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Mechanisms of antihyperuricemic effect of Phyllanthus niruri and its lignan constituents

Murugaiyah V, Chan KL

J Ethnopharmacol, 2009 Jul 15;124(2):233-9.
PMID: 19397979 DOI: 10.1016/j.jep.2009.04.026

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.

Matched MeSH terms: Uric Acid/urine*
Cardiovascular risk factors in pre-pubertal Malays: effects of diabetic parentage

Choo KE, Lau KB, Davis WA, Chew PH, Jenkins AJ, Davis TM

Diabetes Res Clin Pract, 2007 Apr;76(1):119-25.
PMID: 16979774 DOI: 10.1016/j.diabres.2006.08.006

Diabetes prevalence is increasing rapidly in Asian populations but the influence of a family history of diabetes on cardiovascular risk is unknown. To assess this relationship, 120 urban-dwelling Malays were recruited to a cross-sectional case-control study. Sixty were pre-pubertal children, 30 of diabetic parentage (Group 1) and 30 with no diabetes family history (Group 2). Group 1 and 2 subjects were the offspring of adults with (Group 3) or without (Group 4) type 2 diabetes. Subjects were assessed for clinical and biochemical variables defining cardiovascular risk. Principal component analysis assessed clustering of variables in the children. Group 1 subjects had a higher mean waist:hip ratio, diastolic blood pressure and HbA(1c) than those in Group 2, and a lower HDL:total cholesterol ratio (P<0.03). Although there were no correlations between Group 1 and 3 subjects for cardiovascular risk variables, significant associations were found in Groups 2 and 4, especially HbA(1c) and insulin sensitivity (P< or =0.004). Of five separate clusters of variables (factors) identified amongst the children, the strongest comprised diabetic parentage, HbA(1c), insulin sensitivity and blood pressure. Features of the metabolic syndrome are becoming evident in the young non-obese children of diabetic Malays, suggesting that lifestyle factors merit particular attention in this group.

Matched MeSH terms: Uric Acid/blood
Effects of pre and post-treatments with dipyridamole in gentamicin-induced acute nephrotoxicity in the rat

Balakumar P, WitnessKoe WE, Gan YS, JemayPuah SM, Kuganesswari S, Prajapati SK, et al.

Regul Toxicol Pharmacol, 2017 Mar;84:35-44.
PMID: 27993652 DOI: 10.1016/j.yrtph.2016.12.007

This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.

Matched MeSH terms: Uric Acid/blood
Fulltext Association and interaction effect between VEGF receptor-2 (VEGFR-2) gene polymorphisms and dietary pattern on blood uric acid in Malays and Indians

Roseline YW, Shidoji Y, Hon WM, Masaki M

Malays J Nutr, 2012 Dec;18(3):307-17.
PMID: 24568071 MyJurnal

INTRODUCTION: Gout and hyperuricaemia attributed to genetic and lifestyle factors have been associated with several chronic diseases. This study aimed to determine the association and interaction effects between vascular endothelial growth factor receptor-2 (VEGFR-2) gene polymorphisms (rs1870377 and rs2071559) and dietary patterns on blood uric acid in Malay and Indian adults.
METHODS: Dietary intakes of 153 Malays and 177 Indians were obtained using a food frequency questionnaire for the construction of dietary patterns using factor analysis. Genotyping of rs1870377 and rs2071559 was performed by real-time PCR using TaqMan probes. Anthropometric measurements, body mass index (BMI) and blood pressure and biomarkers, uric acid, glycated haemoglobin A1c (HbA1c), and blood lipids were determined.
RESULTS: There were significant differences in the mean values for HbA1c (41±-12 vs 45±-8 mmol/mol, p<0.001) and blood lipids levels (p<0.05) between Malays and Indians. Significant correlations were obtained between uric acid with selected blood lipids (p<0.05) and BMI in Malays (r=0.362, p<0.001) and Indians (r=0.212, p<0.01). Four dietary patterns were extracted from dietary intakes of all subjects: ‘Vegetables diet’; ‘Fruits diet’ (FD); ‘Animal protein and rice diet’; and ‘Fast foods and preserved foods diet’. There were no significant associations between dietary patterns (p=0.054-0.609) and VEGFR-2 gene polymorphisms (p=0.348-0.778) with uric acid. In Malay subjects, the interaction of rs2071559 and FD had a borderline effect (p=0.05) on blood uric acid after adjusting for potential confounders.
CONCLUSION: The associations and gene-diet interactions involving VEGFR-2 gene polymorphisms and FD on uric acid provide new information on gout and hyperuricaemia risks in Malays.
Keywords: Gene-diet interaction, VEGFR-2 gene polymorphisms, dietary pattern, uric acid, Malaysians

Matched MeSH terms: Uric Acid/blood*
Fulltext Correlation of retinal nerve fibre layer and macular thickness with serum uric acid among type 2 diabetes mellitus

Vinuthinee-Naidu MN, Zunaina E, Azreen-Redzal A, Nyi-Nyi N

BMC Ophthalmol, 2017 Jun 14;17(1):91.
PMID: 28615022 DOI: 10.1186/s12886-017-0486-3

BACKGROUND: Uric acid is a final breakdown product of purine catabolism in humans. It's a potent antioxidant and can also act as a pro-oxidant that induces oxidative stress on the vascular endothelial cells, thus mediating progression of diabetic related diseases. Various epidemiological and experimental evidence suggest that uric acid has a role in the etiology of type 2 diabetes mellitus. We conducted a cross-sectional study to evaluate the correlation of retinal nerve fibre layer (RNFL) and macular thickness with serum uric acid in type 2 diabetic patients.

