Ahmed Semim Akhtar, Saikia Kangkon, Basumatary Devi, Gurumayum Shalini, Swargiary Deepsikha, Borah Jagat C
Chemical Biology Laboratory-1, Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati-781035, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Chemical Biology Laboratory-1, Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati-781035, India.
Int Immunopharmacol. 2025 Jun 17;158:114825. doi: 10.1016/j.intimp.2025.114825. Epub 2025 May 14.
Verbascoside, a caffeoyl phenylethanoid glycoside is known to regulate diabetic conditions and its related complications as well as function as an anti-infective, immunosuppressive, and antioxidant agent. It is also an under investigational molecule for patients of IgA Nephropathy. However, its functions in diabetic nephropathy (DN) and underlying mechanisms remain unclear. The study aimed to evaluate the therapeutic effects and mechanisms of verbascoside through the inhibition of sodium glucose transporter 2 (SGLT2) mediated glucose uptake in high glucose (HG) treated proximal tubular cells, HK-2 cells, and in silico studies. In HK-2 cells, verbascoside decreased glucose uptake analog, 6-NBDG through inhibition of SGLT2. The study demonstrated that HG could increase glucose uptake and induce renal inflammation and fibrosis by a significant increase in the intracellular levels of reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX-4) in HK-2 cells. Nuclear factor kappa B (NF-κB) phosphorylation was also found to play a crucial role in HG-induced inflammation and fibrosis. Verbascoside exerted renoprotective effects by activating AMP-activated protein kinase (AMPK) and ameliorated renal dysfunction by suppressing pro-inflammatory factors, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and expression of the extracellular matrix proteins, fibronectin (FN) and collagen-IV (COLIV) in HG-treated HK-2 cells. Molecular docking studies also revealed the SGLT2 inhibition properties of verbascoside. In summary, the study revealed that HG can directly promote glucose uptake through SGLT2 and renal complications and verbascoside is a potential therapeutic agent for ameliorating diabetic nephropathy via regulation of AMPK/NOX4/NF-κB signaling cascade.
毛蕊花糖苷是一种咖啡酰苯乙醇苷，已知其可调节糖尿病病情及其相关并发症，还具有抗感染、免疫抑制和抗氧化作用。它也是IgA肾病患者正在研究的一种分子。然而，其在糖尿病肾病（DN）中的作用及其潜在机制仍不清楚。本研究旨在通过抑制高糖（HG）处理的近端肾小管细胞HK-2细胞中钠-葡萄糖协同转运蛋白2（SGLT2）介导的葡萄糖摄取以及计算机模拟研究，评估毛蕊花糖苷的治疗效果和机制。在HK-2细胞中，毛蕊花糖苷通过抑制SGLT2降低葡萄糖摄取类似物6- NBDG。研究表明，HG可通过显著增加HK-2细胞中烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX-4）产生的细胞内活性氧（ROS）水平来增加葡萄糖摄取，并诱导肾脏炎症和纤维化。还发现核因子κB（NF-κB）磷酸化在HG诱导的炎症和纤维化中起关键作用。毛蕊花糖苷通过激活AMP活化蛋白激酶（AMPK）发挥肾脏保护作用，并通过抑制HG处理的HK-2细胞中的促炎因子白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）以及细胞外基质蛋白纤连蛋白（FN）和IV型胶原（COLIV）的表达来改善肾功能障碍。分子对接研究也揭示了毛蕊花糖苷的SGLT2抑制特性。总之，该研究表明HG可通过SGLT2直接促进葡萄糖摄取和引发肾脏并发症，而毛蕊花糖苷是一种潜在的治疗药物，可通过调节AMPK/NOX4/NF-κB信号级联改善糖尿病肾病。
