MiRNA-21-loaded chitosan nanoparticles ameliorate pancreatic apoptosis and oxidative stress in diabetic rats

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-02-14 DOI:10.1016/j.lfs.2025.123471

Eman H. Thabet , Nehal A. Khalil , Marwa M. Essawy , Sahar A. Harby , Amany A. Solaiman , Hanaa M. El Gazaerly , Yassmin H. Khalifa

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Abstract

Background

Accelerated Pancreatic β-cell apoptosis and oxidative stress are the mainstays of type-1 diabetes. MicroRNA-21's (miRNA-21) role in regulating pancreatic β-cell function remains indefinable.

Material and methods

Five groups of rats were used in this study (healthy controls (Ia), controls that received only chitosan (CS) nanoparticles (NPs)(Ib), streptozotocin (STZ)-induced diabetics rats (II),STZ-induced diabetic rats that received only CS-NPs(III), and STZ-induced diabetic rats treated with mi-RNA-21-CS-NPs(IV). Sera were collected for measurement of fasting blood glucose levels (FBG), insulin, oxidative stress, and intraperitoneal glucose intolerance tests. Pancreatic tissue was collected after sacrifice partly for histological examination and for oxidative stress assessment and evaluation of PTEN/ AKT using qRT-PCR.

Key findings

We showed over-expression of cleaved-caspase-3 indicating accelerated apoptosis in the β-cell of STZ-induced diabetic rats. Apoptosis was significantly ameliorated by miRNA-21-CS. MiRNA-21-CS-NPs faithfully restored serum fasting insulin, and FBG, and reduced serum and pancreatic oxidative stress markers while enhancing the total antioxidant capacity. Histological examination revealed that miRNA-21 restored healthy β-cell architecture, decreased cleaved-caspase-3, and increased insulin secretion. Transmission electron microscopy revealed increased mitochondrial circularity that significantly correlated with an exaggerated oxidative stress profile as shown by high serum and pancreatic malondialdehyde (MDA), low glutathione peroxidase, and total antioxidant capacity in STZ-induced diabetes. This oxidative profile was reversed using miRNA-21-CS-NPs. Mi-RNA-21 therapy downregulated PTEN but increased AKT and pAKT expression. Altogether, we show that miRNA-21 restored normal islet β-cell structure and insulin secretion through PTEN inhibition.

Significance

miRNA-21- CS-NPs are promising targeted therapeutics that may effectively decrease the global burden of diabetes.

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负载mirna -21的壳聚糖纳米颗粒改善糖尿病大鼠胰腺凋亡和氧化应激。

背景：胰腺β细胞凋亡和氧化应激加速是1型糖尿病的主要机制。MicroRNA-21 （miRNA-21）在调节胰腺β细胞功能中的作用尚不清楚。材料与方法：本研究采用五组大鼠，分别为健康对照组（Ia）、仅接受壳聚糖纳米颗粒（CS）治疗的对照组（Ib）、链脲脲素（STZ）诱导的糖尿病大鼠（II）、仅接受壳聚糖纳米颗粒治疗的STZ诱导的糖尿病大鼠（III）和接受mi-RNA-21-CS-NPs治疗的STZ诱导的糖尿病大鼠（IV）。收集血清用于测量空腹血糖水平（FBG）、胰岛素、氧化应激和腹腔内葡萄糖耐受不良试验。取胰腺组织，部分用于组织学检查，部分用于氧化应激评估和PTEN/ AKT的qRT-PCR检测。主要发现：我们发现stz诱导的糖尿病大鼠β-细胞过度表达cleaved-caspase-3，表明凋亡加速。miRNA-21-CS可显著改善细胞凋亡。MiRNA-21-CS-NPs忠实地恢复血清空腹胰岛素和FBG，降低血清和胰腺氧化应激标志物，同时增强总抗氧化能力。组织学检查显示，miRNA-21恢复了健康的β细胞结构，减少了切割的caspase-3，增加了胰岛素分泌。透射电镜显示，stz诱导的糖尿病患者血清和胰腺丙二醛（MDA）升高，谷胱甘肽过氧化物酶降低，总抗氧化能力降低，线粒体圆度增加与氧化应激谱升高显著相关。使用miRNA-21-CS-NPs逆转了这种氧化谱。Mi-RNA-21治疗降低了PTEN的表达，但增加了AKT和pAKT的表达。总之，我们发现miRNA-21通过抑制PTEN恢复了正常的胰岛β细胞结构和胰岛素分泌。意义：miRNA-21- CS-NPs是一种有前景的靶向治疗药物，可能有效地减轻全球糖尿病负担。

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

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.