药学学报, 2021, 56(5): 1229-1237
姜楠, 张晓琳, 田金英, 叶菲*. 具有黄嘌呤氧化酶抑制作用的天然产物之研究进展[J]. 药学学报, 2021, 56(5): 1229-1237.
JIANG Nan, ZHANG Xiao-lin, TIAN Jin-ying, YE Fei*. Recent studies on the natural products with xanthine oxidase inhibitory effect[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1229-1237.

姜楠, 张晓琳, 田金英, 叶菲*
中国医学科学院、北京协和医学院药物研究所, 新药作用机制研究与药效评价北京市重点实验室, 北京 100050
黄嘌呤氧化酶(xanthine oxidase,XOD)参与体内嘌呤的代谢,是尿酸(uric acid,UA)生成的关键酶,成为临床治疗高尿酸血症的重要靶点。抑制XOD对治疗痛风等高尿酸血症相关的疾病以及组织氧化损伤具有重要作用。本文对具有XOD抑制作用的天然产物的研究进展进行综述。
关键词:    天然产物      黄嘌呤氧化酶      尿酸      抑制作用      高尿酸血症     
Recent studies on the natural products with xanthine oxidase inhibitory effect
JIANG Nan, ZHANG Xiao-lin, TIAN Jin-ying, YE Fei*
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
Xanthine oxidase (XOD), catalyzing purine metabolism, is the key enzyme in uric acid (UA) biosynthesis, and becomes an important target for hyperuricemia treatment. The inhibition on XOD plays an important role in the treatment of hyperuricemia-related diseases, such as gout, as well as oxidative stress-induced tissue injury. Here, studies on the natural products with XOD inhibition are reviewed.
Key words:    natural product    xanthine oxidase    uric acid    inhibition    hyperuricemia   
收稿日期: 2020-12-21
DOI: 10.16438/j.0513-4870.2020-1952
基金项目: 国家“重大新药创制”科技重大专项(2018ZX09711001-003-005);国家自然科学基金青年基金项目(81600546,82000820);中国医学科学院医学与健康科技创新工程团队项目(CIFMS-2016-I2M-3-012).
通讯作者: 叶菲,Tel:86-10-83150495,E-mail:yefei@imm.ac.cn
Email: yefei@imm.ac.cn
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姜楠  在本刊中的所有文章
张晓琳  在本刊中的所有文章
田金英  在本刊中的所有文章
叶菲*  在本刊中的所有文章

[1] Yu Y, Zhou Q, Yang N, et al. An analysis of current situation of global clinical practice guidelines on gout[J]. Drug Eval (药品评价), 2018, 15:9-15.
[2] Yamaguchi Y, Matsumura T, Ichida K, et al. Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site:roles of active site residues in binding and activation of purine substrate[J]. J Biochem, 2007, 141:513-524.
[3] Harrison R. Structure and function of xanthine oxidoreductase:where are we now?[J]. Free Radical Biol Med, 2002, 33:774-797.
[4] Borges F, Fernandes E, Roleira F. Progress towards the discovery of xanthine oxidase inhibitors[J]. Curr Med Chem, 2002, 9:195-217.
[5] Stockert AL, Shinde SS, Anderson RF, et al. The reaction mechanism of xanthine oxidase:evidence for two-electron chemistry rather than sequential one-electron steps[J]. J Am Chem Soc, 2002, 124:14554-14555.
[6] Terkeltaub RA. Clinical practice. Gout[J]. N Engl J Med, 2003, 349:1647-1655.
[7] Nishikawa T, Nagata N, Shimakami T, et al. Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice[J]. Sci Rep, 2020, 10:815.
[8] Krakoff IH. Use of allopurinol in preventing hyperuricemia in leukemia and lymphoma[J]. Cancer, 1966, 19:1489-1496.
[9] Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors:renaissance half a century after the discovery of allopurinol[J]. Pharmacol Rev, 2006, 58:87-114.
[10] Abad ASS, Falanji F, Ghanbarabadi M, et al. Assessment of anti-nociceptive effect of allopurinol in a neuropathic pain model[J]. Brain Res, 2019, 1720:146238.
[11] Negi M, Mulla MJ, Han CS, et al. Allopurinol inhibits excess glucose-induced trophoblast IL-1β and ROS production[J]. Reproduction, 2020, 159:73-80.
[12] Lu JM, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase:a potential therapeutic agent for treatment of hyperuricemia and gout[J]. Biochem Pharmacol, 2013, 86:1328-1337.
[13] Zhou H, Li X, Li Y, et al. Synthesis and bioevaluation of 1-phenylimidazole-4-carboxylic acid derivatives as novel xanthine oxidoreductase inhibitors[J]. Eur J Med Chem, 2020, 186:111883.
