Abstract
Searching novel hypouricemic agents of high efficacy and safety has attracted a great attention. Previously, we reported the hypouricemic effect of Ganoderma applanatum, but its bioactives, was not referred. Herein, we report the hypouricemic effect of 2,5-dihydroxyacetophenone (DHAP), a compound screened from Ganoderma applanatum computationally. Serum parameters, such as uric acid (SUA), xanthine oxidase (XOD) activity, blood urea nitrogen (BUN), and creatinine were recorded. Real-time reverse transcription PCR (RT-PCR) and Western blot were exploited to assay RNA and protein expressions of organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9), uric acid transporter 1 (URAT1), and gastrointestinal concentrative nucleoside transporter 2 (CNT2). DHAP at 20, 40, and 80 mg/kg exerted excellent hypouricemic action on hyperuricemic mice, reducing SUA from hyperuricemic control (407 ± 31 μmol/L, p < 0.01) to 180 ± 29, 144 ± 13, and 139 ± 31 μmol/L, respectively. In contrast to the renal toxic allopurinol, DHAP showed some kidney-protective effects. Moreover, its suppression on XOD activity, in vivo and in vitro, suggested that XOD inhibition may be a mechanism for its hypouricemic effect. Given this, its binding mode to XOD was explored by molecular docking and revealed that three hydrogen bonds may play key roles in its binding and orientation. It upregulated OAT1 and downregulated GLUT9, URAT1, and CNT2 too. In summary, its hypouricemic effect may be mediated by regulation of XOD, OAT1, GLUT9, URAT1, and CNT2.
Highlights
Uric acid, as a sparingly soluble compound, is the end product of purine catabolism in humans, since the silent mutation of uricase in human evolution
We examined the hypouricemic action of DHAP using xanthine oxidase (XOD) activity assay in
We examined the hypouricemic action of DHAP using XOD activity assay in vitro, vitro, hyperuricemic mouse models in vivo, and molecular docking analysis in silico
Summary
As a sparingly soluble compound, is the end product of purine catabolism in humans, since the silent mutation of uricase in human evolution. Oxidase (XOD) inhibitors, such as allopurinol or can febuxostat, decreasing the categories: production (i) of xanthine uric acid. Clinical medicines against HUA be classified into three through(XOD). (ii) uricosuric agents, such as benzbromarone andthe probenecid, elevating uric oxidase inhibitors, such as allopurinol or febuxostat, decreasing production of uric acid acid excretion by interacting with renal uric acid transporters; and (iii) uricase analogues, such as through metabolism; (ii) uricosuric agents, such as benzbromarone and probenecid, elevating uric acid pegloticase, metabolizing acid dissolvable allantoin. Several metabolizing uric acid to dissolvable allantoin [8,9] They exert some fatal adverse effects studies have focused on natural products from traditional. The HUA bioactive mechanism against is computational virtual screening was performed using the XOD structure, and not yet clear. Its Firstly, XOD inhibitory effect of DHAP was assayed, in vitro, to verify the prediction.
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