies with a larger-sized cohort and for a longer period are needed to confirm these preliminary results.

Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-ß/SMAD3 signaling.

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.

Baicalein alleviates hyperuricemia by promoting uric acid excretion and inhibiting xanthine oxidase.

BACKGROUND: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities. PURPOSE: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo. METHODS: We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds. RESULTS: BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC50 values of 30.17 ± 8.68 µM and 31.56 ± 1.37 µM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1. CONCLUSION: These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.

Effects of high-dose uric acid on cellular proteome, intracellular ATP, tissue repairing capability and calcium oxalate crystal-binding capability of renal tubular cells: Implications to hyperuricosuria-induced kidney stone disease.

Hyperuricosuria is associated with kidney stone disease, especially uric acid (UA) and calcium oxalate (CaOx) types. Nevertheless, detailed mechanisms of hyperuricosuria-induced kidney stone formation remained unclear. This study examined changes in cellular proteome and function of renal tubular cells after treatment with high-dose UA for 48-h. Quantitative proteomics using 2-DE followed by nanoLC-ESI-ETD MS/MS tandem mass spectrometry revealed significant changes in levels of 22 proteins in the UA-treated cells. These proteomic data could be confirmed by Western blotting. Functional assays revealed an increase in intracellular ATP level and enhancement of tissue repairing capability in the UA-treated cells. Interestingly, levels of HSP70 and HSP90 (the known receptors for CaOx crystals) were increased in apical membranes of the UA-treated cells. CaOx crystal-cell adhesion assay revealed significant increase in CaOx-binding capability of the UA-treated cells, whereas neutralization of the surface HSP70 and/or HSP90 using their specific monoclonal antibodies caused significant reduction in such binding capability. These findings highlighted changes in renal tubular cells in response to high-dose UA that may, at least in part, explain the pathogenic mechanisms of hyperuricosuria-induced mixed kidney stone disease.

Comparison of Two Dietary Supplements for Treatment of Uric Acid Renal Lithiasis: Citrate vs. Citrate + Theobromine.

BACKGROUND: Uric acid (UA) renal lithiasis has a high rate of recurrence and a prevalence ranging from 10% and 15%, depending on the population. The most important etiological factor is persistence of urinary pH below 5.5 and one of the most common treatments is alkalization with citrate. Recent studies demonstrated that theobromine, which is abundant in chocolate and cocoa, is a potent inhibitor of UA crystallization. AIM: The aim was to compare the efficacy of citrate versus citrate + theobromine as treatment for UA lithiasis. METHODS: This randomized cross-over trial investigated the efficacy of two treatments in 47 patients with UA renal lithiasis. Urine volume, pH, UA excretion, theobromine excretion, and risk of UA crystallization (RUAC) at baseline and at the end of each intervention period were measured. RESULTS: Each treatment significantly reduced the risk of UA crystallization compared to basal values. The RUAC after citrate + theobromine was lower than the RUAC after citrate, although this difference was not statistically significant. CONCLUSION: The combined consumption of citrate and theobromine may be a promising strategy for the prevention of UA kidney stones.

Protective effects of spirulina against hemato-biochemical alterations, nephrotoxicity, and DNA damage upon lead exposition.

The current study was aimed at exploring the protective efficacy of spirulina against the hemato-biochemical alterations and nephrotoxicity induced by lead (Pb). Female rats aged 12 weeks were treated for 4 weeks with Pb (0.344 g kg-1 bw) associated or not with spirulina (5.3 g kg-1 bw). Renal damage induced by Pb was related to a severe anemia, increases of oxidative stress-related parameters (thiobarbituric acid reactive substances (TBARS) (+29%), protein carbonyl (PCO) (+66.3%), and advanced oxidation protein product (AOPP) (+110%)), plasma lactate dehydrogenase (LDH) (+80%), creatinine and urea levels in plasma, and uric acid concentration in urine, as well as genotoxic changes (+89.3% and +60% for DNA and mRNA levels, respectively). Conversely, LDH and antioxidant enzyme activities in kidney were decreased, as well as the levels of plasma uric acid, and urinary creatinine and urea levels. Spirulina-supplemented rats exhibited normal peripheral blood and renal parameters and renal histology. It can be suggested that Arthrospira platensis alleviates damages induced by Pb, thanks to its high phenolic content and antioxidant capacity.

