Natural Xanthine Oxidase Inhibitor 5-O-Caffeoylshikimic Acid Ameliorates Kidney Injury Caused by Hyperuricemia in Mice.

Dong Zhang,Yong Yang,Dafang Zhang,Mojiao Zhao,Lijing Li,Yumei Li

doi:10.3390/molecules26237307

Dong Zhang, Yong Yang + Show 4 more

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https://doi.org/10.3390/molecules26237307

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Abstract

Xanthine oxidase (XOD) inhibition has long been considered an effective anti-hyperuricemia strategy. To identify effective natural XOD inhibitors with little side effects, we performed a XOD inhibitory assay-coupled isolation of compounds from Smilacis Glabrae Rhizoma (SGR), a traditional Chinese medicine frequently prescribed as anti-hyperuricemia agent for centuries. Through the in vitro XOD inhibitory assay, we obtained a novel XOD inhibitor, 5-O-caffeoylshikimic acid (#1, 5OCSA) with IC50 of 13.96 μM, as well as two known XOD inhibitors, quercetin (#3) and astilbin (#6). Meanwhile, we performed in silico molecular docking and found 5OCSA could interact with the active sites of XOD (PDB ID: 3NVY) with a binding energy of −8.6 kcal/mol, suggesting 5OCSA inhibits XOD by binding with its active site. To evaluate the in vivo effects on XOD, we generated a hyperuricemia mice model by intraperitoneal injection of potassium oxonate (300 mg/kg) and oral gavage of hypoxanthine (500 mg/kg) for 7 days. 5OCSA could inhibit both hepatic and serum XOD in vivo, together with an improvement of histological and multiple serological parameters in kidney injury and HUA. Collectively, our results suggested that 5OCSA may be developed into a safe and effective XOD inhibitor based on in vitro, in silico and in vivo evidence.

Highlights

Hyperuricemia (HUA) is caused by disorder of purine metabolism, with abnormal elevation of serum uric acid as hallmarks [1].Gout is a typical inflammatory arthritis induced by HUA with strong feeling of pain and has been first described as “feeling of tiger bites” in Danxi xinfa by Danxi Zhu (1347, YuanDynasty) [2]
Determined by bioassay, we found EtOAc soluble fraction (EAF), not BuOH soluble fraction (BUF), showed comparable inhibitory capacity with crude ethanol extracts (CEE), with an inhibition rate of 30.36% in 200 μg/mL (Figure 1c)
Activation of inflammatory cytokines in injury kidney were frequently reported in HUA patients and animal models [36–38].To assess the effects of 5-O-caffeoylshikimic acid (5OCSA) on inflammatory cytokines, we evaluated the changes of inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-18 in kidney by Elisa

Summary

Introduction

Hyperuricemia (HUA) is caused by disorder of purine metabolism, with abnormal elevation of serum uric acid (sUA) as hallmarks (male ≥ 420 μM or female ≥ 360 μM) [1].Gout is a typical inflammatory arthritis induced by HUA with strong feeling of pain and has been first described as “feeling of tiger bites” in Danxi xinfa by Danxi Zhu (1347, YuanDynasty) [2]. Hyperuricemia (HUA) is caused by disorder of purine metabolism, with abnormal elevation of serum uric acid (sUA) as hallmarks (male ≥ 420 μM or female ≥ 360 μM) [1]. HUA could result in other comorbidities, including cardiovascular diseases [3], obesity [4], diabetes [5], hypertension [6], kidney injury [7] and so on. Risk factors for development of HUA include genetics [8] (male gender, SLC2A9, ABCG2, SLC17A1/SLC17A3 and so on), dietary [9,10] (seafood, red meat, beer, spirits and so on), drugs [11] (diuretics, cyclosporin, tacrolimus, angiotensin-converting-enzyme inhibitors, non-losartan angiotensin II receptor blockers, β blockers, pyrazinamide, ritonavir and so on) and others [12]. HUA has already become the “fourth highest” disease after hypertension, hyperlipidemia and hyperglycemia [14]. The development of sUA-lowering drugs has clear clinical significance for HUA and related diseases [15]

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