Abstract
Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways.
Similar content being viewed by others
Data availability
Data will be made available on reasonable request.
References
Amezcua-Castillo LM, Juarez-Vicuna Y, Marquez-Velasco R, Amezcua-Guerra LM (2020) Activation status of NLRP3 Inflammasome in peripheral blood mononuclear cells from patients with Gout flare. J Clin Rheumatol 26:S208–S212
Anzai N, Endou H (2011) Urate transporters: an evolving field. Semin Nephrol 31:400–409
Azevedo VF, Kos IA, Vargas-Santos AB, da Rocha Castelar PG, Dos Santos Paiva E (2019) Benzbromarone in the treatment of gout. Adv Rheumatol 59:37
De Nardo D, Latz E (2011) NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol 32:373–379
Dong Y, Zhao T, Ai W, Zalloum WA, Kang D, Wu T, Liu X, Zhan P (2019) Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016–2019). Expert Opin Ther Pat 29:871–879
Fan SH, Wang YY, Lu J, Zheng YL, Wu DM, Li MQ, Hu B, Zhang ZF, Cheng W, Shan Q (2014) Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome. PLoS ONE 9:e89961
Guo LF, Chen X, Lei SS, Li B, Zhang NY, Ge HZ, Yang K, Lv GY, Chen SH (2020) Effects and mechanisms of Dendrobium officinalis six Nostrum for treatment of Hyperuricemia with Hyperlipidemia. Evid-Based Complement Alternate Med 2020:2914019
Kanbay M, Solak Y, Afsar B, Nistor I, Aslan G, Caglayan OH, Aykanat A, Donciu MD, Lanaspa MA, Ejaz AA, Johnson RJ, Covic A (2017) Serum uric acid and risk for acute kidney injury following contrast. Angiology 68:132–144
Li Q, Tian Z, Wang M, Kou J, Wang C, Rong X, Li J, Xie X, Pang X (2019) Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARgamma/Nrf2/NF-kappaB signaling pathway. Int Immunopharmacol 66:309–316
Lim H, Min DS, Park H, Kim HP (2018) Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol 355:93–102
Lin WQ, Xie JX, Wu XM, Yang L, Wang HD (2014) Inhibition of xanthine oxidase activity by gnaphalium affine extract. Chin Med Sci J 29:225–230
Luan RL, Meng XX, Jiang W (2016) Protective effects of Apigenin against Paraquat-induced acute lung injury in mice. Inflammation 39:752–758
Ma C, Yang X, Lv Q, Yan Z, Chen Z, Xu D, Liu X, Yang W, Xing S (2020) Soluble uric acid induces inflammation via TLR4/NLRP3 pathway in intestinal epithelial cells. Iran J Basic Med Sci 23:744–750
Nishitani Y, Yamamoto K, Yoshida M, Azuma T, Kanazawa K, Hashimoto T, Mizuno M (2013) Intestinal anti-inflammatory activity of luteolin: role of the aglycone in NF-kappaB inactivation in macrophages co-cultured with intestinal epithelial cells. BioFactors 39:522–533
Otani N, Ouchi M, Hayashi K, Jutabha P, Anzai N (2017) Roles of organic anion transporters (OATs) in renal proximal tubules and their localization. Anat Sci Int 92:200–206
Pavelcova K, Bohata J, Pavlikova M, Bubenikova E, Pavelka K, Stiburkova B (2020) Evaluation of the influence of genetic variants of SLC2A9 (GLUT9) and SLC22A12 (URAT1) on the development of hyperuricemia and Gout. J Clin Med 9:2510
Rahmi EP, Kumolosasi E, Jalil J, Husain K, Buang F, Abd Razak AF, Jamal JA (2020) Anti-hyperuricemic and anti-inflammatory effects of Marantodes pumilum as potential treatment for Gout. Front Pharmacol 11:289
Romero CA, Remor A, Latini A, De Paul AL, Torres AI, Mukdsi JH (2017) Uric acid activates NRLP3 inflammasome in an in-vivo model of epithelial to mesenchymal transition in the kidney. J Mol Histol 48:209–218
Serrano JL, Figueiredo J, Almeida P, Silvestre S (2020) From Xanthine oxidase inhibition to in vivo hypouricemic effect: an integrated overview of in vitro and in vivo studies with focus on natural molecules and analogues. Evid-Based Complement Alternat Med 2020:9531725