The Buckwheat Iminosugar d-Fagomine Attenuates Sucrose-Induced Steatosis and Hypertension in Rats.

SCOPE: This study examines the long-term functional effects of d-fagomine on sucrose-induced factors of metabolic dysfunctions and explores possible molecular mechanisms behind its action. METHODS AND RESULTS: Wistar Kyoto rats are fed a 35% sucrose solution with d-fagomine (or not, for comparison) or mineral water (controls) for 24 weeks. The following are recorded: body weight; energy intake; glucose tolerance; plasma leptin concentration and lipid profile; populations of Bacteroidetes, Firmicutes, bacteroidales, clostridiales, enterobacteriales, and Escherichia coli in feces; blood pressure; urine uric acid and F2t isoprostanes (F2 -IsoPs); perigonadal fat deposition; and hepatic histology and diacylglycerols (DAGs) in liver and adipose tissue. d-Fagomine reduces sucrose-induced hypertension, urine uric acid and F2 -IsoPs (markers of oxidative stress), steatosis, and liver DAGs, without significantly affecting perigonadal fat deposition, and impaired glucose tolerance. It also promotes excretion of enterobacteriales generated by the dietary intervention. CONCLUSION: d-fagomine counteracts sucrose-induced steatosis and hypertension, presumably by reducing the postprandial levels of fructose in the liver.

Combined Supplementation with Glycine and Tryptophan Reduces Purine-Induced Serum Uric Acid Elevation by Accelerating Urinary Uric Acid Excretion: A Randomized, Single-Blind, Placebo-Controlled, Crossover Study.

The authors previously confirmed the serum uric acid-lowering effects of the combination of glycine and tryptophan in subjects with mild hyperuricemia. This study examined whether combined supplementation with glycine and tryptophan suppressed the elevation in serum uric acid levels caused by purine ingestion and accelerated urinary uric acid excretion in subjects with lower urate excretion using a randomized, single-blind, placebo-controlled, crossover clinical trial design. Healthy Japanese adult males with lower urate excretion ingested water containing purines in addition to dextrin (placebo), tryptophan, glycine, or a glycine and tryptophan mixture. The combined supplementation with glycine and tryptophan significantly reduced the elevated serum uric acid levels after purine ingestion. Glycine alone and in combination with tryptophan significantly increased urinary uric acid excretion and urate clearance compared with the effects of the placebo. Urinary pH increased by the ingestion of the mixture. These results suggested that the improved water solubility of uric acid due to increased urinary pH contributed to the increase of urinary uric acid excretion.

Therapeutic potential of ethyl acetate fraction of Tephrosia purpurea Linn. leaves in a rat model of gout.

OBJECTIVE: The present study is to determine the potential treatment effects of ethyl acetate fraction of Tephrosia purpurea Linn. leaves (EATP) against gout. METHODS: Gout in experimental rats was induced with potassium oxonate at the dose of 250 mg/kg (intraperitoneal injection) for 7 consecutive days; EATP was administered 1 h after administration of the potassium oxonate on each day of experiment. Potassium oxonate was discontinued on the 8th day; thereafter allopurinol (10 mg/kg, p.o.) and EATP (200 and 400 mg/kg, p.o.) were continued until day 14. The uric acid level was measured from serum and urine during the experiment. Other biochemical parameters were assessed, including blood and urine creatinine, erythrocyte sedimentation rate, and total protein. Blood urea nitrogen, serum aspartate aminotransferase serum alanine aminotransferase and alkaline phosphatase were also measured. The blood was analyzed for levels of malondialdehyde and the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Histopathological and radiological changes in the ankle of rats were observed after completion of the experiment. RESULTS: EATP was able to decrease serum uric acid and creatinine level; it also reduced inflammation, oxidative stress and lysosomal enzyme level, which has a role in acute inflammation. EATP increased uric acid excretion through urine due to its uricosuric effect. CONCLUSION: EATP lowered the serum uric acid level and increased the urine uric acid level through excretion, which is useful in the treatment of gout. Hence the EATP was found to be helpful in the treatment of gout.

Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor.

