橙皮苷负载双分子层脂质体减轻甲氨蝶呤诱导的肾毒性：体内生化和分子研究

Hesperidin loaded bilosomes mitigate the nephrotoxicity induced by methotrexate; biochemical and molecular in vivo investigations.

作者信息

Mahmoud Shiemaa H, Moselhy Walaa A, Azmy Ahmed F, El-Ela Fatma I Abo

机构信息

Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, 62511, Egypt.

Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt.

出版信息

BMC Nephrol. 2025 Jul 21;26(1):404. doi: 10.1186/s12882-025-04328-4.

DOI:10.1186/s12882-025-04328-4

PMID:40691824

Abstract

BACKGROUND

Drugs, chemicals, and poisons may damage kidneys and cause chronic renal disease. About 20% of community and hospital acute renal failures are drug-related.

OBJECTIVES

Hesperidin-loaded bilosomes (HES-BS) nanoformula was tested for nephroprotection against methotrexate (MTX)-induced kidney injury in rats. Thin-film hydration produced HES-BS nanoformula. Drug-loading capacity, encapsulation efficiency (EE %), FTIR, DSC, zeta sizer, and potential were employed for characterization, coupled with an in vitro release study. In vivo pharmacological investigations on White male albino rats measured metabolic parameters, oxidative stress indicators, Nrf2 /Keap1 and BCL2/Bax gene expression, and histopathological alterations.

RESULTS

The HES-BS nanoformula was synthesized with 162 nm particles and - 21.6 mv potential charge. The Transmissions electron microscopy (TEM) showed spherical HES-BS. Hesperidin-excipient compatibility was shown by FTIR and DSC investigations on the modified formulation, with 89.1% EE%. In vitro drug release showed 56% release after eight hours and 60.1% after 24 h, with greater bioavailability than crude HES. The IC₅₀ value of hesperidin decreased from 264 µg/mL to 106.2 µg/mL upon bilosome loading in Vero cells. MTX's nephrotoxicity was mitigated by the HES-BS nano formula's effects on creatinine, urea, uric acid, eGFR, Na, and K levels. Malondialdehyde (MDA) and Nitric Oxide (NO) were notably decreased, whereas Glutathione (GSH) and Superoxide Dismutase (SOD) were markedly elevated. Also, Nrf2 and Bcl2 were upregulated, while Keap1 and Bax were downregulated. Additionally, the produced nanoformula improved the histopathological function.

CONCLUSION

Our novel HES-BS nanoformula had potent nephroprotective activity by reducing the toxic effects of MTX treatment by improving biochemical indicators of kidney function, oxidative stress markers, anti-apoptotic gene expression, and apoptotic gene expression, as well as histopathological improvement.

摘要

背景

药物、化学物质和毒物可能损害肾脏并导致慢性肾脏疾病。社区和医院中约20%的急性肾衰竭与药物有关。

目的

测试载有橙皮苷的双分子层脂质体（HES-BS）纳米制剂对甲氨蝶呤（MTX）诱导的大鼠肾损伤的肾保护作用。通过薄膜水化法制备HES-BS纳米制剂。采用载药量、包封率（EE%）、傅里叶变换红外光谱（FTIR）、差示扫描量热法（DSC）、zeta粒度分析仪和电位仪进行表征，并进行体外释放研究。对白化雄性大鼠进行体内药理学研究，测定代谢参数、氧化应激指标、Nrf2/Keap1和BCL2/Bax基因表达以及组织病理学改变。

结果

合成的HES-BS纳米制剂颗粒大小为162 nm，电位为-21.6 mV。透射电子显微镜（TEM）显示HES-BS呈球形。对改良制剂进行FTIR和DSC研究表明橙皮苷与辅料具有相容性，包封率为89.1%。体外药物释放显示，8小时后释放率为56%，24小时后释放率为60.1%，生物利用度高于粗品HES。在Vero细胞中，载有双分子层脂质体后，橙皮苷的半数抑制浓度（IC₅₀）值从264 µg/mL降至106.2 µg/mL。HES-BS纳米制剂通过对肌酐、尿素、尿酸、估算肾小球滤过率（eGFR）、钠和钾水平的影响减轻了MTX的肾毒性。丙二醛（MDA）和一氧化氮（NO）显著降低，而谷胱甘肽（GSH）和超氧化物歧化酶（SOD）显著升高。此外，Nrf2和Bcl2上调，而Keap1和Bax下调。此外，所制备的纳米制剂改善了组织病理学功能。