METHODS: A cross-sectional study was conducted in the Eye Clinic, Hospital Universiti Sains Malaysia, Kelantan between the period of August 2013 till July 2015 involving type 2 diabetes mellitus patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy (NPDR). An evaluation for RNFL and macular thickness was measured using Spectralis Heidelberg optical coherence tomography. Six ml of venous blood was taken for the measurement of serum uric acid and glycosylated haemoglobin (HbA1C).

RESULTS: A total of 180 diabetic patients were recruited (90 patients with no diabetic retinopathy and 90 patients with NPDR) into the study. The mean level of serum uric acid for both the groups was within normal range and there was no significance difference between the two groups. Based on gender, both male and female gender showed significantly higher level of mean serum uric acid in no diabetic retinopathy group (p = 0.004 respectively). The mean serum uric acid was significantly higher in patient with HbA1C uric acid in both the groups.

CONCLUSION: Serum uric acid showed a poor correlation with RNFL and macular thickness among type 2 diabetic patients.

Study site: Eye clinic, Hospital Universiti Sains Malaysia (HUSM)

Matched MeSH terms: Uric Acid/blood*
Fulltext Antidiabetic, Antihyperlipidemic, Antioxidant, Anti-inflammatory Activities of Ethanolic Seed Extract of Annona reticulata L. in Streptozotocin Induced Diabetic Rats

Wen W, Lin Y, Ti Z

Front Endocrinol (Lausanne), 2019;10:716.
PMID: 31708869 DOI: 10.3389/fendo.2019.00716

Annona reticulata L. (Bullock's heart) is a pantropic tree commonly known as custard apple, which is used therapeutically for a variety of maladies. The present research was carried out to evaluate the possible protective effects of Annona reticulata L. (A. reticulata) ethanolic seed extract on an experimentally induced type 2 diabetes rat model. Male Albino Wistar rats were randomly divided into five groups with six animals in each group viz., control rats in group I, diabetic rats in group II, diabetic rats with 50 and 100 mg/kg/bw of ethanolic seed extract of A. reticulata in groups III and IV, respectively, and diabetic rats with metformin in group V. Treatment was given for 42 consecutive days through oral route by oro-gastric gavage. Administration of A. reticulata seed extract to diabetes rats significantly restored the alterations in the levels of body weight, food and water intake, fasting blood glucose (FBG), insulin levels, insulin sensitivity, HbA1c, HOMA-IR, islet area and insulin positive cells. Furthermore, A. reticulata significantly decreased the levels of triglycerides, cholesterol, LDL, and significantly increased the HDL in diabetic rats. A. reticulata effectively ameliorated the enzymatic (ALT, AST, ALP, GGT) and modification of histopathological changes in diabetic rats. The serum levels of the BUN, creatinine levels, uric acid, urine volume, and urinary protein were significantly declined with a significant elevation in CCr in diabetic rats treated with A. reticulata. MDA and NO levels were significantly reduced with an enhancement in SOD, CAT, and GPx antioxidant enzyme activities in the kidney, liver, and pancreas of diabetic rats treated with A. reticulata. Diabetic rats treated with A. reticulata have shown up-regulation in mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1), Heme oxygenase-1 (HO-1) and protein expression level of Nrf2 with diminution in Keap1 mRNA expression level in pancreas, kidney, and liver. From the outcome of the current results, it can be inferred that seed extract of A. reticulata exhibits a protective effect in diabetic rats through its anti-diabetic, anti-hyperlipidemic, antioxidant and anti-inflammatory effects and could be considered as a promising treatment therapy in the treatment of diabetes mellitus.

Matched MeSH terms: Uric Acid
Fulltext The Antioxidant and Xanthine Oxidase Inhibitory Activity of Plumeria rubra Flowers

