Abstract：
Aldose reductase (AR) is an important enzyme involved in the reduction of various aldehyde and carbonyl compounds, including the highly reactive and toxic 4-hydroxynonenal (4-HNE), which has been linked to the progression of various pathologies such as atherosclerosis, hyperglycemia, inflammation, and tumors. AR inhibitors have potential therapeutic benefits for these diseases by reducing lipid peroxidation and mitigating the harmful effects of reactive aldehydes. In this study, we found that torachrysone-8-O-β-d-glucoside (TG), a natural product isolated from Polygonum multiflorum Thunb., functions as an effective inhibitor of AR, exhibiting potent effects in clearing reactive aldehydes and reducing inflammation. TG up-regulated the mRNA levels of several antioxidant factors downstream of NRF2, especially glutathione S-transferase (GST), which is significantly increased, thus detoxifying 4-HNE by facilitating the conjugation of 4-HNE to glutathione, forming glutathione-4-hydroxynonenal (GS-HNE). By employing a combination of molecular docking, cellular thermal shift assay, and enzyme activity experiments, we demonstrated that TG exhibited strong binding affinity with AR and inhibited its activity and blocked the conversion of GS-HNE to glutathionyl-1,4-dihydroxynonene (GS-DHN), thereby preventing the formation of protein adducts and inducing severe cellular damage. This study provides novel insights into the anti-inflammatory mechanisms of AR inhibitors and offers potential avenues for developing therapeutic strategies for AR-related pathologies. Our findings suggest that TG, as an AR inhibitor, may hold promise as a therapeutic agent for treating conditions characterized by excessive lipid peroxidation and inflammation. Further investigations are needed to fully explore the clinical potential of TG and evaluate its efficacy in the treatment and management of these complex diseases.
摘要：
醛糖还原酶（AR）是一种重要的酶，参与各种醛和羰基化合物的还原，包括高反应性和毒性的4-羟基壬烯醛（4-HNE），这与动脉粥样硬化等各种病理的进展有关，高血糖症,炎症,和肿瘤。AR抑制剂通过减少脂质过氧化和减轻反应性醛的有害作用而对这些疾病具有潜在的治疗益处。在这项研究中,我们发现Torachrysone-8-O-β-d-葡萄糖苷（TG），一种从何首乌中分离出的天然产物。,作为AR的有效抑制剂，在清除反应性醛和减少炎症方面表现出有效的作用。TG上调NRF2下游几种抗氧化因子的mRNA水平,尤其是GST,显着增加，从而通过促进4-HNE与谷胱甘肽的缀合来解毒4-HNE，形成GS-HNE。通过使用分子对接的组合，细胞热转移测定，和酶活性实验，我们证明了TG表现出与AR的强结合亲和力，抑制其活性并阻断GS-HNE向GS-DHN的转化，从而防止蛋白质加合物的形成并诱导严重的细胞损伤。这项研究为AR抑制剂的抗炎机制提供了新的见解，并为开发AR相关病理的治疗策略提供了潜在的途径。我们的研究结果表明，TG，作为AR抑制剂，可能有望作为治疗以过度脂质过氧化和炎症为特征的病症的治疗剂。需要进一步研究以充分探索TG的临床潜力并评估其在这些复杂疾病的治疗和管理中的功效。
