Empagliflozin-loaded nanomicelles responsive to reactive oxygen species for renal ischemia/reperfusion injury protection

IF 2.1 4区化学 Q3 CHEMISTRY, MULTIDISCIPLINARY

Open Chemistry Pub Date : 2024-04-16 DOI:10.1515/chem-2024-0015

Jianjun Cheng, Xin Zhang, Qiang Zheng, Shaohua Shi, Jianping Wang

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引用次数: 0

Abstract

The brain, heart, liver, kidney, and other organs are susceptible to the harmful effects of ischemia-reperfusion injury (IRI), where the excessive production of reactive oxygen species (ROS) following IRI contributes to tissue damage and ensuing inflammation. In recent years, researchers have designed various nanoparticles that are responsive to ROS for the treatment of IRI. Empagliflozin (EMPA), an inhibitor of the sodium-glucose cotransporter-2 commonly used in type 2 diabetes mellitus, shows promise in mitigating IRI. However, its water-insolubility and low bioavailability present challenges in fully realizing its therapeutic efficacy. To tackle this issue, we formulated EMPA-loaded nanomicelles designed to respond to ROS, aiming to prevent renal damage caused by ischemia-reperfusion. Extensive characterization confirmed the effectiveness of the formulated nanomicelles. Through simulations and release studies, we observed structural modifications in the micelles leading to the release of EMPA upon encountering ROS (H2O2). In animal studies, rats treated with EMPA-loaded micelles showed normal renal tissue architecture, with only some remaining tubular swelling. Molecular assessments revealed that IRI triggered cell apoptosis through mechanisms involving hypoxia, metabolic stress, ROS, and TNF-α elevation. EMPA treatment reversed this process by upregulating B-cell lymphoma protein 2 and reducing levels of associated X (BAX) protein, Caspase 3, and Caspase 8. These results indicate that ROS-responsive micelles could act as a spatially targeted delivery system, effectively transporting EMPA directly to the ischemic kidney. This offers a promising therapeutic strategy for alleviating the impact of renal IRI.

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对活性氧反应敏感的 Empagliflozin 负载纳米细胞用于保护肾缺血/再灌注损伤

大脑、心脏、肝脏、肾脏和其他器官很容易受到缺血再灌注损伤（IRI）的危害，IRI 后活性氧（ROS）的过度产生会导致组织损伤和随之而来的炎症。近年来，研究人员设计了多种对 ROS 有反应的纳米粒子，用于治疗 IRI。恩格列净（Empagliflozin，EMPA）是一种钠-葡萄糖共转运体-2抑制剂，常用于治疗2型糖尿病，有望缓解IRI。然而，它的水不溶性和低生物利用度给充分发挥其疗效带来了挑战。为解决这一问题，我们配制了能对 ROS 作出反应的 EMPA 负载纳米微球，旨在防止缺血再灌注造成的肾损伤。广泛的表征证实了所配制纳米簇的有效性。通过模拟和释放研究，我们观察到胶束在遇到 ROS（H2O2）时发生结构改变，导致 EMPA 的释放。在动物实验中，用 EMPA 胶束治疗的大鼠显示出正常的肾组织结构，仅残留一些肾小管肿胀。分子评估显示，IRI 通过涉及缺氧、代谢压力、ROS 和 TNF-α 升高的机制引发细胞凋亡。EMPA 治疗通过上调 B 细胞淋巴瘤蛋白 2 和降低相关 X（BAX）蛋白、Caspase 3 和 Caspase 8 的水平逆转了这一过程。这些结果表明，ROS 响应胶束可作为一种空间靶向递送系统，有效地将 EMPA 直接运送到缺血肾脏。这为减轻肾脏IRI的影响提供了一种前景广阔的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Open Chemistry CHEMISTRY, MULTIDISCIPLINARY-

CiteScore

3.80

自引率

4.30%

发文量

审稿时长

6 weeks

期刊介绍： Open Chemistry is a peer-reviewed, open access journal that publishes original research, reviews and short communications in the fields of chemistry in an ongoing way. The central goal is to provide a hub for researchers working across all subjects to present their discoveries, and to be a forum for the discussion of the important issues in the field. The journal is the premier source for cutting edge research in fundamental chemistry and it provides high quality peer review services for its authors across the world. Moreover, it allows for libraries everywhere to avoid subscribing to multiple local publications, and to receive instead all the necessary chemistry research from a single source available to the entire scientific community.