Mohamed Isa SSP, Ablat A, Mohamad J

Molecules, 2018 Feb 13;23(2).
PMID: 29438299 DOI: 10.3390/molecules23020400

Plumeria rubra Linn of the family Apocynaceae is locally known in Malaysia as "Kemboja". It has been used by local traditional medicine practitioners for the treatment of arthritis-related disease. The LCMS/MS analysis of the methanol extract of flowers (PR-ME) showed that it contains 3-O-caffeyolquinic acid, 5-caffeoquinic acid, 1,3-dicaffeoquinic acid, chlorogenic acid, citric acid, 3,3-di-O-methylellagic acid, kaempferol-3-O-glucoside, kaempferol-3-rutinoside, kaempferol, quercetin 3-O-α-l-arabinopyranoside, quercetin, quinic acid and rutin. The flower PR-ME contained high amounts of phenol and flavonoid at 184.632 mg GAE/g and 203.2.2 mg QE/g, respectively. It also exhibited the highest DPPH, FRAP, metal chelating, hydrogen peroxide, nitric oxide superoxide radical scavenging activity. Similarly, the XO inhibitory activity in vitro assay possesses the highest inhibition effects at an IC50 = 23.91 μg/mL. There was no mortality or signs of toxicity in rats at a dose of 4 g/kg body weight. The administration of the flower PR-ME at doses of 400 mg/kg to the rats significantly reduced serum uric acid 43.77%. Similarly, the XO activity in the liver was significantly inhibited by flower PR-ME at doses of 400 mg/kg. These results confirm that the flower PR-ME of P. rubra contains active phytochemical compounds as detected in LCMS/MS that contribute to the inhibition of XO activity in vitro and in vivo in reducing acid uric level in serum and simultaneously scavenging the free radical to reduce the oxidative stress.

Matched MeSH terms: Uric Acid/antagonists & inhibitors*; Uric Acid/blood
Osteonecrosis with renal damage in HIV patients undergoing HAART

Chitra P, Bakthavatsalam B, Palvannan T

Biomed Pharmacother, 2014 Sep;68(7):881-5.
PMID: 25194446 DOI: 10.1016/j.biopha.2014.07.017

Rheumatoid arthritis in HIV patients undergoing HAART is associated with increased risk of side effect. Elevation of uric acid (UA) is important in tissue damage, deposition of crystal in joints leads to the development of rheumatoid arthritis in the HAART complaint group. This study was carried out to investigate the relationship of uric acid, RA factor, ANA, ESR, cystatin C, urea and creatinine in the HAART complaint group. Moreover; the ratio of uric acid/cystatin C, uric acid/urea and uric acid/creatinine were also studied. To analyze the progression of HIV, the immunological parameters were correlated with uric acid. Our result showed a statistically high significant increase in uric acid, RA factor, ANA, ESR, cystatin C, urea and creatinine in the HAART complaint group when compared to HAART non-complaint group, early stage and control. The ratio of uric acid/cystatin C, uric acid/urea, uric acid/creatinine were significantly increased in the HAART complaint group. Statistically significant positive correlation was observed between uric acid and cystatin C, urea, creatinine, absolute CD4 and CD8 count. The increased level of uric acid, RA factor, ANA, ESR, cystatin C and increased ratio of uric acid/cystatin C in the HAART complaint group might conclude the mechanism underlying the increased risk for rheumatoid arthritis in the HAART complaint group which may relate to the combined effects of low-grade inflammation and renal dysfunction.

Study done in India

Matched MeSH terms: Uric Acid
Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus

Giribabu N, Karim K, Kilari EK, Salleh N

J Ethnopharmacol, 2017 Jun 09;205:123-137.
PMID: 28483637 DOI: 10.1016/j.jep.2017.05.002

ETHNOPHARMACOLOGICAL RELEVANCE: Phylanthus niruri has been used to treat ailments related to the urogenital organs. In this study, this herb was hypothesized to help to ameliorate kidney disease in diabetes mellitus (DM).
AIMS: To investigate P. niruri leaves aqueous extract (PN) effects on kidney functions, histopathological changes and levels of oxidative stress, inflammation, fibrosis, apoptosis and proliferation in DM.
METHODS: PN was orally administered to streptozotocin-nicotinamide-induced male diabetic rats for 28 days. At the end of the treatment, fasting blood glucose (FBG) and kidney functions were measured. Kidney somatic index, histopathological changes and levels of RAGE, Nrf2, oxidative stress markers (TBARS, SOD, CAT and GPx), inflammatory markers (NFkβ-p65, Ikk-β, TNF-α, IL-1β and IL-6), apoptosis markers (caspase-3, caspase-9 and Bax), fibrosis markers (TGF-β1, VEGF and FGF-1) and proliferative markers (PCNA and Ki-67) were determined by biochemical assays, qPCR, Western blotting, immunohistochemistry or immunofluorescence.
RESULTS: Administration of PN helps to maintain near normal FBG, creatinine clearance (CCr), blood urea nitrogen (BUN), BUN/Cr ratio, serum electrolytes, uric acid and urine protein levels in DM. Decreased RAGE, TBARS and increased Nrf2, SOD-1, CAT and GPx-1 were observed in PN-treated diabetic rat kidneys. Expression of inflammatory, fibrosis and apoptosis markers in the kidney reduced but expression of proliferative markers increased following PN treatment. Lesser histopathological changes were observed in the kidney of PN-treated diabetic rats.
CONCLUSION: PN helps to preserve near normal kidney function and prevents histopathological changes via ameliorating oxidative stress, inflammation, fibrosis and apoptosis while enhancing proliferation of the kidney in DM.

Matched MeSH terms: Uric Acid; Thiobarbituric Acid Reactive Substances