[14] Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase[J]. Life Sci, 2005, 76:1835-1847.
[15] Inoue MK, Yamamotoya T, Nakatsu Y, et al. The xanthine oxidase inhibitor febuxostat suppresses the progression of IgA nephropathy, possibly via its anti-inflammatory and anti-fibrotic effects in the gddY mouse model[J]. Int J Mol Sci, 2018, 19:3967.
[16] Kim H, Baek CH, Chang JW, et al. Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression[J]. Clin Exp Nephrol, 2020, 24:205-215.
[17] White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout[J]. N Engl J Med, 2018, 378:1200-1210.
[18] Matsumoto K, Okamoto K, Ashizawa N, et al. FYX-051:a novel and potent hybrid-type inhibitor of xanthine oxidoreductase[J]. J Pharmacol Exp Ther, 2011, 336:95-103.
[19] Tohyo S. Topiroxostat influences circulating lipid concentrations in hyperuricemic patients[J]. Int J Clin Pharmacol Ther, 2019, 57:567-570.
[20] Higa S, Shima D, Tomitani N, et al. The effects of topiroxostat on vascular function in patients with hyperuricemia[J]. J Clin Hypertens, 2019, 21:1713-1720.
[21] Hisayuki K, Hidekatsu Y, Mariko H. Renoprotective effect of xanthine oxidase inhibitor, topiroxostat[J]. J Clin Med Res, 2019, 11:614-616.
[22] Mehmood A, Ishaq M, Zhao L, et al. Natural compounds with xanthine oxidase inhibitory activity:a review[J]. Chem Biol Drug Des, 2019, 93:387-418.
[23] Lemus-Mondaca R, Vega-Galvez A, Zura-Bravo L, et al. Stevia rebaudiana Bertoni, source of a high-potency natural sweetener:a comprehensive review on the biochemical, nutritional and functional aspects[J]. Food Chem, 2012, 132:1121-1132.
[24] Cosola C, Sabatino A, di Bari I, et al. Nutrients, nutraceuticals, and xenobiotics affecting renal health[J]. Nutrients, 2018, 10:808.
[25] Chatsudthipong V, Muanprasat C. Stevioside and related compounds:therapeutic benefits beyond sweetness[J]. Pharmacol Ther, 2009, 121:41-54.
[26] Ramos-Tovar E, Hernandez-Aquino E, Casas-Grajales S, et al. Stevia prevents acute and chronic liver injury induced by carbon tetrachloride by blocking oxidative stress through Nrf2 upregulation[J]. Oxid Med Cell Longev, 2018, 2018:3823426.
[27] Mehmood A, Zhao L, Wang C, et al. Stevia residue extract alone and combination with allopurinol attenuate hyperuricemia in fructose-PO-induced hyperuricemic mice[J]. J Food Biochem, 2020, 44:e13087.
[28] Akbay P, Basaran AA, Undeger U, et al. In vitro immunomodulatory activity of flavonoid glycosides from Urtica dioica L[J]. Phytother Res, 2003, 17:34-37.
[29] Su RN. Research on the Material Basis and Mechanism for Hypouricemia and Anti-BPH of Tibetan Medicine of Urtica hyperborea Jacq.ex Wedd. (藏药高原荨麻降尿酸、抗良性前列腺增生物质基础及作用机制研究)[D]. Nanchang:Jiangxi University of Traditional Chinese Medicine, 2019.
[30] Han S, Wei R, Han D, et al. Hypouricemic effects of extracts from Urtica hyperborea Jacq. ex Wedd. in hyperuricemia mice through XOD, URAT1, and OAT1[J]. Biomed Res Int, 2020, 2020:2968135.
[31] Huang K, Li Y, Tao S, et al. Purification, characterization and biological activity of polysaccharides from Dendrobium officinale[J]. Molecules, 2016, 21:701.
[32] Luo QL, Tang ZH, Zhang XF, et al. Chemical properties and antioxidant activity of a water-soluble polysaccharide from Dendrobium officinale[J]. Int J Biol Macromol, 2016, 89:219-227.
[33] Ruijun W, Shi W, Yijun X, et al. Antitumor effects and immune regulation activities of a purified polysaccharide extracted from Juglan regia[J]. Int J Biol Macromol, 2015, 72:771-775.
[34] Sun L, Wang L, Zhou Y. Immunomodulation and antitumor activities of different-molecular-weight polysaccharides from Porphyridium cruentum[J]. Carbohydr Polym, 2012, 87:1206-1210.
