Antihyperuricemic activities of an ethanolic and aqueous extract of Walnut (Juglans regia L.) shell and a new aldehyde xanthine oxidase inhibitor

Summary Hyperuricemia is a common metabolic disorder disease in human and is associated with increased xanthine oxidase (XOD) activity. This study was aimed to evaluate the antihyperuricemic activities of an ethanolic and aqueous extract of walnut (Juglans regia L.) shell in vivo and obtain active compounds with high xanthine oxidase inhibitory (XOI) activities and distinct chemical structures form allopurinol in vitro. Finally, the structure–XOI activity relationship of the active compound was further discussed based on the molecular docking. The in vivo antihyperuricemic study indicated that the walnut shell extract (WSE) could decrease the serum uric acid levels significantly (20-days treatment, P < 0.05; 30-days treatment, P < 0.01). And a new aldehyde XOD inhibitor with high XOI activity was obtained through XOI activity-guided purification in vitro. The studies of structure–XOI activity relationship and molecular docking indicated that the synergy of aldehyde group, double bond and hydroxyl group at C-4 in p-coumaric aldehyde was the critical contributor for its high XOI activity.

[1]  Mouming Zhao,et al.  In vitro and in vivo studies on adlay-derived seed extracts: phenolic profiles, antioxidant activities, serum uric acid suppression, and xanthine oxidase inhibitory effects. , 2014, Journal of agricultural and food chemistry.

[2]  Jianming Lü,et al.  3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. , 2013, Biochemical pharmacology.

[3]  Haifeng Zhao,et al.  Comparative evaluation of rosmarinic acid, methyl rosmarinate and pedalitin isolated from Rabdosia serra (MAXIM.) HARA as inhibitors of tyrosinase and α-glucosidase. , 2011, Food chemistry.

[4]  Raj Kumar,et al.  N-(1,3-Diaryl-3-oxopropyl)amides as a new template for xanthine oxidase inhibitors. , 2011, Bioorganic & medicinal chemistry.

[5]  G. Falasca,et al.  New and improved strategies for the treatment of gout , 2010, International journal of nephrology and renovascular disease.

[6]  A. Mally,et al.  Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity. , 2010, Toxicology.

[7]  T. Efferth,et al.  Antioxidant activities and xanthine oxidase inhibitory effects of extracts and main polyphenolic compounds obtained from Geranium sibiricum L. , 2010, Journal of agricultural and food chemistry.

[8]  F. Haidari,et al.  Orange Juice and Hesperetin Supplementation to Hyperuricemic Rats Alter Oxidative Stress Markers and Xanthine Oxidoreductase Activity , 2009, Journal of clinical biochemistry and nutrition.

[9]  Jeffrey C Moore,et al.  Antioxidant phenolic compounds from walnut kernels (Juglans regia L.) , 2009 .

[10]  W. Pan,et al.  Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study. , 2009, Arthritis and rheumatism.

[11]  J. Griffith,et al.  Uric acid and incident kidney disease in the community. , 2008, Journal of the American Society of Nephrology : JASN.

[12]  M. H. Najmi,et al.  Pharmacological basis for use of Pistacia integerrima leaves in hyperuricemia and gout. , 2008, Journal of ethnopharmacology.

[13]  E. Fernandes,et al.  Walnut (Juglans regia) leaf extracts are strong scavengers of pro-oxidant reactive species , 2008 .

[14]  Hyon K. Choi,et al.  Prevalence of the metabolic syndrome in individuals with hyperuricemia. , 2007, The American journal of medicine.

[15]  F. Stampar,et al.  Traditional walnut liqueur – cocktail of phenolics , 2006 .

[16]  M. Simmonds,et al.  Dihydroisocoumarins and a tetralone from Cytospora eucalypticola. , 2003, Phytochemistry.

[17]  E. Pai,et al.  An Extremely Potent Inhibitor of Xanthine Oxidoreductase , 2003, The Journal of Biological Chemistry.

[18]  John Ralph,et al.  NMR analysis of lignins in CAD-deficient plants. Part 1. Incorporation of hydroxycinnamaldehydes and hydroxybenzaldehydes into lignins. , 2003, Organic & biomolecular chemistry.

[19]  R. Tan,et al.  Inhibition of xanthine oxidase by some Chinese medicinal plants used to treat gout. , 2000, Journal of ethnopharmacology.

[20]  C. Enroth,et al.  Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Johns,et al.  Xanthine oxidase inhibitory activity of northeastern North American plant remedies used for gout. , 1999, Journal of ethnopharmacology.

[22]  J. Leem,et al.  Isolation of p‐hydroxycinnamaldehyde as an antibacterial substance from the saw fly, Acantholyda parki S , 1999, FEBS letters.

[23]  J. Lancelin,et al.  Insight into naphthoquinone metabolism: beta-glucosidase-catalysed hydrolysis of hydrojuglone beta-D-glucopyranoside. , 1998, The Biochemical journal.

[24]  S. Purcell,et al.  Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. , 1984, The Journal of biological chemistry.

[25]  Mouming Zhao,et al.  The antioxidant activities and the xanthine oxidase inhibition effects of walnut (Juglans regia L.) fruit, stem and leaf , 2015 .

[26]  E. Fernandes,et al.  Progress towards the discovery of xanthine oxidase inhibitors. , 2002, Current medicinal chemistry.