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ 6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 µM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 µM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1-30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT1, respectively. Drugs, including febuxostat as a reference ABCG2 inhibitor, were administered orally before sulfasalazine or adefovir administration. Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates. These results suggested dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3, because of its high efficacy in decreasing plasma urate levels compared with that of other uricosuric agents. SIGNIFICANCE STATEMENT: Our study on the inhibitory effects on urate transport showed that dotinurad had higher selectivity for urate transporter 1 (URAT1) versus ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter (OAT) 1/3 compared to other uricosuric agents. In Cebus monkeys, dotinurad decreased plasma urate levels and increased fractional excretion of urate in a dose-dependent manner. To determine the inhibitory effect of dotinurad on urate secretion transporters, we studied the movement of substrates of ABCG2 and OAT1 in rats. Dotinurad had no effect on these transporters, whereas the other uricosuric agents increased the plasma concentrations of the substrates. These results suggested dotinurad as a potent and selective urate reabsorption inhibitor is characterized by increased efficacy with decreasing plasma urate levels.

Anti-hyperuricemic effect of Alpinia oxyphylla seed extract by enhancing uric acid excretion in the kidney.

BACKGROUND: Alpinia oxyphylla is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. PURPOSE: We investigated the anti-hyperuricemic effects of Alpinia oxyphylla seed extract (AE), and the underlying mechanisms of action through in vitro and in vivo studies. METHODS: We evaluated levels of uric acid in the serum and urine, the expression of renal urate transport proteins, and levels of inflammatory cytokines in potassium oxonate (PO)-induced hyperuricemic rats. Xanthine oxidase activity was analyzed in vitro, while cellular uric acid uptake was assessed in oocytes expressing the human urate transporter 1 (hURAT1). Moreover, the main components of AE were analyzed using UPLC. RESULTS: In PO-induced hyperuricemic rats, 200 and 400 mg/kg of AE significantly decreased levels of uric acid in serum, while 400 mg/kg of AE increased uric acid levels in urine. AE did not inhibit xanthine oxidase in vitro; however, 1, 10, and 100 µg/ml of AE significantly decreased uric acid uptake into oocytes expressing hURAT1. Furthermore, 400 mg/kg of AE increased levels of organic anion transporter (OAT) 1 protein, while 200 and 400 mg/kg of AE decreased the protein content of urate transporter, URAT1 and inflammatory cytokines in the kidneys. Nootkatone was identified as one the main chemical components in AE from UPLC analysis. CONCLUSIONS: These findings suggest that AE exerts anti-hyperuricemic and uricosuric effects, which are related to the promotion of uric acid excretion via enhanced secretion and inhibition of uric acid reabsorption in the kidneys. Thus, AE may be a potential treatment for hyperuricemia and gout.

Study on chemical constituents of herbal formula Er Miao Wan and GC-MS based metabolomics approach to evaluate its therapeutic effects on hyperuricemic rats.

Hyperuricemia strongly correlates with an increased risk of the development of gout, and cardiovascular and kidney diseases, etc. Er Miao Wan (EMW) is a classical traditional Chinese medicine (TCM) formula extensively used for the treatment of hyperuricemia and gout. However, the global components and action mechanism of the formula are still unknown. Here, the chemical constituents of EMW extract were identified by ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). A total of 24 alkaloids, 15 organic acids, 4 terpenoids, 3 lactones, 3 glycosides, 46 volatile constituents and 3 other compounds were tentatively identified from the EMW extract. Additionally, based on the hyperuricemic rat model induced by long-term high-fructose feed, a GC-MS based metabolomics approach was conducted to holistically assess the mechanism of EMW. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were applied for screening differential metabolites. A total of 21 metabolites that markedly changed in hyperuricemic rats were identified. Further univariate analysis showed that 9 differential metabolites among them were profoundly reversed by EMW intervention. Metabolic pathway analysis revealed that the variations of these metabolites were mainly associated with glycerolipid metabolism, amino acid metabolism, primary bile acid metabolism, taurine and hypotaurine metabolism and purine metabolism. It was inferred that EMW possibly induced its anti-hyperuricemic effect through restoring multiple disturbed pathways to the normal state. This study could assist with elucidating the potential mechanisms of EMW.

Daily Green Tea Infusions in Hypercalciuric Renal Stone Patients: No Evidence for Increased Stone Risk Factors or Oxalate-Dependent Stones.

