Department of Biochemistry and Molecular Biology, Zagazig University, Zagazig 44511, Egypt.
Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman; Human Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Egypt.
Life Sci. 2024 May 1;344:122546. doi: 10.1016/j.lfs.2024.122546. Epub 2024 Mar 8.
Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in β-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic β-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats.
Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted.
QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.
自噬是一种广泛存在的机制，对于最小化内质网应激（ER）相关细胞死亡至关重要。β细胞自噬的缺陷与 1 型糖尿病有关，特别是胰岛素分泌缺陷，增加了 ER 应激敏感性，并可能促进胰腺β细胞死亡。槲皮素（QU）是一种有效的抗氧化剂和抗糖尿病类黄酮，其生物利用度低，其确切的抗糖尿病活性机制仍不清楚。目的：本研究旨在设计一种改进的 QU 生物可利用形式（脂质体），并研究其治疗对 STZ 诱导的大鼠 1 型糖尿病的缓解作用。
将 70 只 SD 大鼠分为 7 组，每组 10 只：对照组、STZ 组、STZ+3-MA 组、STZ+QU-Lip 组和 STZ+3-MA+QU-Lip 组。测定空腹血糖、胰岛素、C 肽、血清 IL-6、TNF-α、胰腺氧化应激、TRAF-6、自噬、内质网应激（ER 应激）标志物的表达及其调节 microRNA（miRNA）。并进行了槲皮素、ER 应激和自噬的对接分析。最后，进行了组织病理学和免疫组织化学分析。
QU-Lip 显著降低了胰腺中的葡萄糖水平、氧化和炎症标志物。它还显著下调了 ER 应激和自噬相关标志物的表达。此外，QU-Lip 显著改善了几个 MicroRNAs 的表达，这些 MicroRNAs 既控制自噬又控制 ER 应激信号通路。然而，当与自噬抑制剂（3-MA）联合使用时，STZ 糖尿病大鼠的改善被取消。这些发现表明，QU-Lip 通过调节 ER 应激和自噬，通过表观遗传机制，在治疗 1 型糖尿病方面具有治疗潜力。
