Objective  To explore the effects of Atractylenolide-III (AT-III) on the intestinal immune barrier and kidney of rats with immunoglobulin A nephropathy (IgAN), and develop AT-III nanoparticles to optimize its protective efficacy.

Methods  In this study, the zeolitic imidazolate framework (ZIF-8) loaded with AT-III was used to prepare ZIF-8@ AT- III nanoparticles. Morphological and structural characterization of the prepared samples was conducted using transmission electron microscopy and X-ray powder diffraction. 48 rats were randomly divided into the normal control group, IgAN group, IgAN+AT-III group, and IgAN+ZIF-8@AT-III group. IgAN rats were treated with AT-III and ZIF-8@AT-III, and the detections of hepatic and renal function, glomerular IgA deposition, and intestinal immune barrier function were performed.

Results  The synthesis of ZIF-8@AT-III nanoparticles with elevated drug loading, stability, and pH responsiveness had been successfully accomplished. The average particle size of ZIF-8@AT-III nanoparticles was (70.62±1.07) nm, the Zeta potential was (-26.46±1.22) mV, the drug loading capacity was (19.2±1.3%), and the encapsulation efficiency was (64.0%±0.6%). Furthermore, rapid release was observed in a pH 5.5 environment, which was significantly higher than that in the pH 7.4 environment. Both AT-III and ZIF-8@AT-III could alleviate the destruction of intestinal wall structure and the infiltration of inflammatory cells, significantly downregulate the levels of (DAO) and (D-LA) in the serum. Moreover, there is a noteworthy upregulation in the expression of (ZO-1) and Claudin-5 in intestinal mucosal tissue, thereby substantially improving the immune barrier function and intestinal permeability in IgAN rats. This intervention also inhibited the deposition of IgA in renal glomeruli and alleviated kidney damage, and ZIF- 8@AT-III was more effective than AT-III.

Conclusion  AT- III alleviates IgAN in rats by improving intestinal immune barrier function and permeability. ZIF-8-loaded AT-III serves as an excellent drug delivery system, enhancing the therapeutic efficacy of AT-III in IgAN treatment.

1.Soares MFS, Roberts ISD. Histologic classification of IgA nephropathy: past, present, and future[J]. Semin Nephrol, 2018, 38(5): 477-484. DOI: 10.1016/j.semnephrol. 2018.05.017.

2.Floege J, Rauen T, Tang SCW. Current treatment of IgA nephropathy[J]. Semin Immunopathol, 2021, 43(5): 717-728. DOI: 10.1007/s00281-021-00888-3.

3.任燕, 黄明进, 蒋雯文, 等. 白术内酯Ⅲ通过调节自噬水平清除过氧化物减轻小鼠溃疡性结肠炎[J]. 世界科学技术-中医药现代化, 2022, 24(8): 3219-3225. [Ren Y, Huang MJ, Jiang WW, et al. Atractylenolide Ⅲ alleviates ulcerative colitis in mice by regulating autophagy levels and scavenging peroxide[J]. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, 2022, 24(8): 3219-3225.] DOI: 10.11842/wst.20210704004.

4.汪永国. 防己黄芪汤在肾病综合征治疗中的作用研究[J]. 内蒙古中医药, 2019, 38(12): 52-53. [Wang YG. Study on the role of Fangji Huangqi Tang in the treatment of nephrotic syndrome[J]. Inner Mongolia Journal of Traditional Chinese Medicine, 2019, 38(12): 52-53.] DOI: 10.16040/j.cnki.cn15-1101.2019.12.034.

5.姜晨, 徐荣佳, 崔师妍, 等. 基于HPLC-Q-TOF-MS/MS和网络药理学探讨益肾化湿颗粒治疗IgA肾病作用机制[J]. 中草药, 2021, 52(21): 6576-6585. [Jiang C, Xu  RJ, Cui SY, et al. Mechanism of Yishen Huashi granules in treatment of IgA nephropathy based on HPLC-Q-TOF-MS/MS and network pharmacology[J]. 2021, 52(21): 6576-6585.] DOI: 10.7501/j.issn.0253-2670.2021.21.016.

6.Zhou N, Shen Y, Fan L, et al. The characteristics of intestinal-barrier damage in rats with IgA Nephropathy[J]. Am J Med Sci, 2020, 359(3): 168-176. DOI: 10.1016/j.amjms.2019.11.011.

7.胡彤, 庞智. 炎症性肠病与肠道微生态[J]. 医学新知, 2022, 32(4): 296-302. [Hu T, Pang Z. Inflammatory bowel disease and intestinal microecology[J]. Yixue Xinzhi Zazhi, 2022, 32(4): 296-302.] DOI: 10.12173/j.issn.1004-5511. 202203027.

8.曹正宇, 吴茂雄, 黄图城, 等. 透明质酸-二氧化钛纳米颗粒介导的声动力在动脉粥样硬化斑块治疗中的应用研究[J]. 岭南急诊医学杂志, 2023, 28(1): 8-12. [Cao ZY, Wu MX, Huang TC, et al. Hyaluronic acid-titania nanoparticles mediated sonodynamic therapyfor the treatment of atherosclerotic plaque[J]. Lingnan Journal of Emergency Medicine, 2023, 28(1): 8-12.] DOI: 10.3969/j.issn.1671-301X.2023.01.003.

9.严新安, Chirume WM, 方跃. 银纳米对不同骨科生物材料上金黄色葡萄球菌生物膜的影响[J]. 华西医学, 2023, 38(7): 1047-1052. [Yan XA, Walter M, Fang Y. Effect of silver nanoparticles on Staphylococcus aureus biofilm formation on different orthopedic biomaterials [J]. West China Medical Journal, 2023, 38(7): 1047-1052.] DOI: 10.7507/1002-0179.202110174.