[35] Lou XJ, Wang YZ, Lei SS, et al. Beneficial effects of macroporous resin extract of Dendrobium candidum leaves in rats with hyperuricemia induced by a high-purine diet[J]. Evid Based Complement Alternat Med, 2020, 2020:3086106.
[36] Lai LL, Peng XF, Leng EN, et al. Advances in study on pharmacological effects of Mulberry leaves[J]. Anhui Med Pharm J (安徽医药), 2016, 20:2210-2214.
[37] Wan L, Chen G, Jian S, et al. Antioxidant and xanthine oxidase inhibitory properties and LC-MS/MS identification of compoundsof ethanolic extract from mulberry leaves[J]. Acta Sci Pol Technol Aliment, 2018, 17:313-319.
[38] Liu JC, Wang T. Research progress of rhizome Dioscorea and rhizoma Smilacis Glabrae on treatment of hyperuricemia[J]. J Liaoning Univ Tradit Chin Med (辽宁中医药大学学报), 2018, 20:79-81.
[39] Zhang XX, Sun WF, Hou Y, et al. Clinical observation on Fufang Tufuling Keli treating 40 cases of hyperuricemia:a randomize-controlled study[J]. J Tradit Chin Med (中医杂志), 2016, 57:41-45.
[40] Ding R, Hong Q, Geng XD, et al. Mechanism of rhizoma Smilacis Glabrae in the treatment of hyperuricemia mouse model[J]. Chin J Integr Tradit West Nephrol (中国中西医结合肾病杂志), 2019, 20:97-100.
[41] Liu C, Guo FF, Ping XJ, et al. Research advances in chemical constituents and pharmacological activities of different parts of Eucommia ulmoides[J]. China J Chin Mater Med (中国中药杂志), 2020, 45:497-512.
[42] Fu G, Tong H, Zeng H, et al. Antioxidant and xanthine oxidase inhibitory activity of Eucommia ulmoides oliver leaf extracts[J]. Pak J Pharm Sci, 2018, 31:1333-1339.
[43] Xie X, Tu ZC, Wang H, et al. Antioxidant and enzyme inhibitory activities of extracts from various parts of wild and cultivated Artemisia selengensis Turcz[J]. J Chin Inst Food Sci Tech (中国食品学报), 2020, 20:58-65.
[44] Cao WW, Wu T, Fang YJ, et al. Identification of 1,4-dicaffeoylquinic acid from Artemisia selengensis leaves and structure activity relationship of dicaffeoylquinic acid compounds inhibiting xanthine oxidase and inhibiting sodium urate induced IL-1β in vitro[J]. J Chin Inst Food Sci Tech (中国食品学报), 2020, 20:1-8.
[45] Zou Y, Zhou M. Research progress on chemical constituents and pharmacological effects of Gardenia jasminoides Ellis[J]. Jiangxi Chem Ind (江西化工), 2019, 18:47-48.
[46] Zhu JX, Li XW, Zeng JX, et al. Effects of active components from Gardenia jasminoides Ellis on XOD activity and mRNA expression in A549 cells[J]. Tradit Chin Med J (中医药通报), 2015, 14:65-68.
[47] Malyarenko OS, Zdobnova EV, Silchenko AS, et al. Radiosensitizing effect of the fucoidan from brown alga Fucus evanescens and its derivative in human cancer cells[J]. Carbohydr Polym, 2019, 205:465-471.
[48] Du B, Feng JX, Jin WG. Research progress on structural elucidation and biological activities of Laminaria japonica polysaccharide[J]. Chin J Mar Drug (中国海洋药物), 2020, 39:50-59.
[49] Yan CW, Li J, Jiang L, et al. Inhibitory effects on xathine oxidase activity and regulation on hyperuricemia in mice of Laminaria japonica polysaccharides[J]. Per Ocean Univ China (Nat Sci) (中国海洋大学学报(自然科学版)), 2015, 45:50-55.
[50] Ji EH, Xu J, Wei JY. Active constituents and pharmacological effect of Moringa oleifera leaves research[J]. Chin J Exp Tradit Med Form (中国实验方剂学), 2021, 27:212-223.
[51] Zhong YY, Zhou JM, Ye MF. Inhibition of Moringa leaf extract on xanthine oxidase activity[J]. Food Ind (食品工业), 2020, 41:55-58.
[52] Liang WJ, He JS, Tian Y. Study on extract of Moringa oleifera leaves reducing the level of uric acid in hyperuricemia mice and its mechanism[J]. J Anhui Agric Sci (安徽农业科学), 2017, 45:108-109, 112.
