Tags

Type your tag names separated by a space and hit enter

Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition.
Eur J Pharmacol. 2019 Jun 15; 853:371-380.EJ

Abstract

Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5-4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.

Authors+Show Affiliations

Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China; Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China. Electronic address: gzslh@163.com.Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China. Electronic address: kmli62@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31009635

Citation

Lin, Hua, et al. "Dual Actions of Norathyriol as a New Candidate Hypouricaemic Agent: Uricosuric Effects and Xanthine Oxidase Inhibition." European Journal of Pharmacology, vol. 853, 2019, pp. 371-380.
Lin H, Tu C, Niu Y, et al. Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition. Eur J Pharmacol. 2019;853:371-380.
Lin, H., Tu, C., Niu, Y., Li, F., Yuan, L., Li, N., Xu, A., Gao, L., & Li, L. (2019). Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition. European Journal of Pharmacology, 853, 371-380. https://doi.org/10.1016/j.ejphar.2019.04.034
Lin H, et al. Dual Actions of Norathyriol as a New Candidate Hypouricaemic Agent: Uricosuric Effects and Xanthine Oxidase Inhibition. Eur J Pharmacol. 2019 Jun 15;853:371-380. PubMed PMID: 31009635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual actions of norathyriol as a new candidate hypouricaemic agent: uricosuric effects and xanthine oxidase inhibition. AU - Lin,Hua, AU - Tu,Caixia, AU - Niu,Yanfen, AU - Li,Fashuang, AU - Yuan,Lixian, AU - Li,Na, AU - Xu,Aiping, AU - Gao,Lihui, AU - Li,Ling, Y1 - 2019/04/19/ PY - 2018/11/09/received PY - 2019/04/11/revised PY - 2019/04/16/accepted PY - 2019/4/23/pubmed PY - 2019/9/4/medline PY - 2019/4/23/entrez KW - Hyperuricaemia KW - Norathyriol KW - Organic anion transporter 1 KW - Renal urate transporter KW - Uricosuric effect KW - Xanthine oxidase SP - 371 EP - 380 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 853 N2 - Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5-4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/31009635/Dual_actions_of_norathyriol_as_a_new_candidate_hypouricaemic_agent:_uricosuric_effects_and_xanthine_oxidase_inhibition_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(19)30268-7 DB - PRIME DP - Unbound Medicine ER -