10.Xie H, Liu X, Huang Z, et al. Nanoscale zeolitic imidazolate framework (ZIF)-8 in cancer theranostics: current challenges and prospects[J]. Cancers (Basel), 2022, 14(16): 3935. DOI: 10.3390/cancers14163935.

11.时慧, 汪河滨, 连培涵, 等. ZIF-8纳米载体的制备及负载黄芩素性能研究[J]. 塔里木大学学报, 2021, 33(4): 29-35. [Shi H, Wang HB, Lian PH, et al. Study on preparation of ZIF-8 nanocarrier and performance of loading baicalein[J]. Journal of Tarim University, 2021, 33(4): 29-35.] DOI: 10.3969/j.issn.1009-0568.2021. 04.005.

12.Makita Y, Suzuki H, Kano T, et al. TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy[J]. Kidney Int, 2020, 7(2): 340-349. DOI: 10.1016/j.kint.2019.08.022.

13.Groza Y, Jemelkova J, Kafkova LR, et al. IL-6 and its role in IgA nephropathy development[J]. Cytokine Growth Factor Rev, 2022, 66: 1-14. DOI: 10.1016/j.cytogfr. 2022.04.001.

14.Fan F, Ai Y, Sun T, et al. The role of inflammatory cytokines in anemia and gastrointestinal mucosal injury induced by foot electric stimulation[J]. Sci Rep, 2021, 11(1): 3101. DOI: 10.1038/s41598-021-82604-7.

15.Tang Y, Zhu Y, He H, et al. Gut dysbiosis and intestinal barrier dysfunction promotes IgA nephropathy by increasing the production of Gd-IgA1[J]. Front Med (Lausanne), 2022, 9: 944027. DOI: 10.3389/fmed.2022. 944027.

16.Suzuki H, Novak J. IgA glycosylation and immune complex formation in IgAN[J]. Semin Immunopathol, 2021, 43(5): 669-678. DOI: 10.1007/s00281-021-00883-8.

17.Fellström BC, Barratt J, Cook H, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial[J]. Lancet, 2017, 389(10084): 2117-2127. DOI: 10.1016/s0140-6736(17) 30550-0.

18.Huang M, Jiang W, Luo C, et al. Atractylenolide Ⅲ inhibits epithelial-mesenchymal transition in small intestine epithelial cells by activating the AMPK signaling pathway[J]. Mol Med Rep, 2022, 25(3): 98. DOI: 10.3892/mmr.2022.12614.

19.Schoultz I, Keita ÅV. The intestinal barrier and current techniques for the assessment of gut permeability[J]. Cells, 2020, 9(8): 1909. DOI: 10.3390/cells9081909.

20.孙丽英, 袁文婷, 石雪华. 防己黄芪汤临床应用及作用机制研究进展[J]. 中医药信息, 2023, 40(4): 90-95. [Sun LY, Yuan WT, Shi XH. Research progress in clinical application and action mechanism progress of Fangji Huangqi decoction[J]. Information on Traditional Chinese Medicin, 2023, 40(4): 90-95.] DOI: 10.19656/j.cnki. 1002-2406.20230415.

21.Kiryluk K, Li Y, Scolari F, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens[J]. Nat Genet, 2014, 46(11): 1187-1196. DOI: 10.1038/ng.3118.

22.鲁慧东, 李艳梅. 白术内酯Ⅲ通过调节JAK2/STAT3信号通路减轻溃疡性结肠炎模型小鼠肠道损伤[J]. 中国病理生理杂志, 2023, 39(1): 142-149. [Lu HD, Li YM, Atractylenolide Ⅲ attenuates intestinal damage in ulcerative colitis model mice by regulating JAK2/STAT3 signaling pathway[J]. Chinese Journal of Pathophysiology, 2023, 39(1): 142-149.] DOI: 10.3969/j.issn.1000-4718. 2023.01.017.

23.吴昭全, 蒋远流, 罗怀青, 等. 羟基积雪草酸固体脂质纳米凝胶的制备及体内外透皮特性研究[J]. 中国药师, 2022, 25(7): 1150-1156. [Wu ZQ, Jiang YL, Luo HQ, et al. Preparation and transdermal permeability in vitro and in vivo of madecassic acid solid lipid nanoparticles gel[J]. China Pharmacist, 2022, 25(7): 1150-1156.] DOI: 10.19962/j.cnki.issn1008-049X.2022.07.004.

24.Wang Y, Wu Q, Wang J, et al. Co-delivery of p38α MAPK and p65 siRNA by novel liposomal glomerulus-targeting nano carriers for effective immunoglobulin a nephropathy treatment[J]. J Control Release, 2020, 320: 457-468. DOI: 10.1016/j.jconrel.2020.01.024.

25.Zhang H, He Q, Wang J, et al. Biomimetic micelles to accurately regulate the inflammatory microenvironment for glomerulonephritis treatment[J]. Pharmacol Res, 2022, 181: 106263. DOI: 10.1016/j.phrs.2022.106263.

26.Zhang X, Zhao X, Hua Z, et al. ROS-triggered self-disintegrating and pH-responsive astaxanthin nanoparticles for regulating the intestinal barrier and colitis[J]. Biomaterials, 2023, 292: 121937. DOI: 10.1016/j.biomaterials.2022.121937.

27.Shi Y, Xing Y, Gong C, et al. In situ encapsulation of laccase in mesoporous amorphous ZIF-8 for reactive blue 19 removal[J]. Water Environ Res, 2023, 95(5): e10879. DOI: 10.1002/wer.10879.