[53] Chen YQ, Lin YH, Zou YH. Research progress on identification of crude drugs, active ingredients and pharmacological effects of Anoectochilus[J]. Chin Tradit Pat Med (中成药), 2020, 42:2141-2144.
[54] Xu GH, Zhao SF, Luo YQ. Studies of Anoectochilus roxburghii extracts inhibiting xanthine oxidase activity in vitro and reducing the level of uric acid in hyperuricemia mice[J]. Strait Pharm J (海峡药学), 2017, 29:12-14.
[55] Akaberi M, Sobhani Z, Javadi B, et al. Therapeutic effects of Aloe spp. in traditional and modern medicine:a review[J]. Biomed Pharmacother, 2016, 84:759-772.
[56] Park MY, Kwon HJ, Sung MK. Evaluation of aloin and aloe-emodin as anti-inflammatory agents in aloe by using murine macrophages[J]. Biosci Biotechnol Biochem, 2009, 73:828-832.
[57] Shi DH, Huang W, Li C, et al. Design, synthesis and molecular modeling of aloe-emodin derivatives as potent xanthine oxidase inhibitors[J]. Eur J Med Chem, 2014, 75:289-296.
[58] Fang Y, Cao Z, Hou Q, et al. Cyclin D1 downregulation contributes to anticancer effect of isorhapontigenin on human bladder cancer cells[J]. Mol Cancer Ther, 2013, 12:1492-1503.
[59] Fang Y, Yu Y, Hou Q, et al. The Chinese herb isolate isorhapontigenin induces apoptosis in human cancer cells by down-regulating overexpression of antiapoptotic protein XIAP[J]. J Biol Chem, 2012, 287:35234-35243.
[60] Kongkachuichai R, Charoensiri R, Yakoh K, et al. Nutrients value and antioxidant content of indigenous vegetables from Southern Thailand[J]. Food Chem, 2015, 173:838-846.
[61] Tang X, Tang P, Ma L, et al. Screening and evaluation of xanthine oxidase inhibitors from Gnetum parvifolium in China[J]. Molecules, 2019, 24:2671.
[62] Feng J, Huang X, Li HY, et al. Mechanism of resveratrol inhibiting monosodium urate induced oxidative damage of RAW264.7 macrophages[J]. Acta Pharm Sin (药学学报), 2020, 55:2368-2374.
[63] Chen YM, Zhou LH, Zhang XD, et al. Antinociceptive effects of total Ervatamia yunnansis alkaloid in mice[J]. J Pharm Pract (药学实践杂志), 2006, 24:203-205.
[64] Xuan WD, Chen HS, Yuan ZX, et al. Antiaddictive indole alkaloids in Ervatamia yunnanensis and their bioactivity[J]. Acad J Second Milit Med Univ (第二军医大学学报), 2006, 27:92-96.
[65] Shi BB, Chen J, Bao MF, et al. Alkaloids isolated from Tabernaemontana bufalina display xanthine oxidase inhibitory activity[J]. Phytochemistry, 2019, 166:112060.
[66] Jiang X, Shi L. Research progress on active constituents and pharmacological effects of Salvia miltiorrhiza[J]. J Pharm Res (药学研究), 2017, 36:166-169.
[67] Liu X, Chen R, Shang Y, et al. Lithospermic acid as a novel xanthine oxidase inhibitor has anti-inflammatory and hypouricemic effects in rats[J]. Chem Biol Interact, 2008, 176:137-142.
[68] Fu Y, Mo HY, Gao W, et al. Affinity selection-based two-dimensional chromatography coupled with high-performance liquid chromatography-mass spectrometry for discovering xanthine oxidase inhibitors from Radix Salviae Miltiorrhizae[J]. Anal Bioanal Chem, 2014, 406:4987-4995.
[69] Mei L, Niu RJ, Jiang L, et al. Advances in the study on the chemical constituents and pharmacological activities of Ilex pubescens Hook. et Arn.[J]. Biol Chem Engin (生物化工), 2018, 4:129-131.
[70] Zhou ZL, Feng ZC, Fu CY, et al. A new triterpene saponin from the roots of Ilex pubescens[J]. Nat Prod Res, 2013, 27:1343-1347.
[71] Gu QY. Isolation and Analysis of Chemical Constituents in Chinese Toon (中药香椿叶化学成分的分离与分析)[D]. Zhenjiang:Jiangsu University, 2016.
[72] Yuk HJ, Lee YS, Ryu HW, et al. Effects of Toona sinensis leaf extract and its chemical constituents on xanthine oxidase activity and serum uric acid levels in potassium oxonate-induced hyperuricemic rats[J]. Molecules, 2018, 23:3254.