Green tea is widely used as a ''healthy'' beverage due to its high level of antioxidant polyphenol compounds. However tea is also known to contain significant amount of oxalate. The objective was to determine, in a cross-sectional observational study among a population of 273 hypercalciuric stone-formers referred to our center for metabolic evaluation, whether daily green tea drinkers (n = 41) experienced increased stone risk factors (especially for oxalate) compared to non-drinkers. Stone risk factors and stone composition were analyzed according to green tea status and sex. In 24-h urine collection, the comparison between green tea drinkers and non-drinkers showed no difference for stone risk factors such as urine oxalate, calcium, urate, citrate, and pH. In females, the prevalence of calcium oxalate dihydrate (COD) and calcium phosphate stones, assessed by infrared analysis (IRS) was similar between green tea drinkers and non-drinkers, whereas prevalence of calcium oxalate monohydrate (COM) stones was strikingly decreased in green tea drinkers (0% vs. 42%, p = 0.04), with data in accordance with a decreased oxalate supersaturation index. In males, stone composition and supersaturation indexes were similar between the two groups. Our data show no evidence for increased stone risk factors or oxalate-dependent stones in daily green tea drinkers.

Potential protective effects of the edible alga Arthrospira platensis against lead-induced oxidative stress, anemia, kidney injury, and histopathological changes in adult rats.

Oxidative damage has been proposed as a possible mechanism involved in lead toxicity. This study investigated the possible protective effect of dietary Arthrospira platensis supplementation against lead acetate-induced kidney injury in adult male rats. Rats were divided into 4 groups: normal rats (control rats), rats treated with spirulina, rats treated with lead (Pb) (0.344 g/kg body weight), and rats treated with Pb and spirulina. The exposure of rats to Pb for 30 days provoked renal damage with significant increases in hematological parameters, oxidative stress-related parameters (i.e., thiobarbituric acid reactive substances, protein carbonyl content, advanced oxidation protein products, and hydrogen peroxide), creatinine and urea levels in plasma, and uric acid level in urine. Conversely, antioxidant enzyme activities (i.e., catalase, glutathione peroxidase, and superoxide dismutase) and levels of nonprotein thiols, plasma uric acid, and urinary creatinine and urea decreased. The administration of spirulina to Pb-treated rats significantly improved weight, peripheral blood parameters, oxidative stress-related parameters, renal biomarker levels, and antioxidant enzyme activities. Also, rats treated with Pb and spirulina had normal kidney histology. These healing effects are likely the result of the high phenol content and significant antioxidant capacity of A. platensis. Our data strongly suggest that spirulina supplementation improves kidney function and plays an important role in the prevention of complications of Pb intoxication.

Antidiarrheal and protein conservative activities of Psidium guajava in diarrheal rats.

OBJECTIVE: Psidium guajava occurs worldwide in tropical and subtropical areas. It has been used to treat inflammation, diabetes, fever, hypertension and ulcers. However, its antidiarrheal and protein conservative activities still need to be investigated. METHODS: Fifty-four male rats were divided into normal and diarrheal rats. The normal rats were divided into 4 groups: control, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg) and gallic acid. Treatments were administrated orally in 1 mL saline for a 1-month period. The diarrheal rats were divided into 5 groups: desmopressin (0.2 mg/kg) drug, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg), gallic acid and an untreated control. Doses were given daily for a 1-month period while the untreated control received no treatment. RESULTS: Diarrhea was responsible for an observed decline in kidney weight and serum sodium, potassium and chloride. Further, diarrhea was positively correlated with a significant increase in urine volume, and excretion of electrolytes, serum urea, creatinine and uric acid in the urine. In contrast, there was a proportional increase in the lipid peroxidation value in diarrhea and a significant decline was observed in serum superoxide dismutase, glutathione peroxidase and glutathione levels in diarrhea. Also, diarrhea inhibited blood proteins. The oral intake of P. guajava leaf extract by diarrheal rats restored all of these parameters to near normal levels. High-dose P. guajava leaf extract was more effective than the same compound at a low dose. CONCLUSION: P. guajava leaf extract elicited antidiarrheal and protein conservative effects.

Production Inhibition and Excretion Promotion of Urate by Fucoidan from Laminaria japonica in Adenine-Induced Hyperuricemic Mice.