Shekelle PG, Newberry SJ, FitzGerald JD, Motala A, O’Hanlon CE, Tariq A, Okunogbe A, Han D, Shanman R (2017) Management of Gout: a systematic review in support of an American College of Physicians Clinical Practice Guideline. Ann Intern Med 166:37–51
Shen R, Ma L, Zheng Y (2020) Anti-inflammatory effects of luteolin on acute gouty arthritis rats via TLR/MyD88/NF-kappaB pathway. Zhong Nan Da Xue Xue Bao Yi Xue Ban 45:115–122
So A (2007a) New knowledge on the pathophysiology and therapy of gout. Z Rheumatol 66(562):564–567
So A (2007b) Recent advances in the pathophysiology of hyperuricemia and gout. Rev Med Suisse 3(720):722–724
Su HY, Yang C, Liang D, Liu HF (2020) Research advances in the mechanisms of hyperuricemia-induced renal injury. Biomed Res Int 2020:5817348
Torres RJ, Puig JG (2018) GLUT9 influences uric acid concentration in patients with Lesch-Nyhan disease. Int J Rheum Dis 21:1270–1276
Tsai CW, Lin SY, Kuo CC, Huang CC (2017) Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS ONE 12:e0170393
Wang K, Hu L, Chen JK (2018) RIP3-deficience attenuates potassium oxonate-induced hyperuricemia and kidney injury. Biomed Pharmacother 101:617–626
Xiong W, Zhang H, Wen L, Wang X, Zhong G, Shi Y, DU, X. and Zhu, J. (2018) Effect of Lagotis brachystachya Maxim extract on xanthine oxidase and renal urate transporters in hyperuricemia mice. Chin J New Drugs 27:1538–1543
Xu L, Shi Y, Zhuang S, Liu N (2017) Recent advances on uric acid transporters. Oncotarget 8:100852–100862
Yamagata K, Hashiguchi K, Yamamoto H, Tagami M (2019) Dietary Apigenin reduces induction of LOX-1 and NLRP3 expression, Leukocyte Adhesion, and Acetylated low-density lipoprotein uptake in human endothelial cells exposed to Trimethylamine-N-Oxide. J Cardiovasc Pharmacol 74:558–565
Yan J, Zhang G, Hu Y, Ma Y (2013) Effect of luteolin on xanthine oxidase: inhibition kinetics and interaction mechanism merging with docking simulation. Food Chem 141:3766–3773
Zhang X, Yang X, Wang M, Li X, Xia Q, Xu S, Xu J, Cai G, Wang L, Xin L, Zou Y, Pan F (2016) Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis. Rheumatol Int 36:1157–1165
Zhu J, Shi Y, Cheng H, Wang H, Wang R, Li M (2019) Chemical constituents from Lagotis brachystachy. J Chin Med Mater 42:552–555
Funding
The project was supported by grants from the National Natural Science Foundation of China (No. 82060757), the Science and Technology Research Project of Jiangxi Provincial Department of Education (No. GJJ190632) and the Science and Technology Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (No. 2019A004, 2019A258).
Author information
Authors and Affiliations
Contributions
J.Z., H.C. and L.Y. conceived of the project. J.Z., H.Y., W.H. and J.C. performed the experiments. J.Z., and Y.L. analyzed data. L.Y. did molecular docking. J.Z., H.C. and L.Y. wrote and revised the manuscript. All authors read and approved the submission.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
All animal procedure was in accordance with guidelines from China Council on Animal Care and was approved by the Animal Commission of Jiangxi University of Chinese Medicine (No. JZLLSC2019-0221 on 2019/02/28).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhu, JX., Yang, HY., Hu, WQ. et al. Active components from Lagotis brachystachya maintain uric acid homeostasis by inhibiting renal TLR4-NLRP3 signaling in hyperuricemic mice. Inflammopharmacol 29, 1187–1200 (2021). https://doi.org/10.1007/s10787-021-00844-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-021-00844-5