[73] Zhou YX, Zhang H, Peng C. Puerarin:a review of pharmacological effects[J]. Phytother Res, 2014, 28:961-975.
[74] Shen QR. The Screening and Study on the Inhibition Kinetics of Xanthine Oxidase Inhibitors from Chinese Herbal Medicine (中药黄嘌呤氧化酶抑制剂的筛选及抑制动力学研究)[D]. Nanchang:Nanchang University, 2015.
[75] Shi S, Zhang RT, Shang XY, et al. Effect of Pueraria lobata extract on serum uric acid in hyperuricemia rats[J]. Food Sci Technol (食品科技), 2014, 39:216-220.
[76] Sun LL, Li Q, Tian ZH, et al. Research progress on chemical constituents and pharmacological effects of Curcuma longa[J]. J Shandong Univ Tradit Chin Med (山东中医药大学学报), 2019, 43:207-212.
[77] Ao GZ, Zhou MZ, Li YY, et al. Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents[J]. Bioorg Med Chem, 2017, 25:166-174.
[78] Xiong YG, Shen Y, Zhang H. Advances in pharmacological activity of Alpinia officinaruim Hance[J]. Cent South Pharm (中南药学), 2017, 15:1418-1421.
[79] Pu ZQ, Wang QL, Xu XM. Separation, purification of galangin and its effect on reducing uric acid[J]. J Jiangsu Univ (Med) (江苏大学学报(医学版)), 2017, 27:338-343.
[80] Lu H, Chen XW, Yao H. Pharmacological effect and cellular mechanism of galangin on uric acid nephropathy[J]. Cent South Pharm (中南药学), 2020, 18:1098-1102.
[81] Wang Y, Zhang G, Pan J, et al. Novel insights into the inhibitory mechanism of kaempferol on xanthine oxidase[J]. J Agric Food Chem, 2015, 63:526-534.
[82] An R. Studies on Extraction and Effects on Hyperuricemia of Quercetin from Bud of Sophora japonica L. (槐米中槲皮素的提取及其对高尿酸血症的影响)[D]. Tianjin:Tianjin University of Science and Technology, 2010.
[83] Baek KS, Yi YS, Son YJ, et al. Comparison of anticancer activities of Korean red ginseng-derived fractions[J]. J Ginseng Res, 2017, 41:386-391.
[84] Yan JK. Study on the Inhibition Mechanism of Luteolin on Xanthine Oxidase and α-Glucosidase (木犀草素对黄嘌呤氧化酶、α-葡萄糖苷酶抑制机理的探讨)[D]. Nanchang:Nanchang University, 2014.
[85] Ma WT. Screening Inhibition of Xanthine Oxidase, Lipoxygenase, Cyclooxygenase and Antitumor Activity In Vitro (黄嘌呤氧化酶、脂氧化酶和环氧化酶抑制剂的筛选及其体外抗肿瘤活性研究)[D]. Wuhan:Hubei University of Traditional Chinese Medicine, 2016.
[86] Ye YZ, Hu JL, Gong MJ, et al. The treatment and mechanism study on hyperuricemia of couplet medicines polydatin and cinnamaldehyde[J]. J Chin Med Mater (中药材), 2020, 43:423-428.
[87] Huang CY, Yeh TF, Hsu FL, et al. Xanthine oxidase inhibitory activity and thermostability of cinnamaldehyde-chemotype leaf oil of Cinnamomum osmophloeum microencapsulated with β-cyclodextrin[J]. Molecules, 2018, 23:1107.
[88] Wan Y, Zou B, Zeng H, et al. Inhibitory effect of verbascoside on xanthine oxidase activity[J]. Int J Biol Macromol, 2016, 93:609-614.
[89] Tsai SF, Lee SS. Neolignans as xanthine oxidase inhibitors from Hyptis rhomboides[J]. Phytochemistry, 2014, 101:121-127.
[90] Granato M, Rizzello C, Gilardini Montani MS, et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways[J]. J Nutr Biochem, 2017, 41:124-136.
[91] Rojas A, Del Campo JA, Clement S, et al. Effect of quercetin on hepatitis C virus life cycle:from viral to host targets[J]. Sci Rep, 2016, 6:31777.
[92] Lee JY, Park W. Anti-inflammatory effect of Wogonin on RAW 264.7 mouse macrophages induced with polyinosinic-polycytidylic acid[J]. Molecules, 2015, 20:6888-6900.
[93] Klimaszewska-Wisniewska A, Halas-Wisniewska M, Izdebska M, et al. Antiproliferative and antimetastatic action of quercetin on A549 non-small cell lung cancer cells through its effect on the cytoskeleton[J]. Acta Histochem, 2017, 119:99-112.
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