This work aims to explore the amelioration of fucoidan on adenine-induced hyperuricemia and hepatorental damage. Adenine-induced hyperuricemic mice were administered with fucoidan, allopurinol and vehicle control respectively to compare the effects of the drugs. Serum uric acid, urea nitrogen, hepatorenal functions, activities of hepatic adenosine deaminase (ADA), xanthine oxidase (XOD), renal urate transporter 1 (URAT1) and NF-κB p65 were assessed. As the serum uric acid, urea nitrogen, creatinine, glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) data demonstrated, the adenine not only mediated hepatorenal function disorders, but also induced hyperuricemia in mice. Meanwhile, activities of hepatic ADA and XOD were markedly augmented by adenine, and the expression of URAT1 was promoted, which was conducive to the reabsorption of urate. However, exposure to fucoidan completely reversed those adenine-induced negative alternations in mice, and the activities of hepatic ADA and XOD were recovered to the normal level. It was obvious that hepatic and renal functions were protected by fucoidan treatment. The expression of URAT1 was returned to normal, resulting in an increase of renal urate excretion and consequent healing of adenine-induced hyperuricemia in mice. Expression and activation of NF-κB p65 was promoted in kidneys of adenine treated mice, but suppressed in kidneys of mice exposed to fucoidan from Laminaria japonica or allopurinol. In conclusion, the fucoidan is a potential therapeutic agent for the treatment of hyperuricemia through dual regulatory roles on inhibition of hepatic metabolism and promotion of renal excretion of urate.

DKB114, A Mixture of Chrysanthemum Indicum Linne Flower and Cinnamomum Cassia (L.) J. Presl Bark Extracts, Improves Hyperuricemia through Inhibition of Xanthine Oxidase Activity and Increasing Urine Excretion.

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.

Effect of Consumption of Cocoa-Derived Products on Uric Acid Crystallization in Urine of Healthy Volunteers.

The purpose of this study was to determine the effects of consumption of different cocoa-derived products on uric acid crystallization in urine of 20 healthy volunteers. Participants were requested to select the specific diet that they wished to follow during the 12 h prior to collection of urine. The only restriction was that the diet could not include any product with cocoa, coffee, or caffeine. On the first day, each volunteer followed their selected diet, and an overnight 12 h urine sample was collected as the baseline urine. After seven days on an unrestricted diet, each volunteer repeated the same diet with 20 g of milk chocolate, chocolate powder, or dark chocolate during breakfast and another 20 g during dinner. Overnight 12 h urine samples were then collected. Urine volume, pH, oxalate, creatinine, uric acid, theobromine, and a uric acid crystallization test were determined for each sample. The results for all 20 patients show that uric acid crystallization was significantly lower following the consumption of chocolate powder or dark chocolate relative to baseline or following the consumption of milk chocolate. The results indicated that increased concentrations of urinary theobromine reduced the risk of uric acid crystallization.

Effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention

ABSTRACT Phyllanthus niruri (P.niruri) or stone breaker is a plant commonly used to reduce stone risk, however, clinical studies on this issue are lacking. Objective: To prospectively evaluate the effect of P. niruri on the urinary metabolic parameters of patients with urinary lithiasis. Materials and Methods: We studied 56 patients with kidney stones <10mm. Clinical, metabolic, and ultrasonography assessment was conducted before (baseline) the use of P. niruri infusion for 12-weeks (P. niruri) and after a 12-week (wash out) Statistical analysis included ANOVA for repeated measures and Tukey's/McNemar's test for categorical variables. Significance was set at 5%. Results: Mean age was 44±9.2 and BMI was 27.2±4.4kg/m2. Thirty-six patients (64%) were women. There were no significant changes in all periods for anthropometric and several serum measurements, including total blood count, creatinine, uric acid, sodium, potassium, calcium, urine volume and pH; a significant increase in urinary potassium from 50.5±20.4 to 56.2±21.8 mg/24-hour (p=0.017); magnesium/creatinine ratio 58±22.5 to 69.1±28.6mg/gCr24-hour (p=0.013) and potassium/creatinine ratio 39.3±15.1 to 51.3±34.7mg/gCr24-hour (p=0.008) from baseline to wash out. The kidney stones decreased from 3.2±2 to 2.0±2per patient (p<0.001). In hyperoxaluria patients, urinary oxalate reduced from 59.0±11.7 to 28.8±16.0mg/24-hour (p=0.0002), and in hyperuricosuria there was a decrease in urinary uric acid from 0.77±0.22 to 0.54±0.07mg/24-hour (p=0.0057). Conclusions: P.niruri intake is safe and does not cause significant adverse effects on serum metabolic parameters. It increases urinary excretion of magnesium and potassium caused a significant decrease in urinary oxalate and uric acid in patients with hyperoxaluria and hyperuricosuria. The consumption of P.niruri contributed to the elimination of urinary calculi.